Contents

1 Cannabinoid 1
1.1 Cannabinoid receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Cannabinoid receptor type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.2 Cannabinoid receptor type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Phytocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2.1 Cannabis-derived cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2.2 Cannabinoids from other plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.3 Cannabis plant profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.4 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.5 Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.6 Natural occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.7 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.1 Types of endocannabinoid ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.2 Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4 Synthetic cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.5 Table of natural cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.6 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.8 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.9 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.9.1 Cannabinoid information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.9.2 Cannabinoid research organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2 Entourage effect 11
2.1 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3 Synthetic cannabis 12
3.1 Misnomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.2 Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.2.1 Artificial cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.3 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

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3.4 Drug testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

3.5 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.5.1 Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.5.2 South America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.5.3 Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.5.4 Australasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.5.5 North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.6 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.6.1 Slang terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.8 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4 4-HTMPIPO 21
4.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5 5F-PB-22 22
5.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

6 A-40174 23
6.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

7 A-41988 24
7.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
7.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

8 A-796,260 25
8.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

9 A-834,735 26
9.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
9.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

10 A-836,339 27
10.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

11 AB-001 28
11.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
11.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

12 AB-005 29
12.1 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
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12.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

12.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

13 AB-CHMINACA 30
13.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

14 AB-FUBINACA 31
14.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
14.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

15 AB-PINACA 32
15.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
15.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

16 Abnormal cannabidiol 33
16.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
16.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

17 ADB-FUBINACA 35
17.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
17.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

18 ADB-PINACA 36
18.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
18.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

19 ADBICA 37
19.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
19.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

20 Ajulemic acid 38
20.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

21 AM-087 39
21.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
21.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

22 AM-1220 40
22.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
22.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

23 AM-1221 41
23.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
23.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

24 AM-1235 42
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24.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
24.1.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
24.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
24.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
24.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

25 AM-1241 43
25.1 Effects in bone cancer model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
25.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
25.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

26 AM-1248 45
26.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
26.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

27 AM-1714 46
27.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
27.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

28 AM-2201 47
28.1 Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
28.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
28.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
28.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
28.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
28.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

29 AM-2232 48
29.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
29.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

30 AM-2233 49
30.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
30.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

31 AM-2389 50
31.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
31.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

32 AM-4030 51
32.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
32.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

33 AM-411 52
33.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
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33.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

34 AM-630 53
34.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
34.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

35 AM-6545 54
35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
35.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

36 AM-679 (cannabinoid) 55
36.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
36.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

37 AM-694 56
37.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
37.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
37.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
37.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

38 AM-855 57
38.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

39 AM-905 58
39.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

40 AM-906 59
40.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
40.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

41 AM-919 60
41.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
41.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

42 AM-938 61
42.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
42.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

43 AM404 62
43.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
43.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
43.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

44 AMG-1 63
44.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
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45 AMG-3 64
45.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

46 AMG-36 65
46.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

47 AMG-41 66
47.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

48 APINACA 67
48.1 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
48.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
48.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

49 AR-231,453 68
49.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
49.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

50 Arachidonyl-2'-chloroethylamide 69
50.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

51 Arachidonylcyclopropylamide 70
51.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

52 N-Arachidonylglycine 71
52.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
52.2 Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
52.2.1 Effects on the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
52.2.2 Effects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
52.2.3 Cell migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
52.2.4 Other targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
52.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

53 AZ-11713908 74
53.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
53.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

54 BAY 38-7271 75
54.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

55 BAY 59-3074 76
55.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

56 BML-190 77
56.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
CONTENTS vii

57 (C6)-CP 47,497 78
57.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

58 (C9)-CP 47,497 79
58.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

59 Canbisol 80
59.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
59.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

60 Cannabichromene 81
60.1 Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
60.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

61 Cannabicyclohexanol 82
61.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
61.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

62 Cannabicyclol 83
62.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
62.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

63 Cannabidiol 84
63.1 Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
63.1.1 Antimicrobial actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
63.1.2 Neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
63.1.3 Psychotropic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
63.1.4 Dravet syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.2 CBD-enhanced cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.3 Industrial hemp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.4 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.4.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.4.2 Pharmacokinetic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.4.3 Pharmaceutical preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.5 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
63.6 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
63.6.1 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
63.7 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
63.8 US patent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
63.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
63.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

64 Cannabidivarin 90
64.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
viii CONTENTS

64.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
64.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

65 Cannabigerol 91
65.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
65.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

66 Cannabinoidergic 92
66.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
66.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

67 Cannabinol 93
67.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
67.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
67.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

68 Cannabivarin 94
68.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
68.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
68.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

69 Caryophyllene 95
69.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
69.2 Compendial status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
69.3 Notes and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

70 CB-13 98
70.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
70.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

71 CBS-0550 99
71.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
71.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

72 CP 47,497 100
72.1 Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.1 Germany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.2 France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.3 Latvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.4 Lithuania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.5 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.6 Romania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.7 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
CONTENTS ix

72.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

72.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

73 CP 55,244 102
73.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
73.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

74 CP 55,940 103
74.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
74.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

75 Dexanabinol 104
75.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

76 Dimethylheptylpyran 105
76.1 Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
76.2 Investigation as non-lethal incapacitating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
76.3 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
76.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

77 Docosatetraenoylethanolamide 107
77.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

78 Drinabant 108
78.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
78.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

79 EAM-2201 109
79.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
79.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
79.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
79.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

80 Endocannabinoid reuptake inhibitor 110

80.1 Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.3 Use in medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.4 Examples of eCBRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

81 Endocannabinoid system 112

81.1 Basic overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
81.1.1 Expression of receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
81.1.2 Endocannabinoid synthesis, release, and degradation . . . . . . . . . . . . . . . . . . . . . 112
x CONTENTS

81.1.3 Binding and intracellular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

81.1.4 Binding and neuronal excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
81.2 Functions of the endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.1 Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.2 Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.3 Energy balance & metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.4 Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
81.2.5 Immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
81.2.6 Female reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.7 Autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.8 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.9 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.10 Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.3 Experimental use of CB1 -/- phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
81.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
81.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

82 Endocannabinoid transporters 120

82.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

83 GW-405,833 121
83.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

84 GW-842,166X 122
84.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

85 Hemopressin 123
85.1 Role in diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
85.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
85.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

86 HU-210 124
86.1 Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.2.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.2.2 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.3 Other HU Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
86.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

87 HU-243 126
87.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
CONTENTS xi

87.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

88 HU-308 127
88.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
88.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

89 HU-331 128
89.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
89.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
89.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

90 11-Hydroxy-THC 130
90.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

91 9-nor-9β-Hydroxyhexahydrocannabinol 131
91.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
91.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

92 Ibipinabant 132
92.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
92.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

93 IDFP 133
93.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
93.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

94 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene 134
94.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

95 JTE 7-31 135

95.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
95.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

96 JTE-907 136
96.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
96.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

97 JWH-015 137
97.1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
97.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

98 JWH-051 138
98.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

99 JWH-057 139
99.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
xii CONTENTS

99.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

100JWH-120 140
100.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
100.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

101JWH-122 141
101.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
101.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

102JWH-133 142
102.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
102.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
102.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

103JWH-148 143
103.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
103.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

104JWH-149 144
104.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
104.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

105JWH-161 145
105.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

106JWH-176 146
106.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
106.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

107JWH-359 147
107.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

108JZL184 148
108.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
108.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

109JZL195 149
109.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
109.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

110KM-233 150
110.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
110.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

111L-759,633 151
CONTENTS xiii

111.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

111.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

112L-759,656 152
112.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
112.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

113LASSBio-881 153
113.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

114LBP-1 (drug) 154

114.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
114.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

115Leelamine 155
115.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
115.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

116Levonantradol 156
116.1Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.2Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.3Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.4Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
116.6Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
116.7References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

117List of AM cannabinoids 158

117.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
117.2Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
117.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

118List of JWH cannabinoids 161

118.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
118.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

119LY-2183240 164
119.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
119.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

120LY-320,135 165
120.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

121MAM-2201 166
121.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
xiv CONTENTS

121.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

121.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

122MDA-19 167
122.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
122.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

123Menabitan 168
123.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
123.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

124Methanandamide 169
124.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

125MK-9470 170
125.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

126N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide 171
126.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
126.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
126.3Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

127Nabazenil 173
127.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

128Nabilone 174
128.1Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
128.2Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
128.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
128.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

129Nabitan 176
129.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

130Nabiximols 177
130.1Availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
130.2Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.3Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.4Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

131Naboctate 180
131.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
CONTENTS xv

132NESS-0327 181
132.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
132.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

133NESS-040C5 182
133.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
133.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

134NMP-7 183
134.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

135Nonabine 184
135.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

13611-nor-9-Carboxy-THC 185
136.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

137O-1057 187
137.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
137.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

138O-1125 188
138.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

139O-1238 189
139.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

140O-1269 190
140.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

141O-1602 191
141.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
141.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

142O-1812 192
142.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
142.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

143O-1871 193
143.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
143.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

144O-1918 194
144.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
144.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
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145O-2050 195
145.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
145.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

146O-2113 196
146.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
146.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

147O-2372 197
147.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
147.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

148O-2545 198
148.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
148.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

149O-2694 199
149.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
149.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

150O-774 200
150.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
150.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

151O-806 201
151.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

152O-823 202
152.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

153Org 27569 203

153.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

154Org 28312 204

154.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
154.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

155Org 28611 205

155.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
155.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

156Otenabant 206
156.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
156.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

157Parahexyl 207
CONTENTS xvii

157.1Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
157.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
157.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

158UR-144 208
158.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.2History of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.3Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.6Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

159Perrottetinene 210
159.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

160PF-03550096 211
160.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
160.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

161PF-514273 212
161.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

162PipISB 213
162.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

163Pirnabine 214
163.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

164PSB-SB-1202 215
164.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
164.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

165PSB-SB-487 216
165.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
165.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

166QUCHIC 217
166.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
166.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

167QUPIC 218
167.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.2Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
xviii CONTENTS

168Rimonabant 219
168.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2Uses/potential uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2.1 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2.2 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.3 Addiction behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.4 Short-term memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.5 Blockage of cannabis effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.3Other effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.4Negative side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.5Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.6Brand names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.7References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

169Rosonabant 222
169.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
169.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

170S-444,823 223
170.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
170.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

171SDB-001 224
171.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
171.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

172SDB-006 225
172.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
172.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

173SER-601 226
173.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
173.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

174Serinolamide A 227
174.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
174.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

175SR-144,528 228
175.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
175.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

176Stearoylethanolamide 229
176.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
CONTENTS xix

177STS-135 (drug) 230

177.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
177.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
177.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

178Surinabant 231
178.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
178.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

179Taranabant 232
179.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
179.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

180Tedalinab 233
180.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
180.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

181Tetrad test 234

181.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

182Tetrahydrocannabinol 235
182.1Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.1.1 Appetite and taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.2Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.2.1 Discovery and structure identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.2.2 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.3Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.3.1 Multiple sclerosis symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.2 Neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.3 Other neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.4 Other studies in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4.1 Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4.2 Cognitive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.3 Impact on psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.4 Other potential long-term effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.5 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.5Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.5.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.6Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.7Chemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.8Marinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.8.1 Comparisons with medical marijuana . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
xx CONTENTS

182.9Regulatory history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

182.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
182.11References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
182.12Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
182.13External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

183Tetrahydrocannabinol-C4 246
183.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
183.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

184Tetrahydrocannabinolic acid 247

184.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
184.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

185Tetrahydrocannabivarin 249
185.1Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.2Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.5External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

186THC-O-acetate 250
186.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

187THC-O-phosphate 251
187.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

188Tinabinol 252
188.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
188.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

189URB602 253
189.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

190URB754 254
190.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

191VCHSR 255
191.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

192VDM-11 256
192.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
192.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

193WIN 54,461 257

193.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
CONTENTS xxi

193.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

194WIN 55,212-2 258

194.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
194.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
194.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

195WIN 56,098 260

195.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
195.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

196XLR-11 (drug) 261

196.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.2Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.3Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

197AM251 263
197.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
197.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

198Aminoalkylindole 264
198.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
198.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
198.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

199Cannabipiperidiethanone 265
199.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
199.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

200JWH-193 266
200.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
200.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

201JWH-198 267
201.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
201.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

202JWH-200 268
202.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
202.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

203Pravadoline 269
203.1Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
xxii CONTENTS

203.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

203.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

204RCS-4 270
204.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
204.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
204.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

205Anandamide 271
205.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.2Physiological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.3Synthesis and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.4Medical benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

206N-Arachidonoyl dopamine 274

206.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
206.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
206.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

2072-Arachidonoylglycerol 275
207.1Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.2Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.4Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.6.1 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
207.6.2 General references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

2082-Arachidonyl glyceryl ether 277

208.1Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.2Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.6External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

209Oleamide 279
209.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
209.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
CONTENTS xxiii

210RVD-Hpα 280
210.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

211Virodhamine 281
211.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
211.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

212HU-320 282
212.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
212.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

213HU-336 283
213.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
213.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

214HU-345 284
214.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
214.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

215Raphael Mechoulam 285

215.1Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.2Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.4Podcasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

216John W. Huffman 286

216.1Law enforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
216.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
216.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

217JWH-007 287
217.1Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
217.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
217.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

218Naphthoylindole 288
218.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
xxiv CONTENTS

218.8References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

219JWH-019 292
219.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.1 Poland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.2 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.3 UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.4 USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

220JWH-030 293
220.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
220.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

221JWH-047 294
221.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
221.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

222JWH-048 295
222.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
222.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

223JWH-073 296
223.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.2Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.2 Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.3 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
223.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
223.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

224JWH-081 298
224.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
224.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

225JWH-098 299
225.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
225.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

226JWH-116 300
226.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
CONTENTS xxv

226.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

227JWH-147 301
227.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
227.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

228JWH-164 302
228.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

229Phenylacetylindole 303
229.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

230JWH-175 304
230.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
230.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

231JWH-184 305
231.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
231.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

232JWH-185 306
232.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
232.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

233JWH-196 307
233.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
233.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

234JWH-203 308
234.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
234.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

235JWH-210 309
235.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
235.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

236JWH-249 310
236.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
236.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

237JWH-250 311
237.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
237.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

238JWH-251 312
238.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
xxvi CONTENTS

239JWH-302 313
239.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

240JWH-307 314
240.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
240.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

241JWH-398 315
241.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
241.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

242JWH-424 316
242.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
242.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

243Naphthoylindole 317
243.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.2.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.4Detection in biological fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.8References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

244Phenylacetylindole 321
244.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

245RCS-8 322
245.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
245.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

246Intravenous Marijuana Syndrome 323

246.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323

247Mellow Yellow coffeeshop 324

247.1Citations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

248The Night Train Seizure 325

248.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
248.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
CONTENTS xxvii

249PSN-375,963 326
249.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
249.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

250PSN-632,408 327
250.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
250.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

251Soma Seeds 328

251.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
251.2External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

252TM-38837 329
252.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.4Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 330
252.4.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
252.4.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
252.4.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Chapter 1
Cannabinoid
Cannabinoids are a class of diverse chemical com-
pounds that act on cannabinoid receptors on cells that
repress neurotransmitter release in the brain. These
receptor proteins include the endocannabinoids (pro-
duced naturally in the body by humans and animals),[1]
the phytocannabinoids (found in cannabis and some
other plants), and synthetic cannabinoids (manufac-
tured chemically). The most notable cannabinoid is
the phytocannabinoid ∆9 -tetrahydrocannabinol (THC),
the primary psychoactive compound of cannabis.[2][3]
Cannabidiol (CBD) is another major constituent of the
plant, representing up to 40% in extracts of the plant
resin.[4] There are at least 85 different cannabinoids iso-
lated from cannabis, exhibiting varied effects.[5]
Synthetic cannabinoids encompass a variety of dis-
tinct chemical classes: the classical cannabinoids struc-
turally related to THC, the nonclassical cannabinoids
(cannabimimetics) including the aminoalkylindoles, 1,5-
diarylpyrazoles, quinolines, and arylsulfonamides, as well
as eicosanoids related to the endocannabinoids.[2]
1.1 Cannabinoid receptors
Before the 1980s, it was often speculated that cannabi-
noids produced their physiological and behavioral effects
via nonspecific interaction with cell membranes, instead
of interacting with specific membrane-bound receptors.
The discovery of the first cannabinoid receptors in the
1980s helped to resolve this debate. These receptors are
common in animals, and have been found in mammals,
birds, fish, and reptiles. At present, there are two known
types of cannabinoid receptors, termed CB1 and CB2 ,[1]
with mounting evidence of more.[6] The human brain has
more cannabinoid receptors than any other G protein-
coupled receptor (GPCR) type.[7]
1.1.1 Cannabinoid receptor type 1
Main article: Cannabinoid receptor type 1
CB1 receptors are found primarily in the brain, more 2-carboxylic acids (2-COOH) by decarboxylation (cat-
specifically in the basal ganglia and in the limbic system, alyzed by heat, light, or alkaline conditions).[11]
including the hippocampus.[1] They are also found in the
cerebellum and in both male and female reproductive sys-
tems. CB1 receptors are absent in the medulla oblongata,
the part of the brain stem responsible for respiratory and
cardiovascular functions. Thus, there is not the risk of
respiratory or cardiovascular failure that can be produced
by some drugs. CB1 receptors appear to be responsible
for the euphoric and anticonvulsive effects of cannabis.
1.1.2 Cannabinoid receptor type 2
Main article: Cannabinoid receptor type 2
CB2 receptors are predominantly found in the immune
system, or immune-derived cells[8] with the greatest den-
sity in the spleen. While found only in the peripheral
nervous system, a report does indicate that CB2 is ex-
pressed by a subpopulation of microglia in the human
cerebellum.[9] CB2 receptors appear to be responsible for
the anti-inflammatory and possibly other therapeutic ef-
fects of cannabis.[8]
1.2 Phytocannabinoids
1.2.1 Cannabis-derived cannabinoids
The classical cannabinoids are concentrated in a vis-
cous resin produced in structures known as glandular
trichomes. At least 85 different cannabinoids have been
isolated from the Cannabis plant[5] To the right, the main
classes of cannabinoids from Cannabis are shown. The
best studied cannabinoids include tetrahydrocannabinol
(THC), cannabidiol (CBD) and cannabinol (CBN).
Types
All classes derive from cannabigerol-type compounds and
differ mainly in the way this precursor is cyclized.[10] The
classical cannabinoids are derived from their respective
1
2 CHAPTER 1. CANNABINOID

Tetrahydrocannabinol Main article:

Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoac-

tive component of the Cannabis plant. Delta−9-
tetrahydrocannabinol (Δ9 -THC, THC) and delta−8-
tetrahydrocannabinol (Δ8 -THC), mimic the action of
anandamide, a neurotransmitter produced naturally in the
body. These two THCs produce the effects associated
with cannabis by binding to the CB1 cannabinoid recep-
tors in the brain. THC appears to ease moderate pain
(analgesic) and to be neuroprotective, while also offering
the potential to reduce neuroinflammation and to stimu-
late neurogenesis.[12] THC has approximately equal affin-
ity for the CB1 and CB2 receptors.[13]

The bracts surrounding a cluster of Cannabis sativa flowers are Cannabidiol Main article: Cannabidiol
coated with cannabinoid-laden trichomes

Cannabidiol (CBD) is not psychoactive, and was thought

not to affect the psychoactivity of THC.[14] However,
recent evidence shows that smokers of cannabis with
a higher CBD/THC ratio were less likely to experi-
ence schizophrenia-like symptoms.[15] This is supported
by psychological tests, in which participants experience
less intense psychotic-like effects when intravenous THC
was co-administered with CBD (as measured with a
PANSS test).[16] Cannabidiol has little affinity for CB1
and CB2 receptors but acts as an indirect antagonist of
cannabinoid agonists.[17] Recently it was found to be
an antagonist at the putative new cannabinoid recep-
tor, GPR55, a GPCR expressed in the caudate nucleus
and putamen.[18] Cannabidiol has also been shown to act
as a 5-HT₁A receptor agonist,[19] an action that is in-
volved in its antidepressant,[20][21] anxiolytic,[21][22] and
neuroprotective[23][24] effects.
It appears to relieve convulsion, inflammation, anxiety,
and nausea.[17] CBD has a greater affinity for the CB2
receptor than for the CB1 receptor.[17]
Cannabis indica plant
CBD shares a precursor with THC and is the main
cannabinoid in low-THC Cannabis strains. CBD appar-
• CBG (Cannabigerol) ently plays a role in preventing the short-term memory
loss associated with THC in mammals.
• CBC (Cannabichromene)
Some research suggests that the antipsychotic effects of
• CBL (Cannabicyclol) cannabidiol potentially represent a novel mechanism in
the treatment of schizophrenia.[25]
• CBV (Cannabivarin) Researchers at California Pacific Medical Center discov-
ered CBD’s ability to “turn off” the activity of ID1, the
• THCV (Tetrahydrocannabivarin) gene responsible for metastasis in breast and other types
of cancers, including the particularly aggressive triple
• CBDV (Cannabidivarin)
negative breast cancer.[26][27][28] The researchers hope to
• CBCV (Cannabichromevarin) start human trials soon.[29]

• CBGV (Cannabigerovarin)
Cannabinol Main article: Cannabinol
• CBGM (Cannabigerol Monomethyl Ether)
1.2. PHYTOCANNABINOIDS 3

Cannabinol (CBN) is the primary product of THC degra-
dation, and there is usually little of it in a fresh plant. CBN
content increases as THC degrades in storage, and with
exposure to light and air. It is only mildly psychoactive.
Its affinity to the CB2 receptor is higher than for the CB1
receptor.[30]
Cannabigerol Main article: Cannabigerol
There is potential for confusion because there are dif-
ferent numbering systems used to describe the position
of this double bond. Under the dibenzopyran number-
ing system widely used today, the major form of THC
is called Δ9 -THC, while the minor form is called Δ8 -
THC. Under the alternate terpene numbering system,
these same compounds are called Δ1 -THC and Δ6 -THC,
respectively.

Length Most classical cannabinoids are 21-carbon

Cannabigerol (CBG) is non-psychotomimetic but still af- compounds. However, some do not follow this rule, pri-
fects the overall effects of Cannabis. It acts as an α2 - marily because of variation in the length of the side-chain
adrenergic receptor agonist, 5-HT₁A receptor antagonist, attached to the aromatic ring. In THC, CBD, and CBN,
and CB1 receptor antagonist.[31] It also binds to the CB2 this side-chain is a pentyl (5-carbon) chain. In the most
receptor.[31] common homologue, the pentyl chain is replaced with a
propyl (3-carbon) chain. Cannabinoids with the propyl
side-chain are named using the suffix varin, and are des-
Tetrahydrocannabivarin Main article:
ignated, for example, THCV, CBDV, or CBNV.
Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is prevalent in cer- 1.2.2 Cannabinoids from other plants

tain central Asian and southern African strains of
Cannabis.[32][33] It is an antagonist of THC at CB1 recep- Phytocannabinoids are known to occur in several plant
tors and attenuates the psychoactive effects of THC.[34] species besides cannabis. These include Echinacea
purpurea, Echinacea angustifolia, Echinacea pallida,
Acmella oleracea, Helichrysum umbraculigerum, and
Cannabidivarin Main article: Cannabidivarin Radula marginata.[36] The best-known cannabinoids that
are not derived from Cannabis are the lipophilic alka-
[36]
Although cannabidivarin (CBDV) is usually a minor mides (alkylamides) from Echinacea species. At
constituent of the cannabinoid profile, enhanced levels least 25 different alkylamides (dodeca-2E,4E,8Z,10E/Z-
of CBDV have been reported in feral cannabis plants tetraenoic-acid-isobutylamides) have been identified, and
from the northwest Himalayas, and in hashish from some of[37][38] them have shown affinities to the CB2 -
Nepal. [33][35] receptor. In Echinacea species, cannabinoids are
found throughout the plant structure, but are most con-
centrated in the roots and flowers.[39][40] Yangonin found
Cannabichromene Main article: Cannabichromene in the Kava plant is a ligand on the CB1 receptor.[41]
Tea (Camellia sinensis) catechins have an affinity for
human cannabinoid receptors.[42] A widespread dietary
Cannabichromene (CBC) is non-psychoactive and does
cannabinoid, beta-caryophyllene, a component from the
not affect the psychoactivity of THC.[14] More com-
essential oil of cannabis and other medicinal plants, has
mon in tropical cannabis varieties. Effects include anti-
also been identified as a selective agonist of peripheral
inflammatory and analgesic.
CB2 -receptors, in vivo.[43]
Most of the phytocannabinoids are nearly insoluble in wa-
Biosynthesis Cannabinoid production starts when an ter but are soluble in lipids, alcohols, and other non-polar
enzyme causes geranyl pyrophosphate and olivetolic acid organic solvents.
to combine and form CBGA. Next, CBGA is indepen-
dently converted to either CBG, THCA, CBDA or CBCA
by four separate synthase, FAD-dependent dehydroge- 1.2.3 Cannabis plant profile
nase enzymes. There is no evidence for enzymatic con-
version of CBDA or CBD to THCA or THC. For the Cannabis plants can exhibit wide variation in the quantity
propyl homologues (THCVA, CBDVA and CBCVA), and type of cannabinoids they produce. The mixture of
there is a similar pathway that is based on CBGVA from cannabinoids produced by a plant is known as the plant’s
divarinolic acid instead of olivetolic acid. cannabinoid profile. Selective breeding has been used to
control the genetics of plants and modify the cannabinoid
profile. For example, strains that are used as fiber (com-
Double bond position In addition, each of the com- monly called hemp) are bred such that they are low in psy-
pounds above may be in different forms depending on the choactive chemicals like THC. Strains used in medicine
position of the double bond in the alicyclic carbon ring. are often bred for high CBD content, and strains used for
4 CHAPTER 1. CANNABINOID

recreational purposes are usually bred for high THC con- 1.2.6 Natural occurrence
tent or for a specific chemical balance.
Quantitative analysis of a plant’s cannabinoid profile is of- Main article: Medical_cannabis § Difference between
ten determined by gas chromatography (GC), or more re- C. indica and C. sativa
liably by gas chromatography combined with mass spec-
trometry (GC/MS). Liquid chromatography (LC) tech- Cannabis indica may have a CBD:THC ratio 4–5 times
niques are also possible, and, unlike GC methods, can that of Cannabis sativa.
differentiate between the acid and neutral forms of the
cannabinoids. There have been systematic attempts to
monitor the cannabinoid profile of cannabis over time, 1.2.7 History
but their accuracy is impeded by the illegal status of the
plant in many countries. Cannabinoids were first discovered in the 1940s, when
CBD and CBN were identified. The structure of THC
was first determined in 1964.
Due to molecular similarity and ease of synthetic con-
1.2.4 Pharmacology version, CBD was originally believed to be a natural pre-
cursor to THC. However, it is now known that CBD and
THC are produced independently in the cannabis plant
Cannabinoids can be administered by smoking, vaporiz-
from the precursor CBG.
ing, oral ingestion, transdermal patch, intravenous injec-
tion, sublingual absorption, or rectal suppository. Once in
the body, most cannabinoids are metabolized in the liver,
especially by cytochrome P450 mixed-function oxidases, 1.3 Endocannabinoids
mainly CYP 2C9. Thus supplementing with CYP 2C9
inhibitors leads to extended intoxication. For more details on the roles and regulation of the endo-
Some is also stored in fat in addition to being metabo- cannabinoids, see Endocannabinoid system.
lized in the liver. Δ9 -THC is metabolized to 11-hydroxy- Endocannabinoids are substances produced from within
Δ9 -THC, which is then metabolized to 9-carboxy-THC.
Some cannabis metabolites can be detected in the body
several weeks after administration. These metabolites
are the chemicals recognized by common antibody-based
“drug tests"; in the case of THC or others, these loads
do not represent intoxication (compare to ethanol breath
tests that measure instantaneous blood alcohol levels), but
an integration of past consumption over an approximately
month-long window. This is because they are fat-soluble,
lipophilic molecules that accumulate in fatty tissues.[44]

1.2.5 Separation Anandamide, an endogenous ligand of CB1 and CB2

Cannabinoids can be separated from the plant by the body that activate cannabinoid receptors. After the
extraction with organic solvents. Hydrocarbons and discovery of the first cannabinoid receptor in 1988, sci-
alcohols are often used as solvents. However, these sol- entists began searching for an endogenous ligand for the
vents are flammable and many are toxic. Butane may be receptor.
used, which evaporates extremely quickly. Supercritical
solvent extraction with carbon dioxide is an alternative
technique. Although this process requires high pressures
1.3.1 Types of endocannabinoid ligands
(73 atmospheres or more), there is minimal risk of fire
Arachidonoylethanolamine (Anandamide or AEA)
or toxicity, solvent removal is simple and efficient, and
extract quality can be well controlled. Once extracted,
cannabinoid blends can be separated into individual com- Main article: Arachidonoylethanolamine
ponents using wiped film vacuum distillation or other
distillation techniques. However, to produce high-purity In 1992, in Raphael Mechoulam's lab, the first such com-
cannabinoids, chemical synthesis or semisynthesis is gen- pound was identified as arachidonoyl ethanolamine and
erally required. named anandamide, a name derived from the Sanskrit
1.3. ENDOCANNABINOIDS
word for bliss and -amide. Anandamide is derived from
arachidonic acid. It has a pharmacology similar to THC,
although its chemical structure is different. Anandamide
binds to the central (CB1 ) and, to a lesser extent, pe-
ripheral (CB2 ) cannabinoid receptors, where it acts as a
partial agonist. Anandamide is about as potent as THC
at the CB1 receptor.[45] Anandamide is found in nearly
all tissues in a wide range of animals.[46] Anandamide
has also been found in plants, including small amounts
in chocolate.[47]
Two analogs of anandamide, 7,10,13,16-
docosatetraenoylethanolamide and homo-γ-
linolenoylethanolamine, have similar pharmacology.
All of these are members of a family of signalling
lipids called N-acylethanolamines, which also includes
the noncannabimimetic palmitoylethanolamide and
oleoylethanolamide, which possess anti-inflammatory
and orexigenic effects, respectively. Many N-
acylethanolamines have also been identified in plant
seeds[48] and in molluscs.[49]
2-Arachidonoylglycerol (2-AG)
Main article: 2-Arachidonoylglycerol
Another endocannabinoid, 2-arachidonoylglycerol, binds
to both the CB1 and CB2 receptors with similar affin-
ity, acting as a full agonist at both.[45] 2-AG is present
at significantly higher concentrations in the brain than
anandamide,[50] and there is some controversy over
whether 2-AG rather than anandamide is chiefly respon-
sible for endocannabinoid signalling in vivo.[1] In partic-
ular, one in vitro study suggests that 2-AG is capable of
stimulating higher G-protein activation than anandamide,
although the physiological implications of this finding are
not yet known.[51]
2-Arachidonyl glyceryl ether (noladin ether)
Main article: 2-Arachidonyl glyceryl ether
In 2001, a third, ether-type endocannabinoid, 2-
arachidonyl glyceryl ether (noladin ether), was isolated
from porcine brain.[52] Prior to this discovery, it had been lipophilic molecules that are not very soluble in water.
synthesized as a stable analog of 2-AG; indeed, some con-
troversy remains over its classification as an endocannabi-
noid, as another group failed to detect the substance at
“any appreciable amount” in the brains of several differ-
ent mammalian species.[53] It binds to the CB1 cannabi-
noid receptor (Kᵢ = 21.2 nmol/L) and causes sedation, hy-
pothermia, intestinal immobility, and mild antinocicep-
tion in mice. It binds primarily to the CB1 receptor, and The endocannabinoid 2-AG has been found in bovine and
only weakly to the CB2 receptor.[45]
5
N-Arachidonoyl dopamine (NADA)
Main article: N-Arachidonoyl dopamine
Discovered in 2000, NADA preferentially binds to the
CB1 receptor.[54] Like anandamide, NADA is also an
agonist for the vanilloid receptor subtype 1 (TRPV1), a
member of the vanilloid receptor family.[55][56]
Virodhamine (OAE)
Main article: Virodhamine
A fifth endocannabinoid, virodhamine, or O-
arachidonoyl-ethanolamine (OAE), was discovered
in June 2002. Although it is a full agonist at CB2 and
a partial agonist at CB1 , it behaves as a CB1 antag-
onist in vivo. In rats, virodhamine was found to be
present at comparable or slightly lower concentrations
than anandamide in the brain, but 2- to 9-fold higher
concentrations peripherally.[57]
Lysophosphatidylinositol (LPI)
Recent evidence has highlighted lysophosphatidylinositol
as the endogenous ligand to novel endocannabinoid re-
ceptor GPR55, making it a strong contender as the sixth
endocannabinoid.[58]
1.3.2 Function
Endocannabinoids serve as intercellular 'lipid messen-
gers', signaling molecules that are released from one
cell and activating the cannabinoid receptors present on
other nearby cells. Although in this intercellular signal-
ing role they are similar to the well-known monoamine
neurotransmitters, such as acetylcholine and dopamine,
endocannabinoids differ in numerous ways from them.
For instance, they are used in retrograde signaling be-
tween neurons. Furthermore, endocannabinoids are
They are not stored in vesicles, and exist as integral con-
stituents of the membrane bilayers that make up cells.
They are believed to be synthesized 'on-demand' rather
than made and stored for later use. The mechanisms
and enzymes underlying the biosynthesis of endocannabi-
noids remain elusive and continue to be an area of active
research.
human maternal milk.[59]
6 CHAPTER 1. CANNABINOID

Retrograde signal • Dronabinol (Marinol), is Δ9 -tetrahydrocannabinol

Conventional neurotransmitters are released from a
‘presynaptic’ cell and activate appropriate receptors on
a ‘postsynaptic’ cell, where presynaptic and postsynaptic
designate the sending and receiving sides of a synapse,
respectively. Endocannabinoids, on the other hand, are
described as retrograde transmitters because they most
commonly travel ‘backward’ against the usual synaptic
transmitter flow. They are, in effect, released from the
postsynaptic cell and act on the presynaptic cell, where
the target receptors are densely concentrated on axonal
terminals in the zones from which conventional neuro-
transmitters are released. Activation of cannabinoid re-
ceptors temporarily reduces the amount of conventional
neurotransmitter released. This endocannabinoid medi-
ated system permits the postsynaptic cell to control its
own incoming synaptic traffic. The ultimate effect on
the endocannabinoid-releasing cell depends on the na-
ture of the conventional transmitter being controlled. For Other notable synthetic cannabinoids include:
instance, when the release of the inhibitory transmitter
GABA is reduced, the net effect is an increase in the ex-
citability of the endocannabinoid-releasing cell. On the
converse, when release of the excitatory neurotransmit-
ter glutamate is reduced, the net effect is a decrease in
the excitability of the endocannabinoid-releasing cell.
(THC), used as an appetite stimulant, anti-emetic,
and analgesic
• Nabilone (Cesamet, Canemes), a synthetic cannabi-
noid and an analog of Marinol. It is Schedule II un-
like Marinol, which is Schedule III
• Sativex, a cannabinoid extract oral spray containing
THC, CBD, and other cannabinoids used for neu-
ropathic pain and spasticity in 22 countries includ-
ing England, Canada and Spain. Sativex develops
whole-plant cannabinoid medicines
• Rimonabant (SR141716), a selective cannabinoid
(CB1 ) receptor inverse agonist once used as an anti-
obesity drug under the proprietary name Acomplia.
It was also used for smoking cessation
• JWH-018, a potent synthetic cannabinoid agonist
discovered by Dr. John W. Huffman at Clemson
University. It is being increasingly sold in legal
smoke blends collectively known as “spice”. Several
countries and states have moved to ban it legally.

Range • JWH-073

• CP-55940, produced in 1974, this synthetic

Endocannabinoids are hydrophobic molecules. They can-
cannabinoid receptor agonist is many times more
not travel unaided for long distances in the aqueous
potent than THC.
medium surrounding the cells from which they are re-
leased, and therefore act locally on nearby target cells. • Dimethylheptylpyran
Hence, although emanating diffusely from their source
cells, they have much more restricted spheres of influence • HU-210, about 100 times as potent as THC[60]
than do hormones, which can affect cells throughout the
body. • HU-331 a potential anti-cancer drug derived from
cannabidiol that specifically inhibits topoisomerase
II.
1.4 Synthetic cannabinoids
• SR144528, a CB2 receptor antagonist
Historically, laboratory synthesis of cannabinoids were • WIN 55,212-2, a potent cannabinoid receptor
often based on the structure of herbal cannabinoids, and agonist
a large number of analogs have been produced and tested,
especially in a group led by Roger Adams as early as 1941 • JWH-133, a potent selective CB2 receptor agonist
and later in a group led by Raphael Mechoulam. Newer
compounds are no longer related to natural cannabinoids • Levonantradol (Nantrodolum), an anti-emetic and
or are based on the structure of the endogenous cannabi- analgesic but not currently in use in medicine
noids.
• AM-2201, a potent cannabinoid receptor agonist
Synthetic cannabinoids are particularly useful in exper-
iments to determine the relationship between the struc-
ture and activity of cannabinoid compounds, by mak-
ing systematic, incremental modifications of cannabinoid 1.5 Table of natural cannabinoids
molecules.
Medications containing natural or synthetic cannabinoids From es:Cannabinoide#Tabla de cannabinoides natu-
or cannabinoid analogs: rales.
1.7. REFERENCES
1.6 See also
• Cannabinoid receptor antagonist
• Cancer and nausea
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1751228. PMID 16205722.
[35] Merkus, Frans W. H. M. (1971). “Cannabivarin
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[40] He, X; Lin, L; Bernart, MW; Lian, L (1998). “Analysis
of alkamides in roots and achenes of Echinacea purpurea
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[41] Ligresti, A.; Villano, R.; Allarà, M.; Ujváry, I. N.; Di
Marzo, V. (2012). “Kavalactones and the endocannabi-
noid system: The plant-derived yangonin is a novel CB1
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169. doi:10.1016/j.phrs.2012.04.003. PMID 22525682.
[42] Korte, G.; Dreiseitel, A.; Schreier, P.; Oehme, A.;
Locher, S.; Geiger, S.; Heilmann, J.; Sand, P.G.
(2010). “Tea catechins’ affinity for human cannabi-
noid receptors”. Phytomedicine 17 (1): 19–22.
doi:10.1016/j.phymed.2009.10.001. PMID 19897346.
[43] Gertsch, J; Leonti, M; Raduner, S; Racz, I; Chen, J;
Xie, X; Altmann, K; Karsak, M; Zimmer, A (2008).
“Beta-caryophyllene is a dietary cannabinoid”. PNAS 105
(26): 9099–9104. doi:10.1073/pnas.0803601105. PMC
2449371. PMID 18574142.
[44] Ashton CH (February 2001). “Pharmacology and effects
of cannabis: a brief review”. Br J Psychiatry 178 (2):
101–106. doi:10.1192/bjp.178.2.101. PMID 11157422.
“Because they are extremely lipid soluble, cannabinoids
accumulate in fatty tissues, reaching peak concentrations
in 4-5 days. They are then slowly released back into other
body compartments, including the brain. They are then
slowly released back into other body compartments, in-
cluding the brain. Because of the sequestration in fat, the
tissue elimination half-life of THC is about 7 days, and
complete elimination of a single dose may take up to 30
days.”
[45] Grotenhermen, Franjo (2005). “Cannabinoids”. Current
Drug Target -CNS & Neurological Disorders 4 (5): 507.
doi:10.2174/156800705774322111.
[46] Martin, B.R.; Mechoulam, R.; Razdan, R.K. (1999).
“Discovery and characterization of endogenous cannabi-
noids”. Life Sciences 65 (6–7): 573. doi:10.1016/S0024-
3205(99)00281-7.
[47] Di Tomaso, Emmanuelle; Beltramo, Massimiliano; Pi-
omelli, Daniele (1996). “Brain cannabinoids in choco-
late”. Nature 382 (6593): 677–8. doi:10.1038/382677a0.
PMID 8751435.
[48] Chapman, K. D.; Venables, B; Markovic, R; Blair Jr, RW;
Bettinger, C (1999). “N-Acylethanolamines in Seeds.
Quantification of Molecular Species and Their Degrada-
tion upon Imbibition”. Plant Physiology 120 (4): 1157–
64. doi:10.1104/pp.120.4.1157. PMC 59349. PMID
10444099.
[49] Sepe, Nunzio; De Petrocellis, Luciano; Montanaro,
Francesca; Cimino, Guido; Di Marzo, Vincenzo (1998).
“Bioactive long chain N-acylethanolamines in five species
of edible bivalve molluscs”. Biochimica et Biophysica Acta
(BBA) – Lipids and Lipid Metabolism 1389 (2): 101–11.
doi:10.1016/S0005-2760(97)00132-X. PMID 9461251.
[50] Piomelli, Daniele; Schweitzer, Nephi; Piomelli, Paul
(1997). “A second endogenous cannabinoid that modu-
lates long-term potentiation”. Nature 388 (6644): 773–8.
doi:10.1038/42015. PMID 9285589.
[51] Savinainen, Juha R; Järvinen, Tomi; Laine, Krista; Laiti-
nen, Jarmo T (2001). “Despite substantial degradation, 2-
arachidonoylglycerol is a potent full efficacy agonist medi-
ating CB1receptor-dependent G-protein activation in rat
cerebellar membranes”. British Journal of Pharmacol-
ogy 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC
1572991. PMID 11588122.
9
[52] Hanuš, Lumír; Abu-Lafi, Saleh; Fride, Ester; Breuer,
Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich,
Irina; Mechoulam, Raphael (2001). “2-Arachidonyl glyc-
eryl ether, an endogenous agonist of the cannabinoid CB1
receptor”. Proceedings of the National Academy of Sci-
ences 98 (7): 3662–5. doi:10.1073/pnas.061029898.
PMC 31108. PMID 11259648.
[53] Oka, Saori; Tsuchie, Akiko; Tokumura, Akira; Mu-
ramatsu, Mayumi; Suhara, Yoshitomo; Takayama, Hi-
roaki; Waku, Keizo; Sugiura, Takayuki (2003). “Ether-
linked analogue of 2-arachidonoylglycerol (noladin ether)
was not detected in the brains of various mammalian
species”. Journal of Neurochemistry 85 (6): 1374–
81. doi:10.1046/j.1471-4159.2003.01804.x. PMID
12787057.
[54] Bisogno, Tiziana; Melck, Dominique; Bobrov, Mikhail
Yu.; Gretskaya, Natalia M.; Bezuglov, Vladimir V.;
De Petrocellis, Luciano; Di Marzo, Vincenzo (2000).
“N-acyl-dopamines: Novel synthetic CB1 cannabinoid-
receptor ligands and inhibitors of anandamide inactiva-
tion with cannabimimetic activity in vitro and in vivo”.
Biochemical Journal 351 (3): 817–24. doi:10.1042/0264-
6021:3510817. PMC 1221424. PMID 11042139.
[55] Bisogno, T; Ligresti, A; Dimarzo, V (2005). “The en-
docannabinoid signalling system: Biochemical aspects”.
Pharmacology Biochemistry and Behavior 81 (2): 224–
38. doi:10.1016/j.pbb.2005.01.027. PMID 15935454.
[56] Ralevic, Vera (2003). “Cannabinoid modulation of
peripheral autonomic and sensory neurotransmission”.
European Journal of Pharmacology 472 (1–2): 1–21.
doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.
[57] Porter, A. C.; Sauer, JM; Knierman, MD; Becker, GW;
Berna, MJ; Bao, J; Nomikos, GG; Carter, P; Bymaster,
FP; Leese, AB; Felder, CC (2002). “Characterization
of a Novel Endocannabinoid, Virodhamine, with Antag-
onist Activity at the CB1 Receptor”. Journal of Pharma-
cology and Experimental Therapeutics 301 (3): 1020–4.
doi:10.1124/jpet.301.3.1020. PMID 12023533.
[58] Piñeiro, Roberto; Falasca, Marco (2012). “Lysophos-
phatidylinositol signalling: New wine from an old bot-
tle”. Biochimica et Biophysica Acta (BBA) – Molec-
ular and Cell Biology of Lipids 1821 (4): 694–705.
doi:10.1016/j.bbalip.2012.01.009. PMID 22285325.
[59] Fride, E; Bregman, T; Kirkham, TC (2005). “Endo-
cannabinoids and food intake: Newborn suckling and ap-
petite regulation in adulthood”. Experimental biology and
medicine 230 (4): 225–34. PMID 15792943.
[60] “More medicinal uses for marijuana”. Marijuana.org.
October 18, 2005. Archived from the original on 2005-
12-21. Retrieved 2014-01-15.
1.8 Further reading
• De Meijer, EP; Bagatta, M; Carboni, A; Crucitti, P;
Moliterni, VM; Ranalli, P et al. (2003). “The inher-
itance of chemical phenotype in Cannabis sativa L”.
10 CHAPTER 1. CANNABINOID

Genetics 163 (1): 335–46. PMC 1462421. PMID
12586720.
• Devane, W.; Hanus, L; Breuer, A; Pertwee, R.;
Stevenson, L.; Griffin, G et al. (1992). “Isolation
and structure of a brain constituent that binds to the
cannabinoid receptor”. Science 258 (5090): 1946–
9. doi:10.1126/science.1470919. PMID 1470919.
• Elsohly, Mahmoud A.; Slade, Desmond (2005).
“Chemical constituents of marijuana: The com-
plex mixture of natural cannabinoids”. Life Sciences
78 (5): 539–48. doi:10.1016/j.lfs.2005.09.011.
PMID 16199061.
• Hanus, Lumir; Gopher, Asher; Almog, Shlomo;
Mechoulam, Raphael (1993). “Two new un-
saturated fatty acid ethanolamides in brain 1.9
that bind to the cannabinoid receptor”. Jour-
nal of Medicinal Chemistry 36 (20): 3032–4. 1.9.1
doi:10.1021/jm00072a026. PMID 8411021.
• Hanus, L (1987). “Biogenesis of cannabinoid sub-
stances in the plant”. Acta Universitatis Palackianae
Olomucensis Facultatis Medicae 116: 47–53. PMID
2962461.
• Hanuš, L.; Krejčí, Z. (1975). “Isolation of two
new cannabinoid acids from Cannabis sativa L. of
Czechoslovak origin”. Acta Univ. Olomuc., Fac.
Med 74: 161–166.
• Hanuš, L.; Krejčí, Z.; Hruban, L. (1975). “Isola-
tion of cannabidiolic acid from Turkish variety of
cannabis cultivated for fibre”. Acta Univ. Olomuc.,
Fac. Med 74: 167–172.
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.;
Rehnelt, J.; Martín, M. et al. (2008). “Crucial Role
of CB2 Cannabinoid Receptor in the Regulation
of Central Immune Responses during Neuropathic
Pain”. Journal of Neuroscience 28 (46): 12125–35.
doi:10.1523/JNEUROSCI.3400-08.2008. PMC
3844839. PMID 19005077.
• Turner, C. E.; Mole, M. L.; Hanus, L.; Elsohly, H.
N. (1981). “Constituents of Cannabis sativa. XIX.
Isolation and Structure Elucidation of Cannabiglen-
dol, A Novel Cannabinoid from an Indian Vari-
ant”. Journal of Natural Products 44 (1): 27–33.
doi:10.1021/np50013a005.
External links
Cannabinoid information
• Bela Szabo: Pharmacology of Cannabinoid Recep-
tors BIOTREND Reviews No. 02, February 2008
• Marijuana and Medicine – Assessing the Science
Base (Institute of Medicine) – 1999 at National
Academies Press
• House of Lords Report – Cannabis (United King-
dom) – 1998 at Parliament of the United Kingdom
• Cannabis: A Health Perspective and Research
Agenda – 1997 at World Health Organization
• Chemical Ecology of Cannabis (J. Intl. Hemp Assn.
- 1994)

• Köfalvi, Attila, ed. (2008). “Cannabinoids and • THC (tetrahydrocannabinol) accumulation in glands
the Brain”. doi:10.1007/978-0-387-74349-3. ISBN of Cannabis (Cannabaceae)
978-0-387-74348-6.
• Non-psychotropic plant cannabinoids: new thera-
• Mechoulam, Raphael; Ben-Shabat, Shimon; Hanus, peutic opportunities from an ancient herb
Lumir; Ligumsky, Moshe; Kaminski, Norbert E.;
Schatz, Anthony R. et al. (1995). “Identifica-
tion of an endogenous 2-monoglyceride, present 1.9.2 Cannabinoid research organizations
in canine gut, that binds to cannabinoid recep-
tors”. Biochemical Pharmacology 50 (1): 83– • International Cannabinoid Research Society
90. doi:10.1016/0006-2952(95)00109-D. PMID • The Canadian Consortium for the Investigation of
7605349. Cannabinoids
• Nicoll, Roger A.; Alger, Bradley E. (2004). “The • Therapeutic Potential in Spotlight at Cannabinoid
Brain’s Own Marijuana”. Scientific American 291 Researchers’ Meeting at California Cannabis Re-
(6): 68–75. doi:10.1038/scientificamerican1204- search Medical Group
68. PMID 15597982.
• Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.;
Rehnelt, J.; Martín, M. et al. (2008). “Interferon-
is a Critical Modulator of CB2 Cannabinoid
Receptor Signaling during Neuropathic Pain”.
Journal of Neuroscience 28 (46): 12136–45.
doi:10.1523/JNEUROSCI.3402-08.2008. PMC
3844840. PMID 19005078.
Chapter 2

Entourage effect

Entourage effect is a phrase that was introduced in

cannabinoid science in 1998 by S. Ben-Shabat, with
Raphael Mechoulam, to represent a novel endogenous
cannabinoid molecular regulation route. Biological ac-
tivity assayed together with inactive compounds. Ref-
erences whole plant and whole person caregiver synergy
treatments over isolated compound pharmacological
dosages.[1][2][3][4][5][6][7][8]

2.1 External links

• Dr. Sanjay Gupta: Medical marijuana and 'the en-
tourage effect'

2.2 References
[1] Lee, Martin A. (Sep 13, 2013). Smoke Signals: A Social
History of Marijuana-Medical, Recreational and Scientific.
Scribner. p. 465. ISBN 978-1439102619.
[2] Ben-Shabat, Shimon (July 17, 1998). “An entourage
effect: inactive endogenous fatty acid glycerol esters
enhance 2-arachidonoyl-glycerol cannabinoid activity”.
European Journal of Pharmacology 353 (1): 23–31.
doi:10.1016/S0014-2999(98)00392-6.
[3] Andersson, Karl-Erik (Feb 4, 2011). Urinary Tract.
eBook: Springer Science & Business Media. p. 438.
[4] Newnes (March 5, 2010). Comprehensive Natural Prod-
ucts II: Chemistry and Biology:. eBook: Google. p. 220.
[5] Guy, Geoffrey William (July 1, 2004). The Medicinal
Uses of Cannabis and Cannabinoids (1st ed.). Pharma-
ceutical Press. p. 114. ISBN 978-0853695172.
[6] Castle, David (May 27, 2004). Marijuana and Madness:
Psychiatry and Neurobiology. eBook: Google. p. 8.
[7] Russo, Ethan B (Aug 2011). “Taming THC: poten-
tial cannabis synergy and phytocannabinoid-terpenoid en-
tourage effects”. Br J Pharmacol 163 (7): 1344–1364.
doi:10.1111/j.1476-5381.2011.01238.x.
[8] Gardner, Fred (2011). “Terpenoids, 'minor' cannabi-
noids contribute to 'entourage effect' of Cannabis-based
medicines”. The Journal of Cannavis in Clinical Practice:
1.

11
Chapter 3

Synthetic cannabis

its metabolites in human urine. The synthetic cannabi-

noids contained in synthetic cannabis products have been
made illegal in many European countries. On Novem-
ber 24, 2010, the US Drug Enforcement Administra-
tion announced it would use emergency powers to ban
many synthetic cannabinoids within a month.[4] Prior to
the announcement, several US states had already made
them illegal under state law. In the US, as of March
1, 2011, five cannabinoids, JWH-018, JWH-073, CP-
47,497, JWH-200, and cannabicyclohexanol have been
placed on Schedule I of the Controlled Substances Act
(and are therefore illegal to possess or use in the US); the
Drug Enforcement Administration claims that said action
is “to avoid an imminent hazard to the public safety.”[5][6]
A bag of Spice brand herbal incense In July 2012, the Synthetic Drug Abuse Prevention Act of
2012 was signed into law. It banned synthetic compounds
commonly found in synthetic cannabis, placing them un-
Commercially known as Synthetic cannabis (synthetic
der Schedule I of the Controlled Substances Act.[7]
marijuana), or technically cannabinoid research
chemicals, is any designer drug that mimics the ef-
fects of cannabis.[1] There are several psychoactive arti-
ficial cannabinoid families (eg AM-xxx, HU-xxx, JWH-
xxx, CP xx) that are used as designer drugs sprayed on
herbs and sold as natural highs under brand names like
K2[2] and Spice,[3] both of which are genericized trade- 3.1 Misnomer
marks used for any synthetic cannabis product. Synthetic
cannabis is often termed spice product.
There is controversy about calling Spice and K2 synthetic
When synthetic cannabis blends first went on sale in the cannabis. Synthetic marijuana is a misnomer accord-
early 2000s, it was thought that they achieved an effect ing to Lewis Nelson, MD, a medical toxicologist at the
through a mixture of natural herbs. Laboratory anal- NYU School of Medicine. “It’s really quite different,
ysis in 2008 showed that this is not the case, and that and the effects are much more unpredictable. It’s dan-
they in fact contain synthetic cannabinoids that act on the gerous, and there is no quality control in what you are
body in a similar way to cannabinoids naturally found in getting.”[8] Since the term synthetic does not apply to the
cannabis, such as THC. A large and complex variety of plant but rather to the chemical that the plant contains
synthetic cannabinoids, most often cannabicyclohexanol, (tetrahydrocannabinol), the term synthetic cannabinoid is
JWH-018, JWH-073, or HU-210, are used in an attempt more appropriate.[9] Research on the safety of synthetic
to avoid the laws that make cannabis illegal, making syn- cannabinoids is now becoming available. Initial stud-
thetic cannabis a designer drug. It has been sold under ies are focused on the role of synthetic cannabinoids in
various brand names, online, in head shops, and at some psychosis. Synthetic cannabis may precipitate psychosis
gas stations. and in some cases it may be prolonged. Some studies sug-
It is often marketed as "herbal incense"; however, some gest that synthetic cannabinoid intoxication is associated
brands market their products as “herbal smoking blends”. with acute psychosis, worsening of previously stable psy-
In either case, the products are usually smoked by users. chotic disorders, and it may trigger a chronic (long-term)
Although synthetic cannabis does not produce positive re- psychotic disorder among vulnerable individuals such as
sults in drug tests for cannabis, it is possible to detect those with a family history of mental illness.[10][11]

12
3.3. SAFETY
3.2 Ingredients
Synthetic cannabis is claimed by the manufacturers to
contain a mixture of traditionally used medicinal herbs,
each of which producing mild effects, with the over-
all blend resulting in the cannabis-like intoxication pro-
duced by the product. Herbs listed on the packag-
ing of Spice include Canavalia maritima (Coastal Jack-
bean), Nymphaea caerulea (Blue Egyptian water lily),
Scutellaria nana (dwarf skullcap), Pedicularis densiflora
(Indian warrior), Leonotis leonurus (lion’s tail), Zornia
latifolia (maconha brava), Nelumbo nucifera (lotus), and
Leonurus sibiricus (honeyweed). However, when the
product was analyzed by laboratories in Germany and
elsewhere, it was found that many of the characteris-
tic “fingerprint” molecules expected to be present from
the claimed plant ingredients were not present. There
were also large amounts of synthetic tocopherol present.
This suggested that the actual ingredients might not be
the same as those listed on the packet, and a German
government risk assessment of the product conducted in
November 2008 concluded that it was unclear as to what
the actual plant ingredients were, where the synthetic
tocopherol had come from, and whether the subjective
cannabis-like effects were actually produced by any of
the claimed plant ingredients or instead caused by a syn-
thetic cannabinoid drug.
3.2.1 Artificial cannabinoids
In January 2009, researchers at the University of Freiburg
in Germany announced that an active substance in Spice
was an undisclosed analogue of the synthetic cannabi-
noid CP 47,497.[12] Later that month, CP 47,497 along
with its dimethylhexyl, dimethyloctyl and dimethylnonyl
homologues, were added to the German controlled drug
schedules.[13][14] In May the analogue of CP 47,497 was
named cannabicyclohexanol.[15]
In July 2010, it was announced that JWH-018 is one of
the active components in at least three versions of Spice,
which had been sold in a number of countries around the
world since 2002, often marketed as incense.[16][17][18][19]
Another potent synthetic cannabinoid, HU-210, has been
reported to have been found in Spice seized by U.S.
Customs and Border Protection.[20] An analysis of sam-
ples acquired four weeks after the German prohibition of
JWH-018 took place found that the compound had been
replaced with JWH-073.[21]
Different ratios of JWH-018 and CP 47,497 and their
analogues have been found in different brands of syn-
thetic cannabis[22] and manufacturers constantly change
the composition of their products.[23] The amount of
JWH-018 in Spice has been found to vary from 0.2% to
3%.[24]
Other non-cannabinoid ingredients have also been found girl suffered multiple strokes and subsequent brain dam-
in synthetic cannabis blends around the world, but they do age, leaving her blind and paralyzed.[47]
13
not produce classical cannabis intoxication effects. This
includes substituted cathinone derived stimulant drugs
such as 4-methylbuphedrone and 4-methyl-alpha-PPP,
and psychedelic tryptamine derivatives such as 4-HO-
DET.[25][26] In 2013 a designer opioid drug AH-7921 was
detected in smoking blends in Japan, along with several
novel cannabinoids and a cathinone analogue.[27]
New Zealand
An analysis of 41 different synthetic cannabis blends
sold commercially in New Zealand, conducted by the
Institute of Environmental Science and Research and re-
leased in July 2011, found 11 different synthetic cannabi-
noid ingredients used: including JWH-018, JWH-073,
AM-694, AM-2201, RCS-4, RCS-4 butyl homologue,
JWH-210, JWH-081, JWH-250 (or possibly JWH-302,
isomer not determined), JWH-203, and JWH-122—
with between one and five different active ingredients,
though JWH-018 was present in 37 of the 41 blends
tested. In two brands the benzodiazepine anxiolytic
drug phenazepam was also found, which is classified as
a prescription medicine in New Zealand, and so these
brands were ordered to be removed from the market
by emergency recall.[28][29] Since this time, a further 15
cannabinoid compounds have been detected as ingredi-
ents of synthetic cannabis blends in New Zealand and
banned as temporary class drugs.[30] In 2013 another hyp-
notic medication, zaleplon was found to have been used
as an active ingredient in a blend that had been sold in
New Zealand during 2011-2012.[31]
3.3 Safety
No official studies have been conducted on the effects of
synthetic cannabinoids on humans (as is usually the case
with known toxic and/or illegal compounds).[36] How-
ever, reports describing effects seen in patients seeking
medical care after taking synthetic cannabinoids have
been published. Compared to cannabis and its active
cannabinoid THC, the adverse effects are often much
more severe and can include hypertension, tachycardia,
myocardial infarction,[37] agitation, vomiting, halluci-
nations, psychoses, seizures, convulsions[38] and panic
attacks.[39][40][41][42][43] Among individuals who need
emergency treatment after using synthetic cannabis, the
most common symptoms are accelerated heartbeat, high
blood pressure, nausea, blurred vision, hallucination and
agitation.[44] Other symptoms included epileptic seizures,
acute psychosis, and heart attacks.[44]
At least one death has been linked to overdose of syn-
thetic cannabinoids[45] and in Colorado three deaths in
September 2013 have been investigated for being linked
to synthetic cannabinoids.[46] In December 2012, after
two weeks of daily synthetic cannabis use, a 17-year old
14
These more severe adverse effects in contrast to use of 3.5 Legal status
marijuana are believed to stem from the fact that many
of the synthetic cannabinoids are full agonists to the
cannabinoid receptors, CB1R and CB2R, compared to
THC which is only a partial agonist and thus not able
to saturate and activate all of the receptor population no
[48]
matter of dose and resulting concentration. It has also
been seen that phase 1 metabolism of JWH-018 results
in at least nine monohydroxylated metabolites and with
at least three of the metabolites shown to have full ago-
nistic effect on CB1R which compared to metabolism of
THC only results in one psychoactive monohydroxylated Germany JWH-018, CP 47,497 and the C6, C8 and C9
metabolite. This may further explain the increased toxi-
city of synthetic cannabinoids compared to THC.[45]
Professor John W. Huffman, who first synthesised many
of the cannabinoids used in synthetic cannabis, is quoted Finland Spice blends are classified as a medicine in Fin-
as saying, “People who use it are idiots.”[36] “You don't
know what it’s going to do to you.”[49] A user who con-
sumed 3 g of Spice Gold every day for several months
showed withdrawal symptoms, similar to those associ-
ated with withdrawing from the use of narcotics. Doc- France JWH-018, CP 47,497 (and its homologues) and
tors treating the user also noted that his use of the
product showed signs associated with addiction. [50]
One
case has been reported wherein a user, who had previ-
ously suffered from cannabis-induced recurrent psychotic Ireland From June 2010, JWH-018, along
episodes, suffered reactivation of his symptoms after
using Spice. Psychiatrists treating him have suggested
that the lack of an antipsychotic chemical, similar to
cannabidiol found in natural cannabis, may make syn-
thetic cannabis more likely to induce psychosis than nat-
ural cannabis.[51]
Studies are currently available which suggest an asso-
ciation between synthetic cannabinoids and psychosis.
Physicians should be aware that the use of synthetic
cannabinoids can be associated with psychosis and in-
vestigate possible use of synthetic cannabinoids in pa-
tients with inexplicable psychotic symptoms. In contrast Romania Spice was made illegal in Romania on Febru-
to most other recreational drugs, the dramatic psychotic
state induced by use of synthetic cannabinoids has been
reported in multiple cases to persist for several weeks, Russia On April 9, 2009, the Chief Medical Officer of
and in one case for seven months, after complete cessa-
[52]
tion of drug use. Individuals with risk factors for psy-
chotic disorders should be counseled against using syn-
thetic cannabinoids. [53]
3.4 Drug testing
Spice does not cause a positive drug test for cannabis
or other illegal drugs using GC-MS-screening with
library search, multi-target screening by LC-MS/MS,
or immunological screening procedures.[22][50] A study
has been conducted into the detection of metabolites of
JWH-018 in urine; the metabolites are mainly conjugates
with glucuronic acid and can be reliably detected by GC–
MS/MS and LC–MS/MS.[54]
CHAPTER 3. SYNTHETIC CANNABIS
3.5.1 Europe
Austria The Austrian Ministry of Health announced on
December 18, 2008 that Spice would be controlled
under Paragraph 78 of their drug law on the grounds
that it contains an active substance that affects the
functions of the body, and the legality of JWH-018
is under review.[55][56][57]
homologues of CP 47,497 are illegal in Germany
since January 22, 2009.[14][58]
land, and, therefore, it is illegal to order them with-
out a prescription. In practice, it is not possible to
get a prescription.
HU-210 were all made illegal in France on February
24, 2009.[59]
[60]
with a variety
of other designer drugs, is illegal.
Latvia JWH-018, JWH-073, CP 47,497 (and its homo-
logues) and HU-210 are all banned in Latvia as well
as leonotis leonurus.[61]
Poland JWH-018 and many of the herbs mentioned on
the ingredient lists of Spice and similar prepara-
tions were made illegal in May 2009. The bill was
passed by Polish Sejm,[62][63] Polish Senat[64] and
was signed by the President.[65]
ary 15, 2010.[66]
the Russian Federation issued a resolution on re-
inforcing control over the sales of smoking blends.
These blends, marketed under the trade names AM-
HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-
ses, Yucatán Fire and others, have been declared
to contain Salvia divinorum, Hawaiian Wood Rose,
and Blue Lotus, and are prohibited to be sold. These
substances have been found to have “psychotropic,
narcotic effects, contain poisonous components and
represent potential threat for humans”. The resolu-
tion does not mention JWH-018 or other synthetic
cannabinoids.[67] On January 14, 2010, the Russian
government issued a statement including 23 syn-
thetic cannabinoids found in smoking blends Hawai-
ian Rose and Blue Lotus on the list of prohibited
narcotic and psychotropic substances. Thus, all of
these plants and compounds are now illegal in the
Russian Federation.[68]
3.5. LEGAL STATUS 15

Slovakia Spice is legal in Slovakia. The National Anti- passed on September 18, 2013 that bans entire fam-
Drug Unit is considering adding it to the list of con- ilies of synthetic drugs instead of only banning exist-
trolled substances.[69] The latest anti-drug law ver- ing compounds that have been identified.[82][83] The
sion (468/2009) valid since January 2010 still does introduction of this law makes NSW the first state
not mention active compounds of Spice.[70] in Australia to completely ban substances with psy-
choactive properties.[83]
Sweden CP 47,497-C6, CP 47,497-C7, CP 47,497-C8,
CP 47,497-C9, JWH-018, JWH-073 and HU-210
were all made illegal in Sweden on September 15, New Zealand Spice is illegal in New Zealand,[84]
it is clas-
2009. The bill was accepted on July 30, 2009 and sified as a Class C controlled drug. The New
was put in effect on September 15, 2009.[71] Zealand Parliament passed a law in July 2013 ban-
ning the sale of legal highs in dairies and supermar-
Switzerland Spice has been banned in Switzerland.[72] kets, but allowing some “low risk” drugs to continue
to be sold through speciality licensed shops.[85] Syn-
Turkey Spice a.k.a Bonzai added to the list of drugs thetic cannabinoids, as well as all other 'legal highs’
and psychotropic substances in 07.01.2011 by the were outlawed at midnight on 7 May 2014, after a
law which numbered as 2011/1310 B.K.K. (Febru- law was passed a week prior by the New Zealand
ary 13, 2011 and the Official Gazette No. 27845) government.[86]
[73]

United Kingdom Spice was legal in the United King-

dom until December 2009, when it was classified as
3.5.5 North America
[74]
a Class B drug.
Canada

3.5.2 South America Spice and specific forms of JWHxxx are not specifically
prohibited in Canada, but synthetic cannabis is listed as a
Chile The Chilean Ministry of Health on April 24, schedule II drug.[87][88] Health Canada is debating on the
2009 declared the sale of synthetic cannabis to be subject.[89][90]
illegal.[75]

United States
3.5.3 Asia
See also: JWH-018 § United States
South Korea South Korea officially added JWH-018,
CP 47,497 and HU-210 to the controlled substance The case of David Mitchell Rozga, an American teenager
list on July 1, 2009, effectively making these chem- from Indianola, Iowa, United States, brought interna-
icals illegal.[76] tional attention to K2. Rozga shot himself in the head
Japan Japan has banned JWH-018, CP 47, 497, and ho- with a family owned hunting rifle in an apparent suicide
mologues, and HU-210 since October 2009 in June 6, 2010. After news of Rozga’s death, it was re-
ported by friends that they had smoked K2 with Rozga
United Arab Emirates The United Arab Emirates had approximately one hour before his death. The nature of
stated that Spice was an illegal substance and posses- his death and reports from numerous family members,
sion or intent to sell would be a jailable offense.[77] had led investigators to believe that it was likely Rozga
was under the influence of a mind-altering substance, at
the time of his death. The death of Rozga has been used
3.5.4 Australasia as a face of political lobbying against the continuation of
K2, and other legal synthetic drugs, such as bath salts.[91]
Australia On June 17, 2011, the Western Australian
government banned all of the synthetic cannabi- Following the incident, an act to ban the use and distribu-
noids found in already existing products, including tion of the drug was proposed by the US Senator Chuck
brands such as Kronic, Kalma, Voodoo, Kaos, and Grassley of Iowa as the David Mitchell Rozga Act. It was
Mango Kush. Western Australia was the first state approved into [92] legislation by the United States Congress
in Australia to prohibit the sale of certain synthetic in June 2011. On July 10, 2012, President Barack
cannabinoids. [78][79]
On June 18, 2013, an interim Obama signed the Synthetic Drug Abuse Prevention Act
ban made a large list of product brands and synthetic of 2012 into law. It banned synthetic compounds com-
substances illegal to sell anywhere in Australia. [80] monly found in synthetic marijuana, placing them under
This ban lapsed on October 13, 2013, and a per- Schedule I of the Controlled Substances Act.[7]
manent ban has not been imposed.[81] Synthetic Prior to that, some compounds within synthetic cannabis
cannabis remains illegal in NSW, where a bill was (HU-210) were scheduled in the USA under federal law,
16
while others (JWH-073) have been temporarily sched-
uled until final determination of their status can be
made.[93][94][95][96] The Drug Enforcement Administra-
tion (DEA) considers it to be a “drug of concern”,[97]
citing "...a surge in emergency-room visits and calls to
poison-control centers. Adverse health effects associated
with its use include seizures, hallucinations, paranoid be-
havior, agitation, anxiety, nausea, vomiting, racing heart-
beat, and elevated blood pressure.”[98][99]
Several states independently passed acts making it ille-
gal under state law, including Kansas in March 2010,[100]
Georgia and Alabama in May 2010,[101][102] Tennessee
and Missouri in July 2010,[103][104] Louisiana in August
2010, Mississippi in September 2010, and Iowa.[105] An
emergency order was passed in Arkansas in July 2010
banning the sale of synthetic cannabis.[106] In October
2010, the Oregon Board of Pharmacy listed synthetic
cannabinoid chemicals on its Schedule 1 of controlled
substance, which means that the sale and possession of
these substances is illegal under the Oregon Uniform
Controlled Substances Act.[107] According to the National
Conference of State Legislatures, several other states are
also considering legislation, including New Jersey, New
York, Florida, and Ohio.[104] Illinois passed a law on July
27, 2010 banning all synthetic cannabinoids that goes
into effect January 1, 2011.[108] Michigan banned syn-
thetic cannabinoids in October 2010,[109] and the South
Dakota Legislature passed a ban on these products which
was signed into law by Gov. Dennis Daugaard on Febru-
ary 23, 2012 (and which took immediate effect under an
emergency clause of the state constitution).[110] Indiana
banned synthetic cannabinoids in a law which became ef-
fective in March 2012.[111] North Carolina banned syn-
thetic cannabis by a unanimous vote of the state senate,
due to concerns that its contents and effects are reason-
ably similar to natural cannabis, and may cause equal ef-
fects in terms of psychological dependency.[112][113]
Following cases in Japan involving the use of synthetic
cannabis by Navy, Army and Marine Corps personnel
resulted in the official banning of it,[114] a punitive gen-
eral order issued on January 4, 2010 by the Commander
Marine Corps Forces, Pacific prohibits the actual or at-
tempted possession, use, sale, distribution or manufac-
ture of synthetic cannabis as well as any derivative, ana-
logue or variant of it.[115] On June 8, 2010, the U.S.
Air Force issued a memorandum that banned the pos-
session and use of Spice, or any other mood-altering
substance except alcohol or tobacco, among its service
members.[116]
On November 24, 2010, the DEA announced that
it would make JWH-018, JWH-073, JWH-200, CP-
47,497, and cannabicyclohexanol, which are often
found in synthetic cannabis, illegal using emergency
powers.[117] They will be placed in Schedule I of the Con-
trolled Substances Act, within a month of the announce-
ment, and the ban will last for at least a year.[118][119] The
temporary ban, for at least a year, came into effect on
CHAPTER 3. SYNTHETIC CANNABIS
March 1, 2011.[120]
On October 20, 2011, the Louisiana State University
football program announced that it had suspended three
players, including star cornerback Tyrann Mathieu, who
tested positive for synthetic cannabis.[121]
3.6 History
According to the Psychonaut Web Mapping Research
Project, synthetic cannabis products, sold under the brand
name Spice, first appeared in Europe in 2004.[122] The
brand “Spice” was released in 2004 by the now-dormant
company The Psyche Deli in London, UK. In 2006 the
brand gained popularity. According to the Financial
Times, the assets of The Psyche Deli rose from £65,000 in
2006 to £899,000 in 2007.[123] The EMCDDA reported
in 2009 that 'Spice' products were identified in 21 of the
30 participating countries. Because 'Spice' was the dom-
inant brand until 2009, the competing brands that started
to appear from 2008 on were also dubbed 'Spice'. Spice
can, therefore, refer to both the brand 'Spice', as to all
herbal blends with synthetic cannabinoids added.
A survey of readers of Mixmag in the UK in 2009 found
that one in eight respondents had used synthetic cannabis,
compared to 85% who had used cannabis.[124]
3.6.1 Slang terms
In addition to K2 and Spice, other street names include
Black Mamba (Turnera diffusa), Bombay Blue, Genie,
and Zohai.[7] According to Partnership at Drugfree.org,
other names also include Bliss, Blaze, JWH −018, −073,
−250, Yucatan Fire, Skunk, Moon Rocks[125] and Bonzai
(esp. in Turkey)[73]
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[76] (July 2, 2009). “1 '5- - ’ " ministration website”. Justice.gov. Retrieved June 19,
(in Korean). . Retrieved February 18, 2010.
[77] Dubai Customs foil 126 attempts to smuggle narcotic
[78] Jerga, Josh (June 13, 2011). “Fake cannabis to be out-
lawed in WA”. The Sydney Morning Herald. Retrieved
June 15, 2011.
[79] O'Brien, Amanda (April 11, 2011). “Miners working high
on synthetic grass”. The Australian. Retrieved April 17,
2011.
[80] Bradbury, David (June 18, 2013). “Competition and Con-
sumer Act 2010 - Consumer Protection Notice No. 3 of [100] The Associated Press. How major issues fared in Kansas
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Goods Containing Synthetic Drug Substances”. Retrieved
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[101] Simmons, Andria (May 24, 2010). “Governor signs bill
[81] “Synthetic drug substances - national interim ban”.
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19
[82] “NSW law to ban synthetic drugs passed”. September 18,
2013. Retrieved October 28, 2013.
[83] Coultan, Mark (September 10, 2013). “NSW law to ban
synthetic drugs to stop 'legal highs’". The Australian. Re-
trieved October 28, 2013.
[84] “Cannabis substitute “Spice” now illegal”. TVNZ. April
1, 2009. Retrieved March 2, 2011.
[85] Heather, Ben (October 6, 2013). “Kronic king gets the
green light”. Retrieved October 28, 2013.
[86] “Legal highs banned from midnight”. May 7, 2014. Re-
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[87] “Controlled Drugs and Substances Act”.
Laws.justice.gc.ca. November 15, 2010. Retrieved
November 24, 2010.
[88] “Consolidated Index of Drugs and Substances”. Iso-
merdesign.com. April 24, 2010. Retrieved June 19, 2010.
[89] “Ian Bussières : Le spice: la capitale craque pour les
“herbes magiques” | Société". Cyberpresse.ca. Retrieved
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[90] “Une pilule une petite granule : Le Spice, un substitut
au cannabis ?". Pilule.telequebec.tv. Retrieved June 19,
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[91] “K2 Drug Facts”. K2drugfacts.com. Retrieved 2012-09-
09.
[92] “The David Mitchell Rozga Act (S.605 - Dangerous Syn-
thetic Drug Control Act of 2011)". Opencongress.org.
Retrieved 2012-09-09.
[93] “HU-210”. USDOJ.gov. Retrieved September 16, 2010.
[94] Cook, Morgan (February 28, 2011). “Synthetic marijuana
illegal as of Tuesday”. North County Times (San Diego).
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[95]
[96] “Drug Scheduling from the US Drug Enforcement Ad-
2010.
[97] Donna Leinwand (May 24, 2010). 24, 2010-k2_N.htm
“Places race to outlaw K2 'Spice' drug”. USA Today. Re-
trieved July 26, 2010.
[98] Meserve, Jeanne (February 28, 2011). “DEA imposes
“emergency” ban to control synthetic marijuana”. CNN.
Retrieved March 1, 2011.
[99] Ben Paynter: The Big Business of Synthetic Highs,
Bloomerg Businessweek June, 2011
Legislature. CNBC. May 23, 2010. Accessed: May 23,
2010
to outlaw synthetic marijuana”. ajc.com. Retrieved June
19, 2010.
 20 CHAPTER 3. SYNTHETIC CANNABIS

[102] May 20, 2010 (May 20, 2010). “Alabama Coalition Gets [120] Meserve, Jeanne (February 28, 2011). “DEA imposes
Salvia and K2 Banned in Their State”. CADCA. Re- “emergency” ban to control synthetic marijuana”. CNN.
trieved August 24, 2010. Retrieved March 1, 2011.

[103] Haas, Brian. 'K2', 'K3' synthetic drugs are illegal in TN [121] Schlabach, Mark (October 20, 2011). “Sources: LSU
starting July 1. The Tennessean. May 30, 2010. Ac- players had positive tests”. ESPN.com. Retrieved Novem-
cessed: June 17, 2010 ber 4, 2011.

[104] Gay, Malcolm. (2010-07-10) Synthetic Marijuana Spurs [122] Spice Report Psychonaut Web Mapping Research Project
State Bans. New York Times. Retrieved on August 7,
2011. [123] “The story of Spice”. Financial Times. February 13,
2009. Retrieved September 19, 2010.
[105] Iowa Code § 124.204(4)(u) (defining a Schedule I con-
trolled substance to include “synthetic equivalents of the [124] Winstock, A.; Mitcheson, L.; Deluca, P.; Davey, Z.;
substances contained in the Cannabis plant, or in the Corazza, O.; Schifano, F. (2010). “Mephedrone, new
resinous extractives of such plant, and synthetic sub- kid for the chop?". Addiction (Abingdon, England) 106
stances, derivatives, and their isomers with similar chem- (1): 154–161. doi:10.1111/j.1360-0443.2010.03130.x.
ical structure and pharmacological activity to those sub- PMID 20735367.
stances contained in the plant....”)
[125] K2 – Spice via Partnership at Drugfree.org
[106] Gavin Lesnick (July 2, 2010). “Beebe signs emer-
gency ban on K2”. Arkansas Online (Arkansas Democrat
Gazette). Retrieved July 26, 2010. 3.8 External links
[107] “Synthetic Cannabis — Controlled Substance Informa-
tion”. Retrieved October 16, 2010. • Erowid
[108] Daniel Martynowicz. “Illinois Bans Synthetic Cannabi- • Synthetic cannabinoid profile European Monitoring
noids”. Retrieved September 14, 2010. Centre for Drugs and Drug Addiction
[109] http://www.michigan.gov/lara/0,4601,7-154-10573_
11472-280858--,00.html

[110] Argus Leader, "New law bans synthetic drugs,” by John

Hult (February 23rd 2012 - retrieved on May 14th, 2012).

[111] http://www.in.gov/attorneygeneral/2974.htm

[112] “NC Senate OKs synthetic pot ban”. WRAL-TV. 10

February 2011. Retrieved 27 September 2012.

[113] “Make Synthetic Cannabinoids Illegal”. General Assem-

bly of North Carolina. 31 January 2011. Retrieved 27
September 2012.

[114] Allan, David; Fisher, Cindy. Ruling Clarifies 'Legal' Drug

Policy. Stars and Stripes via Military.com. May 23, 2010.
Accessed: May 23, 2010

[115] Marines Ban Spice Drug. Military.com. May 23, 2010.

Accessed: May 23, 2010

[116] “Air Force officials ban use and possession of spice,

mood-altering substances. Air Force News. June 17,
2010. Accessed: June 18, 2010”. Af.mil. Retrieved June
19, 2010.

[117] “DEA Moves to Emergency Control Synthetic Mari-

juana”. DEA Public Affairs. U.S. Drug Enforcement Ad-
ministration. November 24, 2010. Retrieved February
19, 2011.

[118] Grim, Ryan (November 24, 2010). “K2 Crackdown:

DEA Using Emergency Powers To Ban Fake Pot”. Huff-
ington Post. Retrieved November 24, 2010.

[119] By the CNN Wire Staff (November 24, 2010). “Feds

move to ban 'fake pot'". CNN. Retrieved November 24,
2010.
Chapter 4

4-HTMPIPO

4-HTMPIPO is a synthetic cannabinoid drug first identi-

fied in smoking products purchased from online vendors
in 2012.[1] 4-HTMPIPO is the product resulting from
the electrophilic addition of water to the cyclopropane
moiety of synthetic cannabinoid UR-144.[1] Nothing is
known about the in vitro or in vivo pharmacology of 4-
HTMPIPO.

4.1 See also

• AB-001
• JWH-018

• UR-144
• XLR-11

4.2 References
[1] Kavanagh, P.; Grigoryev, A.; Savchuk, S.; Mikhura, I.;
Formanovsky, A. (2013). “UR-144 in products soldviathe
Internet: Identification of related compounds and charac-
terization of pyrolysis products”. Drug Testing and Anal-
ysis: n/a. doi:10.1002/dta.1456.

21
Chapter 5

5F-PB-22

5F-PB-22 or Quinolin-8-yl 1-(5-fluoropentyl)−1H-

indole-3-8-carboxylate is a designer drug and a possi-
ble cannabinoid agonist. The structure of 5F-PB-22 ap-
pears to have been designed with an understanding of
structure-activity relationships within the indole class of
cannabinoids on the Forendex website of potential drugs
of abuse.[1]
In January 2014, 5F-PB-22 was designated as a Schedule
I controlled substance in the United States.[2]

5.1 See also

• AM-2201
• JWH-018

• QUCHIC
• QUPIC

• SDB-001

5.2 References
[1] 5F-PB-22 page on Forendex

[2] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G;

Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C
(2014). “Four Postmortem Case Reports with Quantita-
tive Detection of the Synthetic Cannabinoid, 5F-PB-22”.
Journal of analytical toxicology. doi:10.1093/jat/bku048.
PMID 24876364.

22
Chapter 6

A-40174

A-40174 (SP-1) is an analgesic drug which acts as a po-

tent cannabinoid receptor agonist, and was developed by
Abbott Laboratories in the 1970s.[1]

6.1 See also

• A-41988
• Menabitan

6.2 References
[1] Reggio, Patricia H., ed. (2009). “The Cannabinoid Re-
ceptors”. doi:10.1007/978-1-59745-503-9. ISBN 978-1-
58829-712-9.

23
Chapter 7

A-41988

A-41988 (BW29Y) is an analgesic drug which acts as a

cannabinoid agonist. It was developed by Abbott Lab-
oratories in the 1970s,[1][2] and researched for potential
use in the treatment of glaucoma,[3] but never commer-
cialised.

7.1 See also

• A-40174
• Menabitan

7.2 References
[1] Winn, M.; Arendsen, D.; Dodge, P.; Dren, A.; Dun-
nigan, D.; Hallas, R.; Hwang, K.; Kyncl, J.; Lee,
Y. H.; Plotnikoff, N.; Young, P.; Zaugg, H. (1976).
“Drugs derived from cannabinoids. 5. Delta6a,10a-
Tetrahydrocannabinol and heterocyclic analogs containing
aromatic side chains”. Journal of Medicinal Chemistry
19 (4): 461–471. doi:10.1021/jm00226a003. PMID
817021.

[2] Guterman A, Somani P, Bachand RT. Clinical Pharma-

cology and Therapeutics 1979; 25:227.

[3] Tiedeman, J. S.; Shields, M. B.; Weber, P. A.; Crow,

J. W.; Cocchetto, D. M.; Harris, W. A.; Howes, J. F.
(1981). “Effect of synthetic cannabinoids on elevated
intraocular pressure”. Ophthalmology 88 (3): 270–277.
doi:10.1016/s0161-6420(81)35052-0. PMID 7015221.

24
Chapter 8

A-796,260

A-796,260 is a drug developed by Abbott Laboratories

that acts as a potent and selective cannabinoid CB2
receptor agonist. Replacing the aromatic 3-benzoyl or
3-naphthoyl group found in most indole derived cannabi-
noids with the 3-tetramethylcyclopropylmethanone
group, imparts significant selectivity for CB2 , and
A-796,260 was found to be a highly selective CB2
agonist with little affinity for CB1 , having a CB2 Kᵢ of
4.6 nM vs 945 nM at CB1 .[1] It has potent analgesic
and anti-inflammatory actions in animal models, being
especially effective in models of neuropathic pain, but
without producing cannabis-like behavioral effects.[2]

8.1 See also

• A-834,735

• A-836,339
• JWH-200

• UR-144
• XLR-11

8.2 References
[1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones:
Effects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity”. Journal of Medic-
inal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.

[2] Yao BB, et al. (January 2008). “In vitro and in vivo char-
acterization of A-796260: a selective cannabinoid CB2
receptor agonist exhibiting analgesic activity in rodent
pain models”. British Journal of Pharmacology 153 (2):
390–401. doi:10.1038/sj.bjp.0707568. PMC 2219533.
PMID 17994110.

25
Chapter 9

A-834,735

A-834,735 is a drug developed by Abbott Laborato-
ries that acts as a potent cannabinoid receptor full
agonist at both the CB1 and CB2 receptors, with
a Kᵢ of 12nM at CB1 and 0.21nM at CB2 . Re-
placing the aromatic 3-benzoyl or 3-naphthoyl group
found in most indole derived cannabinoids, with the 3-
tetramethylcyclopropylmethanone group of A-834,735
and related compounds, imparts significant selectivity for
CB2 , with most compounds from this group found to be
highly selective CB2 agonists with little affinity for CB1 .
However low nanomolar CB1 binding affinity is retained
with certain heterocyclic 1-position substituents such as
(N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM-
1248), or the (tetrahydropyran-4-yl)methyl substituent of
A-834,735, resulting in compounds that still show signif-
icant affinity and efficacy at both receptors despite being
CB2 selective overall.[1][2][3][4][5]
[3] Chin CL, et al. (January 2008). “Differential effects of
cannabinoid receptor agonists on regional brain activity
using pharmacological MRI”. British Journal of Phar-
macology 153 (2): 367–79. doi:10.1038/sj.bjp.0707506.
PMC 2219521. PMID 17965748.
[4] Frost, J. M., et al. (2008). “Indol-3-yl-
tetramethylcyclopropyl Ketones: Effects of Indole
Ring Substitution on CB2 Cannabinoid Receptor Ac-
tivity”. Journal of Medicinal Chemistry 51 (6): 1904.
doi:10.1021/jm7011613. PMID 18311894.
[5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones:
Effects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity”. Journal of Medic-
inal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.

9.1 See also

• A-796,260

• AB-001

• JTE 7-31

• UR-144

• XLR-11

9.2 References
[1] Dart M, et al. (2006). 1-Alkyl-3-keto-indoles: identi-
fication and in vitro characterization of a series of po-
tent cannabinoid ligands. In 2006 Symposium on the
Cannabinoids. International Cannabinoid Research Soci-
ety: Burlington, VT.

[2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabi-

noid CB2 receptor: modelling and structural determinants
of CB2 selective ligands”. British Journal of Pharma-
cology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC
2219524. PMID 17982473.

26
Chapter 10

A-836,339

A-836,339 is a drug developed by Abbott Laboratories

that acts as a potent cannabinoid receptor full agonist. It
is selective for CB2 , with Kᵢ values of 0.64nM at CB2
vs 270nM at the psychoactive CB1 receptor, but while it
exhibits selective analgesic, anti-inflammatory and anti-
hyperalgesic effects at low doses,[1] its high efficacy at
both targets results in typical cannabis-like effects ap-
pearing at higher doses, despite its low binding affinity
for CB1 .[2]

10.1 References
[1] McGaraughty, S., et al. (2009). “A CB(2) receptor ago-
nist, A-836339, modulates wide dynamic range neuronal
activity in neuropathic rats: contributions of spinal and pe-
ripheral CB(2) receptors”. Neuroscience 158 (4): 1652–
1661. doi:10.1016/j.neuroscience.2008.11.015. PMID
19063946.

[2] Yao, B., et al. (2009). “Characterization of a cannabi-

noid CB2 receptor-selective agonist, A-836339 2,2,3,3-
tetramethyl-cyclopropanecarboxylic acid 3-(2-methoxy-
ethyl)−4,5-dimethyl-3H-thiazol-(2Z)-ylidene-amide, us-
ing in vitro pharmacological assays, in vivo pain models,
and pharmacological magnetic resonance imaging”. The
Journal of Pharmacology and Experimental Therapeutics
328 (1): 141–151. doi:10.1124/jpet.108.145011. PMID
18931146.

27
Chapter 11
AB-001
AB-001 or 1-pentyl-3-(1-adamantoyl)indole is a
designer drug that was found as an ingredient in synthetic
cannabis smoking blends in Ireland in 2010 and Hungary
and Germany in 2011.[1][2][3] It is unclear who AB-001
was originally developed by, but it is structurally related
to compounds such as AM-1248 and its corresponding
1-(tetrahydropyran-4-ylmethyl) analogue, which are
known to be potent cannabinoid agonists with moderate
to high selectivity for CB2 over CB1 .[4][5] The first
published synthesis and pharmacological evaluation of
AB-001 revealed that it acts as a full agonist at CB1
(EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM).[6]
However, AB-001 was found to possess only weak
cannabimimetic effects in rats at doses up to 30 mg/kg,
making it less potent than carboxamide analogue SDB-
001, which possesses potent cannabimimetic activity at
doses of 3 mg/kg.[6]
11.1 See also
• A-834,735
• AB-005
• AM-1248
• JWH-018
• JWH-250
• RCS-4
• RCS-8
• SDB-001
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide
• (1-Pentylindol-3-yl)-(2,2,3,3-
tetramethylcyclopropyl)methanone
11.2 References
[1] Jankovics, P. T.; Váradi, A. S.; Tölgyesi, L. S.; Lohner,
S.; Németh-Palotás, J. L.; Balla, J. Z. (2012). “Detection
28
and identification of the new potential synthetic cannabi-
noids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3-
(1-adamantoyl)indole in seized bulk powders in Hun-
gary”. Forensic Science International 214 (1–3): 27–32.
doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
[2] Research on Head Shop drugs in Dublin: Part 2
[3] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). “The
detection of the urinary metabolites of 3-\(adamantan-
1-yl)carbonyl]−1-pentylindole (AB-001), a novel
cannabimimetic, by gas chromatography-mass spec-
trometry”. Drug Testing and Analysis 4 (6): 519–524.
doi:10.1002/dta.350. PMID 22102533.
[4] US patent 7820144, Makriyannis A, Deng H, “Recep-
tor selective cannabimimetic aminoalkylindoles”, granted
2010-10-26
[5] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones:
Effects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity”. Journal of Medic-
inal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.
[6] Banister, S. D.; Wilkinson, S. M.; Longworth, M.;
Stuart, J.; Apetz, N.; English, K.; Brooker, L.;
Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.;
McGregor, I. S.; Kassiou, M. (2013). “The syn-
thesis and pharmacological evaluation of adamantane-
derived indoles: Novel cannabimimetic drugs of abuse”.
ACS Chemical Neuroscience 4 (7): 130403084729007.
doi:10.1021/cn400035r.
Chapter 12

AB-005

AB-005 or [1-[(1-methyl-2-piperidinyl)methyl]−1H- [2] Ministry of Health – Manatū Hauora “Interim Product

indol-3-yl](2,2,3,3-tetramethylcyclopropyl)- Approvals”, Ministry of Health NZ, New Zealand, 2 Jan-
methanone is a designer drug offered by online uary 2013. Retrieved on 2 January 2013.
vendors as a cannabimimetic agent. The structure and
pharmacological activity of AB-005 was published in
2010, prior to its commercial availability in 2012, where
it was reported to have high affinity for both CB1 (Kᵢ =
5.5 nM) and CB2 receptors (Kᵢ = 0.48 nM).[1] AB-005
features groups found in other previously reported
synthetic cannabinoids: the tetramethylcyclopropane
group of UR-144 and XLR-11 as well as the (1-methyl-
2-piperidinyl)methyl substituent of AM-1248 and
AM-1220. No information regarding the in vivo activity
of AB-005 has been published, and only anecdotal
reports are known of its psychoactivity in humans.

12.1 Legal status

Psychoactive products in New Zealand containing this
drug have been given interim approval under recent psy-
choactive substances legislation.[2]

12.2 See also

• AB-001

• AM-1248

• AM-1220

• JWH-018

• UR-144

• XLR-11

12.3 References
[1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones:
Effects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity”. Journal of Medic-
inal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.

29
Chapter 13

AB-CHMINACA

AB-CHMINACA is an indazole-based synthetic

cannabinoid. It is a potent agonist of the CB1 receptor.[1]

13.1 References
[1] AB-CHMINACA, Cayman Chemicals

30
Chapter 14

AB-FUBINACA

AB-FUBINACA is a drug that acts as a potent agonist [3] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G;
for the cannabinoid receptors, with Kᵢ values of 0.9nM Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C
at CB1 and 23.2nM at CB2 . It was originally developed (2014). “Four Postmortem Case Reports with Quantita-
by Pfizer in 2009 as an analgesic medication,[1] but was tive Detection of the Synthetic Cannabinoid, 5F-PB-22”.
never pursued for human use. Subsequently in 2012, this Journal of analytical toxicology. doi:10.1093/jat/bku048.
PMID 24876364.
compound was discovered as an ingredient in synthetic
cannabis blends in Japan,[2] along with a related com-
pound AB-PINACA which had not previously been re-
ported.
In January 2014, AB-FUBINACA was designated as a
Schedule I controlled substance in the United States.[3]

14.1 See also

• AB-PINACA

• ADB-FUBINACA

• ADBICA

• APICA

• APINACA

• Benzydamine

• NESS-040C5

• PF-03550096

14.2 References
[1] Buchler IP et al, INDAZOLE DERIVATIVES. WO
2009/106982

[2] Uchiyama, N.; Matsuda, S.; Wakana, D.; Kikura-

Hanajiri, R.; Goda, Y. (2012). “New cannabimimetic
indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-
2-yl)−1-pentyl-1H-indazole-3-carboxamide (AB-
PINACA) and N-(1-amino-3-methyl-1-oxobutan-2-
yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide
(AB-FUBINACA) identified as designer drugs in
illegal products”. Forensic Toxicology 31: 93.
doi:10.1007/s11419-012-0171-4.

31
Chapter 15

AB-PINACA

AB-PINACA is a compound that was first identified

as a component of synthetic cannabis products in Japan
in 2012.[1] The pharmacological properties of this com-
pound have not been formally studied or reported in the
scientific literature, but it is presumably a cannabinoid
agonist as it was found alongside a structurally related
compound AB-FUBINACA which had previously been
reported as a cannabinoid agonist in a 2009 Pfizer
patent.[2][3]

15.1 See also

• AB-FUBINACA
• ADB-PINACA

• APINACA
• PF-03550096

15.2 References
[1] Uchiyama, N.; Matsuda, S.; Wakana, D.; Kikura-
Hanajiri, R.; Goda, Y. (2012). “New cannabimimetic
indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-
2-yl)−1-pentyl-1H-indazole-3-carboxamide (AB-
PINACA) and N-(1-amino-3-methyl-1-oxobutan-2-
yl)−1-(4-fluorobenzyl)−1H-indazole-3-carboxamide
(AB-FUBINACA) identified as designer drugs in
illegal products”. Forensic Toxicology 31: 93.
doi:10.1007/s11419-012-0171-4.

[2] Buchler IP et al, INDAZOLE DERIVATIVES. WO

2009/106980

[3] Buchler IP et al, INDAZOLE DERIVATIVES. WO

2009/106982

32
Chapter 16
Abnormal cannabidiol
Abnormal cannabidiol (abn-cbd) is a synthetic
regioisomer of cannabidiol, which unlike most other
cannabinoids produces vasodilator effects, lowers blood
pressure, and induces cell migration, cell proliferation
and mitogen-activated protein kinase activation in
microglia, but without producing any psychoactive
effects.[1][2] It has been shown that the actions of abnor-
mal cannabidiol are mediated through a site separate
from the CB1 and CB2 receptors,[2][3] which responds
to abnormal cannabidiol, O-1602, and the endogenous
ligands: anandamide (AEA), N-arachidonoyl glycine
(NAGly) and N-arachidonoyl L-serine.[2][4][5][6] Multiple
lines of evidence support the proposed identification
of this novel target in microglia as the previously
“orphan” receptor GPR18.[2] Another possible tar-
get of abnormal cannabidiol is GPR55, which has
also received much attention as a putative cannabinoid
receptor,[7][8] although a growing body of evidence points
to lysophosphatidylinositol (LPI) as the endogenous lig-
and for GPR55.[9][10] Further research suggests there are
yet more additional cannabinoid receptors.[11][12][13][14]
16.1 See also
• Cannabinoids
• Cannabinoid receptors
• Cannabidiol
• O-1918
16.2 References
[1] Adams, MD; Earnhardt, JT; Martin, BR; Harris, LS;
Dewey, WL; Razdan, RK (1977). “A cannabi-
noid with cardiovascular activity but no overt be-
havioral effects”. Experientia 33 (9): 1204–1205.
doi:10.1007/BF01922330. PMID 891878.
[2] McHugh D, Hu SS, Rimmerman N, Juknat A, Vogil
Z, Walker JM, Bradshaw HB (March 2010). “N-
arachidonoyl glycine, an abundant endogenous lipid, po-
tently drives directed cellular migration through GPR18,
33
the putative abnormal cannabidiol receptor”. BMC Neu-
roscience 11: 44. doi:10.1186/1471-2202-11-44. PMC
2865488. PMID 20346144.
[3] Jarai, Z. (1999). “Cannabinoid-induced mesenteric
vasodilation through an endothelial site distinct from
CB1 or CB2 receptors”. Proceedings of the Na-
tional Academy of Sciences 96 (24): 14136–14141.
doi:10.1073/pnas.96.24.14136. PMC 24203. PMID
10570211.
[4] Walter, L; Franklin, A; Witting, A; Wade, C; Xie, Y;
Kunos, G; MacKie, K; Stella, N (2003). “Nonpsy-
chotropic cannabinoid receptors regulate microglial cell
migration”. Journal of Neuroscience 23 (4): 1398–1405.
PMID 12598628.
[5] Offertáler, L; Mo, FM; Bátkai, S; Liu, J; Begg, M; Razdan,
RK; Martin, BR; Bukoski, RD; Kunos, G (2003). “Selec-
tive ligands and cellular effectors of a G protein-coupled
endothelial cannabinoid receptor”. Molecular Pharmacol-
ogy 63 (3): 699–705. doi:10.1124/mol.63.3.699. PMID
12606780.
[6] Milman, G; Maor, Y; Abu-Lafi, S; Horowitz, M; Gallily,
R; Batkai, S; Mo, FM; Offertaler, L; Pacher, P; Kunos,
G; Mechoulam, R (2006). “N-arachidonoyl l-serine, an
endocannabinoid-like brain constituent with vasodilatory
properties”. Proceedings of the National Academy of Sci-
ences of the United States of America 103 (7): 2428–2433.
doi:10.1073/pnas.0510676103. PMC 1413724. PMID
16467152.
[7] McCollum, L; Howlett, AC; Mukhopadhyay, S
(2007). “Anandamide-mediated CB1/CB2 cannabinoid
receptor—independent nitric oxide production in rabbit
aortic endothelial cells”. The Journal of Pharmacology
and Experimental Therapeutics 321 (3): 930–937.
doi:10.1124/jpet.106.117549. PMID 17379772.
[8] Ryberg, E; Larsson, N; Sjögren, S; Hjorth, S; Hermans-
son, NO; Leonova, J; Elebring, T; Nilsson, K; Drmota, T;
Greasley, PJ (2007). “The orphan receptor GPR55 is a
novel cannabinoid receptor”. British Journal of Pharma-
cology 152 (7): 1092–1101. doi:10.1038/sj.bjp.0707460.
PMC 2095107. PMID 17876302.
[9] Kapur, A; Zhao, P; Sharir, H; Bai, Y; Caron, MG; Barak,
LS; Abood, ME (2009). “Atypical Responsiveness of the
Orphan Receptor GPR55 to Cannabinoid Ligands”. The
Journal of Biological Chemistry 284 (43): 29817–29827.
34 CHAPTER 16. ABNORMAL CANNABIDIOL

doi:10.1074/jbc.M109.050187. PMC 2785612. PMID

19723626.

[10] Henstridge, CM; Balenga, NA; Ford, LA; Ross, RA;

Waldhoer, M; Irving, AJ (2009). “The GPR55 lig-
and L-alpha-lysophosphatidylinositol promotes RhoA-
dependent Ca2+ signaling and NFAT activation”. The
FASEB journal : official publication of the Federation of
American Societies for Experimental Biology 23 (1): 183–
193. doi:10.1096/fj.08-108670. PMID 18757503.

[11] Brown AJ (November 2007). “Novel cannabinoid recep-

tors”. British Journal of Pharmacology 152 (5): 567–
575. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID
17906678.

[12] Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Sha-
pland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.;
Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.;
Yue, T. -L.; Brown, A. J.; Morrison, A. D.; Douglas, S.
A. (2009). “The novel endocannabinoid receptor GPR55
is activated by atypical cannabinoids but does not medi-
ate their vasodilator effects”. British Journal of Pharma-
cology 152 (5): 825–831. doi:10.1038/sj.bjp.0707419.
PMC 2190033. PMID 17704827.

[13] McHugh, D; Tanner, C; Mechoulam, R; Pertwee, RG;

Ross, RA (2008). “Inhibition of human neutrophil
chemotaxis by endogenous cannabinoids and phyto-
cannabinoids: evidence for a site distinct from CB1
and CB2”. Molecular Pharmacology 73 (2): 441–450.
doi:10.1124/mol.107.041863. PMID 17965195.

[14] Kreutz, S; Koch, M; Böttger, C; Ghadban, C; Korf,

HW; Dehghani, F (2009). “2-Arachidonoylglycerol elic-
its neuroprotective effects on excitotoxically lesioned den-
tate gyrus granule cells via abnormal-cannabidiol-sensitive
receptors on microglial cells”. Glia 57 (3): 286–294.
doi:10.1002/glia.20756. PMID 18837048.
Chapter 17

ADB-FUBINACA

ADB-FUBINACA is a designer drug identified in

synthetic cannabis blends in Japan in 2013.[1] The (S)
enantiomer of ADB-FUBINACA is claimed in Pfizer
patent WO 2009/106982, with a Kᵢ value of 0.36nM at
CB1 .[2] ADB-FUBINACA features a carboxamide group
at the 3-indazole position, like SDB-001 and STS-135.
ADB-FUBINACA appears to be the product of rational
drug design, since it differs from AB-FUBINACA only
by the replacement of the isopropyl group with a tert-
butyl group. The stereochemistry of the tert-butyl side-
chain in the illicitly sold product is unresolved. Noth-
ing is known of the pharmacological activity of ADB-
FUBINACA in humans or other animals.

17.1 See also

• AB-FUBINACA
• ADB-PINACA

• ADBICA
• APINACA

• PF-03550096
• SDB-001

• STS-135

17.2 References
[1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; Kikura-
Hanajiri, R.; Goda, Y. (2013). “Two new-type
cannabimimetic quinolinyl carboxylates, QUPIC and
QUCHIC, two new cannabimimetic carboxamide deriva-
tives, ADB-FUBINACA and ADBICA, and five synthetic
cannabinoids detected with a thiophene derivative α-PVT
and an opioid receptor agonist AH-7921 identified in ille-
gal products”. Forensic Toxicology. doi:10.1007/s11419-
013-0182-9.

[2] Buchler IP et al, INDAZOLE DERIVATIVES. WO

2009/106982

35
Chapter 18

ADB-PINACA

ADB-PINACA is a cannabinoid designer drug that is an

ingredient in some synthetic cannabis products.[1][2] It has
been linked to multiple hospitalizations due to its use.[3]
In the United States, it is a Schedule I controlled sub-
stance.[4]

18.1 See also

• AB-PINACA
• APINACA

• ADB-FUBINACA

18.2 References
[1] “ADB-PINACA”. Forendex.

[2] “ADB-PINACA”. Forensic Drug Review.

[3] “CDC: 221 sickened by synthetic pot in Colorado”. USA

Today. December 12, 2013.

[4] “Schedules of controlled substances: temporary place-

ment of four synthetic cannabinoids into Schedule I. Final
order”. Fed Regist. 79 (27): 7577–7582. Feb 10, 2014.
PMID 24605391.

36
Chapter 19

ADBICA

ADBICA is a designer drug identified in synthetic

cannabis blends in Japan in 2013.[1] ADBICA had not
previously been reported in the scientific literature prior
to its sale as a component of synthetic cannabis blends.
ADBICA features a carboxamide group at the 3-indole
position, like SDB-001 and STS-135. The stereochem-
istry of the tert-butyl side-chain in the illicitly sold prod-
uct is unresolved, though in a large series of indazole
derivatives structurally similar to ADBICA that are dis-
closed in Pfizer patent WO 2009/106980, activity resides
exclusively in the (S) enantiomers.[2] Nothing is known
of the pharmacological activity of ADBICA in humans
or other animals.

19.1 See also

• AB-FUBINACA
• ADB-FUBINACA

• APINACA
• PF-03550096

• SDB-001
• STS-135

19.2 References
[1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; Kikura-
Hanajiri, R.; Goda, Y. (2013). “Two new-type
cannabimimetic quinolinyl carboxylates, QUPIC and
QUCHIC, two new cannabimimetic carboxamide deriva-
tives, ADB-FUBINACA and ADBICA, and five synthetic
cannabinoids detected with a thiophene derivative α-PVT
and an opioid receptor agonist AH-7921 identified in ille-
gal products”. Forensic Toxicology. doi:10.1007/s11419-
013-0182-9.

[2] Buchler IP et al, INDAZOLE DERIVATIVES. WO

2009/106980

37
Chapter 20

Ajulemic acid

Ajulemic acid (AB-III-56, HU-239, IP-751, CPL 7075, nal of Pharmacology and Experimental Therapeutics 320
CT-3, Resunab) is a synthetic cannabinoid derivative of (2): 678–686. doi:10.1124/jpet.106.111625. PMC
the non-psychoactive THC metabolite 11-nor-9-carboxy- 2633725. PMID 17105826.
THC that shows useful analgesic and anti-inflammatory
[5] Sumariwalla, P.; Gallily, R.; Tchilibon, S.; Fride, E.;
effects without causing a subjective “high”.[1] It is be- Mechoulam, R.; Feldmann, M. (2004). “A novel syn-
ing developed for the treatment of neuropathic pain and thetic, nonpsychoactive cannabinoid acid (HU-320) with
inflammatory conditions such as arthritis.[2] It does not antiinflammatory properties in murine collagen-induced
however share the anti-emetic effects of other cannabi- arthritis”. Arthritis and rheumatism 50 (3): 985–998.
noids but may be useful for treating pain and chronic doi:10.1002/art.20050. PMID 15022343.
inflammatory conditions where nausea is not present.[3]
[6] Sumariwalla, P.F., et al. (2004). “Reply”. Arthritis &
Side effects include dry mouth, tiredness and dizziness.
Rheumatism 50 (12): 4079. doi:10.1002/art.20806.
The mechanism of action has not yet been fully estab-
lished, but ajulemic acid may activate the CB2 recep-
tor in the periphery leading to production of resolving
eicosanoids. Studies in animals at doses up to 40 mg/kg
show minimal psychoactivity of ajulemic acid, compa-
rable to that produced by tetrahydrocannabinol,.[4] Like-
wise, there was no difference between ajulemic acid and
placebo on the “cannabimimetic” assay when used in hu-
mans at therapeutic doses.[5][6] A new highly purified
composition of ajulemic acid named Resunab is being de-
veloped by Corbus Pharmaceuticals (formerly JB Ther-
apeutics)for the treatment of orphan life-threatening in-
flammatory diseases.

20.1 References
[1] Burstein, S.; Karst, M.; Schneider, U.; Zurier, R. (2004).
“Ajulemic acid: A novel cannabinoid produces analge-
sia without a “high"". Life Sciences 75 (12): 1513–1522.
doi:10.1016/j.lfs.2004.04.010. PMID 15240185.

[2] Mitchell, V.; Aslan, S.; Safaei, R.; Vaughan, C. (2005).

“Effect of the cannabinoid ajulemic acid on rat models of
neuropathic and inflammatory pain”. Neuroscience letters
382 (3): 231–235. doi:10.1016/j.neulet.2005.03.019.
PMID 15925096.

[3] Burstein, S. (2005). “Ajulemic acid (IP-751): syn-

thesis, proof of principle, toxicity studies, and clin-
ical trials”. The AAPS journal 7 (1): E143–E148.
doi:10.1208/aapsj070115. PMC 2751505. PMID
16146336.

[4] Vann, R.; Cook, C.; Martin, B.; Wiley, J. (2007).

“Cannabimimetic properties of ajulemic acid”. The Jour-

38
Chapter 21

AM-087

AM-087 is an analgesic drug that is a cannabinoid

agonist. It is a derivative of Δ8THC substituted on the
3-position side chain. AM-087 is a potent CB1 agonist
with a Ki of 0.43nM, making it around 100x more po-
tent than THC itself. This is most likely due to the bulky
bromine substituent on the side chain.[1][2][3]

21.1 See also

• AM-411

21.2 References
[1] Charalambous A, et al. Pharmacological evaluation
of halogenated delta 8-THC analogs. Pharmacology,
Biochemistry and Behaviour. 1991 Nov;40(3):509-12.
PMID 1666915

[2] Nikas SP, et al. The role of halogen substitution in clas-

sical cannabinoids: a CB1 pharmacophore model. AAPS
Journal. 2004 Oct 19;6(4):e30. PMID 15760095

[3] Roger Pertwee. Cannabinoids. Handbook of Experimen-

tal Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X

39
Chapter 22

AM-1220

AM-1220 is a drug that acts as a potent and moder- • AM-2201

ately selective agonist for the cannabinoid receptor CB1 ,
with around 19x selectivity for CB1 over the related • AM-2233
CB2 receptor.[1] It was originally invented in the early • Cannabipiperidiethanone
1990s by a team led by Thomas D'Ambra at Sterling
Winthrop,[2] but has subsequently been researched by
many others, most notably the team led by Alexandros
Makriyannis at the University of Connecticut. The
22.2 References
(piperidin-2-yl)methyl side chain of AM-1220 contains
a stereocenter, so there are two enantiomers with quite [1] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
different potency, the (R) enantiomer having a Kᵢ of
07
0.27nM at CB1 while the (S) enantiomer has a much
weaker Kᵢ of 217nM.[3] A number of related compounds [2] US patent 5068234, Thomas E. D'Ambra et al., “3-
are known with similar potent cannabinoid activity, with arylcarbonyl-1-(C-attached-N-heteryl)−1H-indoles”,
modifications such as substitution of the indole ring at granted 1991-11-26
the 2- or 6- positions, the naphthoyl ring substituted at
[3] D'ambra, T. (1996). “C-Attached aminoalkylindoles:
the 4- position or replaced by substituted benzoyl rings
potent cannabinoid mimetics”. Bioorganic & Medic-
or other groups, or the 1-(N-methylpiperidin-2-ylmethyl) inal Chemistry Letters 6: 17–14. doi:10.1016/0960-
group replaced by similar heterocyclic groups such as 894X(95)00560-G.
N-methylpyrrolidin-2-ylmethyl or N-methylmorpholin-
3-ylmethyl.[4][5][6] AM-1220 was first detected as an in- [4] Hongfeng Deng (2000). Design and synthesis of selective
gredient of synthetic cannabis smoking blends in 2010.[7] cannabinoid receptor ligands: Aminoalkylindole and other
heterocyclic analogs (PhD. Dissertation). University of
Connecticut.

[5] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D.

B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis
and Structure−Activity Relationship of a Novel Series of
Aminoalkylindoles with Potential for Imaging the Neu-
ronal Cannabinoid Receptor by Positron Emission To-
mography”. Journal of Medicinal Chemistry 48 (18):
5813. doi:10.1021/jm0502743. PMID 16134948.

[6] US patent 7820144, Alexandros Makriyannis, et al.,

“Receptor selective cannabimimetic aminoalkylindoles”,
granted 2010-10-26

Related 1-(N-methylpyrrolidin-2-ylmethyl) and 1-(N- [7] Head Shop ‘Legal Highs’ Active Constituents Identifica-
methylmorpholin-3-ylmethyl) derivatives tion Chart (July - August 2010)

22.1 See also

• A-834,735
• AM-1221
• AM-1248

40
Chapter 23

AM-1221

AM-1221 is a drug that acts as a potent and selective

agonist for the cannabinoid receptor CB2 , with a Kᵢ of
0.28nM at CB2 and 52.3nM at the CB1 receptor, giving
it around 180x selectivity for CB2 .[1] The 2-methyl and
6-nitro groups on the indole ring both tend to increase
CB2 affinity while generally reducing affinity at CB1 , ex-
plaining the high CB2 selectivity of AM-1221. However
despite this relatively high selectivity for CB2 , its CB1
affinity is still too strong to make it useful as a truly se-
lective CB2 agonist, so the related compound AM-1241
is generally preferred for research purposes.[2][3]

23.1 See also

• AM-630
• AM-1220

• AM-1235
• AM-2233

• UR-144
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide

23.2 References
[1] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
07

[2] Hongfeng Deng (2000). Design and synthesis of selective

cannabinoid receptor ligands: Aminoalkylindole and other
heterocyclic analogs (PhD. Dissertation). University of
Connecticut.

[3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

41
Chapter 24

AM-1235

AM-1235 (1-(5-fluoropentyl)−3-(naphthalen-1- 24.3 References

oyl)−6-nitroindole) is a drug that acts as a potent and
reasonably selective agonist for the cannabinoid receptor [1] US patent 7241799, Makriyannis A, Deng H,
CB1 . “Cannabimimetic indole derivatives”, granted 2007-
07-10

[2] Deng, Hongfeng (2000). Design and synthesis of selec-

24.1 Pharmacology
24.1.1 Pharmacodynamics
AM-1235 is a cannabinoid receptor agonist with Kᵢ of
1.5nM at CB1 compared to 20.4nM at CB2 .[1] While
the 6-nitro substitution on the indole ring reduces affinity
for both CB1 and CB2 relative to the unsubstituted par-
ent compound AM-2201, CB2 affinity is reduced much
more, resulting in a CB1 selectivity of around 13x.[2] This
is in contrast to other related compounds such as AM-
1221 where a 6-nitro substitution instead confers signifi-
cant selectivity for CB2 .[3]
tive cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs (PhD. Dissertation). University
of Connecticut.
[3] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
07
[4] Millington JE, Pattison FLM. TOXIC FLUO-
RINE COMPOUNDS: XII. ESTERS OF ω-
FLUOROALCOHOLS. Canadian Journal of Chemistry.
1956 Nov;34(11):1532-1541.
[5] Pattison FLM, Howell WC, Woolford RG. TOXIC
FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL
ETHERS. Canadian Journal of Chemistry. 1957
Feb;35(2):141-148.

24.1.2 Pharmacokinetics

Main article: Pharmacokinetic data of JWH-018 are

generally applicable to AM-1235.

AM-1235 metabolism differs only slightly from that

of JWH-018. AM-1235 N-dealkylation produces fluo-
ropentane instead of pentane (or plain alkanes in gen-
eral). It has been speculated that the fluoropentane might
function as an alkylating agent or is further metabo-
lized into toxic fluoroacetic acid. This is not true since
fluoroalkanes do not act as alkylating agents under nor-
mal conditions and uneven fluoroalkane chains metabo-
lize into substantially less toxic fluoropropanoic acid.[4][5]

24.2 See also

• AM-906

• AM-2389

• O-1812

42
Chapter 25
AM-1241
AM-1241 (1-(methylpiperidin-2-ylmethyl)−3-(2-
iodo-5-nitrobenzoyl)indole) is a chemical from the
aminoalkylindole family that acts as a potent and se-
lective agonist for the cannabinoid receptor CB2 ,[1][2]
with a Kᵢ of 3.4nM at CB2 and 80x selectivity over the
related CB1 receptor.[3][4] It has analgesic effects in
animal studies, particularly against “atypical” pain such
as hyperalgesia and allodynia.[5] This is thought to be
mediated through CB2 -mediated peripheral release of
endogeous opioid peptides,[6] as well as direct activation
of the TRPA1 channel.[7] It has also shown efficacy in
the treatment of amyotrophic lateral sclerosis in animal
models.[8][9]
25.1 Effects in bone cancer model
The antihyperalgesic effects of AM-1241 were investi-
gated in a murine bone cancer model. Sarcoma cells were
injected into the femur of a mouse, and then mice were
injected twice daily with AM-1241. Treatment with AM-
1241 reduced both spontaneous and evoked pain, as well
as reducing the bone loss and subsequent fractures due
to the tumor. Pretreatment with the CB2 antagonist SR-
144,528 reversed the acute effects of AM-1241 on both
spontaneous and evoked pain, while having no effect on
its own.[10]
25.2 See also
• AM-1220
• AM-1248
• AM-2233
25.3 References
[1] Yao BB, et al. (September 2006). “In vitro pharmaco-
logical characterization of AM1241: a protean agonist at
the cannabinoid CB2 receptor?". British Journal of Phar-
macology 149 (2): 145–54. doi:10.1038/sj.bjp.0706838.
PMC 2013801. PMID 16894349.
43
[2] Bingham B, et al. (August 2007). “Species-specific in
vitro pharmacological effects of the cannabinoid receptor
2 (CB2) selective ligand AM1241 and its resolved enan-
tiomers”. British Journal of Pharmacology 151 (7): 1061–
70. doi:10.1038/sj.bjp.0707303. PMC 2042933. PMID
17549048.
[3] Ibrahim MM, et al. (September 2003). “Activation of
CB2 cannabinoid receptors by AM1241 inhibits exper-
imental neuropathic pain: pain inhibition by receptors
not present in the CNS”. Proceedings of the National
Academy of Sciences of the United States of America 100
(18): 10529–33. doi:10.1073/pnas.1834309100. PMC
193595. PMID 12917492.
[4] Marriott KS, Huffman JW (2008). “Recent advances in
the development of selective ligands for the cannabinoid
CB(2) receptor”. Current Topics in Medicinal Chemistry
8 (3): 187–204. doi:10.2174/156802608783498014.
PMID 18289088.
[5] Beltramo M, et al. (March 2006). “CB2 receptor-
mediated antihyperalgesia: possible direct involvement
of neural mechanisms”. The European Journal of
Neuroscience 23 (6): 1530–8. doi:10.1111/j.1460-
9568.2006.04684.x. PMID 16553616.
[6] Ibrahim MM, et al. (February 2005). “CB2
cannabinoid receptor activation produces antinocicep-
tion by stimulating peripheral release of endogenous opi-
oids”. Proceedings of the National Academy of Sci-
ences of the United States of America 102 (8): 3093–
8. doi:10.1073/pnas.0409888102. PMC 549497. PMID
15705714.
[7] Akopian AN, Ruparel NB, Patwardhan A, Hargreaves
KM (January 2008). “Cannabinoids desensitize capsaicin
and mustard oil responses in sensory neurons via TRPA1
activation”. Journal of Neuroscience 28 (5): 1064–
75. doi:10.1523/JNEUROSCI.1565-06.2008. PMID
18234885.
[8] Kim K, Moore DH, Makriyannis A, Abood ME (Au-
gust 2006). “AM1241, a cannabinoid CB2 recep-
tor selective compound, delays disease progression in
a mouse model of amyotrophic lateral sclerosis”. Eu-
ropean Journal of Pharmacology 542 (1-3): 100–5.
doi:10.1016/j.ejphar.2006.05.025. PMID 16781706.
[9] Shoemaker JL, et al (April 2007). “The CB2 cannabi-
noid agonist AM-1241 prolongs survival in a transgenic
44 CHAPTER 25. AM-1241

mouse model of amyotrophic lateral sclerosis when ini-

tiated at symptom onset”. Journal of Neurochemistry
101 (1): 87–98. doi:10.1111/j.1471-4159.2006.04346.x.
PMC 2819701. PMID 17241118.

[10] Lozano, Alysia (April 2010). “A cannabinoid 2

receptor agonist attenuates bone cancer-induced pain
and bone loss”. Life Sciences 86 (17-18): 646–53.
doi:10.1016/j.lfs.2010.02.014. PMC 2871326. PMID
20176037. Retrieved 18 December 2011.
Chapter 26

AM-1248

AM-1248 is a drug that acts as a moderately potent [4] Jankovics P, et al. (August 2011). “Detection and
agonist for both the cannabinoid receptors CB1 and CB2 , identification of the new potential synthetic cannabi-
but with some dispute between sources over its exact noids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3-
potency and selectivity. Replacing the 3-(1-naphthoyl) (1-adamantoyl)indole in seized bulk powders in Hun-
group found in many indole derived cannabinoid ligands, gary”. Forensic Science International 214 (1-3): 27–32.
doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.
with an adamantoyl group, generally confers significant
CB2 selectivity,[1] but reasonable CB1 affinity and selec-
tivity is retained when an N-methylpiperidin-2-ylmethyl
substitution is used at the indole 1-position.[2][3] The
related compound 1-pentyl-3-(1-adamantoyl)indole was
identified as having been sold as a cannabinoid designer
drug in Hungary in 2011, along with another synthetic
cannabinoid AM-679.[4]

26.1 See also

• A-834,735

• AB-001

• AM-411

• AM-1220

• AM-2233

• Cannabipiperidiethanone

26.2 References
[1] Frost, J. M., et al. (2010). “Indol-3-ylcycloalkyl Ketones:
Effects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity”. Journal of Medic-
inal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.

[2] US patent 7820144, Makriyannis A, Deng H, “Recep-

tor selective cannabimimetic aminoalkylindoles”, granted
2010-10-26

[3] WO patent 200128557, Makriyannis A, Deng H,

“Cannabimimetic indole derivatives”, granted 2001-06-
07

45
Chapter 27

AM-1714

AM-1714 is a drug that acts as a reasonably selective

agonist of the peripheral cannabinoid receptor CB2 , with
sub-nanomolar affinity and 490x selectivity over the re-
lated CB1 receptor. In animal studies it has both analgesic
and anti-allodynia effects. The 9-methoxy derivative
AM-1710 has similar CB2 affinity but only 54x selectiv-
ity over CB1 .[1][2]

27.1 See also

• Cannabinol
• Canbisol

27.2 References
[1] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur
GA, Malan TP Jr, Porreca F, Veerappan V, Tian X,
George C, Parrish DA, Papahatjis DP, Makriyannis A.
Cannabilactones: a novel class of CB2 selective agonists
with peripheral analgesic activity. Journal of Medici-
nal Chemistry. 2007 Dec 27;50(26):6493-500. PMID
18038967

[2] Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD,

Makriyannis A, Hohmann AG. Selective activation of
cannabinoid CB2 receptors suppresses neuropathic noci-
ception induced by treatment with the chemotherapeutic
agent paclitaxel in rats. Journal of Pharmacology and Ex-
perimental Therapeutics. 2008 Nov;327(2):584-91. doi:
10.1124/jpet.108.141994. PMID 18664590

46
Chapter 28

AM-2201

AM-2201 (1-(5-fluoropentyl)−3-(1- AM-2201 metabolism differs only slightly from that

naphthoyl)indole) is a research chemical that acts as a of JWH-018. AM-2201 N-dealkylation produces fluo-
potent but nonselective full agonist for the cannabinoid ropentane instead of pentane (or plain alkanes in general).
receptor. It is part of the AM series of cannabinoids
discovered by Alexandros Makriyannis at Northeastern
University. 28.3 Detection
A forensic standard of AM-2201 is available, and the
28.1 Hazards compound has been posted on the Forendex website of
potential drugs of abuse.[5]
AM-2201 is widely regarded by recreational users of syn-
thetic cannabinoids as one of the most potent and pos-
sibly the most potent substance available in this class of 28.4 See also
drugs. As the dosage is much smaller than other synthetic
cannabinoids, accidental overdose becomes more likely. • AM-2233
There have been anecdotal reports of individuals experi-
encing panic attacks and vomiting at doses as small as 2 • AM-694
mg. Convulsions have been reported[1] including at doses
as low as 10 mg.[2] Caution should be taken if using this • AM-1235
substance as it is active at doses as small as 500 µg, has • AM-2232
a very steep dose-response curve, and tolerance builds up
very quickly to the effects. • JWH-018
Recreational use of AM-2201 in the United States has led
to it being specifically listed in a proposed 2011 amend-
ment to the Controlled Substances Act, aiming to add 28.5 References
a number of synthetic drugs into Schedule I.[3] As of
November 2011, there have been no reports of death as- [1] David McQuade, Simon Hudson, Paul I. Dargan, David
sociated with the drug. The acute toxicity and long term M. Wood (March 2013). “First European case of convul-
side effects associated with the use of AM-2201 are un- sions related to analytically confirmed use of the synthetic
cannabinoid receptor agonist AM-2201”. European Jour-
known.
nal of Clinical Pharmacology 69 (3): 373–376.

[2] ekaJ (20 February 2011). “The Night I Killed My

28.2 Pharmacology Friends”. Erowid.org. Retrieved 11 June 2012.

[3] Synthetic Drug Control Act of 2011. H.R. 1254, 112th

AM-2201 is a full agonist for cannabinoid receptors. Congress, 1st Session (2011).
Affinities are: with a Kᵢ of 1.0nM at CB1 and 2.6nM
[4] WO patent 0128557, Makriyannis A, Deng H,
at CB2 .[4] The 4-methyl functional analog MAM-2201 “Cannabimimetic indole derivatives”, granted 2001-
probably has similar affinities. 06-07

[5] Southern Association of Forensic Scientists

28.2.1 Pharmacokinetics

See also: JWH-018 § Pharmacokinetics

47
Chapter 29

AM-2232

AM-2232 (1-(4-cyanobutyl)−3-(naphthalen-1-
oyl)indole) is a drug that acts as a potent but unselective
agonist for the cannabinoid receptors, with a Kᵢ of
0.28nM at CB1 and 1.48nM at CB2 .[1]

29.1 See also

• AM-2201
• O-1057

• O-1812

29.2 References
[1] US patent 7241799, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2007-
07-10

48
Chapter 30

AM-2233

AM-2233 is a drug that acts as a highly potent full ago-
nist for the cannabinoid receptors, with a Kᵢ of 1.8nM at
CB1 and 2.2nM at CB2 as the active (R) enantiomer.[1] It
was developed as a selective radioligand for the cannabi-
noid receptors and has been used as its 131 I derivative
for mapping the distribution of the CB1 receptor in the
brain.[2][3][4][5][6][7] AM-2233 was found to fully substi-
tute for THC in rats, with a potency lower than that of
JWH-018 but higher than WIN 55,212-2.[8]
30.1 See also
• AM-679
• AM-694
• AM-1220
• AM-1221
• AM-1241
• Cannabipiperidiethanone
[5] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.;
Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gif-
ford, A. N. (2006). “Evaluation of the in vivo re-
ceptor occupancy for the behavioral effects of cannabi-
noids using a radiolabeled cannabinoid receptor ago-
nist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101.
doi:10.1002/syn.20277. PMID 16715483.
[6] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl-
(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3-
yl)methanone”. Molecular Imaging and Contrast
Agent Database (MICAD) [Internet]. PMID 20641836.
[7] Pei, Y., et al. (2008). “Ligand-Binding Architecture
of Human CB2 Cannabinoid Receptor: Evidence for
Receptor Subtype-Specific Binding Motif and Model-
ing GPCR Activation”. Chemistry & Biology 15: 1207.
doi:10.1016/j.chembiol.2008.10.011.
[8] Järbe TU, Deng H, Vadivel SK, Makriyannis A (Septem-
ber 2011). “Cannabinergic aminoalkylindoles, includ-
ing AM678=JWH018 found in 'Spice', examined us-
ing drug (Δ9-tetrahydrocannabinol) discrimination for
rats”. Behavioural Pharmacology 22 (5-6): 498–507.
doi:10.1097/FBP.0b013e328349fbd5. PMC 3212432.
PMID 21836461.

30.2 References
[1] Hongfeng Deng (2000). Design and synthesis of selec-
tive cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs (PhD Dissertation). University
of Connecticut.
[2] Deng H, et al. (October 2005). “Potent cannabinergic in-
dole analogues as radioiodinatable brain imaging agents
for the CB1 cannabinoid receptor”. Journal of Medicinal
Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l.
PMID 16190764.
[3] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabi-
noid chemistry: an overview”. “Cannabinoids as Ther-
apeutics”. Milestones in Drug Therapy MDT. p. 23.
doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6.
[4] Shen CP, et al. (February 2006). “F200A substitution
in the third transmembrane helix of human cannabinoid
CB1 receptor converts AM2233 from receptor agonist to
inverse agonist”. European Journal of Pharmacology 531
(1–3): 41–6. doi:10.1016/j.ejphar.2005.12.026. PMID
16438957.

49
Chapter 31

AM-2389

AM-2389 is a classical cannabinoid derivative which acts

as a potent and reasonably selective agonist for the CB1
receptor, with a Kᵢ of 0.16 nM, and 26x selectivity over
the related CB2 receptor. It has high potency in animal
tests of cannabinoid activity, and a medium duration of
action.[1][2] Replacing the 1',1'-dimethyl substitution of
the dimethylheptyl side chain of classical cannabinoids
with cyclopropyl or cyclopentyl results in higher potency
than cyclobutyl, but only the cyclobutyl derivatives show
selectivity for CB1 over CB2 .[3] High selectivity for CB1
over CB2 is difficult to achieve (cf. AM-906, AM-1235),
as almost all commonly used CB1 agonists have simi-
lar or greater affinity for CB2 than CB1 , and the only
truly highly selective CB1 agonists known as of 2012 are
eicosanoid derivatives such as O-1812.

31.1 See also

• HHC

• AMG-36
• AMG-41

31.2 References
[1] Nikas SP, et al. Novel 1',1'-chain substituted hexahy-
drocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-
hexahydrocannabinol (AM2389) a highly potent cannabi-
noid receptor 1 (CB1) agonist. Journal of Medicinal
Chemistry. 2010 Oct 14;53(19):6996-7010. PMID
20925434

[2] Järbe TU, et al. AM2389, a high-affinity, in vivo po-

tent CB(1)-receptor-selective cannabinergic ligand as ev-
idenced by drug discrimination in rats and hypothermia
testing in mice. Psychopharmacology (Berlin). 2011 Oct
12. PMID 21989802

[3] Papahatjis DP, et al. C1'-cycloalkyl side chain phar-

macophore in tetrahydrocannabinols. Journal of Medic-
inal Chemistry. 2007 Aug 23;50(17):4048-60. PMID
17672444

50
Chapter 32

AM-4030

AM-4030 is an analgesic drug which is a cannabinoid re- novel chiral cannabinoid receptor ligand. Journal of Bio-
ceptor agonist. It is a derivative of HU-210 which has chemical and Biophysical Methods. 2002 Dec 31;54(1-
been substituted with a 6β-((E)−3-hydroxyprop-1-enyl) 3):415-22. PMID 12543516
group. This adds a “southern” aliphatic hydroxyl group
to the molecule as seen in the CP-series of nonclassical
cannabinoid drugs, and so AM-4030 represents a hybrid
structure between the classical and nonclassical cannabi-
noid families,[1] with the 6-hydroxyalkyl chain rigidified
with a double bond with defined stereochemistry. This
gives AM-4030 a greater degree of selectivity, so while
it is still a potent agonist at both CB1 and CB2 , it is rea-
sonably selective for CB1 , with a Kᵢ of 0.7nM at CB1 and
8.6nM at CB2 , a selectivity of around 12x.[2][3] Resolu-
tion of the enantiomers of AM-4030 yields an even more
potent compound, although with less selectivity, with the
(-) enantiomer AM-4030a having a Kᵢ of 0.6nM at CB1
and 1.1nM at CB2 .[4]

32.1 See also

• AM-919
• AM-938

32.2 References
[1] Roger Pertwee. Cannabinoids. Handbook of Experimen-
tal Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X

[2] Tius MA, Hill WA, Zou XL, Busch-Petersen J,

Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji
V, Makriyannis A. Classical/non-classical cannabinoid
hybrids; stereochemical requirements for the southern
hydroxyalkyl chain. Life Sciences. 1995;56(23-24):2007-
12. PMID 7776825

[3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK,

Concepcion Fernandez-Garcia M, Fan P, Makriyannis
A, Tius MA. Classical/nonclassical hybrid cannabinoids:
southern aliphatic chain-functionalized C-6beta methyl,
ethyl, and propyl analogues. Journal of Medicinal Chem-
istry. 1998 Sep 10;41(19):3596-608. PMID 9733485

[4] Thakur GA, Palmer SL, Harrington PE, Stergiades IA,

Tius MA, Makriyannis A. Enantiomeric resolution of a

51
Chapter 33

AM-411

AM-411 is an analgesic drug that is a cannabinoid

agonist. It is a derivative of Δ8THC substituted with an
adamantyl group at the 3-position, demonstrating that the
binding pocket for the alkyl chain at this position can ac-
commodate significant bulk.
AM-411 is a potent and fairly selective CB1 full agonist
with a Kᵢ of 6.80nM, but is still also a moderately potent
CB2 agonist with a Kᵢ of 52.0nM.[1] It produces similar
effects to other cannabinoid agonists such as analgesia,
sedation, and anxiolysis.[2][3]

33.1 See also

• AM-087

• AM-1248
• KM-233

33.2 References
[1] Lu D, et al. Adamantyl cannabinoids: a novel class of
cannabinergic ligands. Journal of Medicinal Chemistry.
2005 Jul 14;48(14):4576-85. PMID 15999995

[2] Järbe TU, DiPatrizio NV, Lu D, Makriyannis A. (-)-

Adamantyl-delta8-tetrahydrocannabinol (AM-411), a se-
lective cannabinoid CB1 receptor agonist: effects on
open-field behaviors and antagonism by SR-141716 in
rats. Behavioural Pharmacology. 2004 Nov;15(7):517-
21. PMID 15472574

[3] McLaughlin PJ, et al. Behavioral effects of the novel

cannabinoid full agonist AM 411. Pharmacology, Bio-
chemistry and Behaviour. 2005 May;81(1):78-88. PMID
15894067

52
Chapter 34

AM-630

AM-630 (6-Iodopravadoline) is a drug that acts as a po- 974–82. doi:10.1016/j.biopsych.2009.09.024. PMID

tent and selective inverse agonist for the cannabinoid re-
ceptor CB2 , with a Kᵢ of 32.1nM at CB2 and 165x selec-
tivity over CB1 , at which it acted as a weak partial ago-
nist.[1][2] It is used in the study of CB2 mediated responses
and has been used to investigate the possible role of CB2
receptors in the brain.[3][4] AM-630 is significant as one
of the first indole derived cannabinoid ligands substituted
on the 6-position of the indole ring, a position that has
subsequently been found to be important in determining
affinity and efficacy at both the CB1 and CB2 receptors,
and has led to the development of a large number of re-
lated derivatives.[5][6][7][8][9]
34.1 See also
• WIN 48,098 (Pravadoline)
• WIN 54,461 (6-Bromopravadoline)
• AM-1221
34.2 References
19931854.
[5] Eissenstat, M. A.. et al. (1995). “Aminoalkylindoles:
Structure-Activity Relationships of Novel Cannabinoid
Mimetics”. Journal of Medicinal Chemistry 38 (16):
3094. doi:10.1021/jm00016a013. PMID 7636873.
[6] Hongfeng Deng. Design and synthesis of selective
cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs. PhD Dissertation, University
of Connecticut, 2000.
[7] Hynes J, et al. (September 2002). “C-3 Amido-
indole cannabinoid receptor modulators”. Bioorganic
& Medicinal Chemistry Letters 12 (17): 2399–
402. doi:10.1016/S0960-894X(02)00466-3. PMID
12161142.
[8] Frost, J. M., et al. (2008). “Indol-3-yl-
tetramethylcyclopropyl Ketones: Effects of Indole
Ring Substitution on CB2 Cannabinoid Receptor Ac-
tivity”. Journal of Medicinal Chemistry 51 (6): 1904.
doi:10.1021/jm7011613. PMID 18311894.
[9] Adam, J. M., et al. (2010). “Design, synthesis, and
structure–activity relationships of indole-3-carboxamides
as novel water soluble cannabinoid CB1 receptor ago-
nists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.

[1] Ross RA, et al. (February 1999). “Agonist-inverse

agonist characterization at CB1 and CB2 cannabi-
noid receptors of L759633, L759656, and AM630”.
British Journal of Pharmacology 126 (3): 665–72.
doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID
10188977.

[2] Murataeva, N.; MacKie, K.; Straiker, A. (2012). “The

CB2-preferring agonist JWH015 also potently and ef-
ficaciously activates CB1 in autaptic hippocampal neu-
rons”. Pharmacological Research 66 (5): 437–42.
doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID
22921769.

[3] Morgan NH, Stanford IM, Woodhall GL (September

2009). “Functional CB2 type cannabinoid receptors
at CNS synapses”. Neuropharmacology 57 (4): 356–
68. doi:10.1016/j.neuropharm.2009.07.017. PMID
19616018.

[4] Ishiguro H, et al. (May 2010). “Brain cannabinoid CB2

receptor in schizophrenia”. Biological Psychiatry 67 (10):

53
Chapter 35

AM-6545

AM-6545 is a drug which acts as a peripherally selec-
tive silent antagonist for the CB1 receptor, and was de-
veloped for the treatment of obesity. Other cannabinoid
antagonists such as rimonabant have been marketed for
this application, but have subsequently been withdrawn
from sale because of centrally mediated side effects such
as depression and nausea. Because AM-6545 does not
cross the blood–brain barrier to any significant extent, it
does not produce these kinds of side effects, but has still
been shown to effectively reduce appetite and food con-
sumption in animal studies.[1][2][3][4]
Makriyannis A, Sharkey KA. A novel peripherally re-
stricted cannabinoid receptor antagonist, AM6545, re-
duces food intake and body weight, but does not cause
malaise, in rodents. British Journal of Pharmacology.
2010 Oct;161(3):629-42. PMID 20880401
[4] Järbe TU, LeMay BJ, Vemuri VK, Vadivel SK, Zvonok
A, Makriyannis A. Central mediation and differential
blockade by cannabinergics of the discriminative stimu-
lus effects of the cannabinoid CB1 receptor antagonist
rimonabant in rats. Psychopharmacology (Berlin). 2011
Aug;216(3):355-65. PMID 21369753

35.1 See also

• CB-13 – a peripherally selective cannabinoid agonist

• O-2050 – a centrally active CB1 silent antagonist

• Methylnaltrexone – a peripherally selective mu opi-

oid receptor antagonist

• TM-38837 - another peripherally selective cannabi-

noid antagonist

35.2 References
[1] Tam, J.; Vemuri, V. K.; Liu, J.; Bátkai, S. N.; Mukhopad-
hyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.;
Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G.
(2010). “Peripheral CB1 cannabinoid receptor blockade
improves cardiometabolic risk in mouse models of obe-
sity”. Journal of Clinical Investigation 120 (8): 2953–
2966. doi:10.1172/JCI42551. PMC 2912197. PMID
20664173. PMID 20664173

[2] Randall PA, Vemuri VK, Segovia KN, Torres EF,

Hosmer S, Nunes EJ, Santerre JL, Makriyannis A,
Salamone JD. The novel cannabinoid CB1 antagonist
AM6545 suppresses food intake and food-reinforced be-
havior. Pharmacology, Biochemistry and Behavior. 2010
Nov;97(1):179-84. PMID 20713079

[3] Cluny NL, Vemuri VK, Chambers AP, Limebeer CL,

Bedard H, Wood JT, Lutz B, Zimmer A, Parker LA,

54
Chapter 36

AM-679 (cannabinoid)

This article is about the cannabinoid agonist. For the

FLAP inhibitor, see AM-679 (FLAP inhibitor).

AM-679 is a drug that acts as a moderately potent agonist

for the cannabinoid receptors, with a Kᵢ of 13.5nM at
CB1 and 49.5nM at CB2 .[1] AM-679 was one of the
first 3-(2-iodobenzoyl)indole derivatives that was found to
have significant cannabinoid receptor affinity, and while
AM-679 itself has only modest affinity for these recep-
tors, it was subsequently used as a base to develop sev-
eral more specialised cannabinoid ligands that are now
widely used in research, including the potent CB1 ago-
nists AM-694 and AM-2233, and the selective CB2 ag-
onist AM-1241.[2] AM-679 was first identified as having
been sold as a cannabinoid designer drug in Hungary in
2011, along with another novel compound 1-pentyl-3-(1-
adamantoyl)indole.[3]

36.1 See also

• RCS-4

• AM-694
• AM-2233

36.2 References
[1] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
07

[2] Hongfeng Deng (2000). Design and synthesis of selective

cannabinoid receptor ligands: Aminoalkylindole and other
heterocyclic analogs (PhD. Dissertation). University of
Connecticut.

[3] Jankovics P, et al. (August 2011). “Detection and

identification of the new potential synthetic cannabi-
noids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3-
(1-adamantoyl)indole in seized bulk powders in Hun-
gary”. Forensic Science International 214 (1-3): 27–32.
doi:10.1016/j.forsciint.2011.07.011. PMID 21813254.

55
Chapter 37

AM-694

AM-694 (1-(5-fluoropentyl)−3-(2-iodobenzoyl)indole) 37.3 References

is a drug that acts as a potent and selective agonist for the
cannabinoid receptor CB1 . It is used in scientific research
for mapping the distribution of CB1 receptors. No public
data about AM-694 metabolism is known. AM-694 has
already emerged as a designer drug.
37.1 Pharmacology
AM-694 is an agonist for cannabinoid receptors. Affini-
ties are: with a Kᵢ of 0.08nM at CB1 and 18x selectiv-
ity over CB2 with a Kᵢ 1.44nM.[1] It is unclear what is
responsible for this unusually high CB1 binding affinity,
but it makes the 18 F radiolabelled derivative of AM-694
useful for mapping the distribution of CB1 receptors in
the body.[2]
[1] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
07
[2] Willis PG, Katoch-Rouse R, Horti AG. Regioselective F-
18 radiolabeling of AM694, a CB1 cannabinoid receptor
ligand. Journal of Labelled Compounds and Radiophar-
maceuticals 2003;46(9):799-804. doi:10.1002/jlcr.720
[3] Millington JE, Pattison FLM. TOXIC FLUO-
RINE COMPOUNDS: XII. ESTERS OF ω-
FLUOROALCOHOLS. Canadian Journal of Chemistry.
1956 Nov;34(11):1532-1541.
[4] Pattison FLM, Howell WC, Woolford RG. TOXIC
FLUORINE COMPOUNDS: XIII. ω-FLUOROALKYL
ETHERS. Canadian Journal of Chemistry. 1957
Feb;35(2):141-148.

37.1.1 Pharmacokinetics

Main article: Pharmacokinetic data of JWH-018 are

generally applicable to AM-694.

AM-694 metabolism differs only slightly from that of

JWH-018. AM-694 N-dealkylation produces fluoropen-
tane instead of pentane (or plain alkanes in general). It
has been speculated that the fluoropentane might function
as an alkylating agent or is further metabolized into toxic
fluoroacetic acid. This is not true since fluoroalkanes do
not act as alkylating agents under normal conditions and
uneven fluoroalkane chains metabolize into substantially
less toxic fluoropropanoic acid.[3][4]

37.2 See also

• AM-679

• AM-2201

• AM-2233

56
Chapter 38

AM-855

AM-855 is an analgesic drug which is a cannabinoid

agonist. It is a derivative of Δ8 Tetrahydrocannabinol with
a conformationally restricted side chain which has been
bound into a fourth ring fused to the aromatic A-ring of
the cannabinoid skeleton. AM-855 is an agonist at both
CB1 and CB2 with moderate selectivity for CB1 , with a
Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 .[1]

38.1 References
[1] Khanolkara, Atmaram D.; Dai Lua, Pusheng Fana, Xi-
aoyu Tiana and Alexandros Makriyannis (August 1999).
“Novel conformationally restricted tetracyclic analogs
of Δ8 -tetrahydrocannabinol”. Bioorganic & Medicinal
Chemistry Letters 9 (15): 2119–24. doi:10.1016/S0960-
894X(99)00355-8. PMID 10465529.

57
Chapter 39

AM-905

AM-905 is an analgesic drug which is a cannabinoid

agonist with a conformationally restricted side chain. It
is a potent and reasonably selective agonist for the CB1
cannabinoid receptor, with a Kᵢ of 1.2nM at CB1 and
5.3nM at CB2 .[1]

39.1 References
[1] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos
A, Makriyannis A. Pharmacophoric requirements for
cannabinoid side chains: multiple bond and C1'-
substituted delta 8-tetrahydrocannabinols. Journal of
Medicinal Chemistry. 1998 Mar 26;41(7):1195-200.
PMID 9544219

58
Chapter 40

AM-906

AM-906 is an analgesic drug which is a cannabinoid

agonist with a conformationally restricted side chain. It
is a potent and selective agonist for the CB1 cannabinoid
receptor, with a Kᵢ of 0.8nM at CB1 and 9.5nM at CB2 ,
a selectivity of almost 12x.[1]

40.1 See also

• AM-1235
• AM-2389

40.2 References
[1] Papahatjis DP, et al. Pharmacophoric requirements
for cannabinoid side chains: multiple bond and C1'-
substituted delta 8-tetrahydrocannabinols. Journal of
Medicinal Chemistry. 1998 Mar 26;41(7):1195-200.
PMID 9544219

59
Chapter 41

AM-919

AM-919 is an analgesic drug which is a cannabinoid

receptor agonist. It is a derivative of HU-210 which
has been substituted with a 6β-(3-hydroxypropyl) group.
This adds a “southern” aliphatic hydroxyl group to the
molecule as seen in the CP-series of nonclassical cannabi-
noid drugs, and so AM-919 represents a hybrid struc-
ture between the classical and nonclassical cannabinoid
families.[1]
AM-919 is somewhat less potent than HU-210 itself, but
is still a potent agonist at both CB1 and CB2 with mod-
erate selectivity for CB1 , with a Kᵢ of 2.2nM at CB1 and
3.4nM at CB2 .[2][3]

41.1 See also

• AM-4030

41.2 References
[1] Roger Pertwee. Cannabinoids. Handbook of Experimen-
tal Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X

[2] Tius MA, Hill WA, Zou XL, Busch-Petersen J,

Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji
V, Makriyannis A. Classical/non-classical cannabinoid
hybrids; stereochemical requirements for the southern
hydroxyalkyl chain. Life Sciences. 1995;56(23-24):2007-
12. PMID 7776825

[3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK,

Concepcion Fernandez-Garcia M, Fan P, Makriyannis
A, Tius MA. Classical/nonclassical hybrid cannabinoids:
southern aliphatic chain-functionalized C-6beta methyl,
ethyl, and propyl analogues. Journal of Medicinal Chem-
istry. 1998 Sep 10;41(19):3596-608. PMID 9733485

60
Chapter 42

AM-938

AM-938 is an analgesic drug which is a cannabinoid

receptor agonist. It is a derivative of HU-210 which
has been substituted with a 6β-(3-hydroxyprop-1-ynyl)
group. This adds a “southern” aliphatic hydroxyl group
to the molecule as seen in the CP-series of nonclas-
sical cannabinoid drugs, and so AM-938 represents a
hybrid structure between the classical and nonclassical
cannabinoid families,[1] with the 6-hydroxyalkyl chain
rigidified with a triple bond. This gives AM-938 a greater
degree of selectivity, so while it is still a potent agonist at
both CB1 and CB2 , it is reasonably selective for CB2 ,
with a Kᵢ of 0.3nM at CB2 and 1.2nM at CB1 , a selectiv-
ity of around 4x.[2][3]

42.1 See also

• AM-4030

42.2 References
[1] Roger Pertwee. Cannabinoids. Handbook of Experimen-
tal Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X

[2] Tius MA, Hill WA, Zou XL, Busch-Petersen J,

Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji
V, Makriyannis A. Classical/non-classical cannabinoid
hybrids; stereochemical requirements for the southern
hydroxyalkyl chain. Life Sciences. 1995;56(23-24):2007-
12. PMID 7776825

[3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK,

Concepcion Fernandez-Garcia M, Fan P, Makriyannis
A, Tius MA. Classical/nonclassical hybrid cannabinoids:
southern aliphatic chain-functionalized C-6beta methyl,
ethyl, and propyl analogues. Journal of Medicinal Chem-
istry. 1998 Sep 10;41(19):3596-608. PMID 9733485

61
Chapter 43
AM404
AM404, also known as N-
arachidonoylaminophenol,[1] is an active metabolite
of paracetamol (acetaminophen), responsible for all or
part of its analgesic action.[2] Chemically, it is the amide
formed from 4-aminophenol and arachidonic acid.
43.1 Pharmacology
AM404 was originally reported to be an endogenous
cannabinoid reuptake inhibitor, preventing the transport
of anandamide and other related compounds back from
the synaptic cleft, much in the same way that com-
mon selective serotonin reuptake inhibitor (SSRI) an-
tidepressants prevent the reuptake of serotonin. Ear-
lier work on the mechanism of AM404 suggested that
the inhibition of fatty acid amide hydrolase (FAAH) by
AM404 was responsible for all of its attributed reup-
take properties, since intracellular FAAH hydrolysis of
anandamide changes the intra/extracellular anandamide
equilibrium.[3] However, this is not the case, as newer
research on FAAH knockout mice has found that brain
cells internalize anandamide through a selective transport
mechanism which is independent of FAAH activity.[4]
This mechanism is inhibited by AM404.
AM404 is also a TRPV1 agonist and inhibitor of
cyclooxygenase COX-1 and COX-2, thus attenuating
prostaglandin synthesis. AM404 is thought to in-
duce its analgesic action through its activity on the
endocannabinoid, COX, and TRPV systems, all of which
are present in pain and thermoregulatory pathways.[5]
43.2 See also
• VDM-11
43.3 References
[1] Rogosch T, Sinning C, Podlewski A, Watzer B, Schlos-
burg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo
V, Nüsing R, Imming P (January 2012). “Novel bioac-
tive metabolites of dipyrone (metamizol)". Bioorg. Med.
62
Chem. 20 (1): 101–7. doi:10.1016/j.bmc.2011.11.028.
PMC 3248997. PMID 22172309.
[2] Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A
(February 2006). “The analgesic activity of paraceta-
mol is prevented by the blockade of cannabinoid CB1
receptors”. Eur. J. Pharmacol. 531 (1–3): 280–1.
doi:10.1016/j.ejphar.2005.12.015. PMID 16438952.
[3] Glaser ST, Abumrad NA, Fatade F, Kaczocha M,
Studholme KM, Deutsch DG (April 2003). “Evidence
against the presence of an anandamide transporter”.
Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4269–74.
doi:10.1073/pnas.0730816100. PMC 153082. PMID
12655057.
[4] Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopou-
los, A.; Makriyannis, A.; Piomelli, D. (11 May 2004).
“Anandamide transport is independent of fatty-acid amide
hydrolase activity and is blocked by the hydrolysis-
resistant inhibitor AM1172”. Proceedings of the Na-
tional Academy of Sciences 101 (23): 8756–8761.
doi:10.1073/pnas.0400997101.
[5] Högestätt ED, Jönsson BA, Ermund A, Andersson DA,
Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zyg-
munt PM (September 2005). “Conversion of ac-
etaminophen to the bioactive N-acylphenolamine AM404
via fatty acid amide hydrolase-dependent arachidonic acid
conjugation in the nervous system” (pdf). J. Biol. Chem.
280 (36): 31405–12. doi:10.1074/jbc.M501489200.
PMID 15987694.
Chapter 44

AMG-1

AMG-1 is an analgesic drug which is a cannabinoid

agonist. It is a derivative of Δ8THC with a rigidified and
extended 3-position side chain. AMG-1 is a potent ago-
nist at both CB1 and CB2 with moderate selectivity for
CB1 , with a Kᵢ of 0.6nM at CB1 vs 3.1nM at CB2 .[1]

44.1 References
[1] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu
W, Pertwee RG, Makriyannis A. Pharmacophoric re-
quirements for the cannabinoid side chain. Probing the
cannabinoid receptor subsite at C1'. Journal of Medicinal
Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753

63
Chapter 45

AMG-3

AMG-3 is an analgesic drug which is a cannabinoid

agonist. It is a derivative of Δ8THC substituted with a
dithiolane group on the 3-position side chain.[1] AMG-3
is a potent agonist at both CB1 and CB2 receptors with
a Kᵢ of 0.32nM at CB1 and 0.52nM at CB2 ,[2][3] and
its particularly high binding affinity has led to it being
used as a template for further structural development of
novel cannabinoid drugs.[4] It has sedative and analgesic
effects, with analgesia lasting for up to 36 hours after
administration.[5]

45.1 References
[1] Mavromoustakos T, Theodoropoulou E, Zervou M,
Kourouli T, Papahatjis D. Structure elucidation and
conformational properties of synthetic cannabinoids (-
)−2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-
6H-dibenzo[b,d]pyranyl)−2-hexyl-1,3-dithiolane and
its methylated analog. Journal of Pharmaceutical and
Biomedical Analysis. 1999 Jan;18(6):947-56. PMID
9925329
[2] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos
A, Makriyannis A. Pharmacophoric requirements for
cannabinoid side chains: multiple bond and C1'-
substituted delta 8-tetrahydrocannabinols. Journal of
Medicinal Chemistry. 1998 Mar 26;41(7):1195-200.
PMID 9544219
[3] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu
W, Pertwee RG, Makriyannis A. Pharmacophoric re-
quirements for the cannabinoid side chain. Probing the
cannabinoid receptor subsite at C1'. Journal of Medicinal
Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753
[4] Durdagi S, Papadopoulos MG, Papahatjis DP, Mavro-
moustakos T. Combined 3D QSAR and molecular dock-
ing studies to reveal novel cannabinoid ligands with opti-
mum binding activity. Bioorganic and Medicinal Chem-
istry Letters. 2007 Dec 15;17(24):6754-63. PMID
17980589
[5] Antoniou K, Galanopoulos A, Vlachou S, Kourouli T,
Nahmias V, Thermos K, Panagis G, Daifoti Z, Marselos
M, Papahatjis D, Spyraki C. Behavioral pharmacological
properties of a novel cannabinoid 1',1'-dithiolane delta8-
THC analog, AMG-3. Behavioural Pharmacology. 2005
Sep;16(5-6):499-510. PMID 16148456

64
Chapter 46

AMG-36

AMG-36 is an analgesic drug which is a cannabinoid

agonist. It is a derivative of Δ8THC substituted with a
cyclopentane group on the 3-position side chain. AMG-
36 is a potent agonist at both CB1 and CB2 with moderate
selectivity for CB1 , with a Kᵢ of 0.4nM at CB1 vs 1.9nM
at CB2 .[1][2]

46.1 References
[1] Papahatjis DP, et al. Pharmacophoric requirements for
the cannabinoid side chain. Probing the cannabinoid re-
ceptor subsite at C1'. Journal of Medicinal Chemistry.
2003 Jul 17;46(15):3221-9. PMID 12852753

[2] Papahatjis DP, et al. C1'-cycloalkyl side chain phar-

macophore in tetrahydrocannabinols. Journal of Medic-
inal Chemistry. 2007 Aug 23;50(17):4048-60. PMID
17672444

65
Chapter 47

AMG-41

AMG-41 is an analgesic drug which is a cannabinoid

agonist. It is a derivative of Δ8-THC substituted with a
cyclopropyl group on the C1'-position of the C3-alkyl side
chain. AMG-41 is a potent agonist at both CB1 and CB2 ,
with a Kᵢ of 0.4nM at CB1 vs 0.9nM at CB2 .[1][2][3]

47.1 References
[1] Papahatjis DP, Nikas SP, Andreou T, Makriyan-
nis A. Novel 1',1'-chain substituted Delta(8)-
tetrahydrocannabinols. Bioorganic and Medicinal
Chemistry Letters. 2002 Dec 16;12(24):3583-6. PMID
12443781

[2] Papahatjis DP, et al. Pharmacophoric requirements for

the cannabinoid side chain. Probing the cannabinoid re-
ceptor subsite at C1'. Journal of Medicinal Chemistry.
2003 Jul 17;46(15):3221-9. PMID 12852753

[3] Papahatjis DP, et al. C1'-cycloalkyl side chain phar-

macophore in tetrahydrocannabinols. Journal of Medic-
inal Chemistry. 2007 Aug 23;50(17):4048-60. PMID
17672444

66
Chapter 48

APINACA

This article is about the synthetic cannabinoid drug. For
the Japanese girl group, see AKB48.
AKB48 (APINACA, N-(1-adamantyl)−1-pentyl-1H-
indazole-3-carboxamide) is a drug that acts as a rea-
sonably potent agonist for the cannabinoid receptors,[1]
with a Kᵢ of 304.5nM and a EC50 of 585nM at CB1 .
It had never previously been reported in the scientific
or patent literature, and was first identified by labo-
ratories in Japan in March 2012 as an ingredient in
synthetic cannabis smoking blends, along with a related
compound APICA.[2] Structurally it closely resembles
cannabinoid compounds from patent WO 2003/035005
but with a simple pentyl chain on the indazole 1-position,
and AKB48 falls within the claims of this patent despite
not being disclosed as an example. AKB48 was made il-
legal in Japan in 2012,[3] and was banned as a temporary
class drug in New Zealand from 13 July 2012.[4] It has
been banned in Latvia since 14 November 2013. The
DEA announced its intent to schedule 16 May 2013. [5]
48.3 References
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.;
Goda, Y. (2012). “URB-754: A new class of de-
signer drug and 12 synthetic cannabinoids detected in il-
legal products”. Forensic Science International 227 (1–
3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID
23063179.
[2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri,
R.; Goda, Y. (2012). “Identification of two new-
type synthetic cannabinoids, N-(1-adamantyl)−1-
pentyl-1H-indole-3-carboxamide (APICA) and N-(1-
adamantyl)−1-pentyl-1H-indazole-3-carboxamide (AP-
INACA), and detection of five synthetic cannabinoids,
AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and
AM-1248, as designer drugs in illegal products”. Forensic
Toxicology 30 (2): 114. doi:10.1007/s11419-012-0136-
7.
[3] “Designation of “Shitei Yakubutsu” (designated sub-
stances) based on the provision of the Pharmaceutical Af-
fairs Law (1960, Law No.145)" (PDF).

[4] “Temporary Class Drug Notice”. Department of Internal

48.1 Detection Affairs. New Zealand. 5 July 2012.

A forensic standard of AKB48 is available, and the com-
pound has been posted on the Forendex website of poten-
tial drugs of abuse.[6]
[5] url=http://www.justice.gov/dea/divisions/hq/2013/
hq051613.shtml
[6] http://forendex.southernforensic.org/index.php/detail/
index/1221

48.2 See also • http://www.gpo.gov/fdsys/pkg/FR-2013-04-12/

html/2013-08671.htm
• AB-001
• AB-FUBINACA
• AB-PINACA
• ADB-FUBINACA
• ADB-PINACA
• RCS-4
• RCS-8
• SDB-001
• STS-135

67
Chapter 49

AR-231,453

AR-231,453 is an agonist for the suggested novel

cannabinoid receptor GPR119.[1]

49.1 See also

• PSN-375,963

• PSN-632,408

49.2 References
[1] Semple G, Fioravanti B, Pereira G, Calderon I, Uy J, Choi
K, Xiong Y, Ren A, Morgan M, Dave V, Thomsen W, Un-
ett DJ, Xing C, Bossie S, Carroll C, Chu ZL, Grottick AJ,
Hauser EK, Leonard J, Jones RM. (2008). “Discovery of
the first potent and orally efficacious agonist of the orphan
G-protein coupled receptor 119.”. J Med Chem. 51 (17):
5172–5175. doi:10.1021/jm8006867. PMID 18698756.

68
Chapter 50

Arachidonyl-2'-chloroethylamide

Arachidonyl-2'-chloroethylamide (ACEA) is a syn-

thetic agonist of the cannabinoid receptor 1 (CB1R).
ACEA is considered to be a selective cannabinoid ago-
nist as it binds primarily to the CB1R and has low affinity
to the cannabinoid receptor 2 (CB2R) (Kᵢ = 1.4 nM for
CB1R; Kᵢ = 3100 nM for CB2R). [1]

50.1 References
[1] Hillard, CJ; Manna, S; Greenberg, MJ; Dicamelli, R;
Ross, RA; Stevenson, LA; Murphy, V; Pertwee, RG;
Campbell, WB (1999). “Synthesis and characterization
of potent and selective agonists of the neuronal cannabi-
noid receptor (CB1)". The Journal of Pharmacology and
Experimental Therapeutics 289 (3): 1427–33. PMID
10336536.

69
Chapter 51

Arachidonylcyclopropylamide

Arachidonylcyclopropylamide (ACPA) is a synthetic

agonist of the cannabinoid receptor 1 (CB1R). ACPA
is considered to be a selective cannabinoid agonist as it
binds primarily to the CB1R and has low affinity to the
cannabinoid receptor 2 (CB2R) (Kᵢ = 2.2 nM for CB1R;
Kᵢ = 700 nM for CB2R).[1]

51.1 References
[1] Hillard, CJ, et al. (1999). “Synthesis and characteri-
zation of potent and selective agonists of the neuronal
cannabinoid receptor (CB1)". The Journal of Pharma-
cology and Experimental Therapeutics 289 (3): 1427–33.
PMID 10336536.

70
Chapter 52
N-Arachidonylglycine
N-Arachidonylglycine (NAGly) is a carboxylic analog
of the endocannabinoid anandamide.[1] Since it was first
synthesized in 1996,[2] NAGly has been a primary fo-
cus of the relatively contemporary field of lipidomics
due to its wide range of signaling targets in the brain,
the immune system and throughout various other bod-
ily systems. In combination with 2‐arachidonoyl glyc-
erol (2‐AG), NAGly has enabled the identification of a
family of lipids often referred to as endocannabinoids.[3]
Recently, NAGly has been found to bind to G-protein
coupled receptor 18 (GPR18), the putative abnormal
cannabidiol receptor.[4][5] NaGly is found throughout the
body and research on its explicit functions is on going.
52.1 Synthesis
The exact biosynthesis of NaGly is not completely un-
derstood, but there are two proposed pathways found
in vitro for its biosynthesis: 1) enzymatically regulated
conjugation of arachidonic acid and glycine and 2) the
oxidative metabolism of the endogenous cannabinoid
anandamide.[6][7] In the first pathway, Cytochrome c cat-
alyzes the in vitro synthesis of NaGly from arachidonoyl
coenzyme A and glycine in the presence of hydrogen
peroxide.[8] In the second pathway, alcohol dehydro-
genase catalyzes the oxidation of anandamide into N-
arachidonoyl glycine.[9]
52.2 Research
52.2.1 Effects on the nervous system
NAGly has been hypothesized to have a neurophysio-
logical function of pain suppression, supported by ev-
idence that it suppresses formalin-induced pain behav-
ior in rats.[10] In particular, peripherally administered
NAGly inhibited phase 2 pain behavior, suggesting ei-
ther a direct suppresion of nociceptive afferents on the
nerve or an indirect modulation of the afferents’ inter-
stitial environment.[10] In either case, these findings hold
promise for NAGly as a means of mitigating postopera-
tive or chronic pain. NAGly is also effective in acute pain
71
models, reducing mechanical allodynia and thermal hy-
peralgesia induced by intraplantar injection of Fruend’s
complete adjuvant.[11] Similar mechanical allydonia in-
duced by partial ligation of the sciatic nerve was also re-
duced by NaGly.[12] Other arachidonic acid-amino acid
conjugates did not have the same effects and the actions
of NaGly were not affected by cannabinoid receptor ago-
nists in either study, suggesting a novel non-cannabinoid
receptor mediated approach to alleviate inflammatory
pain.[11][12]
NaGly was shown to be endogenous ligand for the G-
protein couple receptor GPR92 along with farnesyl py-
rophosphate.[13] In the dorsal root ganglia (DRG), where
GPR92 was found to be localized NaGly increased intra-
cellular calcium levels in DRG neurons, indicating a role
of NaGly in the sensory nervous system through the acti-
vation of GPR92.[13]
52.2.2 Effects on the immune system
NAGly has been the focus of research on the immune sys-
tem because of its antinociceptive effects and inhibitory
action on components of the immune system. Specif-
ically, it significantly inhibited TNFα and IFNγ pro-
duction, and it shows potential as a therapeutic treat-
ment for chronic inflammation.[14] Moreover, NAGly has
been shown to act as a substrate for cyclooxygenase-2
(COX-2), the enzyme primarily known for producing
prostaglandins associated with increases in inflammation
and hyperalgesia. In many mammalian tissues that ex-
press COX-2, significant levels of NAGly are naturally
present, and in these tissues COX-2 selectively metabo-
lizes NAGly prostaglandin (PG) H2 glycine and HETE-
Gly.[15]
52.2.3 Cell migration
NAGly has been hypothesized to induce cell migra-
tion in BV-2 microglia cells.[4] The same research
suggests that this migration occurs through GPR18.
This was verified using GPR18 transfected HEK-293
cells. The same migration wasn't witnessed using non-
transfected and GPR55 transfected HEK-293.[4] Addi-
72
tionally, tetrahydrocannabinol and NaGly are full agonists
at the GPR18 receptors and induce migration in human
endometrial HEC-1B cells.[16] Understanding functions
of NaGly in such structures provides a promising future
in helping treat diseases such as endometriosis.
52.2.4 Other targets
Insulin secretion
NaGly was identified as a novel insulin secretagogue and
was shown to increase intracellular calcium concentra-
tion through stimulation of voltage dependent calcium
channels.[17] Additionally, this action was dependent on
extracellular glucose level.[17]
Additional biochemical interactions
NaGly has been shown to inhibit the glycine transporter
GLYT2a in a non-competitive fashion with arachidonic
acids and secondary messenger systems of GLYT2a, sug-
gesting a novel recognition site for the N-arachodnoyl
amino acids, especially because other conjugated amino
acids had similar effects.[18]
52.3 References
[1] Burstein, Sumner; Huang, S.M.; Petros, T.J.; Ros-
setti, R.G.; Walker, J.M.; Zurier, R.B. (30 April
2002). “Regulation of anandamide tissue levels by
N-arachidonylglycine”. Biochemical Pharmacology 64
(7): 1147–1150. doi:10.1016/S0006-2952(02)01301-1.
PMID 12234618.
[2] Sheskin, Tzviel; Hanus, L.; Slager, J.; Vogel, Z.;
Mechoulam, R. (1997). “Structural Requirements for
Binding of Anandamide-Type Compounds to the Brain
Cannabinoid Receptor”. Journal of Medicinal Chem-
istry 40 (5): 659–667. doi:10.1021/jm960752x. PMID
9057852.
[3] Bradshaw, Heather; Rimmerman, N.; Hu, S.J.; Burstein,
S.; Walker, J.M. (2009). “Novel Endogenous N-Acyl
Glycines: Identification and Characterization”. Vi-
tamins and Hormones. Vitamins & Hormones 81:
191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN
9780123747822. PMID 19647113.
[4] McHugh, Douglas; Hu, Sherry SJ; Rimmerman, Neta;
Juknat, Ana; Vogel, Zvi; Walker, J Michael; Bradshaw,
Heather B (1 January 2010). “N-arachidonoyl glycine,
an abundant endogenous lipid, potently drives directed
cellular migration through GPR18, the putative abnor-
mal cannabidiol receptor”. BMC Neuroscience 11 (1): 44.
doi:10.1186/1471-2202-11-44.
[5] Kohno, M; Hasegawa, H; Inoue, A; Muraoka, M;
Miyazaki, T; Oka, K; Yasukawa, M (Sep 1, 2006).
“Identification of N-arachidonylglycine as the endogenous
CHAPTER 52. N-ARACHIDONYLGLYCINE
ligand for orphan G-protein-coupled receptor GPR18.”.
Biochemical and biophysical research communications 347
(3): 827–32. PMID 16844083.
[6] Bradshaw, Heather B; Rimmerman, Neta; Hu, Sherry;
Benton, Valery M; Stuart, Jordyn M; Masuda, Kim; Cra-
vatt, Benjamin F; O'Dell, David K; Walker, J Michael (1
January 2009). “The endocannabinoid anandamide is a
precursor for the signaling lipid N-arachidonoyl glycine
by two distinct pathways”. BMC Biochemistry 10 (1): 14.
doi:10.1186/1471-2091-10-14.
[7] Aneetha, Halikhedkar; O’Dell, David K.; Tan, Bo;
Walker, J. Michael; Hurley, Thomas D. (1 January
2009). “Alcohol dehydrogenase-catalyzed in vitro ox-
idation of anandamide to N-arachidonoyl glycine, a
lipid mediator: Synthesis of N-acyl glycinals”. Bioor-
ganic & Medicinal Chemistry Letters 19 (1): 237–241.
doi:10.1016/j.bmcl.2008.10.087.
[8] McCue, JM; Driscoll, WJ; Mueller, GP (Jan 11, 2008).
“Cytochrome c catalyzes the in vitro synthesis of arachi-
donoyl glycine.”. Biochemical and biophysical research
communications 365 (2): 322–7. PMID 17986381.
[9] Aneetha, H; O'Dell, DK; Tan, B; Walker, JM; Hurley,
TD (Jan 1, 2009). “Alcohol dehydrogenase-catalyzed in
vitro oxidation of anandamide to N-arachidonoyl glycine,
a lipid mediator: synthesis of N-acyl glycinals.”. Bioor-
ganic & medicinal chemistry letters 19 (1): 237–41. PMID
19013794.
[10] Huang, Susan M.; Bisogno, T., Petros, T.J., Chang, S.Y.,
Zavitsanos, P.A., Zipkin, R.E., Sivakumar, R., Coop, A.,
Maeda, D.Y., De Petrocellis, L., Burstein, S., Di Marzo,
V., Walker, J.M. (November 16, 2001). “Identification
of a New Class of Molecules, the Arachidonyl Amino
Acids, and Characterization of One Member That Inhibits
Pain”. The Journal of Biological Chemistry 276 (46):
42639–42644. doi:10.1074/jbc.M107351200. PMID
11518719.
[11] Succar, Rebecca; Mitchell, Vanessa A; Vaughan, Christo-
pher W (August 2007). “Actions of N-arachidonyl-
glycine in a rat inflammatory pain model”. Molecular Pain
3 (1): 24. doi:10.1186/1744-8069-3-24.
[12] Vuong, Leeza A.Q.; Mitchell, Vanessa A.; Vaughan,
Christopher W. (1 January 2008). “Actions of
N-arachidonyl-glycine in a rat neuropathic pain
model”. Neuropharmacology 54 (1): 189–193.
doi:10.1016/j.neuropharm.2007.05.004.
[13] Oh, D. Y.; Yoon, J. M.; Moon, M. J.; Hwang, J.-
I.; Choe, H.; Lee, J. Y.; Kim, J. I.; Kim, S.; Rhim,
H.; O'Dell, D. K.; Walker, J. M.; Na, H. S.; Lee,
M. G.; Kwon, H. B.; Kim, K.; Seong, J. Y. (22 May
2008). “Identification of Farnesyl Pyrophosphate and N-
Arachidonylglycine as Endogenous Ligands for GPR92”.
Journal of Biological Chemistry 283 (30): 21054–21064.
doi:10.1074/jbc.M708908200.
[14] Ferrante, A; Poulos A; Pitt M; Easton C; Sleigh M; Rath-
jen D; Widmer F. “Methods of Treating Immunopatholo-
gies Using Polyunsaturated Fatty Acids”. United States
patent publication WO 97/38688.
52.3. REFERENCES 73

[15] Prusakiewicz, J; Kingsley P; Kozak K; Marnett L

(2002). “Selective oxygenation of N-arachidonylglycine
by cyclooxygenase-2”. Biochemical and Biophysical Re-
search Communications (296): 612–617.

[16] McHugh, Douglas; Page, Jeremy; Dunn, Emily;

Bradshaw, Heather B (1 April 2012). "Δ9-
Tetrahydrocannabinol and N-arachidonyl glycine
are full agonists at GPR18 receptors and induce
migration in human endometrial HEC-1B cells”.
British Journal of Pharmacology 165 (8): 2414–2424.
doi:10.1111/j.1476-5381.2011.01497.x.

[17] Ikeda, Yukio; Iguchi, Haruhisa; Nakata, Masanori; Ioka,

Ryoichi X.; Tanaka, Toshiya; Iwasaki, Satoshi; Magoori,
Kenta; Takayasu, Shinobu; Yamamoto, Tokuo T.; Ko-
dama, Tatsuhiko; Yada, Toshihiko; Sakurai, Takeshi;
Yanagisawa, Masashi; Sakai, Juro (1 August 2005).
“Identification of N-arachidonylglycine, U18666A, and
4-androstene-3,17-dione as novel insulin Secretagogues”.
Biochemical and Biophysical Research Communications
333 (3): 778–786. doi:10.1016/j.bbrc.2005.06.005.

[18] Wiles, Amy L.; Pearlman, Rhonda-Jo; Rosvall, Mari;

Aubrey, Karin R.; Vandenberg, Robert J. (1 November
2006). “N-Arachidonyl-glycine inhibits the glycine trans-
porter, GLYT2a”. Journal of Neurochemistry 99 (3):
781–786. doi:10.1111/j.1471-4159.2006.04107.x.
Chapter 53

AZ-11713908

AZ-11713908 is a drug developed by AstraZeneca which [5] WO patent 2004/108712, LIU Z, PAGÈ D, WALPOLE
is a peripherally selective cannabinoid agonist, acting as C, YANG H, “BENZIMIDAZOLE DERIVATIVES,
a potent agonist at the CB1 receptor and a partial ag- COMPOSITIONS CONTAINING THEM, PREPARA-
onist at CB2 . It has poor blood–brain barrier penetra- TION THEREOF AND USES THEREOF”, granted
tion, and so while it is an effective analgesic in animal 16.12.2004
tests, it produces only peripheral effects at low doses,
with much weaker symptoms of central effects compared
to other cannabinoid drugs such as WIN 55,212-2.[1] A
large number of related benzimidazole derived cannabi-
noid ligands are known.[2][3][4][5]

53.1 See also

• AM-6545
• CB-13

53.2 References
[1] Yu XH, Cao CQ, Martino G, Puma C, Morinville A, St-
Onge S, Lessard E, Perkins MN, Laird JM (November
2010). “A peripherally restricted cannabinoid receptor
agonist produces robust anti-nociceptive effects in rodent
models of inflammatory and neuropathic pain”. Pain 151
(2): 337–44. doi:10.1016/j.pain.2010.07.019. PMID
20696525.
[2] Verbist BM, De Cleyn MA, Surkyn M, Fraiponts
E, Aerssens J, Nijsen MJ, Gijsen HJ (April 2008).
“5-Sulfonyl-benzimidazoles as selective CB2 agonists”.
Bioorganic & Medicinal Chemistry Letters 18 (8): 2574–9.
doi:10.1016/j.bmcl.2008.03.048. PMID 18394887.
[3] Pagé D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay
M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava
S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic
L, St-Onge S, Godbout C, Salois D, Payza K, Payza K
(July 2008). “Novel benzimidazole derivatives as selective
CB2 agonists”. Bioorganic & Medicinal Chemistry Letters
18 (13): 3695–700. doi:10.1016/j.bmcl.2008.05.073.
PMID 18522867.
[4] WO patent 2004/108688, LIU Z, PAGÈ D, WALPOLE
C, YANG H, “BENZIMIDAZOLE DERIVATIVES,
COMPOSITIONS CONTAINING THEM, PREPARA-
TION THEREOF AND USES THEREOF”, granted
16.12.2004

74
Chapter 54

BAY 38-7271

Originally synthesized by chemist Wayne E. Kenney,

BAY 38-7271 (KN 38-7271) is a drug which is a
cannabinoid receptor agonist developed by Bayer AG. It
has analgesic and neuroprotective effects and is used in
scientific research, with proposed uses in the treatment of
traumatic brain injury.[1][2] It is a full agonist with around
the same potency as CP 55,940 in animal studies, and has
fairly high affinity for both CB1 and CB2 receptors, with
Kᵢ values of 2.91nM at CB1 and 4.24nM at CB2 .[3][4] It
has now been licensed to KeyNeurotek Pharmaceuticals
for clinical development,[5] and is currently in Phase II
trials.[6] But its development appears stopped.

54.1 References
[1] Mauler F, Horváth E, De Vry J, Jäger R, Schwarz T, Sand-
mann S, Weinz C, Heinig R, Böttcher M. BAY 38-7271:
a novel highly selective and highly potent cannabinoid re-
ceptor agonist for the treatment of traumatic brain injury.
CNS Drug Reviews. 2003 Winter;9(4):343-58. PMID
14647528

[2] Mauler F, Hinz V, Augstein KH, Fassbender M, Horváth

E. Neuroprotective and brain edema-reducing efficacy of
the novel cannabinoid receptor agonist BAY 38-7271.
Brain Research. 2003 Oct 31;989(1):99-111. PMID
14519516

[3] Mauler F, Mittendorf J, Horváth E, De Vry J. Char-

acterization of the diarylether sulfonylester (-)-(R)−3-
(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-
1-sulfonate (BAY 38-7271) as a potent cannabinoid
receptor agonist with neuroprotective properties. Journal
of Pharmacology and Experimental Therapeutics. 2002
Jul;302(1):359-68. PMID 12065738

[4] De Vry J, Rüdiger Jentzsch K. Discriminative stimulus

effects of BAY 38-7271, a novel cannabinoid receptor
agonist. European Journal of Pharmacology. 2002 Dec
20;457(2-3):147-52. PMID 12464360

[5] Pipeline

[6] KeyNeurotek Pharmaceuticals AG Reports Positive

Phase I Data of Its Cannabinoid Receptor-Agonist

75
Chapter 55

BAY 59-3074

BAY 59-3074 is a drug which is a cannabinoid receptor

partial agonist developed by Bayer AG. It has analgesic
effects and is used in scientific research. It is orally active
in animals, and has modest affinity for both CB1 and CB2
receptors, with Kᵢ values of 48.3nM at CB1 and 45.5nM
at CB2 .[1][2]

55.1 References
[1] De Vry J, Denzer D, Reissmueller E, Eijckenboom
M, Heil M, Meier H, Mauler F. 3-[2-cyano-3-
(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-
butanesulfonate (BAY 59-3074): a novel cannabinoid
Cb1/Cb2 receptor partial agonist with antihyperalgesic
and antiallodynic effects. Journal of Pharmacology and
Experimental Therapeutics. 2004 Aug;310(2):620-32.
PMID 15140913

[2] De Vry J, Jentzsch KR. Discriminative stimulus effects

of the structurally novel cannabinoid CB1/CB2 receptor
partial agonist BAY 59-3074 in the rat. European Journal
of Pharmacology. 2004 Nov 28;505(1-3):127-33. PMID
15556145

76
Chapter 56

BML-190

BML-190 (Indomethacin morpholinylamide) is a drug

used in scientific research that acts as a selective CB2
inverse agonist.[1] BML-190 is structurally derived from
the NSAID indomethacin but has a quite different biolog-
ical activity.[2] The activity produced by this compound
is disputed, with some sources referring to it as a CB2
agonist rather than an inverse agonist;[3][4] this may re-
flect an error in classification, or alternatively it may pro-
duce different effects in different tissues, more research
is required to resolve this dispute.

56.1 References
[1] New, DC; Wong, YH (2003). “BML-190 and AM251
act as inverse agonists at the human cannabinoid CB2
receptor: signalling via cAMP and inositol phosphates”.
FEBS Letters 536 (1–3): 157–60. doi:10.1016/S0014-
5793(03)00048-6. PMID 12586356.

[2] Klegeris, A; Bissonnette, CJ; McGeer, PL (2003).

“Reduction of human monocytic cell neurotoxicity and
cytokine secretion by ligands of the cannabinoid-type CB2
receptor”. British Journal of Pharmacology 139 (4): 775–
86. doi:10.1038/sj.bjp.0705304. PMC 1573900. PMID
12813001.

[3] Melck, D; De Petrocellis, L; Orlando, P; Bisogno, T;

Laezza, C; Bifulco, M; Di Marzo, V (2000). “Suppres-
sion of nerve growth factor Trk receptors and prolactin re-
ceptors by endocannabinoids leads to inhibition of human
breast and prostate cancer cell proliferation”. Endocrinol-
ogy 141 (1): 118–26. doi:10.1210/en.141.1.118. PMID
10614630.

[4] Scutt, A; Williamson, EM (2007). “Cannabinoids stimu-

late fibroblastic colony formation by bone marrow cells in-
directly via CB2 receptors”. Calcified tissue international
80 (1): 50–9. doi:10.1007/s00223-006-0171-7. PMID
17205329.

77
Chapter 57

(C6)-CP 47,497

(C6)-CP 47,497 (CP 47,497 dimethylhexyl homologue)

is a synthetic cannabinoid, a CP 47,497 homologue.
Its systematic name is 2-[(1R,3S)−3-
hydroxycyclohexyl]−5-(1,1-dimethylhexyl)phenol.

57.1 See also

• Synthetic cannabis

• (C7)-CP 47,497 (CP 47,497 itself)

• (C8)-CP 47,497

• (C9)-CP 47,497

78
Chapter 58

(C9)-CP 47,497

(C9)-CP 47,497 (CP 47,497 dimethylnonyl homologue)

is a synthetic cannabinoid, a CP 47,497 homologue.
Its systematic name is 2-[(1R,3S)−3-
hydroxycyclohexyl]−5-(1,1-dimethylnonyl)phenol.

58.1 See also

• Synthetic cannabis

• (C6)-CP 47,497
• (C7)-CP 47,497 (CP 47,497 itself)

• (C8)-CP 47,497

79
Chapter 59

Canbisol

Canbisol (Nabidrox), is a synthetic cannabinoid deriva-

tive that is the dimethylheptyl homologue of 9-nor−9β-
hydroxyhexahydrocannabinol (HHC). It is a potent
agonist at both the CB1 and CB2 receptors, with a binding
affinity of 0.1nM at CB1 and 0.2nM at CB2 .[1] It is
mainly used in scientific research, in receptor binding
studies to determine the structure and function of the
cannabinoid receptors,[2][3][4] but has been made illegal
in some countries due to its possible abuse potential as a
cannabinomimetic drug.[5]

59.1 See also

• HU-210

• HU-243
• Nabilone

59.2 References
[1] Rhee MH, et al. (September 1997). “Cannabinol deriva-
tives: binding to cannabinoid receptors and inhibition of
adenylylcyclase”. Journal of Medicinal Chemistry 40 (20):
3228–33. doi:10.1021/jm970126f. PMID 9379442.

[2] Rhee MH, et al. (December 2000). “Functional role of

tryptophan residues in the fourth transmembrane domain
of the CB(2) cannabinoid receptor”. Journal of Neuro-
chemistry 75 (6): 2485–91. PMID 11080201.

[3] Rhee MH (September 2002). “Functional role of serine

residues of transmembrane dopamin VII in signal trans-
duction of CB2 cannabinoid receptor”. Journal of Veteri-
nary Science 3 (3): 185–91. PMID 12514330.

[4] Zhang R, et al. (July 2005). “Cysteine 2.59(89) in

the second transmembrane domain of human CB2 re-
ceptor is accessible within the ligand binding crevice:
evidence for possible CB2 deviation from a rhodopsin
template”. Molecular Pharmacology 68 (1): 69–83.
doi:10.1124/mol.104.007823. PMID 15840841.

[5] The Misuse of Drugs Act 1971 (Amendment) Order 2009

80
Chapter 60

Cannabichromene

Cannabichromene (abbreviated as CBC) is a cannabi- [3] Shinjyo, Noriko; Di Marzo, Vincenzo (2013). “The ef-
noid found in the cannabis plant. It bears struc- fect of cannabichromene on adult neural stem/progenitor
tural similarity to the other natural cannabinoids, in- cells”. Neurochemistry International 63 (5): 432–7.
cluding tetrahydrocannabinol, tetrahydrocannabivarin, doi:10.1016/j.neuint.2013.08.002. PMID 23941747.
cannabidiol, and cannabinol, among others. Evidence has
suggested that it may play a role in the anti-inflammatory
and anti-viral effects of cannabis, and may contribute to
the overall analgesic effects of medical cannabis. How-
ever, more research into the compound may be needed
before any definite medical effects can be verified.[1]
CBC has two stereoisomers. It is not scheduled by the
Convention on Psychotropic Substances. CBC is non-
psychotropic.[2]

60.1 Medical uses

A 2011 study in the British Journal of Pharmacology
found that CBD and CBC stimulated descending path-
ways of antinociception and caused analgesia by interact-
ing with several target proteins involved in nociceptive
control.[2] A study in Neurochemistry International sug-
gested that cannabichromene might stimulate the growth
of brain cells by stimulating adult neural stem progeni-
tor cells (NSPCs). The study said “our results suggest
that CBC raises the viability of NSPCs while inhibiting
their differentiation into astroglia, possibly through up-
regulation of ATP and adenosine signalling.[3]

60.2 References
[1] Gaoni, Y.; Mechoulam, R. (1966). “Cannabichromene, a
new active principle in hashish”. Chemical Communica-
tions 1: 20–1. doi:10.1039/C19660000020.

[2] Maione, Sabatino; Piscitelli, Fabiana; Gatta, Luisa; Vita,

Daniela; De Petrocellis, Luciano; Palazzo, Enza; De
Novellis, Vito; Di Marzo, Vincenzo (2011). “Non-
psychoactive cannabinoids modulate the descending path-
way of antinociception in anaesthetized rats through
several mechanisms of action”. British Journal of
Pharmacology 162 (3): 584–96. doi:10.1111/j.1476-
5381.2010.01063.x. PMID 20942863.

81
Chapter 61

Cannabicyclohexanol

Cannabicyclohexanol (CCH, CP 47,497 dimethy- [5] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda

loctyl homologue, (C8)-CP 47,497) is a cannabinoid re-
ceptor agonist drug, developed by Pfizer in 1979. On 19
January 2009, the University of Freiburg in Germany an-
nounced that an analog of CP 47,497 was the main ac-
tive ingredient in the herbal incense product Spice, specif-
ically the 1,1-dimethyloctyl homologue of CP 47,497,
which is now known as cannabicyclohexanol.[2][3][4][5]
The 1,1-dimethyloctyl homologue of CP 47,497 is in fact
several times more potent than the parent compound,[6]
which is somewhat unexpected as the 1,1-dimethylheptyl
is the most potent substituent in classical cannabinoid
compounds such as HU-210.[7]
Y (May 2010). “Chemical analysis of synthetic
cannabinoids as designer drugs in herbal products”.
Forensic Science International 198 (1-3): 31–8.
doi:10.1016/j.forsciint.2010.01.004. PMID 20117892.
[6] Compton DR, Johnson MR, Melvin LS, Martin BR. Phar-
macological profile of a series of bicyclic cannabinoid
analogs: classification as cannabimimetic agents. Journal
of Pharmacology and Experimental Therapeutics. 1992
Jan;260(1):201-9. PMID 1309872
[7] Martin BR, et al. Behavioral, biochemical, and molecular
modeling evaluations of cannabinoid analogs. Pharmacol-
ogy, Biochemistry and Behavior. 1991 Nov;40(3):471-8.
PMID 1666911

61.1 See also

• Synthetic cannabis

• (C6)-CP 47,497

• (C7)-CP 47,497 (CP 47,497 itself)

• (C9)-CP 47,497

• O-1871

61.2 References
[1] Cook, Morgan (2011-02-28). “Synthetic marijuana ille-
gal as of Tuesday”. North County Times (San Diego). Re-
trieved 2011-02-28.

[2] Hauptwirkstoff von „Spice“ identifiziert, University

of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm.
2009-01-19.19/

[3] Spice - weitere Analyseresultate http://www.

basg.at/servlet/sls/Tornado/web/ages/content/
4E5A4B86295BF5C0C125753E006A5E3C

[4] Auwärter V, et al. 'Spice' and other herbal blends: harm-

less incense or cannabinoid designer drugs? Journal of
Mass Spectrometry. 2 February 2009. PMID 19189348

82
Chapter 62

Cannabicyclol

Cannabicyclol (CBL) is a non-psychotomimetic

cannabinoid found in the Cannabis species. CBL is
a degradative product like cannabinol. Light converts
cannabichromene to CBL.
It has 16 stereoisomers. It is not scheduled by Convention
on Psychotropic Substances.

62.1 See also

• Cannabinoids

• Cannabis
• Medical marijuana

62.2 External links

• CTD’s Cannabicyclol page from the Comparative
Toxicogenomics Database
• Erowid Compounds found in Cannabis sativa

• http://www.wiley-vch.de/stmdata/pdf/
CompoundList.pdf

• http://www.a1b2c3.com/drugs/mj028.htm

83
Chapter 63
Cannabidiol
Not to be confused with Cannabinol.
Cannabidiol (CBD) is one of at least 85 active
cannabinoids identified in cannabis.[4] It is a major
phytocannabinoid, accounting for up to 40% of the
plant’s extract.[5] CBD is considered to have a wider
scope of medical applications than tetrahydrocannabinol
(THC).[5] An orally-administered liquid containing CBD
has received orphan drug status in the US, for use as a
treatment for dravet syndrome, under the brand name
Epidiolex.[6]
63.1 Clinical applications
The bud of a Cannabis sativa flower coated with trichomes
63.1.1 Antimicrobial actions
CBD absorbed transcutaneously may attenuate the in- Chronic cannabidiol administration in rats was found
creased sebum production at the root of acne, according to produce anxiogenic-like effects, indicating that
to an untested hypothesis.[7]
63.1.2 Neurological effects
A 2010 study found that strains of cannabis contain-
ing higher concentrations of cannabidiol did not produce
short-term memory impairment vs. strains with simi-
lar concentrations of THC, but lower concentrations of
CBD. The researchers attributed this attenuation of mem-
ory effects to CBD’s role as a CB1 antagonist. Transder-
mal CBD is neuroprotective in animals.[8]
Cannabidiol’s strong antioxidant properties have been
shown to play a role in the compound’s neuroprotective
and anti-ischemic effects.[9]
63.1.3 Psychotropic effect
CBD has anti-psychotic effects and may counteract the
potential psychotomimetic effects of THC on individu-
als with latent schizophrenia;[5] some reports show it to
be an alternative treatment for schizophrenia that is safe
and well-tolerated.[10] Studies have shown CBD may re-
duce schizophrenic symptoms due to its apparent ability
to stabilize disrupted or disabled NMDA receptor path-
ways in the brain, which are shared and sometimes con-
tested by norepinephrine and GABA.[10][11] Leweke et al.
performed a double blind, 4 week, explorative controlled
clinical trial to compare the effects of purified cannabid-
iol and the atypical antipsychotic amisulpride on improv-
ing the symptoms of schizophrenia in 42 patients with
acute paranoid schizophrenia. Both treatments were as-
sociated with a significant decrease of psychotic symp-
toms after 2 and 4 weeks as assessed by Brief Psychiatric
Rating Scale and Positive and Negative Syndrome Scale.
While there was no statistical difference between the
two treatment groups, cannabidiol induced significantly
fewer side effects (extrapyramidal symptoms, increase in
prolactin, weight gain) when compared to amisulpride.[12]
Studies have shown cannabidiol decreases activity of the
limbic system[13] and decreases social isolation induced
by THC.[14] Cannabidiol has also been shown to reduce
anxiety in social anxiety disorder.[15][16]
prolonged treatment with cannabidiol might incite
84
63.4. PHARMACOLOGY 85

anxiogenic effects.[17] Those results have been contested cannabionoid profile consistently around 1% cannabidiol
by,[18] and contradict [19] whose experimentation cover (CBD) with THC less than 0.1%.[32]
the same duration. Extraction can be done with olive oil, ethanol, or CO2,
Cannabidiol has demonstrated antidepressant-like effects and other nonpolar to semipolar solvents.
in animal models of depression.[20][21][22]
Hemp world production is around 30000 tonnes per year.

63.1.4 Dravet syndrome

63.4 Pharmacology
See also: Charlotte’s Web (cannabis)
63.4.1 Pharmacodynamics
Dravet syndrome is a rare form of epilepsy that is diffi-
cult to treat. Dravet syndrome, also known as Severe My- Cannabidiol has a very low affinity for CB1 and CB2
oclonic Epilepsy of Infancy (SMEI), is a rare and catas- receptors but acts as an indirect antagonist of their
trophic form of intractable epilepsy that begins in infancy.
agonists.[9] While one would assume that this would cause
Initial seizures are most often prolonged events and in the
cannabidiol to reduce the effects of THC, it may potenti-
second year of life other seizure types begin to emerge.[23]
ate THC’s effects by increasing CB1 receptor density or
While high profile and anecdotal reports of results from through another CB1 -related mechanism.[33] It is also an
high-CBD/low-THC preparations have sparked interest inverse agonist of CB2 receptors.[9][34] Recently, it was
in treatment with cannabinoids,[24] there is insufficient found to be an antagonist at the putative new cannabinoid
medical evidence to draw conclusions about their safety receptor, GPR55, a GPCR expressed in the caudate nu-
or efficacy.[24][25] cleus and putamen.[35] Cannabidiol has also been shown
to act as a 5-HT₁A receptor agonist,[36] an action which
is involved in its antidepressant,[20][37] anxiolytic,[37][38]
63.2 CBD-enhanced cannabis and neuroprotective[39][40] effects. Cannabidiol is an
allosteric modulator of μ and δ-opioid receptors.[41]
Decades ago, selective breeding by growers in US dra- Cannabidiol’s pharmacological effects have also been at-
matically lowered the CBD content of cannabis; their cus- tributed to PPAR-γ[5]
receptor agonism and intracellular
tomers preferred varietals that were more mind-altering calcium release.
due to a higher THC, lower CBD content.[26] To meet the
demands of medical cannabis patients, growers are cur-
rently developing more CBD-rich strains.[27] 63.4.2 Pharmacokinetic interactions
In November 2012, Tikun Olam, an Israeli medical
There is some preclinical evidence to suggest that
cannabis facility announced a new strain of the plant
cannabidiol may reduce THC clearance, modestly in-
which has only cannabidiol as an active ingredient, and
creasing THC’s plasma concentrations resulting in a
virtually no THC, providing some of the medicinal ben-
greater amount of THC available to receptors, increas-
efits of cannabis without the euphoria.[28][29] The re-
ing the effect of THC in a dose-dependent manner.[42][43]
searchers said the cannabis plant, enriched with CBD,
Despite this the available evidence in humans suggests no
“can be used for treating diseases like rheumatoid arthri-
significant effect of CBD on THC plasma levels.[44]
tis, colitis, liver inflammation, heart disease and dia-
betes”. Research on CBD enhanced cannabis began in
2009, resulting in Avidekel, a cannabis strain that con-
tains 15.8% CBD and less than 1% THC. Raphael Me- 63.4.3 Pharmaceutical preparations
choulam, a cannabinoid researcher, said "...Avidekel is
thought to be the first CBD-enriched cannabis plant with Nabiximols (USAN, trade name Sativex) is an
no THC to have been developed in Israel”.[30] In February aerosolized mist for oral administration containing
2014, a patent application was filed for a cannabis plant a near 1:1 ratio of CBD and THC. The drug was
named 'avidekel'.[31] approved by Canadian authorities in 2005 to alleviate
pain associated with multiple sclerosis.[45][46][47]

63.3 Industrial hemp

63.5 Isomerism
Several industrial hemp varieties can be legally culti-
vated in western Europe. They might seem to contain Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of
very small portion of cannabinoid, which is true in one delta-3-cannabidiol and the derived rigid analogs, Ari-
sense. Nevertheless a variety such as “Fedora 17” has a zona University 1987.
86 CHAPTER 63. CANNABIDIOL

hemp oil high in cannabidiol, are legal in the United States

for this reason.
Some cannabidiol oil is derived from marijuana and is
therefore high in THC.[61] This type of cannabidiol oil
would be considered a Schedule I as a result. However,
cannabidiol derived from industrial hemp is legal and un-
scheduled itself.[61] In other words, cannabidiol’s legal
status depends on where it is derived from, as cannabidiol
itself is not scheduled.[57]

Cannabidiol numbering
63.8 US patent
See also: Tetrahydrocannabinol#Isomerism, Abnormal
cannabidiol. In October 2003, U.S. patent #6630507 entitled
“Cannabinoids as antioxidants and neuroprotectants” was
assigned to “The United States Of America As Repre-
sented By The Department Of Health And Human Ser-
63.6 Chemistry vices.” The patent was filed in April 1999 and listed as the
inventors: Aidan J. Hampson, Julius Axelrod, and Maur-
Cannabidiol is insoluble in water but soluble in organic izio Grimaldi, who all held positions at the National Insti-
solvents, such as pentane. At room temperature it is a tute of Mental Health (NIMH) in Bethesda, MD, which is
colorless crystalline solid.[48] In strongly basic medium part of the National Institutes of Health (NIH), an agency
and the presence of air it is oxidized to a quinone.[49] Un- of the United States Department of Health and Human
der acidic conditions it cyclizes to THC.[50] The synthesis Services (HHS). The patent mentions cannabidiol’s abil-
of cannabidiol has been accomplished by several research ity as an antiepileptic, to lower intraocular pressure in the
groups.[51][52][53] treatment of glaucoma, lack of toxicity or serious side ef-
fects in large acute doses, its neuroprotectant properties,
its ability to prevent neurotoxicity mediated by NMDA,
63.6.1 Biosynthesis AMPA, or kainate receptors; its ability to attenuate glu-
tamate toxicity, its ability to protect against cellular dam-
Cannabis produces CBD-carboxylic acid through the age, its ability to protect brains from ischemic damage,
same metabolic pathway as THC, until the last step, its anxiolytic effect, and its superior antioxidant activity
where CBDA synthase performs catalysis instead of which can be used in the prophylaxis and treatment of
THCA synthase.[54] oxidation associated diseases.[62]
On November 17, 2011, the Federal Register published
that the National Institutes of Health of the United States
63.7 Legal status Department of Health and Human Services was “contem-
plating the grant of an exclusive patent license to practice
the invention embodied in U.S. Patent 6,630,507” to the
Cannabidiol is not scheduled by the Convention on Psy- company KannaLife based in New York, for the devel-
chotropic Substances. opment and sale of cannabinoid and cannabidiol based
Cannabidiol is a Schedule II drug in Canada.[55] therapeutics for the treatment of hepatic encephalopathy
Cannabidiol’s legal status in the United States: in humans.[63][64][65]

While the DEA Drug Schedule classifies THC (Tetrahy- On July 9, 2012 — KannaLife Sciences, Inc. (“Kan-
drocannabinols) and marijuana as Schedule I, cannabidiol naLife”) Signed an Exclusive License Agreement With
is not found on the list.[56] Other synthetic cannabinoids National Institutes of Health – Office of Technology
such as JWH-019,073,081,122,200,203,250,398 are also Transfer (“NIH-OTT”) aka the United States Federal
listed in Schedule I, but cannabidiol is absent.[56] Government for the Commercialization of U.S. Patent
6,630,507, “Cannabinoids as Antioxidants and Neuro-
Marijuana is defined by 21 U.S.C. §802(16), which is part protectants” (the “’507 Patent”).
of the Controlled Substances Act. The mature stalks and
seeds of the Cannabis sativa L. plant, as well as prod- http://www.kannalife.com/
ucts derived from the mature stalks and seeds are ex- kannalife-sciences-inc-signs-exclusive-license-agreement-with-national-in
plicitly exempt from classification as marijuana.[57][58][59] On March 31, 2014 KannaLife Sciences, Inc.
Under this exception, what are known as industrial hemp- (“KannaLife”) and Kannaway LLC (“Kannaway”, a
finished products are legally imported into the United multi-level marketing program similar to Amway),
States each year.[60] Hemp finished products, including have entered into a five year sales, marketing
63.9. REFERENCES
and product development agreement (the “Agree- [10] Zuardi AW, Crippa JA, Hallak JE, Moreira FA,
ment”). - See more at: http://globenewswire.com/ Guimarães FS (April 2006). “Cannabidiol, a Cannabis
news-release/2014/03/31/622898/10074649/en/ sativa constituent, as an antipsychotic drug”. Braz. J. Med.
Biol. Res. (Review) 39 (4): 421–9. doi:10.1590/S0100-
KannaLife-Sciences-Inc-and-Kannaway-LLC-Sign-Long-Term-Sales-Marketing-and-Product-Development-Agreement.
html#sthash.pnvD6OXs.dpuf 879X2006000400001. PMID 16612464.
KannaLife-Sciences-Inc-and-Kannaway-LLC-
Sign-Long-Term-Sales-Marketing-and-Product-
Development-Agreement
63.9 References
[1] Mechoulam R, Parker LA, Gallily R (November 2002).
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[19] Réus, Gislaine Z. (2011). “Administration of cannabid-
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[20] Zanelati, T; Biojone, C; Moreira, F; Guimarães, F; Joca, S
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[21] Réus, GZ; Stringari, RB; Ribeiro, KF; Luft, T; Abelaira,
HM; Fries, GR; Aguiar, BW; Kapczinski, F; Hallak, JE;
Zuardi, AW; Crippa JA; Quevedo, J (October 2011).
“Administration of cannabidiol and imipramine induces
antidepressant-like effects in the forced swimming test
and increases brain-derived neurotrophic factor levels in
the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241–
248. doi:10.1111/j.1601-5215.2011.00579.x.
[22] El-Alfy, AT; Ivey, K; Robinson, K; Ahmed, S; Radwan,
M; Slade, D; Khan, I; ElSohly, M; Ross, S (June 2010).
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[23] http://www.dravetfoundation.org/dravet-syndrome/
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[26] Romney, Lee (13 September 2012). “On the frontier of
medical pot to treat boy’s epilepsy”. Los Angeles Times.
[27] Good, Alastair (26 October 2010). “Growing marijuana
that won't get you high”. The Daily Telegraph (London).
[28] Sidner, Sara (8 November 2012). “Medical marijuana
without the high” (video). CNN. “An Israeli company has
cultivated a new type of medical marijuana.”
[29] Solon, Olivia (5 July 2012). “Medical Marijuana Without
the High”. Wired.com
[30] Lubell, Maayan (3 July 2012). “What a drag, Israeli firm
grows 'highless’ marijuana”. Reuters. Retrieved 31 Jan
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[31] Cohen, Ytzchak (11 September 2014). “Cannabis plant
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[32] Fournier, G.; Beherec, O.; Bertucelli, S. (2003). “Intérêt
du rapport Δ−9-THC / CBD dans le contrôle des cultures
de chanvre industriel”. Annales de Toxicologie Analytique
15 (4): 250. doi:10.1051/ata/2003003.
[33] Hayakawa, K.; Mishima, K.; Hazekawa, M.; Sano, K.;
Irie, K.; Orito, K.; Egawa, T.; Kitamura, Y.; Uchida,
N.; Nishimura, R.; Egashira, N.; Iwasaki, K.; Fuji-
wara, M. (2008). “Cannabidiol potentiates pharmacolog-
ical effects of Δ9-tetrahydrocannabinol via CB1 receptor-
dependent mechanism”. Brain Research 1188: 157–164.
doi:10.1016/j.brainres.2007.09.090. PMID 18021759.
[34] Pertwee, R. G. (2008). “The diverse CB1 and
CB2 receptor pharmacology of three plant cannabi-
noids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-
tetrahydrocannabivarin”. British Journal of Pharmacol-
ogy 153 (2): 199–215. doi:10.1038/sj.bjp.0707442.
PMC 2219532. PMID 17828291.
[35] Ryberg E, Larsson N, Sjögren S, et al. (2007). “The
orphan receptor GPR55 is a novel cannabinoid recep-
tor”. British Journal of Pharmacology 152 (7): 1092–
101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID
17876302.
[36] Russo EB, Burnett A, Hall B, Parker KK (August
2005). “Agonistic properties of cannabidiol at 5-HT1a
receptors”. Neurochemical Research 30 (8): 1037–43.
doi:10.1007/s11064-005-6978-1. PMID 16258853.
[37] Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM,
Guimarães FS (January 2009). “5-HT1A receptors are
involved in the cannabidiol-induced attenuation of be-
havioural and cardiovascular responses to acute restraint
stress in rats”. British Journal of Pharmacology 156 (1):
181–8. doi:10.1111/j.1476-5381.2008.00046.x. PMC
2697769. PMID 19133999.
[38] Campos AC, Guimarães FS (August 2008). “Involve-
ment of 5HT1A receptors in the anxiolytic-like effects
of cannabidiol injected into the dorsolateral periaqueduc-
tal gray of rats”. Psychopharmacology 199 (2): 223–30.
doi:10.1007/s00213-008-1168-x. PMID 18446323.
[39] Mishima K, Hayakawa K, Abe K, et al. (May 2005).
“Cannabidiol prevents cerebral infarction via a seroton-
ergic 5-hydroxytryptamine1A receptor-dependent mech-
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1077–82. doi:10.1161/01.STR.0000163083.59201.34.
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[40] Hayakawa K, Mishima K, Nozako M, et al. (March 2007).
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the development of tolerance”. Neuropharmacology 52
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[41] Kathmann, Markus; Flau, Karsten; Redmer, Agnes; Trän-
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ceptors”. Naunyn-Schmiedeberg’s Archives of Pharmacol-
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PMID 16489449.
63.10. EXTERNAL LINKS 89

[42] Bornheim, LM; Kim, KY; Li, J; Perotti, BY; Benet, LZ
(August 1995). “Effect of cannabidiol pretreatment on
the kinetics of tetrahydrocannabinol metabolites in mouse
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[43] Klein, C; Karanges, E; Spiro, A; Wong, A; Spencer, J;
Huynh, T; Gunasekaran, N; Karl, T; Long, LE; Huang,
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2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol
(THC) behavioural effects and alters THC pharmacoki-
netics during acute and chronic treatment in adoles-
cent rats”. Psychopharmacology 218 (2): 443–457.
doi:10.1007/s00213-011-2342-0. PMID 21667074.
[55] Controlled Drugs and Substances Act - Schedule II
[56] CSA Schedule, List of drugs by schedule.
[57] Definition of marijuana under the Controlled Substances
Act.
[58] Title 21 US Code Controlled Substances Act, text of the
CSA.
[59] Hemp Industries Assn., v. Drug Enforcement Admin., 9th
Circuit Court of Appeals case involving industrial hemp.
[60] Hemp, Many definitions of common terms associated with
hemp, including the history of hemp use.

[44] Hunt, CA; Jones, RT; Herning, RI; Bachman, J (June
1981). “Evidence that Cannabidiol Does Not Signifi-
cantly Alter the Pharmacokinetics of Tetrahydrocannabi-
nol in Man”. Journal of Pharmacokinetics and Biophar-
maceutics 9 (3): 245–260. doi:10.1007/BF01059266.
PMID 6270295.
[45] United States Adopted Names Council: Statement on a
nonproprietary name
[46] “Fact Sheet — Sativex”. Health Canada. Retrieved 16
May 2013.
[47] GWPharma- Welcome
[48] Jones PG, Falvello L, Kennard O, Sheldrick GM Me-
choulam R (1977). “Cannabidiol”. Acta Cryst. B33 (10):
3211–3214. doi:10.1107/S0567740877010577.
[49] Mechoulam R, Ben-Zvi Z (1968). “Hashish—XIII On the
nature of the beam test”. Tetrahedron 24 (16): 5615–
5624. doi:10.1016/0040-4020(68)88159-1. PMID
5732891.
[61] Cannabidiol: The side of marijuana you don't know
[62] US patent 6630507, Hampson, Aidan J.; Axelrod, Julius;
Grimaldi, Maurizio, “Cannabinoids as antioxidants and
neuroprotectants”, issued 2003-10-07
[63] “Federal Register | Prospective Grant of Exclusive Li-
cense: Development of Cannabinoid(s) and Cannabid-
iol(s) Based Therapeutics To Treat Hepatic Encephalopa-
thy in Humans”. Federalregister.gov. November 17,
2011. Retrieved August 13, 2013.
[64] “KannaLife Sciences, Inc. Signs Exclusive License
Agreement With National Institutes Of Health Office Of
Technology Transfer (NIH-OTT)". thestreet.com. Re-
trieved 2012-07-09.
[65] “KannaLife in R&D Collaboration for Cannabinoid-
Based Drugs”. Genengnews.com. Retrieved 2013-04-04.
63.10 External links

[50] Gaoni Y, Mechoulam R (1966). “Hashish—VII The • Project CBD Non-profit educational service dedi-
isomerization of cannabidiol to tetrahydrocannabinols”. cated to promoting and publicizing research into the
Tetrahedron 22 (4): 1481–1488. doi:10.1016/S0040- medical utility of cannabidiol.
4020(01)99446-3.

[51] Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Es-

chenmoser A (1967). “Synthese und Chiralität des (-
)-Cannabidiols”. Helv. Chim. Acta 50 (2): 719–723.
doi:10.1002/hlca.19670500235. PMID 5587099.

[52] Gaoni Y, Mechoulam R (1985). “Boron trifluoride ether-

ate on alumuna — a modified Lewis acid reagent. An im-
proved synthesis of cannabidiol”. Tetrahedron Letters 26
(8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6.

[53] Kobayashi Y, Takeuchi A, Wang YG (2006). “Syn-

thesis of cannabidiols via alkenylation of cyclohexenyl
monoacetate”. Org. Lett. 8 (13): 2699–2702.
doi:10.1021/ol060692h. PMID 16774235.

[54] Marks, M.; Tian, L.; Wenger, J.; Omburo, S.; Soto-
Fuentes, W.; He, J.; Gang, D.; Weiblen, G.; Dixon,
R. (2009). “Identification of candidate genes affect-
ing Δ9-tetrahydrocannabinol biosynthesis in Cannabis
sativa”. Journal of Experimental Botany 60 (13): 3715–
3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID
19581347.
Chapter 64

Cannabidivarin

Cannabidivarin (CBDV) is a non-psychoactive

cannabinoid found in Cannabis. It is a homolog of
cannabidiol (CBD), with the side-chain shortened by
two methylene bridges (CH2 units). Plants with rela-
tively high levels of CBDV have been reported in feral
populations of C. indica ( = C. sativa ssp. indica var.
kafiristanica) from northwest India, and in hashish from
Nepal.[1][2]
Similarly to CBD, it has 7 double bond isomers and
30 stereoisomers (see: Cannabidiol#Double bond iso-
mers and their stereoisomers). It is not scheduled by
Convention on Psychotropic Substances.

64.1 See also

• Cannabinoids

• Cannabis
• Medical marijuana

64.2 References
[1] Turner, C.E., P. C. Cheng, G.S. Lewis, M.H.Russell and
G.K. Sharma. 1979. Constituents of Cannabis sativa XV:
Botanical and chemical profile of Indian variants. Planta
medica 37(3): 217-225.

[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemo-

taxonomic analysis of cannabinoid variation in Cannabis
(Cannabaceae). American Journal of Botany 91(6): 966-
975.

64.3 External links

• Erowid Compounds found in Cannabis sativa

90
Chapter 65

Cannabigerol

Cannabigerol (CBG) is a non-psychoactive cannabinoid [4] http://www.ncbi.nlm.nih.gov/pubmed/23415610

found in the Cannabis genus of plants. Cannabigerol is
found in higher concentrations in hemp rather than in va-
rieties of Cannabis cultivated for high THC content and
their corresponding psychoactive properties.
Cannabigerol has been found to act as a high affinity
α2 -adrenergic receptor agonist, moderate affinity 5-
HT₁A receptor antagonist, and low affinity CB1 recep-
tor antagonist.[1] It also binds to the CB2 receptor, but
whether it acts as an agonist or antagonist at this site is
unknown.[1]
Cannabigerol has been shown to relieve interocular pres-
sure, which may be of benefit in the treatment of
glaucoma.[2][3] It can also be used to treat inflammatory
bowel disease. [4]
It has two E/Z isomers. It is not scheduled by Convention
on Psychotropic Substances.

65.1 See also

• Cannabinoid
• Medical cannabis

65.2 References
[1] Cascio MG, Gauson LA, Stevenson LA, Ross RA, Per-
twee R (December 2009). “Evidence that the plant
cannabinoid cannabigerol is a highly potent alpha(2)-
adrenoceptor agonist and moderately potent 5HT recep-
tor antagonist”. British Journal of Pharmacology 159
(1): 129–141. doi:10.1111/j.1476-5381.2009.00515.x.
PMC 2823359. PMID 20002104.
[2] Colasanti, B. (1990). “A comparison of the ocular
and central effects of delta 9-tetrahydrocannabinol and
cannabigerol”. Journal of ocular pharmacology 6 (4):
259–269. doi:10.1089/jop.1990.6.259. PMID 1965836.
[3] Colasanti, B.; Craig, C.; Allara, R. (1984). “Intraocu-
lar pressure, ocular toxicity and neurotoxicity after ad-
ministration of cannabinol or cannabigerol”. Experimen-
tal eye research 39 (3): 251–259. doi:10.1016/0014-
4835(84)90013-7. PMID 6499952.

91
Chapter 66

Cannabinoidergic

Cannabinoidergic, or cannabinergic, means related to

the endocannabinoid neurotransmitters. As with terms
such as dopaminergic and serotonergic, related proteins
and cellular components involved endocannabinoid sig-
naling, such as the cannabinoid (CB1 ) receptor, as well
as exogenous compounds, such as phytocannabinoids
or other cannabinoids which modulate the activity of
endocannabinoid system, can be described as cannabi-
noidergic.[1]

66.1 See also

• Adenosinergic

• Cholinergic
• GABAergic

• Glutamatergic
• Glycinergic

• Histaminergic
• Monoaminergic

• Opioidergic

66.2 References
[1] Palmer, SL; Thakur GA; Makriyannis A (December
31, 2002). “Cannabinergic ligands”. Chemistry and
physics of lipids 121 (1-2): 3–19. doi:10.1016/s0009-
3084(02)00143-3. PMID 12505686.

92
Chapter 67

Cannabinol

Not to be confused with Cannabidiol.
Cannabinol (CBN) is a weak psychoactive cannabinoid
found only in trace amounts in Cannabis sativa
and Cannabis indica.[5] It is mostly a metabolite of
tetrahydrocannabinol (THC).[6] CBN acts as a weak
agonist of CB1 receptors but has a higher affinity to
CB2 receptors, with lower affinities in comparison to
THC.[7][8] Because of its somewhat selective CB2 ago-
nism, it is used experimentally as an immunosuppressant.
In contrast to tetrahydrocannabinol, it has no double
bond isomers nor stereoisomers. It is not scheduled by
Convention on Psychotropic Substances.
[8] Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq
MC (1998). “Complex pharmacology of natural cannabi-
noids: evidence for partial agonist activity of delta9-
tetrahydrocannabinol and antagonist activity of cannabid-
iol on rat brain cannabinoid receptors”. Life Sciences
63 (1): PL1–6. doi:10.1016/S0024-3205(98)00238-0.
PMID 9667767.
67.3 External links
• Erowid Compounds found in Cannabis sativa

67.1 See also

• Cannabinoids

67.2 References
[1] Cannabinol in the ChemIDplus database.

[2] David R. Lide (2012). CRC Handbook of Chemistry and

Physics. CRC Press. pp. 3–90. ISBN 1-43988049-2.

[3] Sigma-Aldrich Co., Cannabinol solution, 1.0 mg/mL in

methanol, analytical standard, for drug analysis.

[4] Biotrend: Cannabinol (PDF: 21 kB)

[5] Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty

RE (1975). “Effects of delta9-tetrahydrocannabinol and
cannabinol in man”. Pharmacology 13 (6): 502–12.
doi:10.1159/000136944. PMID 1221432.

[6] McCallum ND, Yagen B, Levy S, Mechoulam R (May

1975). “Cannabinol: a rapidly formed metabolite of delta-
1- and delta-6-tetrahydrocannabinol”. Experientia 31 (5):
520–1. doi:10.1007/bf01932433. PMID 1140243.

[7] Mahadevan A, Siegel C, Martin BR, Abood ME, Belet-

skaya I, Razdan RK (October 2000). “Novel cannabi-
nol probes for CB1 and CB2 cannabinoid receptors”.
Journal of Medicinal Chemistry 43 (20): 3778–85.
doi:10.1021/jm0001572. PMID 11020293.

93
Chapter 68

Cannabivarin

Cannabivarin, also known as cannabivarol or CBV, is

a non-psychoactive cannabinoid found in minor amounts
in the hemp plant Cannabis sativa. It is an analog of
cannabinol (CBN) with the side chain shortened by two
methylene bridges (-CH2 -). CBV is an oxidation product
of tetrahydrocannabivarin (THCV, THV).[1]
It has no double bond isomers nor stereoisomers. It is not
scheduled by Convention on Psychotropic Substances.

68.1 References
[1] Keith Bailey, Denise Gagné (October 1975). “Distinction
of synthetic cannabidiol, cannabichromene, and cannabi-
varin by GLC using on-column methylation”. Jour-
nal of Pharmaceutical Sciences 64 (10): 1719–1720.
doi:10.1002/jps.2600641033.

68.2 See also

• Cannabinoids
• Cannabis

• Medical marijuana

68.3 External links

• Erowid Compounds found in Cannabis sativa

94
Chapter 69
Caryophyllene
Caryophyllene /ˌkæri.ɵfɪˈliːn/, or (−)-β-caryophyllene, is
a natural bicyclic sesquiterpene that is a constituent of
many essential oils, especially clove oil, the oil from the
stems and flowers of Syzygium aromaticum (cloves),[1]
the essential oil of hemp Cannabis sativa,[2] rosemary
Rosmarinus oficinalis,[3] and hops.[4] It is usually found as
a mixture with isocaryophyllene (the cis double bond iso-
mer) and α-humulene (obsolete name: α-caryophyllene),
a ring-opened isomer. Caryophyllene is notable for hav-
ing a cyclobutane ring, a rarity in nature.
Caryophyllene is one of the chemical compounds that
contributes to the spiciness of black pepper. In a
study conducted by Jürg Gertsch et al. from the Swiss
Federal Institute of Technology (ETH Zurich), beta-
caryophyllene was shown to be selective agonist of
cannabinoid receptor type-2 (CB2 ) and to exert signifi-
cant cannabimimetic antiinflammatory effects in mice.[2]
Antinociceptive,[5] neuroprotective,[6] anxiolytic and an-
tidepressant [7] and anti-alcoholism [8] activity have been
uncovered. Because the widespread plant natural product
beta-caryophyllene is an FDA approved food additive and
ingested daily with food it is the first dietary cannabinoid.
Whether this compound is able to modulate inflammatory
processes in humans via the endocannabinoid system is
yet unknown. Beta-caryophyllene does not bind to the
centrally expressed cannabinoid receptor type-1 (CB1 )
and therefore does not exert psychomimetic effects.
The first total synthesis of caryophyllene in 1964 by E.J.
Corey was considered one of the classic demonstrations
of the possibilities of synthetic organic chemistry at the
time.[9]
Caryophyllene oxide is the component responsible for
cannabis identification by drug-sniffing dogs[10][11]
69.1 Natural sources
The approximate quantity of caryophyllene in the
essential oil of each source is given in square brackets
([ ]):
• Cannabis, hemp, marijuana (Cannabis sativa)[2]
[3.8–37.5% of cannabis flower essential oil][12]
95
• Black Caraway (Carum nigrum) [7.8%][13]
• Cloves (Syzygium aromaticum)[1] [1.7%−19,5% of
clove bud essential oil][14][15]
• Hops (Humulus lupulus)[16] [5.1–14.5%][17]
• Basil (Ocimum spp.)[18] [5.3–10.5% O. gratissimum;
4.0–19.8% O. micranthum][19]
• Oregano (Origanum vulgare)[20]
[4.9%−15.7][21][22]
• Black pepper (Piper nigrum) [7.29%][23]
• West African Pepper (Piper guineense) [57.59%
(black); 51.75% (white)][23]
• Lavender (Lavandula angustifolia) [4.62% of
lavender oil][24]
• Rosemary (Rosmarinus officinalis)[3] [0.1–8.3%][25]
• True cinnamon (Cinnamomum zeylanicum) [6.9–
11.1%][26]
• Malabathrum (Cinnamomum tamala) [25.3%][27]
• Cananga odorata [3.1%−10.7%][28]
• Copaiba oil (Copaifera spp.) [29][30][31][32]
69.2 Compendial status
• Food Chemical Codex [33], [34]
69.3 Notes and references
[1] Ghelardini C, Galeotti N, Di Cesare Mannelli L, Maz-
zanti G, Bartolini A (2001). “Local anaesthetic ac-
tivity of beta-caryophyllene”. Farmaco 56 (5–7):
387–9. doi:10.1016/S0014-827X(01)01092-8. PMID
11482764.
96
[2] Gertsch J, Leonti M, Raduner S, et al. (July 2008).
“Beta-caryophyllene is a dietary cannabinoid”. Pro-
ceedings of the National Academy of Sciences of
the United States of America 105 (26): 9099–104.
doi:10.1073/pnas.0803601105. PMC 2449371. PMID
18574142.
[3] Ormeño E, Baldy V, Ballini C, Fernandez C (Septem-
ber 2008). “Production and diversity of volatile ter-
penes from plants on calcareous and siliceous soils: ef-
fect of soil nutrients”. J. Chem. Ecol. 34 (9): 1219–29.
doi:10.1007/s10886-008-9515-2. PMID 18670820.
[4] Glenn Tinseth, “Hop Aroma and Flavor”, Jan-
uary/February 1993, Brewing Techniques.
<http://realbeer.com/hops/aroma.html> Accessed
July 21, 2010.
[5] Katsuyama S., Mizoguchi H., Kuwahata H., et al.
(2013). “Involvement of peripheral cannabinoid and
opioid receptors in β-caryophyllene-induced antinocicep-
tion”. European journal of pain 17 (5): 664–675.
doi:10.1002/j.1532-2149.2012.00242.x.
[6] Guimarães-Santos, Adriano (2012). “Copaiba Oil-
Resin Treatment Is Neuroprotective and Reduces Neu-
trophil Recruitment and Microglia Activation after
Motor Cortex Excitotoxic Injury”. Evidence-Based
Complementary and Alternative Medicine 2012: 1–9.
doi:10.1155/2012/918174. PMC 3291111.
[7] Bahi Amine, Al Mansouri Shamma, Al Memari Elyazia,
Al Ameri Mouza, Nurulain Syed M., Ojha Shreesh.
(2014). "β-Caryophyllene, a CB2 receptor agonist pro-
duces multiple behavioral changes relevant to anxiety and
depression in mice.”. Physiology & behavior 135: 119–
124. doi:10.1016/j.physbeh.2014.06.003.
[8] Al Mansouri Shamma, Ojha Shreesh, Al Maamari
Elyazia, Al Ameri Mouza, Nurulain Syed M., Bahi
Amine. (2014). “The cannabinoid receptor 2 ag-
onist, β-caryophyllene, reduced voluntary alcohol in-
take and attenuated ethanol-induced place preference
and sensitivity in mice.”. Pharmacology, biochem-
istry, and behavior. 2014;124C:260-268 124: 260–268.
doi:10.1016/j.pbb.2014.06.025.
[9] Corey EJ, Mitra RB, Uda H (1964). “Total Synthe-
sis of d,l-Caryophyllene and d,l-Isocaryophyllene”. Jour-
nal of the American Chemical Society 86 (3): 485–492.
doi:10.1021/ja01057a040.
[10] Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects Ethan
B Russo. Br J Pharmacol. 2011 August; 163(7):
1344–1364.
[11] Stahl E, Kunde R. Die Leitsubstanzen der Haschisch-
Suchhunde. Kriminalistik: Z Gesamte Kriminal Wiss
Prax. 1973;27:385–389.
[12] Mediavilla, Vito; Simon Steinemann. “Essential oil of
Cannabis sativa L. strains”. International Hemp Associa-
tion. Retrieved 11 July 2008.
CHAPTER 69. CARYOPHYLLENE
[13] Singh G, Marimuthu P, de Heluani CS, Catalan CA (Jan-
uary 2006). “Antioxidant and biocidal activities of Carum
nigrum (seed) essential oil, oleoresin, and their selected
components”. J. Agric. Food Chem. 54 (1): 174–81.
doi:10.1021/jf0518610. PMID 16390196.
[14] Alma, M. Hakkı; Ertaş, Murat; Nitz, Siegfrie; Koll-
mannsberger, Hubert (May 2007). Lucia, Lucian A.;
Hubbe, Martin A., eds. “Chemical composition and con-
tent of essential oil from the bud of cultivated Turk-
ish clove” (PDF). BioResources (Raleigh, North Carolina,
USA: North Carolina State University) 2 (2): 265–269.
ISSN 1930-2126. Retrieved September 6, 2010. “The re-
sults showed that the essential oils mainly contained about
[...] 3.56% β-Caryophyllene”
[15] Clove Essential Oil
[16] Wang G, Tian L, Aziz N, et al. (November
2008). “Terpene Biosynthesis in Glandular Tri-
chomes of Hop”. Plant Physiol. 148 (3): 1254–66.
doi:10.1104/pp.108.125187. PMC 2577278. PMID
18775972.
[17] Bernotienë, Genovaitë; Nivinskienë, Ona; Butkienë, Rita;
Mockutë, Danutë (2004). “Chemical composition of es-
sential oils of hops (Humulus lupulus L.) growing wild in
Auk taitija”. Chemija. 2 (Vilnius, Lithuania: Lithuanian
Academy of Sciences) 4: 31–36. ISSN 0235-7216. Re-
trieved September 6, 2010.
[18] Zheljazkov VD, Cantrell CL, Tekwani B, Khan SI (Jan-
uary 2008). “Content, composition, and bioactivity of
the essential oils of three basil genotypes as a function
of harvesting”. J. Agric. Food Chem. 56 (2): 380–5.
doi:10.1021/jf0725629. PMID 18095647.
[19] Silva, Maria Goretti de Vasconcelos; Matos, Francisco
José de Abreu; Lopes, Paulo Roberto Oliveira; Silva,
Fábio Oliveira; Holanda, Márcio Tavares (August 2,
2004). Cragg, Gordon M.; Bolzani, Vanderlan S.; Rao,
G. S. R. Subba, eds. “Composition of essential oils
from three Ocimum species obtained by steam and mi-
crowave distillation and supercritical CO2 extraction”
(PDF). Arkivoc (ARKAT USA, Inc.) 2004 (vi): 66–71.
doi:10.3998/ark.5550190.0005.609. ISSN 1424-6376.
Retrieved September 6, 2010.
[20] Harvala C, Menounos P, Argyriadou N (February 1987).
“Essential Oil from Origanum dictamnus”. Planta Med.
53 (1): 107–9. doi:10.1055/s-2006-962640. PMID
17268981.
[21] Calvo-Irabien, L. M.; Yam-Puc, J. A.; Dzib, G.;
Escalante-Erosa, F.; Peña-Rodriguez, L. M. (July
2009). “Effect of Postharvest Drying on the Compo-
sition of Mexican Oregano (Lippia graveolens) Essen-
tial Oil”. Journal of Herbs, Spices & Medicinal Plants
(London, UK: Taylor & Francis) 15 (3): 281–287.
doi:10.1080/10496470903379001. ISSN 1540-3580.
[22] The essential oil of Origanum vulgare L. ssp. vulgare
growing wild in vilnius district (Lithuania) Phytochem-
istry. 2001 May;57(1):65-9.
69.3. NOTES AND REFERENCES 97

[23] Jirovetz L, Buchbauer G, Ngassoum MB, Geissler M

(November 2002). “Aroma compound analysis of Piper
nigrum and Piper guineense essential oils from Cameroon
using solid-phase microextraction-gas chromatography,
solid-phase microextraction-gas chromatography-mass
spectrometry and olfactometry”. J Chromatogr A 976
(1–2): 265–75. doi:10.1016/S0021-9673(02)00376-X.
PMID 12462618.

[24] A. Prashar, I. C. Locke, C. S. Evans (2004). Cytotoxicity

of lavender oil and its major components to human skin
cells. Cell Proliferation 37 (3), 221–229.

[25] Jamshidi, R.; Afzali, Z.; Afzali, D. (February 2009).

“Chemical Composition of Hydrodistillation Essential Oil
of Rosemary in Different Origins in Iran and Comparison
with Other Countries” (PDF). American-Eurasian Jour-
nal of Agricultural & Environmental Sciences (Pakistan:
IDOSI Publications) 5 (1): 78–81. ISSN 1990-4053. Re-
trieved September 6, 2010.

[26] Kaul PN, Bhattacharya AK, Rao BRR, et al. (2003).

“Volatile constituents of essential oils isolated from
different parts of cinnamon (Cinnamomum zeylanicum
Blume)". Journal of the Science of Food and Agriculture
83 (1): 53–55. doi:10.1002/jsfa.1277.

[27] Ahmed A, Choudhary MI, Farooq A, et al. (2000).

“Essential oil constituents of the spice Cinnamomum
tamala (Ham.) Nees & Eberm.”. Flavour and Fra-
grance Journal 15 (6): 388–390. doi:10.1002/1099-
1026(200011/12)15:6<388::AID-FFJ928>3.0.CO;2-F.

[28] Ylang Ylang Essential Oil

[29] . PMID 22466849. Missing or empty |title= (help)

[30] . PMID 21095089. Missing or empty |title= (help)

[31] http://staff.najah.edu/sites/default/files/Within_plant_
distribution_and_emission_of_sesquiterpenes_from_
Copaifera_officinalis.pdf

[32] http://www.rain-tree.com/copaiba.htm

[33] The United States Pharmacopeial Convention. “Revisions

to FCC, First Supplement”. Retrieved 29 June 2009.

[34] Therapeutic Goods Administration. “Chemical sub-

stances”. Retrieved 29 June 2009.
Chapter 70

CB-13

CB-13 (SAB-378)[1] is a cannabinoid drug, which acts

as a potent agonist at both the CB1 and CB2 receptors,
but has poor blood–brain barrier penetration, and so pro-
duces only peripheral effects at low doses, with symp-
toms of central effects such as catalepsy only appearing
at much higher dose ranges. It has antihyperalgesic prop-
erties in animal studies,[2] and has progressed to prelimi-
nary human trials.[3]

70.1 See also

• AM-6545

• AZ-11713908

70.2 References
[1] Cluny, N. L.; Keenan, C. M.; Duncan, M.; Fox, A.;
Lutz, B.; Sharkey, K. A. (2010). “Naphthalen-1-yl-
(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Pe-
ripherally Restricted Cannabinoid CB1/CB2 Receptor
Agonist, Inhibits Gastrointestinal Motility but Has No Ef-
fect on Experimental Colitis in Mice”. Journal of Phar-
macology and Experimental Therapeutics 334 (3): 973.
doi:10.1124/jpet.110.169946. PMID 20571060.

[2] Dziadulewicz, E. K.; Bevan, S. J.; Brain, C. T.; Coote,

P. R.; Culshaw, A. J.; Davis, A. J.; Edwards, L. J.;
Fisher, A. J.; Fox, A. J.; Gentry, C.; Groarke, A.;
Hart, T. W.; Huber, W.; James, I. F.; Kesingland, A.;
La Vecchia, L.; Loong, Y.; Lyothier, I.; McNair, K.;
O'Farrell, C.; Peacock, M.; Portmann, R.; Schopfer, U.;
Yaqoob, M.; Zadrobilek, J. (2007). “Naphthalen-1-yl-(4-
pentyloxynaphthalen-1-yl)methanone: A Potent, Orally
Bioavailable Human CB1/CB2Dual Agonist with Antihy-
peralgesic Properties and Restricted Central Nervous Sys-
tem Penetration”. Journal of Medicinal Chemistry 50 (16):
3851–3856. doi:10.1021/jm070317a. PMID 17630726.

[3] Gardin A, Kucher K, Kiese B, Appel-Dingemanse S

(April 2009). “Cannabinoid receptor agonist 13, a
novel cannabinoid agonist: first in human pharma-
cokinetics and safety”. Drug Metabolism and Disposi-
tion: the Biological Fate of Chemicals 37 (4): 827–33.
doi:10.1124/dmd.108.024000. PMID 19144772.

98
Chapter 71

CBS-0550

CBS-0550 is a drug developed by Taisho Pharmaceu-

tical, which acts as a potent and selective cannabinoid
CB2 receptor agonist, with 1400x selectivity for CB2 over
the related CB1 receptor. Unlike most cannabinoid ago-
nists, CBS-0550 has good solubility in water, and in an-
imal studies it was found to produce analgesic and anti-
hyperalgesic effects.[1]

71.1 See also

• A-836,339
• SER-601

71.2 References
[1] Ohta H, et al. Imine derivatives as new potent and selec-
tive CB2 cannabinoid receptor agonists with an analgesic
action. Bioorganic and Medicinal Chemistry. 2008 Feb
1;16(3):1111-24. PMID 18006322

99
Chapter 72

CP 47,497

CP 47,497 or (C7)-CP 47,497 is a cannabinoid receptor 72.2 Legal status

agonist drug, developed by Pfizer in the 1980s.[1] It has
analgesic effects and is used in scientific research. It is a
potent CB1 agonist with a K of 2.1nM.[2][3][4]
72.2.1 Germany

On 22 January 2009, CP 47,497 was added

to the German controlled drug schedules
(“Betäubungsmittelgesetz”),[12] along with its dimethyl-
72.1 Homologue hexyl, dimethyloctyl and dimethylnonyl homologues.[13]

On the 19th of January 2009, the University of Freiburg

in Germany announced that an analog of CP 47,497 is 72.2.2 France
the main active ingredient in the herbal “incense” prod-
uct Spice, specifically the 1,1-dimethyloctyl homologue CP 47,497 and its C6, C8, and C9 homologues were
of CP 47,497. Both the dimethylheptyl and dimethy- made illegal in France on 24 February 2009.[14]
loctyl homologues were detected in different batches,
with considerable variation in the concentration present
in different samples that were analysed. The weaker 72.2.3 Latvia
dimethylhexyl and dimethylnonyl homologues were not
found in any batches of smoking blends tested, but CP 47,497 and its C6, C8, and C9 homologues were
have been legally scheduled alongside the others in made illegal in Latvia on 28 November 2009.[15]
some jurisdictions, to forestall any potential use for this
purpose.[5][6][7] The 1,1-dimethyloctyl homologue of CP
47,497 is in fact several times more potent than the par-
72.2.4 Lithuania
ent compound,[8] which is somewhat unexpected as the
1,1-dimethylheptyl is the most potent substituent in clas-
CP 47,497 and its C6, C8, and C9 homologues were
sical cannabinoid compounds such as HU-210.[9] The
made illegal in Lithuania on 5 June 2009.[16]
unapproved use of these compounds in herbal smoking
blends has led to a resurgence in legitimate scientific re-
search into their use,[10] and consequently the C8 homo-
logue of CP 47,497 has been assigned a proper name,
72.2.5 Sweden
cannabicyclohexanol.[11]
CP 47,497 and its C6, C7, C8, and C9 homologues were
made illegal in Sweden on 15 September 2009.

72.2.6 Romania

CP 47,497 and its C6, C7, C8, and C9 homologues were

made illegal in Romania on 15 February 2010.(Illegal
Substances in Romania after 15.02.2010

72.2.7 United States

Cannabicyclohexanol
As of March 1, 2011, it is a schedule 1 drug.[17][18]

100
72.4. REFERENCES 101

72.3 See also [10] Uchiyama N, et al. Effects of synthetic cannabinoids on

electroencephalogram power spectra in rats. Forensic Sci-
ence International. 2011 Jun 1. PMID 21640532
• (C6)-CP 47,497
[11] Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda
• (C8)-CP 47,497 Y (May 2010). “Chemical analysis of synthetic
cannabinoids as designer drugs in herbal products”.
• (C9)-CP 47,497
Forensic Science International 198 (1-3): 31–8.
• CP 50,556-1 doi:10.1016/j.forsciint.2010.01.004. PMID 20117892.

[12] Modedroge “Spice” ist verboten!

• CP 55,244
[13] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19.
• CP 55,940 Januar 2009, S. 49–50.
• CP-945,598 [14] Décrets, arrêtés, circulaires: Arrêté du 24 février 2009
modifiant l’arrêté du 22 février 1990 fixant la liste des sub-
• HHC stances classées comme stupéfiants
• O-1871 [15] Grozījumi Ministru kabineta 2005.gada 8.novembra
noteikumos Nr.847 “Noteikumi par Latvijā kontrolēja-
majām narkotiskajām vielām, psihotropajām vielām un
prekursoriem”
72.4 References
[16] http://www3.lrs.lt/pls/inter3/dokpaieska.showdoc_l?p_
[1] Weissman A, Milne GM, Melvin LS Jr. Cannabimimetic id=345197
activity from CP-47,497, a derivative of 3-
phenylcyclohexanol. Journal of Pharmacology and [17] Cook, Morgan (2011-02-28). “Synthetic marijuana ille-
Experimental Therapeutics. 1982 Nov;223(2):516-23. gal as of Tuesday”. North County Times (San Diego). Re-
PMID 6290642 trieved 2011-02-28.

[18] https://federalregister.gov/a/2011-4428
[2] Shim JY, Welsh WJ, Howlett AC. Homology model of
the CB1 cannabinoid receptor: sites critical for non-
classical cannabinoid agonist interaction. Biopolymers.
2003;71(2):169-89. PMID 12767117

[3] Roger Pertwee. Cannabinoids. Handbook of Experimen-

tal Pharmacology Volume 168. Springer. ISBN 3-540-
22565-X

[4] Little PJ, et al. Pharmacology and stereoselectivity

of structurally novel cannabinoids in mice. Journal
of Pharmacology and Experimental Therapeutics 1988;
247:1046–1051.

[5] Hauptwirkstoff von „Spice“ identifiziert, University

of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm.
2009-01-19.19/

[6] Spice - weitere Analyseresultate http://www.

basg.at/servlet/sls/Tornado/web/ages/content/
4E5A4B86295BF5C0C125753E006A5E3C

[7] Auwärter V, et al. 'Spice' and other herbal blends: harm-

less incense or cannabinoid designer drugs? Journal of
Mass Spectrometry. 2009 Feb 2. PMID 19189348

[8] Compton DR, Johnson MR, Melvin LS, Martin BR. Phar-
macological profile of a series of bicyclic cannabinoid
analogs: classification as cannabimimetic agents. Journal
of Pharmacology and Experimental Therapeutics. 1992
Jan;260(1):201-9. PMID 1309872

[9] Martin BR, et al. Behavioral, biochemical, and molecular

modeling evaluations of cannabinoid analogs. Pharmacol-
ogy, Biochemistry and Behavior. 1991 Nov;40(3):471-8.
PMID 1666911
Chapter 73

CP 55,244

CP 55,244 is a compound which is a cannabinoid recep-

tor agonist. It has analgesic effects and is used in scientific
research. It is an extremely potent CB1 full agonist with a
Kᵢ of 0.21nM, making it more potent than the commonly
used full agonist HU-210.[1]

73.1 See also

• CP 47,497

73.2 References
[1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid
agonists and antagonists discriminated by receptor bind-
ing in rat cerebellum. British Journal of Pharmacology.
1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806
PMID 10516649

102
Chapter 74
CP 55,940
CP 55,940 is a cannabinoid which mimics the effects of
naturally occurring THC (one of the psychoactive com-
pounds found in cannabis). CP 55,940 was created by
Pfizer in 1974 but was never marketed. It is currently
used to study the endocannabinoid system. Some effects
that have been noted are a greatly decreased rates of lever
pressing in exposed mice, and a greater reaction to opi-
ates in exposed mice.
A study found that CP 55,940 can upregulate 5-HT2A
receptors in mice.[1]
CP 55,940 is 45 times more potent than Δ9 -THC, and
fully antagonized by rimonabant (SR141716A).[2]
CP 55,940 is considered a full agonist at both CB1 and
CB2 receptors and has Kᵢ values of 0.58nM and 0.68nM
respectively, but is an antagonist at GPR55, the putative
“CB3 " receptor.[3]
CP 55,940 showed protective effects on rat brain mito-
chondria upon paraquat exposure.[4]
It also showed neuroprotective effects by reducing intra-
cellular calcium release and reducing hippocampal cell
death in cultured neurons subjected to high levels of
NMDA.[5]
CP 55,940 induced cell death in NG 108-15 Mouse neu-
roblastoma x Rat glioma hybrid brain cancer (genetically
engineered mouse x rat brain cancer) cells.[6][7]
74.1 See also
• CP 47,497
74.2 References
[1] Franklin, J. M.; Carrasco, G. A. (2013). “Cannabi-
noid receptor agonists upregulate and enhance serotonin
2A (5-HT₂A) receptor activity via ERK1/2 signaling”.
Synapse 67 (3): 145–159. doi:10.1002/syn.21626. PMID
23151877.
[2] Rinaldi-Carmona, M.; Pialot, F.; Congy, C.; Redon,
E.; Barth, F.; Bachy, A.; Brelière, J. C.; Soubrié, P.;
le Fur, G. (1996). “Characterization and distribution
103
of binding sites for [3 H]-SR 141716A, a selective brain
(CB1) cannabinoid receptor antagonist, in rodent brain”.
Life Sciences 58 (15): 1239–1247. doi:10.1016/0024-
3205(96)00085-9. PMID 8614277.
[3] Kapur, A.; Zhao, P.; Sharir, H.; Bai, Y.; Caron, M. G.;
Barak, L. S.; Abood, M. E. (2009). “Atypical respon-
siveness of the orphan receptor GPR55 to cannabinoid
ligands”. The Journal of Biological Chemistry 284 (43):
29817–29827. doi:10.1074/jbc.M109.050187. PMC
2785612. PMID 19723626.
[4] Velez-Pardo, C.; Jimenez-Del-Rio, M.; Lores-Arnaiz, S.;
Bustamante, J. (2010). “Protective effects of the syn-
thetic cannabinoids CP55,940 and JWH-015 on rat brain
mitochondria upon paraquat exposure”. Neurochemical
Research 35 (9): 1323–1332. doi:10.1007/s11064-010-
0188-1. PMID 20514518.
[5] Zhuang, S. Y.; Bridges, D.; Grigorenko, E.; Mc-
Cloud, S.; Boon, A.; Hampson, R. E.; Deadwyler, S.
A. (2005). “Cannabinoids produce neuroprotection by
reducing intracellular calcium release from ryanodine-
sensitive stores”. Neuropharmacology 48 (8): 1086–
1096. doi:10.1016/j.neuropharm.2005.01.005. PMID
15910885.
[6] Tomiyama, K.; Funada, M. (2011). “Cytotoxicity of syn-
thetic cannabinoids found in 'Spice' products: The role
of cannabinoid receptors and the caspase cascade in the
NG 108-15 cell line”. Toxicology Letters 207 (1): 12–17.
doi:10.1016/j.toxlet.2011.08.021. PMID 21907772.
[7] “General Cell Collection: NG108-15”. Public Health
England Culture Collections.
Chapter 75

Dexanabinol

Dexanabinol (HU-211 or ETS2101[1] ) is a synthetic [8] University of California, San Diego "Synthetic Cannabi-
cannabinoid derivative that is the “unnatural” enantiomer noid May Be Used as Brain Cancer Treatment". (28
of the potent cannabinoid agonist HU-210.[2] Unlike September 2012) Laboratory Equipment. Retrieved 28
other cannabinoid derivatives, HU-211 does not act as a September 2012.
cannabinoid receptor agonist, but instead has NMDA an-
tagonist effects.[3] It therefore does not produce cannabis-
like effects, but is anticonvulsant and neuroprotective,
and is widely used in scientific research as well as cur-
rently being studied for practical applications such as
treatment of head injury or stroke or cancer.[4][5][6] It was
shown to be safe in clinical trials[7] and is currently under-
going Phase I trials for the treatment of brain cancer.[8]

75.1 References
[1] e-therapeutics Clinical Development Pipeline

[2] Pop E (September 2000). “Nonpsychotropic synthetic

cannabinoids”. Current Pharmaceutical Design 6 (13):
1347–60. doi:10.2174/1381612003399446. PMID
10903397.

[3] Feigenbaum JJ, et al. (December 1989).

“Nonpsychotropic cannabinoid acts as a functional
N-methyl-D-aspartate receptor blocker”. Proceedings of
the National Academy of Sciences of the United States of
America 86 (23): 9584–7. doi:10.1073/pnas.86.23.9584.
PMC 298542. PMID 2556719.

[4] Biegon A; Joseph AB (August 1995). “Development of

HU-211 as a neuroprotectant for ischemic brain damage”.
Neurological Research 17 (4): 275–80. PMID 7477742.

[5] Darlington CL (October 2003). “Dexanabinol: a novel

cannabinoid with neuroprotective properties”. IDrugs :
the Investigational Drugs Journal 6 (10): 976–9. PMID
14534855.

[6] Vink R; Nimmo AJ (January 2009). “Multifunctional

drugs for head injury”. Neurotherapeutics : the Journal
of the American Society for Experimental NeuroTherapeu-
tics 6 (1): 28–42. doi:10.1016/j.nurt.2008.10.036. PMID
19110197.

[7] Maas AI, et al. (January 2006). “Efficacy and safety

of dexanabinol in severe traumatic brain injury: results
of a phase III randomised, placebo-controlled, clinical
trial”. Lancet Neurol 5 (1): 38–45. doi:10.1016/S1474-
4422(05)70253-2. PMID 16361021.

104
Chapter 76
Dimethylheptylpyran
Dimethylheptylpyran (DMHP, 3-(1,2-
dimethylheptyl)-Δ6a,10a -THC, 1,2-dimethylheptyl-
Δ3 THC, A-40824, EA-1476) is a synthetic analogue of
THC, which was invented in 1949 during attempts to
elucidate the structure of Δ9 -THC, the active component
of cannabis.[1] DMHP is a pale yellow, viscous oil which
is insoluble in water, but dissolves in alcohol or non-polar
solvents.
76.1 Effects
DMHP is similar in structure to THC, differing only in
the position of one double bond, and the replacement of
the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain.[2]
It produces similar activity to THC, such as sedative ef-
fects, but is considerably more potent,[3] especially having
much stronger analgesic and anticonvulsant effects than
THC, although comparatively weaker psychological ef-
fects. It is thought to act as a CB1 agonist, in a similar
manner to other cannabinoid derivatives.[4]
76.2 Investigation as non-lethal in-
capacitating agent
DMHP and its O-acetate ester were extensively inves-
tigated by the US military chemical weapons program
in the Edgewood Arsenal experiments, as possible non-
lethal incapacitating agents.[5]
DMHP has three stereocenters and consequently has
eight possible stereoisomers, which differ considerably
in potency. The racemic mix of all eight isomers of
the O-acetyl ester was given the code number EA-2233,
with the eight individual isomers numbered EA-2233-1
through EA-2233-8. The most potent isomer was EA-
2233-2, with an active dose range in humans of 0.5–2.8
μg/kg (i.e. ~35–200 μg for a 70 kg adult). Active doses
varied markedly between individuals, but when the dose
of EA-2233 was taken up to 1–2 mg, all volunteers were
considered to be incapable of performing military duties,
with the effects lasting as long as 2–3 days.
DMHP is metabolised in a similar manner to THC, pro-
105
ducing the active metabolite 11-hydroxy-DMHP, but the
lipophilicity of DMHP is even higher than that of THC
itself, giving it a long duration of action and an ex-
tended half-life in the body of between 20–39 hours, with
the half-life of the 11-hydroxy-DMHP metabolite being
longer than 48 hours.
Cannabinoids as a class are generally safe compounds
with a large safety margin, making potent cannabi-
noid drugs ideal as potential non-lethal incapacitating
agents. DMHP and its esters produce sedation and
mild hallucinogenic effects similar to large doses of
THC, but in addition to this they also cause pronounced
hypotension (low blood pressure) which occurs at doses
well below the hallucinogenic dose, and can lead to severe
dizziness, fainting, ataxia and muscle weakness, sufficient
to make it difficult to stand upright or carry out any kind
of vigorous physical activity (an effect known colloqui-
ally as “couch lock”). The acute toxicity of DMHP was
found to be low in both human and animal studies, with
the ratio of ED50 to LD50 (Therapeutic Index) in animals
being around 2000x, with death ultimately resulting from
a combination of hypotension and hypothermia and pre-
ventable with supportive treatment.
The combination of strong incapacitating effects and a
favourable safety margin led the Edgewood Arsenal team
to conclude that DMHP and its derivatives, especially
the O-acetyl ester of the most active isomer, EA-2233-2,
were among the more promising non-lethal incapacitating
agents to come out of their research program. However
they were disadvantaged by producing severe hypoten-
sion at incapacitating doses, and were not as effective as
the more widely publicised anticholinergic agents such
as 3-Quinuclidinyl benzilate which had also already been
weaponised.[6] Funding for continued development was
ultimately not approved, and the cannabinoid research
program was indefinitely suspended along with the rest
of the Edgewood Arsenal experiments in the late 1970s,
in accordance with the US commitment to cease research
into chemical weapons under disarmament treaties.
106 CHAPTER 76. DIMETHYLHEPTYLPYRAN

Dibenzopyran and monoterpenoid numbering of tetrahydro-

cannabinol derivatives

76.3 Isomerism
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-
benzo[c]chromen-1-ol.
See also: Tetrahydrocannabinol § Isomerism

76.4 References
[1] Adams R, Harfenist M, Loewe S (1949). Jour-
nal of the American Chemical Society 71 (5): 1624.
doi:10.1021/ja01173a023.

[2] Razdan RK (1980). “The Total Synthesis of Cannabi-

noids”. Total Synthesis of Natural Products, Volume 4.
Wiley-Interscience. doi:10.1002/9780470129678.ch2.
ISBN 9780471054603.

[3] Wilkison, DM; Pontzer, N; Hosko, MJ (1982). “Slow-

ing of cortical somatosensory evoked activity by delta 9-
tetrahydrocannabinol and dimethylheptylpyran in alpha-
chloralose-anesthetized cats”. Neuropharmacology 21
(7): 705–9. doi:10.1016/0028-3908(82)90014-4. PMID
6289158.

[4] Parker, LA; Mechoulam, R (2003). “Cannabinoid ag-

onists and antagonists modulate lithium-induced condi-
tioned gaping in rats”. Integrative physiological and be-
havioral science : the official journal of the Pavlovian So-
ciety 38 (2): 133–45. doi:10.1007/BF02688831. PMID
14527182.

[5] Possible Long-Term Health Effects of Short-Term Expo-

sure To Chemical Agents. Vol. 2: Cholinesterase Re-
activators, Psychochemicals and Irritants and Vesicants.
Commission on Life Sciences. The National Academies
Press. 1984. pp. 79–99.

[6] Ketchum, James S. (2006) Chemical Warfare Secrets Al-

most Forgotten. ChemBooks Inc. ISBN 978-1-4243-
0080-8
Chapter 77

Docosatetraenoylethanolamide

Docosatetraenoylethanolamide (DEA) is an endoge-

nous ethanolamide that has been shown to act on the
cannabinoid (CB1 ) receptor.[1] DEA is similar in struc-
ture to anandamide (AEA, a recognized endogenous lig-
and for the CB1 receptor), containing docosatetraenoic
acid in place of arachidonic acid. While DEA has been
shown to bind to the CB1 receptor with similar potency
and efficacy as AEA, its role as a cannabinergic neuro-
transmitter is not well understood.

77.1 References
[1] Hanus, L., Gopher, A., Almog, S., et al. (1993). “Two
new unsaturated fatty acid ethanolamides in brain that
bind to the cannabinoid receptor”. J Med Chem 36
(20): 3032–3034. doi:10.1021/jm00072a026. PMID
8411021.

107
Chapter 78

Drinabant

Drinabant (INN; AVE-1625) is a drug that acts as a receptor 1 antagonists as anti-obesity agents”. Cur-
selective CB1 receptor antagonist, which was under in- rent Topics in Medicinal Chemistry 9 (6): 482–503.
vestigation varyingly by Sanofi-Aventis as a treatment for doi:10.2174/156802609788897844. PMID 19689362.
obesity, schizophrenia, Alzheimer’s disease, Parkinson’s
disease, and nicotine dependence.[1][2][3] Though initially
studied as a potential treatment for a variety of differ-
ent medical conditions, Sanofi-Aventis eventually nar-
rowed down the therapeutic indications of the compound
to just appetite suppression. Drinabant reached phase IIb
clinical trials for this purpose in the treatment of obe-
sity but was shortly thereafter discontinued,[4] likely due
to the observation of severe psychiatric side effects in-
cluding anxiety, depression, and thoughts of suicide in
patients treated with the now-withdrawn rimonabant, an-
other CB1 antagonist that was also under development by
Sanofi-Aventis.[5]

78.1 See also

• Cannabinoid receptor antagonist

78.2 References
[1] Lange JH, Kruse CG (2008). “Cannabinoid CB1 re-
ceptor antagonists in therapeutic and structural perspec-
tives”. Chemical Record (New York, N.Y.) 8 (3): 156–68.
doi:10.1002/tcr.20147. PMID 18563799.

[2] Kwon MO, Herrling P (2005). “List of drugs in devel-

opment for neurodegenerative diseases. Update Septem-
ber 2005”. Neuro-degenerative Diseases 2 (2): 61–108.
doi:10.1159/000089285. PMID 16909049.

[3] Gerald Litwack (14 August 2009). Anandamide. Aca-

demic Press. p. 172. ISBN 978-0-12-374782-2. Re-
trieved 13 May 2012.

[4] Reggio, Patricia H. (2009). “Toward the design of

cannabinoid CB1 receptor inverse agonists and neu-
tral antagonists”. Drug Development Research 70 (8).
doi:10.1002/ddr.20337. ISSN 0272-4391.

[5] Lee HK, Choi EB, Pak CS (2009). “The current sta-
tus and future perspectives of studies of cannabinoid

108
Chapter 79

EAM-2201

EAM-2201 (4'-ethyl-AM-2201, 5"-fluoro-JWH-210) 79.4 References

is a drug that presumably acts as a potent agonist for the
cannabinoid receptors. It had never previously been re-
ported in the scientific or patent literature, and was first
identified by laboratories in Japan in July 2012 as an in-
gredient in synthetic cannabis smoking blends.[1] Like the
closely related MAM-2201 which had been first reported
around a year earlier, EAM-2201 thus appears to be an-
other novel compound invented by designer drug suppli-
ers specifically for recreational use. Structurally, EAM-
2201 is a hybrid of two known cannabinoid compounds
JWH-210 and AM-2201, both of which had previously
been used as active ingredients in synthetic cannabis
blends before being banned in many countries.
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.;
Goda, Y. (2012). “URB-754: A new class of de-
signer drug and 12 synthetic cannabinoids detected in il-
legal products”. Forensic Science International 227 (1–
3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID
23063179.
[2] I was possessed by a demon, says ex-legal high user. New
Zealand Herald, Monday 1 Oct 2012
[3] Amputee: K2 'takes away my pain'. New Zealand Herald,
Wednesday 28 Nov 2012
[4] https://www.caymanchem.com/app/template/Product.
vm/catalog/ISO00127

[5] Peter Rösner, G. Fritschi, Southern Association of

79.1 Pharmacology Forensic Scientists, http://forendex.southernforensic.
org/uploads/references/Molecular_Index_Of_
Nothing has been published on the pharmacology of _Cannabimimetics_(2).pdf
EAM-2201, though it presumably has similar properties
to the closely related AM-2201 and JWH-210, which are
both full agonists and unselectively bind to CB1 and CB2
cannabinoid receptors with low nanomolar affinity.

79.2 Legal status

EAM-2201 was banned in New Zealand as a temporary
class drug from 6 December 2012, after reports of ad-
diction and psychosis associated with use of products
containing EAM-2201 as an active ingredient, however
this has been protested by some users who claim to have
found medical benefits in the treatment of conditions such
as phantom limb pain, since medicinal marijuana is not
available in New Zealand and synthetic cannabis products
are used as a legal alternative.[2][3]

79.3 Detection
A forensic standard of EAM-2201 is available and com-
monly used in mass spectrometry, and the compound has
been cited on the Forendex website of potential drugs of
abuse.[4][5]

109
Chapter 80
Endocannabinoid reuptake inhibitor
Endocannabinoid reuptake inhibitors (eCBRIs), also
called cannabinoid reuptake inhibitors (CBRIs), are
drugs which limit or completely stop the reabsorption
of endocannabinoid neurotransmitters into their corre-
sponding pre-synaptic neurons.
80.1 Etymology
There are several parts to the phrase endocannabinoid
reuptake inhibitor. First, a reuptake inhibitor is a sub-
stance that prevents its respective neurotransmitters from
being reabsorbed into the pre-sypnatic neurones, which
makes them continually recycle themselves, thus creating
a large increase in neurotransmission. Next, a cannabi-
noid is simply a class of closely related substances such as
Tetrahydrocannabinol and Cannabidiol. 'Endo' is a pre-
fix used to describe a cannabinoid that is naturally found
within an animal. In retrospect, an endocannabinoid re-
uptake inhibitor is a substance that when ingested by an
animal prevents reuptake of its endogenous cannabinoids.
Endocannabinoid uptake inhibitors that bind to fatty acid
binding protons (FABPs) have been described.
80.2 Pharmacology
The inhibition of endocannabinoid reuptake raises the
amount of those neurotransmitters available in the
synaptic cleft and therefore increases neurotransmission.
Following the increase of neurotransmission in the en-
docannabinoid system is the stimulation of its functions
which, in humans, include: suppression of pain percep-
tion (analgesia), increased appetite, mood elevation and
inhibition of short-term memory.
80.3 Use in medicine
Other than toxicity research and recreational use, eCBRIs
could have some potential in fighting tumors and pos-
sibly cancer. A study done in 2004 on rats with thy-
roid tumors showed that reuptake inhibition of the en-
110
docannabinoid system using VDM-11 and AA-5-HT re-
duced the ultimate size of the tumors in the treated rats.
These findings suggest that the use of cannabinoids and/or
eCBR inhibitors could be used to effectively treat tumors
and/or cancer, which only adds to the controversy around
cannabinoids and the cannabis plant as medicine.
As one might expect, combining a cannabinoid receptor
antagonist with an eCBRI reverses the effects of the re-
uptake inhibitor, and therefore could hinder treatment.
Cannabinoid receptor antagonists aren't something com-
mon, so normally this isn't something to worry about. But
if smoked cannabis or cannabis extract is to be used as
a treatment, it would be necessary to cultivate varieties
with little to no amounts of these compounds, as they are
found in low concentrations in most varieties. One exam-
ple of these antagonist compounds which is found in the
cannabis plant is THCV (tetrahydrocannabivarin).
80.4 Examples of eCBRIs
• AM404
• O-2093
• OMDM-2
• UCM-707
• VDM-11
• URB597
80.5 See also
• Endocannabinoid system
• Reuptake inhibitor
• Cannabinoid receptor antagonist
• Endocannabinoid transporters
80.6. REFERENCES 111

80.6 References
1. http://www.fasebj.org/cgi/content/full/18/13/1606

2. http://www.ncbi.nlm.nih.gov/pubmed/16770320
3. PLOS ONE
Chapter 81

Endocannabinoid system

The endocannabinoid system is a group of neuromod- that cannabinoids will have in modulating specific aspects
ulatory lipids and their receptors in the brain that are in-
of behavior related to the site of expression. For example,
volved in a variety of physiological processes includingin rodents, the highest concentration of cannabinoid bind-
appetite, pain-sensation, mood, and memory; it mediates ing sites are in the basal ganglia and cerebellum, regions
the psychoactive effects of cannabis and, broadly speak- of the brain involved in the initiation and coordination of
ing, includes: movement.[10] In humans, cannabinoid receptors exist in
much lower concentration in these regions, which helps
• The endogenous arachidonate-based lipids, explain why cannabinoids possess a greater efficacy in al-
anandamide (N-arachidonoylethanolamide, AEA) tering rodent motor movements than they do in humans.
and 2-arachidonoylglycerol (2-AG); these are A recent analysis of cannabinoid binding in CB1 and
known as "endocannabinoids" and are physio- CB2 receptor knockout-mice found cannabinoid respon-
logical ligands for the cannabinoid receptors. siveness even when these receptors were not being ex-
Endocannabinoids are all eicosanoids.[1] pressed, indicating that an additional binding receptor
may be present in the brain.[10] Binding has been demon-
• The enzymes that synthesize and degrade the endo- strated by 2-arachidonoylglycerol (2-AG) on the TRPV1
cannabinoids, such as fatty acid amide hydrolase or receptor suggesting that this receptor may be a candidate
monoacylglycerol lipase. for the established response.[11]
• The cannabinoid receptors CB1 and CB2 , two G
protein-coupled receptors that are located in the
central and peripheral nervous systems. 81.1.2 Endocannabinoid synthesis, re-
lease, and degradation
The endocannabinoid system has been studied using ge-
netic and pharmacological methods. These studies have During neurotransmission, the pre-synaptic neuron re-
revealed that cannabinoids act as neuromodulators[2][3][4] leases neurotransmitters into the synaptic cleft which bind
for a variety of physiological processes, including motor to cognate receptors expressed on the post-synaptic neu-
learning,[5] synaptic plasticity,[6] appetite,[7] and pain ron. Based upon the interaction between the transmitter
sensation.[8] and receptor, neurotransmitters may trigger a variety of
effects in the post-synaptic cell, such as excitation, in-
hibition, or the initiation of second messenger cascades.
Based on the cell, these effects may result in the on-
81.1 Basic overview site synthesis of endogenous cannabinoids anandamide
or 2-AG by a process that is not entirely clear, but re-
81.1.1 Expression of receptors sults from an elevation in intracellular calcium.[9] Expres-
sion appears to be exclusive, so that both types of endo-
For a more thorough description on receptor localization, cannabinoids are not co-synthesized. This exclusion is
see Cannabinoid receptor type 1 (CB1 ) and Cannabinoid based on synthesis-specific channel activation: a recent
receptor type 2 (CB2 ). study found that in the bed nucleus of the stria terminalis,
calcium entry through voltage-sensitive calcium channels
Cannabinoid binding sites exist throughout the central produced an L-type current resulting in 2-AG produc-
and peripheral nervous systems. The two most rele- tion, while activation of mGluR1/5 receptors triggered
vant receptors for cannabinoids are the CB1 and CB2 re- the synthesis of anandamide.[11]
ceptors, which are expressed predominantly in the brain Evidence suggests that the depolarization-induced influx
and immune system respectively.[9] Density of expression of calcium into the post-synaptic neuron causes the ac-
varies based on species and correlates with the efficacy tivation of an enzyme called transacylase. This enzyme

112
81.1. BASIC OVERVIEW 113

is suggested to catalyze the first step of endocannabinoid but also the PI3/PKB and MEK/ERK pathway (Galve-
biosynthesis by converting phosphatidylethanolamine, Roperh et al., 2002; Davis et al., 2005; Jones et al.,
a membrane-resident phospholipid, into N-acyl- 2005; Graham et al., 2006). Results from rat hip-
phosphatidylethanolamine (NAPE). Experiments pocampal gene chip data after acute administration of
have shown that phospholipase D cleaves NAPE to tetrahydrocannabinol (THC) showed an increase in the
yield anandamide.[12][13] In NAPE-phospholipase D expression of transcripts encoding myelin basic protein,
(NAPEPLD)-knockout mice, cleavage of NAPE is re- endoplasmic proteins, cytochrome oxidase, and two cell
duced in low calcium concentrations, but not abolished, adhesion molecules: NCAM, and SC1; decreases in ex-
suggesting multiple, distinct pathways are involved in pression were seen in both calmodulin and ribosomal
anandamide synthesis.[14] The synthesis of 2-AG is less RNAs (Kittler et al., 2000). In addition, CB1 activation
established and warrants further research. has been demonstrated to increase the activity of tran-
Once released into the extracellular space by a puta- scription factors like c-Fos and Krox-24 (Graham et al.,
2006).
tive endocannabinoid transporter, messengers are vul-
nerable to glial cell inactivation. Endocannabinoids are
taken up by a transporter on the glial cell and degraded
by fatty acid amide hydrolase (FAAH), which cleaves 81.1.4 Binding and neuronal excitability
anandamide into arachidonic acid and ethanolamine or
monoacylglycerol lipase (MAGL), and 2-AG into arachi- The molecular mechanisms of CB1 -mediated changes
donic acid and glycerol.[15] While arachidonic acid is a to the membrane voltage have also been studied in de-
substrate for leukotriene and prostaglandin synthesis, it tail. CB1 agonists reduce calcium influx by blocking
is unclear whether this degradative byproduct has novel the activity of voltage-dependent
[19][20]
N-, P/Q- and L-type
functions in the central nervous system. [16][17]
Emerging calcium channels. In addition to acting on cal-
data in the field also points to FAAH being expressed cium channels, activation of Gi/o and Gs, the two most
in postsynaptic neurons complementary to presynaptic commonly coupled G-proteins to cannabinoid receptors,
neurons expressing cannabinoid receptors, supporting the has been shown to modulate potassium channel activity.
conclusion that it is major contributor to the clearance Recent studies have found that CB 1 activation specif-
and inactivation of anandamide and 2-AG after endo- ically facilitates GIRK, a potassium channel belonging
[20]
cannabinoid reuptake.[10] A neuropharmacological study to the Kir3 family. Both Guo & Ikeda and Binzen et
demonstrated that an inhibitor of FAAH (URB597) se- al. performed a series of immunohistochemistry exper-
lectively increases anandamide levels in the brain of ro- iments that demonstrated CB1 co-localized with GIRK
dents and primates. Such approaches could lead to the and Kv1.4 potassium channels, suggesting that these two
[21]
development of new drugs with analgesic, anxiolytic-like may interact in physiological contexts.
and antidepressant-like effects, which are not accompa- In the central nervous system, CB1 receptors influence
nied by overt signs of abuse liability.[18] neuronal excitability, reducing the incoming synaptic
[22]
Notably, a series of recent studies have found that the input. This mechanism, known as presynaptic inhi-
expression of endocannabinoids does not correlate with bition, occurs when a postsynaptic neuron releases en-
the distribution of cannabinoid receptors in the brain, docannabinoids in retrograde transmission, which then
suggesting that these molecules may also be interact- bind to cannabinoid receptors on the presynaptic termi-
ing with other receptors or be involved with other cell nal. CB 1 receptors then reduce the amount of neurotrans-
processes. [10] mitter released, so that subsequent excitation in the presy-
naptic neuron results in diminished effects on the postsy-
naptic neuron. It is likely that presynaptic inhibition uses
81.1.3 Binding and intracellular effects many of the same ion channel mechanisms listed above,
although recent evidence has shown that CB1 receptors
Cannabinoid receptors are G-protein coupled receptors can also regulate neurotransmitter release by a non-ion
located on the pre-synaptic membrane. While there have channel mechanism, i.e. through Gi/o-mediated inhibi-
been some papers that have linked concurrent stimula- tion of adenylyl cyclase and Protein Kinase A.[23] Still,
tion of dopamine and CB1 receptors to an acute rise in direct effects of CB1 receptors on membrane excitabil-
cyclic adenosine monophosphate (cAMP) production, it ity have been reported, and strongly impact the firing of
is generally accepted that CB1 activation via cannabi- cortical neurons[24] In a series of behavioral experiments,
noids causes a decrease in cAMP concentration by inhi- Palazzo et al. demonstrated that NMDA, an ionotropic
bition of adenylyl cyclase and a rise in the concentration glutamate receptor, and the metabotropic glutamate re-
of mitogen-activated protein kinase (MAP kinase).[1][10] ceptors (mGluRs) work in concert with CB1 to induce
The relative potency of different cannabinoids in inhi- analgesia in mice, although the mechanism underlying
bition of adenylyl cyclase correlates with their varying this effect is unclear. Together, these findings suggest that
efficacy in behavioral assays. This inhibition of cAMP CB1 influences neuronal excitability by a variety of mech-
is followed by phosphorylation and subsequent activa- anisms, and these effects are relevant to perception and
tion of not only a suite of MAP kinases (p38/p42/p44), behavior.
114 CHAPTER 81. ENDOCANNABINOID SYSTEM

81.2 Functions of the endocannabi- ilar post-synaptic receptor dependencies were found in
the striatum, but here both effects relied on presynaptic
noid system CB1 receptors.[11] These findings provide the brain a di-
rect mechanism to selectively inhibit neuronal excitabil-
81.2.1 Memory ity over variable time scales. By selectively internalizing
different receptors, the brain may limit the production of
Mice treated with tetrahydrocannabinol (THC) show sup- specific endocannabinoids to favor a time scale in accor-
pression of long-term potentiation in the hippocampus, a dance with its needs.
process that is essential for the formation and storage of
long-term memory.[25] These results concur with anec-
dotal evidence suggesting that smoking Cannabis impairs
short-term memory.[26] Consistent with this finding, mice
without the CB1 receptor show enhanced memory and 81.2.2 Appetite
long-term potentiation indicating that the endocannabi-
noid system may play a pivotal role in the extinction of old Evidence for the role of the endocannabinoid system in
memories. In contrast, a recent study found that the high- food-seeking behavior comes from a variety of cannabi-
dose treatment of rats with the synthetic cannabinoid HU- noid studies. Emerging data suggests that THC acts via
210 over several weeks resulted in stimulation of neural CB1 receptors in the hypothalamic nuclei to directly in-
growth in the rats’ hippocampus region, a part of the lim- crease appetite.[30] It is thought that hypothalamic neu-
bic system playing a part in the formation of declarative rons tonically produce endocannabinoids that work to
and spatial memories.[27] Taken together, these findings tightly regulate hunger. The amount of endocannabi-
suggest that the effects of endocannabinoids on memory noids produced is inversely correlated with the amount of
are dependent on what type of neurons are being targeted leptin in the blood.[31] For example, mice without leptin
(excitatory vs. inhibitory) and the location of these net- not only become massively obese but express abnormally
works in the brain. high levels of hypothalamic endocannabinoids as a com-
pensatory mechanism.[7] Similarly, when these mice were
treated with an endocannabinoid inverse agonists, such as
Role in hippocampal neurogenesis
rimonabant, food intake was reduced.[7] When the CB1
receptor is knocked-out in mice, these animals tend to
In the adult brain, the endocannabinoid system facilitates
be leaner and less hungry than wild-type mice. A related
the neurogenesis of hippocampal granule cells.[27][28] In
study examined the effect of THC on the hedonic (plea-
the subgranular zone of the dentate gyrus, multipotent
sure) value of food and found enhanced dopamine release
neural progenitors (NP) give rise to daughter cells that,
in the nucleus accumbens and increased pleasure-related
over the course of several weeks, mature into granule
behavior after administration of a sucrose solution.[32]
cells whose axons project to and synapse onto dendrites
A related study found that endocannabinoids affect taste
on the CA3 region.[29] NPs in the hippocampus have been
perception in taste cells[33] In taste cells, endocannabi-
shown to possess fatty acid amide hydrolase (FAAH) and
noids were shown to selectively enhance the strength of
express CB1 and utilize 2-AG.[28] Intriguingly, CB1 ac-
neural signaling for sweet tastes, whereas leptin decreased
tivation by endogenous or exogenous cannabinoids pro-
the strength of this same response. While there is need
mote NP proliferation and differentiation; this activation
for more research, these results suggest that cannabinoid
is absent in CB1 knockouts and abolished in the presence
activity in the hypothalamus and nucleus accumbens is
of antagonist.[27][28]
related to appetitive, food-seeking behavior.[30]

Induction of synaptic depression

The inhibitory effects of cannabinoid receptor stimula-

tion on neurotransmitter release have caused this system
to be connected to various forms of depressant plastic-
ity. A recent study conducted with the bed nucleus of
the stria terminalis found that the endurance of the de-
pressant effects was mediated by two different signaling
pathways based on the type of receptor activated. 2-
AG was found to act on presynaptic CB1 receptors to
mediate retrograde short-term depression (STD) follow-
ing activation of L-type calcium currents, while anan-
damide was synthesized after mGluR5 activation and
triggered autocrine signalling onto postsynapic TRPV1
receptors that induced long-term depression (LTD). Sim-
81.2.3 Energy balance & metabolism
The endocannabinoid system has been shown to have a
homeostatic role by controlling several metabolic func-
tions, such as energy storage and nutrient transport. It
acts on peripheral tissues such as adipocytes, hepatocytes,
the gastrointestinal tract, the skeletal muscles and the en-
docrine pancreas. It has also been implied in modulating
insulin sensitivity. Through all of this, the endocannabi-
noid system may play a role in clinical conditions, such
as obesity, diabetes, and atherosclerosis, which may also
give it a cardiovascular role.[34]
81.2. FUNCTIONS OF THE ENDOCANNABINOID SYSTEM
81.2.4 Stress response
While the secretion of glucocorticoids in response to
stressful stimuli is an adaptive response necessary for
an organism to respond appropriately to a stressor, per-
sistent secretion may be harmful. The endocannabi-
noid system has been implicated in the habituation of
the hypothalamic-pituitary-adrenal axis (HPA axis) to re-
peated exposure to restraint stress. Studies have demon-
strated differential synthesis of anandamide and 2-AG
during tonic stress. A decrease of anandamide was found
along the axis that contributed to basal hypersecretion
of corticosterone; in contrast, an increase of 2-AG was
found in the amygdala after repeated stress, which was
negatively correlated to magnitude of the corticosterone
response. All effects were abolished by the CB1 antago-
nist AM251, supporting the conclusion that these effects
were cannabinoid-receptor dependent.[35] These findings
show that anandamide and 2-AG divergently regulate the
HPA axis response to stress: while habituation of the
stress-induced HPA axis via 2-AG prevents excessive se-
cretion of glucocorticoids to non-threatening stimuli, the
increase of basal corticosterone secretion resulting from
decreased anandamide allows for a facilitated response of
the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety
Prolonged, systemic exposure to cannabinoids has of-
ten been associated with anti-social effects. To investi-
gate this theory, a cannabinoid receptor-knockout mouse
study examined the effect that these receptors play on
exploratory behavior. Researchers selectively targeted
glutamatergic and GABAergic cortical interneurons and
studied results in open field, novel object, and socia-
bility tests. Eliminating glutamaterigic cannabinoid re-
ceptors led to decreased object exploration, social in-
teractions, and increased aggressive behavior. In con-
trast, GABAergic cannabinoid receptor-knockout mice
showed increased exploration of objects, socialization,
and open field movement.[36] These contrasting effects
reveal the importance of the endocannabinoid system
in regulating anxiety-dependent behavior. Results sug-
gest that glutamatergic cannabinoid receptors are not only
responsible for mediating aggression, but produce an
anxiolytic-like function by inhibiting excessive arousal:
excessive excitation produces anxiety that limited the
mice from exploring both animate and inanimate ob-
jects. In contrast, GABAergic neurons appear to control
an anxiogenic-like function by limiting inhibitory trans-
mitter release. Taken together, these two sets of neurons
appear to help regulate the organism’s overall sense of
arousal during novel situations.
115
81.2.5 Immune function
Evidence suggests that endocannabinoids may function as
both neuromodulators and immunomodulators in the im-
mune system. Here, they seem to serve an autoprotec-
tive role to ameliorate muscle spasms, inflammation, and
other symptoms of multiple sclerosis and skeletal mus-
cle spasms.[1] Functionally, the activation of cannabinoid
receptors has been demonstrated to play a role in the
activation of GTPases in macrophages, neutrophils, and
BM cells. These receptors have also been implicated in
the proper migration of B cells into the marginal zone
(MZ) and the regulation of healthy IgM levels.[37] Inter-
estingly, some disorders seem to trigger an upregulation
of cannabinoid receptors selectively in cells or tissues re-
lated to symptom relief and inhibition of disease progres-
sion, such as in that rodent neuropathic pain model, where
receptors are increased in the spinal cord microglia, dor-
sal root ganglion, and thalmic neurons.[9]
Multiple sclerosis
Historical records from ancient China and Greece sug-
gest that preparations of Cannabis Indica were commonly
prescribed to ameliorate multiple sclerosis-like symp-
toms such as tremors and muscle pain. Modern research
has confirmed these effects in a study on diseased mice,
wherein both endogenous and exogenous agonists showed
ameliorating effects on tremor and spasticity. It remains
to be seen whether pharmaceutical preparations such as
dronabinol have the same effects in humans.[38][39] Due to
increasing use of medical Cannabis and rising incidence
of multiple sclerosis patients who self-medicate with the
drug, there has been much interest in exploiting the en-
docannabinoid system in the cerebellum to provide a le-
gal and effective relief.[26] In mouse models of multiple
sclerosis, there is a profound reduction and reorganization
of CB1 receptors in the cerebellum.[40] Serial sections of
cerebellar tissue subjected to immunohistochemistry re-
vealed that this aberrant expression occurred during the
relapse phase but returned to normal during the remitting
phase of the disease.[40] Other studies suggest that CB1
agonists promote the survival of oligodendrocytes in vitro
in the absence of growth and trophic factors; in addition,
these agonist have been shown to promote mRNA expres-
sion of myelin lipid protein. (Kittler et al., 2000; Mollna-
Holgado et al., 2002). Taken together, these studies point
to the exciting possibility that cannabinoid treatment may
not only be able to attenuate the symptoms of multiple
sclerosis but also improve oligodendrocyte function (re-
viewed in Pertwee, 2001; Mollna-Holgado et al., 2002).
2-AG stimulates proliferation of a microglial cell line by
a CB2 receptor dependent mechanism, and the number
of microglial cells is increased in multiple sclerosis.[41]
116 CHAPTER 81. ENDOCANNABINOID SYSTEM

81.2.6 Female reproduction names Normast and PeaPure as nutraceuticals.

Endocannabinoids are involved in placebo induced anal-
See also: Cannabis in pregnancy
gesia responses.[46]

The developing embryo expresses cannabinoid receptors

early in development that are responsive to anandamide 81.2.9 Thermoregulation
secreted in the uterus. This signaling is important in reg-
ulating the timing of embryonic implantation and uter- Anandamide and N-arachidonoyl dopamine (NADA)
ine receptivity. In mice, it has been shown that anan- have been shown to act on temperature-sensing TRPV1
damide modulates the probability of implantation to the channels, which are involved in thermoregulation.[47]
uterine wall. For example, in humans, the likelihood of TRPV1 is activated by the exogenous ligand capsaicin,
miscarriage increases if uterine anandamide levels are too the active component of chili peppers, which is struc-
high or low.[42] These results suggest that intake of exoge- turally similar to endocannabinoids. NADA activates
nous cannabinoids (e.g. marijuana) can decrease the like- the TRPV1 channel with an EC50 of approximately of
lihood for pregnancy for women with high anandamide 50 nM. The high potency makes it the putative en-
levels, and alternatively, it can increase the likelihood for dogenous TRPV1 agonist.[48] Anandamide has also been
pregnancy in women whose anandamide levels were too found to activate TRPV1 on sensory neuron terminals,
low.[43][44] and subsequently cause vasodilation.[10] TRPV1 may also
be activated by methanandamide and arachidonyl-2'-
chloroethylamide (ACEA).[1]
81.2.7 Autonomic nervous system
Peripheral expression of cannabinoid receptors led re-
searchers to investigate the role of cannabinoids in the 81.2.10 Sleep
autonomic nervous system. Research found that the CB1
receptor is expressed presynaptically by motor neurons Increased endocannabinoid signaling within the central
that innervate visceral organs. Cannabinoid-mediated in- nervous system promotes sleep-inducing effects.
hibition of electric potentials results in a reduction inIntercerebroventricular administration of anandamide in
noradrenaline release from sympathetic nervous system rats has been shown to decrease wakefulness and increase
nerves. Other studies have found similar effects in en- slow-wave sleep and REM sleep.[49] Administration of
anandamide into the basal forebrain of rats has also
docannabinoid regulation of intestinal motility, including
the innervation of smooth muscles associated with the di-been shown to increase levels of adenosine, which plays
gestive, urinary, and reproductive systems.[10] a role in promoting sleep and suppressing arousal.[50]
REM sleep deprivation in rats has been demonstrated to
increase CB1 receptor expression in the central nervous
81.2.8 Analgesia system.[51] Furthermore, anandamide levels possess a
circadian rhythm in the rat, with levels being higher in
At the spinal cord, cannabinoids suppress noxious- the light phase of the day, which is when rats are usually
stimulus-evoked responses of neurons in the dorsal horn, asleep or less active, since they are nocturnal.[52]
possibly by modulating descending noradrenaline input
from the brainstem.[10] As many of these fibers are pri-
marily GABAergic, cannabinoid stimulation in the spinal
column results in disinhibition that should increase no-
81.3 Experimental use of CB1 -/-
radrenaline release and attenuation of noxious-stimuli- phenotype
processing in the periphery and dorsal root ganglion.
The endocannabinoid most researched in pain is Neuroscientists often utilize transgenic CB1 knock-out
palmitoylethanolamide. Palmitoylethanolamide is a fatty mice to discern novel roles for the endocannabinoid
amine related to anandamide, but saturated and although system. While CB1 knock-out mice are healthy and
initially it was thought that palmitoylethanolamide would live into adulthood, there are significant differences be-
bind to the CB1 and the CB2 receptor, later it was found tween CB1 knock-out and wild-type mice. When sub-
that the most important receptors are the PPAR-alpha jected to a high-fat diet, CB1 knockout mice tend to
receptor, the TRPV receptor and the GRP55 receptor. be about sixty percent leaner and slightly less hungry
Palmitoylethanolamide has been evaluated for its anal- than wildtype.[53] Compared to wildtype, CB1 knock-
gesic actions in a great variety of pain indications[45] out mice exhibit severe deficits in motor learning, mem-
and found to be safe and effective. Basically these data ory retrieval, and increased difficulty in completing the
are proof of concept for endocannabinoids and related Morris water maze.[5][54][55] There is also evidence indi-
fatty amines to be therapeutically useful analgesics; cating that these knockout animals have an increased in-
palmitoylethanolamide is available under the brand cidence and severity of stroke and seizure.[56][57]
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81.5 Further reading
• Neumeister A, Normandin MD, Pietrzak RH, et
al. (2013). “Elevated brain cannabinoid CB1 re-
ceptor availability in post-traumatic stress disorder:
A positron emission tomography study”. Molecu-
lar Psychiatry. doi:10.1038/mp.2013.61. Lay sum-
mary – ScienceDaily (May 14, 2013).
• Földy C, Malenka RC, Südhof TC (May
2013). “Autism-associated neuroligin-3 mu-
tations commonly disrupt tonic endocannabi-
noid signaling”. Neuron 78 (3): 498–509.
doi:10.1016/j.neuron.2013.02.036. PMC
3663050. PMID 23583622. Lay summary –
ScienceDaily (April 11, 2013).
• Puighermanal E, Marsicano G, Busquets-Garcia
A, Lutz B, Maldonado R, Ozaita A (September
2009). “Cannabinoid modulation of hippocam-
pal long-term memory is mediated by mTOR sig-
naling”. Nat. Neurosci. 12 (9): 1152–8.
doi:10.1038/nn.2369. PMID 19648913. Lay sum-
mary – ScienceDaily (August 4, 2009).
• Niehaus JL, Liu Y, Wallis KT, et al. (December
2007). “CB1 cannabinoid receptor activity is mod-
ulated by the cannabinoid receptor interacting pro-
tein CRIP 1a”. Mol. Pharmacol. 72 (6): 1557–
66. doi:10.1124/mol.107.039263. PMC 2644445.
PMID 17895407. Lay summary – ScienceDaily
(November 30, 2007).
81.6 External links
• Homepage of the ICRS - The International Cannabi-
noid Research Society
• Homepage of the ECSN - The Endocannabinoid
System Network
Chapter 82
Endocannabinoid transporters
Most neurotransmitters are water-soluble and require
transmembrane proteins to transport them across the
cell membrane. The endocannabinoids (anandamide,
AEA, and 2-arachidonoylglycerol, 2-AG) on the other
hand, are non-charged lipids that readily cross lipid
membranes.[1][2][3][4][5] However, since the endocannabi-
noids are water immiscible, protein transporters have
been described that act as carriers to solubilize and
transport the endocannabinoids through the aqueous
cytoplasm. These include the heat shock proteins
(Hsp70s) and fatty acid binding proteins for anandamide
(FABPs).[6][7] FABP inhibitors attenuate the breakdown
of anandamide by the enzyme fatty acid amide hydro-
lase (FAAH) in cell culture.[6] One of these inhibitors
(SB-FI-26), isolated from a virtual library of a million
compounds, belongs to a class of compounds (named
the “truxilloids’) that act as a anti-nociceptive agent
with mild anti-inflammatory activity in mice.[8] These
truxillic acids and their derivatives have been known to
have anti-inflammatory and anti-nociceptive effects in
mice[9] and are active components of a Chinese herbal
medicine ((-)-Incarvillateine Incarvillea sinensis) used to
treat rheumatism and pain in human. The blockade of
anandamide transport may, at least in part, be the mech-
anism through which these compounds exert their anti-
nociceptive effects.
82.1 References
[1] Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.;
McKinney, Michelle K.; Cravatt, Benjamin F.; London,
Erwin; Deutsch, Deutsch (2012). “Anandamide Exter-
nally Added to Lipid Vesicles Containing-Trapped Fatty
Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed
in a Sterol-Modulated Fashion”. ACS Chemical Neuro-
science 3 (5): 364–368. doi:10.1021/cn300001w. PMID
22860204.
[2] Bojesen, Inge N.; Hansen, Harald S. (2005). “Membrane
transport of anandamide through resealed human red
blood cell membranes”. The Journal of Lipid Research.
46 no. (8): 1652–1659. doi:10.1194/jlr.M400498-
JLR200.
[3] Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.;
Bojesen, Inge N.; Deutsch, Dale G. (2006). “Anandamide
120
Uptake Is Consistent with Rate-limited Diffusion and Is
Regulated by the Degree of Its Hydrolysis by Fatty Acid
Amide Hydrolase”. The Journal of Biological Chemistry
281 (14): 9066–9075. doi:10.1074/jbc.M509721200.
PMID 16461355.
[4] Sandberg, A.; Fowler, C.J. (2005). “Measurement
of saturable and non-saturable components of anan-
damide uptake into P19 embryonic carcinoma cells
in the presence of fatty acid-free bovine serum albu-
min.”. Chemistry and Physics of Lipids 134 (2): 131–
139. doi:10.1016/j.chemphyslip.2004.12.010. PMID
15784231.
[5] Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J.
(2009). “The Insertion and Transport of Anandamide
in Synthetic Lipid Membranes Are Both Cholesterol-
Dependent” [Translated title]. PLoS ONE 4 (3): e4989.
doi:10.1371/journal.pone.0004989. PMID 19330032.
[6] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009).
“Identification of intracellular carriers for the endo-
cannabinoid anandamide”. Proceedings of the National
Academy of Sciences of the United States of America 106
(15): 6375–6380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[7] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-
Agro, A.; Maccarrone, M. (2009). “Molecular identifi-
cation of albumin and Hsp70 as cytosolic anandamide-
binding proteins”. Chemistry & Biology 16 (6): 624–632.
doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
[8] Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Bal-
ius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.;
Deutsch, D.G. (2012). “Targeting Fatty Acid Binding
Protein (FABP) Anandamide Transporters – A Novel
Strategy for Development of Anti-Inflammatory and
Anti-Nociceptive Drugs”. PLoS ONE 12 (7): e50968.
doi:10.1371/journal.pone.0050968.
[9] Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.;
Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Na-
hara, T.; Sakurada, S. (1999). “Strong antinociceptive ef-
fect of incarvillateine, a novel monoterpene alkaloid from
Incarvillea sinensis”. Journal of Natural Products 62 (9):
1293–1294. doi:10.1021/np990041c. PMID 10514316.
Chapter 83

GW-405,833

GW-405,833 (L-768,242) is a drug that acts as a potent [6] Leichsenring A, Andriske M, Bäcker I, Stichel CC,
and selective partial agonist for the cannabinoid recep- Lübbert H. Analgesic and antiinflammatory effects of
tor subtype CB2 , with an EC50 of 0.65nM and selectivity cannabinoid receptor agonists in a rat model of neuro-
of around 1200x for CB2 over CB1 receptors.[1][2] Ani- pathic pain. Naunyn Schmiedebergs Archives of Pharma-
mal studies have shown it to possess antiinflammatory and cology. 2009 Jan 18. PMID 19152053
anti-hyperalgesic effects at low doses, followed by ataxia
and analgesic effects when the dose is increased.[3][4] Se-
lective CB2 agonist drugs such as GW-405,833 are hoped
to be particularly useful in the treatment of allodynia and
neuropathic pain for which current treatment options are
often inadequate.[5][6]

83.1 References
[1] Huffman JW. The search for selective ligands for the
CB2 receptor. Current Pharmaceutical Design. 2000
Sep;6(13):1323-37. doi:10.2174/1381612003399347
PMID 10903395

[2] Marriott KS, Huffman JW. Recent advances in the

development of selective ligands for the cannabinoid
CB(2) receptor. Current Topics in Medicinal Chemistry.
2008;8(3):187-204. doi:10.2174/156802608783498014
PMID 18289088

[3] Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT.

CB1 and CB2 cannabinoid receptors are implicated in in-
flammatory pain. Pain. 2002 Apr;96(3):253-60. PMID
11972997

[4] Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM,

Gottshall SL, Mark L, Pearson MS, Miller W, Shan S,
Rabadi L, Rotshteyn Y, Chaffer SM, Turchin PI, Else-
more DA, Toth M, Koetzner L, Whiteside GT. Phar-
macological and pharmacokinetic characterization of the
cannabinoid receptor 2 agonist, GW405833, utilizing ro-
dent models of acute and chronic pain, anxiety, ataxia and
catalepsy. Neuropharmacology. 2005 Apr;48(5):658-72.
PMID 15814101

[5] Beltramo M, Bernardini N, Bertorelli R, Campanella M,

Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptor-
mediated antihyperalgesia: possible direct involvement
of neural mechanisms. European Journal of Neuro-
science. 2006 Mar;23(6):1530-8. doi:10.1111/j.1460-
9568.2006.04684.x PMID 16553616

121
Chapter 84

GW-842,166X

GW-842,166X is a drug which acts as a potent and se-

lective cannabinoid CB2 receptor agonist, with a novel
chemical structure based on a pyrimidine core. It has
potent analgesic, anti-inflammatory and anti-hyperalgesic
actions in animal models, but without cannabis-like be-
havioural effects due to its extremely low affinity for the
CB1 receptor.[1][2][3]

84.1 References
[1] Giblin GM, O'Shaughnessy CT, Naylor A, Mitchell WL,
Eatherton AJ, Slingsby BP, Rawlings DA, Goldsmith P,
Brown AJ, Haslam CP, Clayton NM, Wilson AW, Ches-
sell IP, Wittington AR, Green R (May 2007). “Discovery
of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-
2H-pyran-4-yl)methyl]−4-(trifluoromethyl)- 5-
pyrimidinecarboxamide, a selective CB2 receptor
agonist for the treatment of inflammatory pain”.
Journal of Medicinal Chemistry 50 (11): 2597–600.
doi:10.1021/jm061195+. PMID 17477516.

[2] Giblin GM, Billinton A, Briggs M, Brown AJ, Ches-

sell IP, Clayton NM, Eatherton AJ, Goldsmith P,
Haslam C, Johnson MR, Mitchell WL, Naylor
A, Perboni A, Slingsby BP, Wilson AW (October
2009). “Discovery of 1-[4-(3-chlorophenylamino)−1-
methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]−1-morpholin-
4-ylmethanone (GSK554418A), a brain penetrant
5-azaindole CB2 agonist for the treatment of chronic
pain”. Journal of Medicinal Chemistry 52 (19): 5785–8.
doi:10.1021/jm9009857. PMID 19743867.

[3] Han, S.; Thatte, J.; Jones, R. M. (2009). “Chapter 11:

Recent Advances in the Discovery of CB2 Selective Ag-
onists”. Annual Reports in Medicinal Chemistry 44: 227.
doi:10.1016/S0065-7743(09)04411-X.

122
Chapter 85
Hemopressin
Hemopressin (Hp) is an alpha hemoglobin fragment with
the sequence PVNFKFLSH, originally identified in ex-
tracts of rat brain using an enzyme capture technique.[1]
It binds cannabinoid receptors, acting as an inverse ag-
onist at CB1 receptors.[2] Longer forms of hemopressin
containing 2-3 additional amino acids on the N-terminus
have been identified in extracts of mouse brain. These
longer hemopressin peptides, named RVD-Hpα and VD-
Hpα, bind to CB1 receptors and are agonists.[3] In addi-
tion to the Hp peptides from alpha hemoglobin, a related
peptide from beta hemoglobin has been found in mouse
brain extracts; this peptide, named VD-Hpβ, is also an
agonist at CB1 cannabinoid receptors.[3]
The original Hp peptide reduces sensitivity to painful
stimuli in an experimental model of hyperalgesia.[4] Hp
also reduces food intake in mice.[5] However, it remains
to be shown if Hp is an endogenous brain peptide. The
original purification used boiling acid to extract the pep-
tide from rat brain, and hot acid can specifically cleave
D-P bonds. The N-terminally-extended forms RVD-
Hpα and VD-Hpα may represent the true endogenous
forms.[6]
85.1 Role in diet
Scientists at the University of Manchester have discov-
ered that hemopressin could be used as an appetite sup-
pressant without having the side effects of many other
drugs that are used for this purpose. In laboratory tests
hemopressin was administrated to mice and rats, which
significantly reduced food intake. Hemopressin works by
affecting the reward centres of the brain which make us
feel happy when we eat too much. A further research
should be carried out in order to confirm these effects
and the safety on people.[7]
85.2 See also
• RVD-Hpα
123
85.3 References
[1] Rioli V, Gozzo FC, Heimann AS, et al. (March
2003). “Novel natural peptide substrates for endopep-
tidase 24.15, neurolysin, and angiotensin-converting en-
zyme”. J. Biol. Chem. 278 (10): 8547–55.
doi:10.1074/jbc.M212030200. PMID 12500972.
[2] Heimann AS, Gomes I, Dale CS, et al. (December 2007).
“Hemopressin is an inverse agonist of CB1 cannabi-
noid receptors”. Proc. Natl. Acad. Sci. U.S.A.
104 (51): 20588–93. Bibcode:2007PNAS..10420588H.
doi:10.1073/pnas.0706980105. PMC 2154475. PMID
18077343.
[3] Gomes I, Grushko JS, Golebiewska U, et al. (Septem-
ber 2009). “Novel endogenous peptide agonists of
cannabinoid receptors”. FASEB J. 23 (9): 3020–
9. doi:10.1096/fj.09-132142. PMC 2735371. PMID
19380512.
[4] Dale CS, Pagano Rde L, Rioli V, et al. (March
2005). “Antinociceptive action of hemopressin in ex-
perimental hyperalgesia”. Peptides 26 (3): 431–6.
doi:10.1016/j.peptides.2004.10.026. PMID 15652650.
[5] Dodd GT, Mancini G, Lutz B, et al. (May 2010). “The
peptide hemopressin acts through CB1 cannabinoid recep-
tors to reduce food intake in rats and mice”. J Neurosci.
30 (21): 7369–76. doi:10.1523/JNEUROSCI.5455-
09.2010. PMID 20505104.
[6] Gelman JS, Sironi J, Castro LM, et al. (May 2010).
“Hemopressins and other hemoglobin-derived peptides
in mouse brain: comparison between brain, blood, and
heart peptidome and regulation in Cpefat/fat mice”. J
Neurochem. 113 (4): 871–80. doi:10.1111/j.1471-
4159.2010.06653.x. PMC 2867603. PMID 20202081.
[7] http://uk.health.lifestyle.yahoo.net/
hemopressin-naturally-supresses-appetite.htm
Chapter 86

HU-210

HU-210 is a synthetic cannabinoid that was first 86.2 Legal status

synthesized in 1988 from (1R,5S)-myrtenol[3] by a group
led by Professor Raphael Mechoulam at the Hebrew Uni-
versity.[4][5][6] HU-210 is 100 to 800 times more potent
86.2.1 United States
than natural THC from cannabis and has an extended du-
ration of action.[7] HU-210 is the (–)−1,1-dimethylheptyl HU-210 is a schedule I controlled substance under the
analog of 11-hydroxy- Δ8 - tetrahydrocannabinol; in Controlled Substances Act. [14]
some references it is called 1,1-dimethylheptyl- 11- To view national schedule, see: List of Schedule I drugs
hydroxytetrahydrocannabinol. The abbreviation “HU” (US),
stands for Hebrew University.
The (+) enantiomer of HU-210 has almost all of the
cannabinoid activity, with the (−) enantiomer HU-211 86.2.2 New Zealand
being inactive as a cannabinoid but instead acting as an
[15]
NMDA antagonist having neuroprotective effects.[8][9] Banned in New Zealand as of 8 May 2014.
HU-210 promotes proliferation, but not differentiation,
of cultured embryonic hippocampal neural stem and
progenitor cells likely via a sequential activation of CB1 86.3 Other HU Cannabinoids
receptors, Gᵢ/ₒ proteins, and ERK signaling. It was
also indicated by this increased neural growth to entail
antianxiety and antidepressant effects.[10] • HU-211
HU-210, alongside other synthetic cannabinoids like
• HU-239
WIN 55,212-2 and JWH-133, is implicated in prevent-
ing the inflammation caused by amyloid beta proteins
• HU-243
involved in Alzheimer’s disease, in addition to prevent-
ing cognitive impairment and loss of neuronal mark-
ers. This anti-inflammatory action is induced through • HU-308
the activation of cannabinoid receptors, which prevents
microglial activation that elicits the inflammation. In ad- • HU-320
dition, cannabinoids completely abolish neurotoxicity re-
lated to microglia activation in rat models.[11] • HU-331
HU-210 is a potent analgesic with many of the same ef-
• HU-336
fects as natural THC.
• HU-345

86.1 Recreational use

86.4 See also
According to the U.S. Customs and Border Protection,
HU-210 was discovered in Spice Gold incense prod- • Spice (drug)
ucts seized at the US border in January 2009. Over
100 pounds of Spice products were seized based on • CP 47,497
this finding.[12] HU-210 was also detected in three Spice
products in the UK, as reported in June 2009.[13] • JWH-018

124
86.6. EXTERNAL LINKS 125

86.5 References [13] “EMCDDA Action on new drugs briefing paper: Under-
standing the ‘Spice’ phenomenon”.
[1] http://www.deadiversion.usdoj.gov/drugs_concern/ [14] “Spice Cannabinoid - HU-210”.
spice/spice_hu210.htm
[15] https://www.drugfoundation.org.nz/
[2] http://www.deadiversion.usdoj.gov/schedules/ synthetic-cannabinoids/what-they-are
orangebook/c_cs_alpha.pdf

[3] Mechoulam, R., Lander, N., Breuer, A., Zahalka,

J. Synthesis of the Individual, Pharmacologically Dis- 86.6 External links
tinct, Enantiomers of a Tetrahydrocannabinol Derivative.
Tetrahedron: Asymmetry. 1990. Vol 1, No 5. pp 315- • Comment in Nature on the article about neurogene-
318. sis.
[4] Mechoulam, R., et al. (1988). “Enantiomeric cannabi-
noids: stereospecificity of psychotropic activity”. Experi-
entia 44 (9): 762–764. doi:10.1007/BF01959156. PMID
3416993.

[5] Little PJ, Compton DR, Mechoulam R, Martin BR. Stere-

ochemical effects of 11-OH-Δ8-THC-dimethylheptyl in
mice and dogs. Pharmacology, Biochemistry, and Behav-
ior. 1989 Mar;32(3):661-666.

[6] Järbe, T.; Hiltunen, A.; Mechoulam, R. (1989). “Stere-

ospecificity of the discriminative stimulus functions of
the dimethylheptyl homologs of 11-hydroxy-delta 8-
tetrahydrocannabinol in rats and pigeons”. The Journal
of Pharmacology and Experimental Therapeutics 250 (3):
1000–1005. PMID 2550611.

[7] Devane, W. A., et al. (1992). “A novel probe for the

cannabinoid receptor”. Journal of Medical Chemistry 35
(11): 2065–2069. doi:10.1021/jm00089a018. PMID
1317925.

[8] Howlett, A.; Champion, T.; Wilken, G.; Mechoulam,

R. (1990). “Stereochemical effects of 11-OH-Δ8-
tetrahydrocannabinol-dimethylheptyl to inhibit adeny-
late cyclase and bind to the cannabinoid receptor”.
Neuropharmacology 29 (2): 161. doi:10.1016/0028-
3908(90)90056-W. PMID 2158635.

[9] Darlington CL (October 2003). “Dexanabinol: a novel

cannabinoid with neuroprotective properties”. IDrugs :
the Investigational Drugs Journal 6 (10): 976–9. PMID
14534855.

[10] Jiang, W., et al. (2005). “Cannabinoids promote em-

bryonic and adult hippocampus neurogenesis and pro-
duce anxiolytic- and antidepressant-like effects”. The
Journal of Clinical Investigation 115 (11): 3104–
3116. doi:10.1172/JCI25509. PMC 1253627. PMID
16224541.

[11] Ramírez Bg, E. A. ; Blázquez, C.; Gómez Del Pulgar,

T.; Guzmán, M.; De Ceballos, M. L. (2005). “Pre-
vention of Alzheimer’s disease pathology by cannabi-
noids: neuroprotection mediated by blockade of mi-
croglial activation”. Journal of Neuroscience 25 (8):
1904–1913. doi:10.1523/JNEUROSCI.4540-04.2005.
PMID 15728830.

[12] “Lab Results Confirm CBP in Ohio Discover Synthetic

Narcotics in Incense Packets - CBP.gov”.
Chapter 87

HU-243

HU-243 (AM-4056) is a synthetic cannabinoid drug that

is a single enantiomer of the hydrogenated derivative of
the commonly used reference agonist HU-210. It is a po-
tent agonist at both the CB1 and CB2 receptors, with a
binding affinity of 0.041nM at the CB1 receptor, mak-
ing it marginally more potent than HU-210, which had
an affinity of 0.061nM in the same assay.[1]

87.1 See also

• AM-2389
• Nabidrox

• Nabilone

87.2 References
[1] Stern, E.; Lambert, D. M. (2007). “Medicinal
Chemistry Endeavors around the Phytocannabi-
noids”. Chemistry & Biodiversity 4 (8): 1707–1728.
doi:10.1002/cbdv.200790149. PMID 17712816.

126
Chapter 88

HU-308

HU-308 is a drug that acts as a cannabinoid agonist. It
is highly selective for the CB2 receptor subtype, with
a selectivity of over 5000x for CB2 vs CB1 .[1] The
synthesis and characterization took place in the labora-
tory of Prof. Mechoulam at the Hebrew University of
Jerusalem in the late 1990s. It has analgesic effects,[2]
promotes proliferation of neural stem cells,[3] and pro-
tects both liver and blood vessel tissues against oxidative
stress via inhibition of TNF-α.[4][5]
[5] Rajesh, M., et al. (2007). “CB2-receptor stimula-
tion attenuates TNF-α-induced human endothelial cell
activation, transendothelial migration of monocytes, and
monocyte-endothelial adhesion”. American journal of
physiology. Heart and circulatory physiology 293 (4):
H2210–H2218. doi:10.1152/ajpheart.00688.2007. PMC
2229632. PMID 17660390.

88.1 See also

• HU-210
• HU-320

88.2 References
[1] Hanus, L., et al. (1999). “HU-308: a specific
agonist for CB(2), a peripheral cannabinoid re-
ceptor”. Proceedings of the National Academy of
Sciences of the United States of America 96 (25):
14228–14233. Bibcode:1999PNAS...9614228H.
doi:10.1073/pnas.96.25.14228. PMC 24419. PMID
10588688.
[2] Labuda, C.; Koblish, M.; Little, P. (2005). “Cannabi-
noid CB2 receptor agonist activity in the hindpaw
incision model of postoperative pain”. European
Journal of Pharmacology 527 (1–3): 172–174.
doi:10.1016/j.ejphar.2005.10.020. PMID 16316653.
[3] Palazuelos, J., et al. (2006). “Non-psychoactive CB2
cannabinoid agonists stimulate neural progenitor prolif-
eration”. The FASEB journal : official publication of the
Federation of American Societies for Experimental Biology
20 (13): 2405–2407. doi:10.1096/fj.06-6164fje. PMID
17015409.
[4] Rajesh, M.; Pan, H.; Mukhopadhyay, P.; Batkai, S.; Osei-
Hyiaman, D.; Hasko, G.; Liaudet, L.; Gao, B.; Pacher, P.
(2007). “Pivotal Advance: Cannabinoid-2 receptor ago-
nist HU-308 protects against hepatic ischemia/reperfusion
injury by attenuating oxidative stress, inflammatory re-
sponse, and apoptosis”. Journal of leukocyte biology
82 (6): 1382–1389. doi:10.1189/jlb.0307180. PMC
2225476. PMID 17652447.

127
Chapter 89
HU-331
HU-331 is a quinone anticarcinogenic drug synthesized
from cannabidiol, a cannabinoid in the Cannabis sativa
plant. It showed a great efficacy against oncogenic hu-
man cells. HU-331 does not cause arrest in cell cy-
cle, cell apoptosis or caspase activation. HU-331 in-
hibits DNA topoisomerase II even at nanomolar concen-
trations, but has shown a negligible effect on the action
of DNA topoisomerase I. The cannabinoid quinone HU-
331 is a very specific inhibitor of topoisomerase II, com-
pared with most known anticancer quinones.[1] One of
the main objectives of these studies is the development
of a new quinone derived compound that produces anti-
neoplastic activity while maintaining low toxicity at ther-
apeutic doses.
89.1 Mechanism of action
Inhibitors of topoisomerases can act at two different lev-
els. First inhibiting topoisomerase, which stabilize the
topoisomerase-DNA complex and thus introduce DNA
breaks in the wires that lead to apoptosis, then inhibit-
ing the catalytic activity of topoisomerase, which hinders
the activity of these enzymes without introducing breaks
into the DNA chains. HU-331 seems to be a catalytic
inhibitor of topoisomerase II, probably by enzymatic lig-
ation to the protein. This molecule does not cause damage
to DNA, but protects cells from damage, natural, or in-
duced by other inhibitors of topoisomerase II that act as
inhibitors of topoisomerase. Even when 60% of the tar-
get cells are killed by treatment with HU-331, other cells’
nucleic content remains unharmed, with less breakage of
DNA chains that control important cellular functions.[2]
Doxorubicin, like other anticancer quinones, was used for
chemotherapy in human cancers for many years. The
mechanism of action of these drugs has been the sub-
ject of considerable controversy since chemotherapeutic
drugs exert their cytotoxic effect on target cells by non-
specific mechanisms. The doxorubicin damages DNA by
intercalation, the generation of reactive oxygen species
and inhibition of DNA topoisomerase I and II. This
leads to breaking the chains of DNA single and dou-
ble strands. The protein associated with these ruptures
are the topoisomerase II and DNA damage is catalyzed
128
by this enzyme.[2] Thus, while doxorubicin and other
anthraquinones act through many mechanisms such as
apoptosis, abrogation of the cell cycle cell, activation of
caspases, generation of ROS, inhibition of both topoi-
somerases, activation of intracellular secondary messen-
gers, etc. Hu-331 is more active and less toxic, since it
generates reactive oxygen species in the heart and has a
specific activity that gives great potential to develop as a
new anticancer drug, according to Kogan et al.[2]
Cannabinoids can act as anticancer compounds killing
several oncogenic cells followed by direct interaction with
cannabinoid receptors. The growth of glioma is inhibited
by a selective activation of the CB2 cannabinoid receptor
and endogenous cannabinoids such as anandamide inhibit
the proliferation of cells involved in lung cancer. The
reason behind the antitumor effect of HU-331 appears
unknown as cannabinoid receptor antagonists do not in-
hibit HU-331, despite being mediated by a cannabinoid
receptor. The HU-331 exerts an antiangiogenic effect ac-
companied by apoptosis of endothelial cells. Although in
some studies. HU-331 has not caused the death of cells
by oncogenic apoptosis. The conclusion that would lead
cells to apoptosis based on treatment with the drug did not
increase the proportion of cells containing DNA Lues in
the sub-G1 phase and have not found the expression of
caspase-3 in cancer cells.[2]
89.2 See also
• HU-210
• HU-320
• HU-336
89.3 References
[1] Kogan N.M. et al. (2007). “HU-331, a novel cannabinoid-
based anticancer topoisomerase II inhibitor”. Mol. Can-
cer Ther. 6 (1): 173–183. doi:10.1158/1535-7163.MCT-
06-0039. PMID 17237277.
[2] Kogan N.M. et al. (2007). “A Cannabinoid Anti-
cancer Quinone, HU-331, Is More Potent and Less Car-
89.3. REFERENCES 129

diotoxic Than Doxorubicin: A Comparative in Vivo

Study”. J. Pharmacol. Exp. Ther. 322 (2): 646–653.
doi:10.1124/jpet.107.120865. PMID 17478614.
Chapter 90

11-Hydroxy-THC

11-Hydroxy-Δ9 -tetrahydrocannabinol, abbreviated

as 11-OH-THC, is the main active metabolite of
THC which is formed in the body after cannabis
consumption.[1] 11-Hydroxy-THC has been shown to
be active in its own right,[2] but the effects produced
are not necessarily identical to those of THC.[3] This
might partially explain the biphasic effects of cannabis,
whereby some effects such as increased appetite tend to
be delayed rather than occurring immediately when the
drug is consumed.[4]
11-Hydroxy-THC is subsequently metabolised further
to 11-nor-9-carboxy-THC, which is not psychoactive
but might still play a role in the analgesic and anti-
inflammatory effects of cannabis.

90.1 References
[1] Johnson JR, Jennison TA, Peat MA, Foltz RL (1984).
“Stability of delta 9-tetrahydrocannabinol (THC), 11-
hydroxy-THC, and 11-nor-9-carboxy-THC in blood and
plasma”. Journal of analytical toxicology 8 (5): 202–4.
doi:10.1093/jat/8.5.202. PMID 6094914.

[2] Turkanis SA, Karler R (1988). “Changes in neurotrans-

mitter release at a neuromuscular junction of the lob-
ster caused by cannabinoids”. Neuropharmacology 27 (7):
737–42. doi:10.1016/0028-3908(88)90083-4. PMID
2901683.

[3] Hollister LE, Gillespie HK (1975). “Action of delta-9-

tetrahydrocannabinol. An approach to the active metabo-
lite hypothesis”. Clin. Pharmacol. Ther. 18 (6): 714–9.
PMID 1204277.

[4] Lemberger, L; Martz, R; Rodda, B; Forney, R;

Rowe, H (1973). “Comparative Pharmacology of Δ9-
Tetrahydrocannabinol and its Metabolite, 11-OH-Δ9-
Tetrahydrocannabinol”. The Journal of Clinical Investi-
gation 52 (10): 2411–7. doi:10.1172/JCI107431. PMC
302499. PMID 4729039.

130
Chapter 91

9-nor-9β-Hydroxyhexahydrocannabinol

9-nor−9β-Hydroxyhexahydrocannabinol (HHC), is a [2] Melvin LS, Johnson MR. Structure-Activity Relation-

synthetic cannabinoid derivative which resulted from
early modifications to the structure of THC, in a search
for the simplest compound that could still fulfil the bind-
ing requirements to produce cannabis-like activity.[1][2]
HHC is active in its own right with similar potency to
THC, but further simplification and variation of this par-
ent structure lead to more potent, yet structurally sim-
pler derivatives such as CP 47,497 and CP 55,940,[3][4][5]
which after several steps of modification have become
quite structurally distinct from THC, while HHC on the
other hand is still substantially similar in structure to
THC.
The discovery of this simplified class of cannabinoid
derivatives was highly significant in terms of the
widespread use of CP 55,940 for early scientific research
into the cannabinoid receptors,[6] as well as later work us-
ing more complex compounds such as CP 55,244 to map
the CB1 binding site in more detail, but aside from these
specific applications, these compounds attracted little at-
tention and no compounds from this series were devel-
oped for medical use despite favourable safety profiles in
animal studies. Unexpectedly, some 25 years later, these
compounds came back into prominence when an obscure
derivative (C8)-CP 47,497 was found to have been sold
as the active ingredient in the “herbal” cannabis substitute
product Spice,[7] which ironically has led to a resurgence
of interest into laboratory-conducted scientific research
of this family of drugs.
ships of Tricyclic and Nonclassical Bicyclic Cannabi-
noids. NIDA Research Monograph 79; 1987. pp 31-47.
[3] Weissman, A; Milne, GM; Melvin Jr, LS (1982).
“Cannabimimetic activity from CP-47,497, a derivative
of 3-phenylcyclohexanol”. The Journal of Pharmacology
and Experimental Therapeutics 223 (2): 516–23. PMID
6290642.
[4] Melvin, LS, et al. (1984). “A cannabinoid derived proto-
typical analgesic”. Journal of Medical Chemistry 27 (1):
67–71. doi:10.1021/jm00367a013. PMID 6690685.
[5] Compton, DR; Johnson, MR; Melvin, LS; Martin, BR
(1992). “Pharmacological profile of a series of bicyclic
cannabinoid analogs: classification as cannabimimetic
agents”. The Journal of Pharmacology and Experimental
Therapeutics 260 (1): 201–9. PMID 1309872.
[6] Devane, WA, et al. (1988). “Determination and charac-
terization of a cannabinoid receptor in rat brain”. Molec-
ular Pharmacology 34 (5): 605–13. PMID 2848184.
[7] Auwärter, V, et al. (2009). "'Spice' and other herbal
blends: harmless incense or cannabinoid designer drugs?".
Journal of mass spectrometry : JMS 44 (5): 832–7.
doi:10.1002/jms.1558. PMID 19189348.

91.1 See also

• AM-2389

• HU-243

91.2 References
[1] Johnson MR, et al. Potent Analgetics Derived From 9-
Nor-9β-Hydroxyhexahydrocannabinol. NIDA Research
Monograph 34; 1980. pp 68-74.

131
Chapter 92

Ibipinabant

Ibipinabant (SLV319, BMS-646,256) is a drug used
in scientific research which acts as a potent and highly
selective CB1 antagonist.[1] It has potent anorectic ef-
fects in animals,[2] and was researched for the treatment
[5] Srivastava, BK; Soni, R; Joharapurkar, A; Sairam,
of obesity, although CB1 antagonists as a class have
now fallen out of favour as potential anorectics follow-
ing the problems seen with rimonabant, and so ibip-
inabant is now only used for laboratory research, es-
pecially structure-activity relationship studies into novel
CB1 antagonists.[3][4][5]
92.1 See also
• Cannabinoid receptor antagonist
modeling in the homology model”. Journal of Medical
Chemistry 50 (24): 5951–66. doi:10.1021/jm061490u.
PMID 17979261.
KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS et
al. (2008). “Bioisosteric replacement of dihydropy-
razole of 4S-(-)−3-(4-chlorophenyl)-N-methyl-N'-
(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-
pyrazole-1-caboxamidine (SLV-319) a potent CB1
receptor antagonist by imidazole and oxazole”. Bioor-
ganic & Medicinal Chemistry Letters 18 (3): 963–8.
doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.

92.2 References
[1] Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman,
JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K et
al. (2004). “Synthesis, biological properties, and molecu-
lar modeling investigations of novel 3,4-diarylpyrazolines
as potent and selective CB(1) cannabinoid receptor an-
tagonists”. Journal of Medical Chemistry 47 (3): 627–43.
doi:10.1021/jm031019q. PMID 14736243.
[2] Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood,
B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG
(2006). “The relationship of in vivo central CB1 receptor
occupancy to changes in cortical monoamine release and
feeding elicited by CB1 receptor antagonists in rats”. Psy-
chopharmacology 184 (1): 26–35. doi:10.1007/s00213-
005-0234-x. PMID 16328376.
[3] Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals,
HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ;
Kruse, CG (2005). “Novel 3,4-diarylpyrazolines as po-
tent cannabinoid CB1 receptor antagonists with lower
lipophilicity”. Bioorganic & Medicinal Chemistry Let-
ters 15 (21): 4794–8. doi:10.1016/j.bmcl.2005.07.054.
PMID 16140010.
[4] Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni,
R; Raval, P; Gite, A; Goswami, A et al. (2007). “Di-
aryl dihydropyrazole-3-carboxamides with significant in
vivo antiobesity activity related to CB1 receptor antag-
onism: synthesis, biological evaluation, and molecular

132
Chapter 93

IDFP

IDFP is an organophosphorus compound related to the
nerve agent sarin. Like sarin, IDFP is an irreversible
inhibitor for a number of different enzymes that normally
serve to break down neurotransmitters, however the long
alkyl chain of IDFP makes it dramatically weaker as an
inhibitor of acetylcholinesterase (AChE), with an IC50
of only 6300nM, while it is a potent inhibitor of two
enzymes monoacylglycerol lipase (MAGL), the primary
enzyme responsible for degrading the endocannabinoid
2-arachidonoylglycerol (2-AG), and fatty acid amide hy-
drolase (FAAH), the primary enzyme that degrades the
other main endocannabinoid anandamide. The IC50 of
IDFP is 0.8nM at MAGL, and 3.0nM at FAAH. Inhibi-
tion of these two enzymes causes markedly increased lev-
els of both anandamide and 2-AG in the brain, resulting
in increased cannabinoid signalling and typical cannabi-
noid behavioral effects in animal studies, while its lack of
potency at AChE means that no cholinergic symptoms are
produced.[1][2][3][4] Despite its similar chemical structure
to the banned nerve agents, the long alkyl chain of IDFP
causes it to fall outside the definition of “toxic chemicals”
under the Chemical Weapons Convention,[5] and since it
also does not exhibit the potent AChE inhibition of re-
lated organophosphorus compounds, IDFP is not subject
to the same stringent legal controls.
brain lysophospholipids, ether lipids and endocannabi-
noids”. Chemico-Biological Interactions 175 (1–3): 355–
364. doi:10.1016/j.cbi.2008.04.008. PMC 2582404.
PMID 18495101.
[3] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.;
Mangravite, L. M.; Chiu, S.; Casida, J. E.; Krauss,
R. M. (2008). “Overactive endocannabinoid signal-
ing impairs apolipoprotein E-mediated clearance of
triglyceride-rich lipoproteins”. Proceedings of the Na-
tional Academy of Sciences 105 (38): 14561–14566.
doi:10.1073/pnas.0807232105. PMC 2567196. PMID
18794527.
[4] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Bar-
ber, A.; Casida, J. E.; Krauss, R. M. (2011). Bar-
tolomucci, Alessandro, ed. “Acute Overactive En-
docannabinoid Signaling Induces Glucose Intolerance,
Hepatic Steatosis, and Novel Cannabinoid Receptor 1
Responsive Genes”. PLoS ONE 6 (11): e26415.
doi:10.1371/journal.pone.0026415. PMC 3208546.
PMID 22073164.
[5] CWC Schedule 1 Part A. Toxic Chemicals

93.1 See also

• Methoxy arachidonyl fluorophosphonate

• 4-Nonylphenylboronic acid

93.2 References
[1] Nomura, D. K.; Blankman, J. L.; Simon, G. M.; Fujioka,
K.; Issa, R. S.; Ward, A. M.; Cravatt, B. F.; Casida, J.
E. (2008). “Activation of the endocannabinoid system by
organophosphorus nerve agents”. Nature Chemical Biol-
ogy 4 (6): 373–378. doi:10.1038/nchembio.86. PMC
2597283. PMID 18438404.

[2] Casida, J. E.; Nomura, D. K.; Vose, S. C.; Fujioka,

K. (2008). “Organophosphate-sensitive lipases modulate

133
Chapter 94

2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-
nonylphenyl)cyclohex-1-ene

2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-
nonylphenyl)cyclohex-1-ene is an analgesic compound
which is a cannabinoid agonist. It is a ring-opened
cannabinoid derivative, an analogue of cannabidiol.
However, unlike cannabidiol, this compound produces
potent cannabis-like effects in animals, suggesting it acts
as a CB1 agonist.[1]
It can be synthesized by Birch reduction from the nonyl-
analog of cannabidiol.[2]

94.1 References
[1] Razdan, K. (1981). “The Total Synthesis of Cannabi-
noids”. In John Apsimon. The Total Synthesis of Natural
Products. Wiley Interscience. p. 245. ISBN 978-0-471-
05460-3. OCLC 19487018.

[2] Razdan RK, Pars HG, Thompson WR, Granchelli FE

(1974). “Lithium-ammonia reduction of tetrahydro-
cannabinols”. Tetrahedron Letters 15 (49–50): 4315.
doi:10.1016/S0040-4039(01)92152-5.

134
Chapter 95

JTE 7-31

JTE 7-31 is a selective cannabinoid receptor agonist in-

vented by Japan Tobacco.[1][2] It is a reasonably highly
selective CB2 agonist, but still retains appreciable affinity
at CB1 , with a Kᵢ of 0.088nM at CB2 vs 11nM at CB1 .

95.1 See also

• A-834,735
• JTE-907

• MDA-19

• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide

• S-444,823

95.2 References
[1] WO patent 1997/029079, Inaba T, Kaya T, Iwamura
H, “Novel compounds and pharmaceutical use thereof”,
granted 1997-14-08

[2] US patent 6017919, Inaba T, Kaya T, Iwamura H, “Com-

pounds and pharmaceutical use thereof”, granted 2000-
01-25

135
Chapter 96

JTE-907

JTE-907 is a drug used in scientific research that

acts as a selective CB2 inverse agonist.[1][2] It has
antiinflammatory effects in animal studies,[3] thought to
be mediated by an interaction between the CB2 receptor
and IgE.[4]

96.1 See also

• JTE 7-31

96.2 References
[1] Iwamura, H, et al. (2001). “In vitro and in vivo phar-
macological characterization of JTE-907, a novel selec-
tive ligand for cannabinoid CB2 receptor”. The Journal
of Pharmacology and Experimental Therapeutics 296 (2):
420–5. PMID 11160626.

[2] Raitio, KH, et al. (2006). “Synthesis and SAR studies

of 2-oxoquinoline derivatives as CB2 receptor inverse ag-
onists”. Journal of Medical Chemistry 49 (6): 2022–7.
doi:10.1021/jm050879z. PMID 16539390.

[3] Ueda, Y, et al. (2005). “Involvement of cannabi-

noid CB(2) receptor-mediated response and efficacy
of cannabinoid CB(2) receptor inverse agonist, JTE-
907, in cutaneous inflammation in mice”. Euro-
pean Journal of Pharmacology 520 (1–3): 164–71.
doi:10.1016/j.ejphar.2005.08.013. PMID 16153638.

[4] Ueda, Y; Miyagawa, N; Wakitani, K (2007). “Involve-

ment of cannabinoid CB2 receptors in the IgE-mediated
triphasic cutaneous reaction in mice”. Life Sciences 80 (5):
414–9. doi:10.1016/j.lfs.2006.09.026. PMID 17055000.

136
Chapter 97
JWH-015
JWH-015 is a chemical from the naphthoylindole fam-
ily that acts as a subtype-selective cannabinoid agonist.
Its affinity for CB2 receptors is 13.8 nM, while its affin-
ity for CB1 is 383 nM, meaning that it binds almost 28x
more strongly to CB2 than CB1 [1] However it still dis-
plays some CB1 activity, and in some model systems
can be very potent and efficacious at activating CB1
receptors,[2] and therefore it is not as selective as newer
drugs such as JWH-133.[3] It has been shown to possess
immunomodulatory effects,[4][5] and CB2 agonists may
be useful in the treatment of pain and inflammation.[6][7]
It was discovered and named after Dr. John W. Huffman.
97.1 Metabolism
JWH-015 has been shown in vitro to be metabolised
primarily by hydroxylation and N-dealkylation, and also
by epoxidation of the naphthalene ring,[8] similar to
the metabolic pathways seen for other aminoalkylindole
cannabinoids such as WIN 55,212-2.[9] Epoxidation
of polycyclic aromatic hydrocarbons (see for exam-
ple benzo(a)pyrene toxicity) can produce carcinogenic
metabolites, although there is no evidence to show that
JWH-015 or other aminoalkylindole cannabinoids are ac-
tually carcinogenic in vivo. A study published in the
British Journal of Cancer shows that JWH-015 may sig-
nal certain cancers to shrink through a process called
apoptosis.[10]
97.2 References
[1] Aung MM, Griffin G, Huffman JW, Wu M, Keel C,
Yang B, Showalter VM, Abood ME, Martin BR (Au-
gust 2000). “Influence of the N-1 alkyl chain length
of cannabimimetic indoles upon CB1 and CB2 )receptor
binding”. Drug Alcohol Depend 60 (2): 133–40.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
[2] Murataeva N, Mackie K, Straiker A (November 2012).
“The CB2-preferring agonist JWH015 also potently
and efficaciously activates CB1 in autaptic hippocam-
pal neurons”. Pharmacol. Res. 66 (5): 437–42.
doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID
22921769.
137
[3] Marriott KS, Huffman JW (2008). “Recent advances in
the development of selective ligands for the cannabinoid
CB(2) receptor”. Curr Top Med Chem 8 (3): 187–204.
doi:10.2174/156802608783498014. PMID 18289088.
[4] Ghosh S, Preet A, Groopman JE, Ganju RK (July
2006). “Cannabinoid receptor CB2 modulates the
CXCL12/CXCR4-mediated chemotaxis of T lympho-
cytes”. Mol. Immunol. 43 (14): 2169–79.
doi:10.1016/j.molimm.2006.01.005. PMID 16503355.
[5] Montecucco F, Burger F, Mach F, Steffens S (March
2008). “CB2 cannabinoid receptor agonist JWH-
015 modulates human monocyte migration through de-
fined intracellular signaling pathways”. Am. J. Phys-
iol. Heart Circ. Physiol. 294 (3): H1145–55.
doi:10.1152/ajpheart.01328.2007. PMID 18178718.
[6] Balter MB, Uhlenhuth EH (1992). “Prescribing and use
of benzodiazepines: an epidemiologic perspective”. J
Psychoactive Drugs 24 (1): 63–4. doi:10.1186/1742-
2094-2-29. PMID 1352348.
[7] Romero-Sandoval A, Eisenach JC (April 2007).
“Spinal cannabinoid receptor type 2 activation reduces
hypersensitivity and spinal cord glial activation af-
ter paw incision”. Anesthesiology 106 (4): 787–94.
doi:10.1097/01.anes.0000264765.33673.6c. PMID
17413917.
[8] Zhang Q, Ma P, Cole RB, Wang G. Identification of in
vitro metabolites of JWH-015, an aminoalkylindole ag-
onist for the peripheral cannabinoid receptor (CB2) by
HPLC-MS/MS. Analytical and Bioanalytical Chemistry.
2006 Nov;386(5):1345-55. PMID 16955257
[9] Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang
G (October 2002). “In vitro metabolism of R(+)-
[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo
[1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone
mesylate, a cannabinoid receptor agonist”. Drug Metab.
Dispos. 30 (10): 1077–86. doi:10.1124/dmd.30.10.1077.
PMID 12228183.
[10] N Olea-Herrero, D Vara, S Malagarie-Cazenave, Díaz-
Laviada (18 August 2009). “Inhibition of human
tumour prostate PC-3 cell growth by cannabinoids
R(+)-Methanandamide and JWH-015: Involvement of
CB2”. British Journal of Cancer: 101, 940–950.
doi:10.1038/sj.bjc.6605248. Retrieved 10 July 2014.
Chapter 98

JWH-051

JWH-051 is an analgesic drug which is a cannabinoid

agonist. Its chemical structure is closely related to that
of the potent cannabinoid agonist HU-210, with the only
difference being the removal of the hydroxyl group at po-
sition 1 of the aromatic ring. It was discovered and named
after Dr. John W. Huffman.
JWH-051 retains high affinity for the CB1 receptor, but
is a much stronger agonist for CB2 , with a Ki value of
14nM at CB2 vs 19nM at CB1 .[1] It was one of the first
CB2 -selective ligands developed, although its selectivity
for CB2 is modest compared to newer compounds such
as HU-308.
It has similar effects to other cannabinoid agonists such
as sedation and analgesia, but with a relatively strong
antiinflammatory effect due to its strong activity at
CB2 .[2][3][4]

98.1 References
[1] Huffman, JW, Yu, S, Showalter, V, Abood, ME, Wiley,
JL, Compton, DR, Martin, BR, Bramblett, RD, Reggio,
PH (1996). “Synthesis and pharmacology of a very potent
cannabinoid lacking a phenolic hydroxyl with high affinity
for the CB2 receptor”. Journal of Medical Chemistry 39
(20): 3875–7. doi:10.1021/jm960394y. PMID 8831752.

[2] Huffman, JW (2000). “The search for selective ligands

for the CB2 receptor”. Current pharmaceutical design 6
(13): 1323–37. doi:10.2174/1381612003399347. PMID
10903395.

[3] Klein, TW, Newton, C, Friedman, H (1998). “Cannabi-

noid receptors and the cytokine network”. Advances
in experimental medicine and biology. Advances in
Experimental Medicine and Biology 437: 215–22.
doi:10.1007/978-1-4615-5347-2_24. ISBN 978-0-306-
45838-5. PMID 9666274.

[4] Griffin, G, Fernando, SR, Ross, RA, McKay, NG, Ash-

ford, ML, Shire, D, Huffman, JW, Yu, S et al. (1997).
“Evidence for the presence of CB2-like cannabinoid re-
ceptors on peripheral nerve terminals”. European Journal
of Pharmacology 339 (1): 53–61. doi:10.1016/S0014-
2999(97)01336-8. PMID 9450616.

138
Chapter 99

JWH-057

JWH-057, also known as deoxy-Δ8-THC-DMH, is a se-

lective cannabinoid ligand, with a binding affinity of Kᵢ =
2.9 ± 1.6 nM for the CB2 subtype, and Kᵢ = 23 ± 7 nM
for CB1 .[1]

99.1 See also

• JWH-015
• JWH-018

• JWH-019

• JWH-073

99.2 References
[1] Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL,
Compton DR, Martin BR, Bramblett RD, Reggio PH
(1996). “Synthesis and Pharmacology of a Very Po-
tent Cannabinoid Lacking a Phenolic Hydroxyl with High
Affinity for the CB2 Receptor”. J. Med. Chem. 39 (20):
3875–3877. doi:10.1021/JM960394Y.

139
Chapter 100

JWH-120

JWH-120 is a synthetic cannabimimetic that was discov-

ered by John W. Huffman. It is the N-propyl analog of
JWH-122. It is a potent and selective ligand for the CB2
receptor, with a binding affinity of Kᵢ = 6.1 ± 0.7 nM
at this subtype, and 173 times selectivity over the CB1
subtype.[1]

100.1 See also

• JWH-122
• JWH-193

• JWH-210

• JWH-398

100.2 References
[1] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.

140
Chapter 101

JWH-122

JWH-122 is a synthetic cannabimimetic that was discov-

ered by John W. Huffman. It is a methylated analogue of
JWH-018. It has a Kᵢ of 0.69 nM at CB1 and 1.2 nM at
CB2 .[1]

101.1 See also

• JWH-193
• JWH-210

• JWH-398

101.2 References
[1] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.

141
Chapter 102

JWH-133

JWH-133 is a potent selective CB2 receptor agonist, with 102.3 External links
a Ki of 3.4nM and selectivity of around 200x for CB2
over CB1 receptors. It was discovered by, and named • JNeurosci.org Prevention of Alzheimer’s Disease
after, John W. Huffman. Pathology by Cannabinoids: Neuroprotection Me-
JWH-133, alongside WIN 55,212-2 and HU-210, is diated by Blockade of Microglial Activation Also
implicated in preventing the inflammation caused by has been shown to block grown of tumors. More
Amyloid beta proteins involved in Alzheimer’s Disease, clinical studies and trials are needed.
in addition to preventing cognitive impairment and loss of
neuronal markers. This antiinflamatory action is induced
through agonist action at cannabinoid receptors, which
prevents microglial activation that elicits the inflamma-
tion. Additionally, cannabinoids completely abolish neu-
rotoxicity related to microglia activation in rat models.
It may be linked with anti-cancer properties, according to
pre-trial data from a 2010 study in Madrid. [1]

102.1 Legal Status

The substance commonly referred to as “JWH-133”

is not a scheduled substance in the U.S., although its
young age prevents it from having received the level of
government attention as with the older, more widely used
and well known chemicals. Low abuse potential makes
it less likely for regulation a priori relative to its sister
drugs such as JWH-018, as JWH-133 (chemical name
(6aR,10aR)−3-(1,1-Dimethylbutyl)−6a,7,10,10a-
tetrahydro −6,6,9-trimethyl-6H-dibenzo[b,d]pyran) is
selective for the non-psychoactive CB2 receptor and
hence devoid of any psychoactive side effects or abuse
potential.[2]

102.2 References

[1] http://www.enewspf.com/index.
php/latest-news/health-and-fitness/
18029-marijuana-compound-halts-breast-cancer-tumor-growth-

[2] http://www.usdoj.gov/dea/pubs/scheduling.html

142
Chapter 103

JWH-148

JWH-148 is a synthetic cannabimimetic that was discov-

ered by John W. Huffman. It is the indole 2-methyl ana-
log of JWH-120. It is a moderately selective ligand for
the CB2 receptor, with a binding affinity of Kᵢ = 14.0 ±
1.0 nM at this subtype, and more than 8 times selectivity
over the CB1 subtype.[1]

103.1 See also

• JWH-120
• JWH-122

• JWH-193

• JWH-210
• JWH-398

103.2 References
[1] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.

143
Chapter 104

JWH-149

JWH-149 is a synthetic cannabimimetic that was discov-

ered by John W. Huffman. It is the N-pentyl analog of
JWH-148. It is a potent but only moderately selective lig-
and for the CB2 receptor, with a binding affinity of Kᵢ =
0.73 ± 0.03 nM at this subtype, and more than 6 times
selectivity over the CB1 subtype.[1]

104.1 See also

• JWH-120
• JWH-122

• JWH-148

• JWH-193
• JWH-210

• JWH-398

104.2 References
[1] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.

144
Chapter 105

JWH-161

JWH-161 is a cannabinoid derivative that was designed

by Dr John W. Huffman's team as a hybrid between the
dibenzopyran “classical” cannabinoid drugs and the novel
indole derivatives, in an attempt to unravel the differences
in their binding modes to the CB1 receptor. While retain-
ing structural elements from both families, JWH-161 has
a CB1 Kᵢ of 19.0nM, although it was found to be slightly
weaker than THC in animal tests.[1]

105.1 References
[1] Huffman JW, Padgett LW (2005). “Recent develop-
ments in the medicinal chemistry of cannabimimetic in-
doles, pyrroles and indenes”. Current Medicinal Chemistry
12 (12): 1395–411. doi:10.2174/0929867054020864.
PMID 15974991.

145
Chapter 106

JWH-176

JWH-176 is an analgesic drug which acts as a

cannabinoid receptor agonist. Its binding affinity at the
CB1 receptor is only 26.0nM, making it more potent than
THC itself,[1] however JWH-176 is particularly notable in
that it is a hydrocarbon containing no heteroatoms. This
demonstrates that reasonably high-affinity cannabinoid
binding and agonist effects can be produced by com-
pounds with no hydrogen bonding capacity at all, rely-
ing merely on Van der Waals interactions to bind to the
receptor.[2] It was discovered by, and named after, Dr.
John W. Huffman.

106.1 See also

• JWH-175

106.2 References
[1] Huffman JW, Padgett LW. Recent Developments in
the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.

[2] Roger Pertwee. Cannabinoids. Handbook of Experimen-

tal Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X

146
Chapter 107

JWH-359

JWH-359 is a dibenzopyran “classical” cannabinoid

drug, which is a potent and selective CB2 receptor ago-
nist, with a Kᵢ of 13.0nM and selectivity of around 220x
for CB2 over CB1 receptors. It is related to other diben-
zopyran CB2 agonists such as JWH-133 and L-759,656
but with a chiral side chain which has made it useful in
mapping the shape of the CB2 binding site.[1][2] It was
discovered by, and named after, Dr. John W. Huffman.

107.1 References
[1] Huffman, J.; Bushell, S.; Joshi, S.; Wiley, J.; Martin,
B. (2006). “Enantioselective synthesis of 1-methoxy-
and 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols:
new selective ligands for the CB2 receptor”. Bioor-
ganic & Medicinal Chemistry 14 (1): 247–262.
doi:10.1016/j.bmc.2005.08.013. PMID 16165365.

[2] “Recent advances in the development of selec-

tive ligands for the cannabinoid CB(2) recep-
tor”. Curr Top Med Chem 8 (3): 187–204. 2008.
doi:10.2174/156802608783498014. PMID 18289088.

147
Chapter 108

JZL184

JZL184 is an irreversible inhibitor for monoacylglycerol

lipase (MAGL), the primary enzyme responsible for
degrading the endocannabinoid 2-arachidonoylglycerol
(2-AG).[1] It displays high selectivity for MAGL over
other brain serine hydrolases, including the anandamide-
degrading enzyme fatty acid amide hydrolase (FAAH),
thereby making it a useful tool for studying the effects
of endogenous 2-AG signaling, in vivo. Administration
of JZL184 to mice was reported to cause dramatic eleva-
tion of brain 2-AG leading to several cannabinoid-related
behavioral effects.

108.1 See also

• JZL195

108.2 References
[1] Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlos-
burg JE, Pavón FJ, Serrano AM, Selley DE, Parsons LH,
Lichtman AH, Cravatt BF (November 2008). “Selective
blockade of 2-arachidonoylglycerol hydrolysis produces
cannabinoid behavioral effects”. Nat. Chem. Biol. 5
(1): 37–44. doi:10.1038/nchembio.129. PMC 2605181.
PMID 19029917.

148
Chapter 109

JZL195

JZL195 is a potent inhibitor of both fatty acid

amide hydrolase (FAAH) and monoacylglycerol lipase
(MAGL), the primary enzymes responsible for degrad-
ing the endocannabinoids anandamide (AEA) and 2-
arachidonoylglycerol (2-AG), respectively.[1]

109.1 See also

• JZL184

109.2 References
[1] Long, J. Z.; Nomura, D. K.; Vann, R. E.; Walentiny, D.
M.; Booker, L.; Jin, X.; Burston, J. J.; Sim-Selley, L.
J.; Lichtman, A. H.; Wiley, J. L.; Cravatt, B. F. (2009).
“Dual blockade of FAAH and MAGL identifies behav-
ioral processes regulated by endocannabinoid crosstalk in
vivo”. Proceedings of the National Academy of Sciences
106 (48): 20270. doi:10.1073/pnas.0909411106.

149
Chapter 110

KM-233

KM-233 is a drug which is an analogue of Δ8-
tetrahydrocannabinol (THC), the less active but more sta-
ble isomer of the active component of Cannabis. km-233
differs from Δ8-THC by the pentyl side chain being re-
placed by a 1,1-dimethylbenzyl group. It has high bind-
ing affinity in vitro for both the CB1 and CB2 receptors,
with a CB2 affinity of 0.91nM and 13x selectivity over
the CB1 receptor.[1] In animal studies it has been found
to be effective for the treatment of glioma, a form of
brain tumor.[2] A large number of related analogues are
known where the 1,1-dimethylbenzyl group is substituted
or replaced by other groups, with a fairly well established
structure-activity relationship.[3][4][5][6][7]
110.1 See also
[5] Krishnamurthy M, Gurley S, Moore BM 2nd. Exploring
the substituent effects on a novel series of C1'-dimethyl-
aryl Delta8-tetrahydrocannabinol analogs. Bioorganic
and Medicinal Chemistry. 2008 Jul 1;16(13):6489-500.
PMID 18524604
[6] Ferreira AM, et al. Quantitative structure-activity re-
lationship (QSAR) for a series of novel cannabinoid
derivatives using descriptors derived from semi-empirical
quantum-chemical calculations. Bioorganic and Medic-
inal Chemistry. 2009 Mar 15;17(6):2598-606. PMID
19250829
[7] Brogi S, et al. Three-dimensional quantitative structure-
selectivity relationships analysis guided rational design
of a highly selective ligand for the cannabinoid recep-
tor 2. European Journal of Medicinal Chemistry. 2011
Feb;46(2):547-55. PMID 21183257

• AM-411

• AMG-36

110.2 References
[1] Krishnamurthy M, Ferreira AM, Moore BM 2nd. Synthe-
sis and testing of novel phenyl substituted side-chain ana-
logues of classical cannabinoids. Bioorganic and Medic-
inal Chemistry Letters. 2003 Oct 20;13(20):3487-90.
PMID 14505654

[2] Duntsch C, et al. Safety and efficacy of a novel cannabi-

noid chemotherapeutic, KM-233, for the treatment of
high-grade glioma. Journal of Neuro-oncology. 2006
Apr;77(2):143-52. PMID 16314952

[3] Nadipuram AK, et al. Synthesis and testing of novel clas-

sical cannabinoids: exploring the side chain ligand bind-
ing pocket of the CB1 and CB2 receptors. Bioorganic
and Medicinal Chemistry. 2003 Jul 17;11(14):3121-32.
PMID 12818675

[4] Durdagi S, et al. The application of 3D-QSAR studies

for novel cannabinoid ligands substituted at the C1' posi-
tion of the alkyl side chain on the structural requirements
for binding to cannabinoid receptors CB1 and CB2. Jour-
nal of Medicinal Chemistry. 2007 Jun 14;50(12):2875-85.
PMID 17521177

150
Chapter 111

L-759,633

L-759,633 is an analgesic drug that is a cannabinoid

agonist. It is a fairly selective agonist for the CB2
receptor, with selectivity of 163x for CB2 over CB1 .[1]
It produces some similar effects to other cannabinoid ag-
onists such as analgesia, but with little or no sedative or
psychoactive effects due to its weak CB1 activity, and a
relatively strong antiinflammatory effect due to its strong
activity at CB2 .[2][3]

111.1 See also

• L-759,656

• L-768,242

111.2 References
[1] Ross, RA, Brockie, HC, Stevenson, LA, Murphy, VL,
Templeton, F, Makriyannis, A, Pertwee, RG (1999).
“Agonist-inverse agonist characterization at CB1 and
CB2 cannabinoid receptors of L759633, L759656 and
AM630”. British Journal of Pharmacology 126 (3): 665–
72. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID
10188977.

[2] Huffman, JW (2000). “The search for selective ligands

for the CB2 receptor”. Current pharmaceutical design 6
(13): 1323–37. doi:10.2174/1381612003399347. PMID
10903395.

[3] Huffman, JW (2005). “CB2 receptor ligands”.

Mini reviews in medicinal chemistry 5 (7): 641–9.
doi:10.2174/1389557054368844. PMID 16026310.

151
Chapter 112

L-759,656

L-759,656 is an analgesic drug that is a cannabinoid

agonist. It is a highly selective agonist for the CB2
receptor, with selectivity of 414x for CB2 over CB1 ,[1]
although it is still not as selective as newer agents such as
HU-308.
It produces some similar effects to other cannabinoid ag-
onists such as analgesia, but with little or no sedative or
psychoactive effects due to its weak CB1 activity, and a
relatively strong antiinflammatory effect due to its strong
activity at CB2 .[2][3]

112.1 See also

• L-759,633

• L-768,242

112.2 References
[1] Ross, R.; Brockie, H.; Stevenson, L.; Murphy, V.;
Templeton, F.; Makriyannis, A.; Pertwee, R. (1999).
“Agonist-inverse agonist characterization at CB1 and
CB2 cannabinoid receptors of L759633, L759656, and
AM630”. British Journal of Pharmacology 126 (3): 665–
672. doi:10.1038/sj.bjp.0702351. PMC 1565857. PMID
10188977.

[2] Huffman, J. W. (2000). “The search for selective ligands

for the CB2 receptor”. Current pharmaceutical design
6 (13): 1323–1337. doi:10.2174/1381612003399347.
PMID 10903395.

[3] Huffman, J. W. (2005). “CB2 receptor ligands”.

Mini reviews in medicinal chemistry 5 (7): 641–649.
doi:10.2174/1389557054368844. PMID 16026310.

152
Chapter 113

LASSBio-881

LASSBio-881 is a drug which acts as both a non-selective

partial agonist of the CB1 and CB2 cannabinoid recep-
tors, and also as an antagonist of the TRPV1 recep-
tor, as well as having antioxidant effects. It has potent
anti-inflammatory and anti-hyperalgesic effects in animal
studies.[1][2][3]

113.1 References
[1] Duarte CD, Tributino JL, Lacerda DI, Martins MV,
Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula
FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP,
Bertho AL, Miranda AL, Barreiro EJ, Fraga CA. Syn-
thesis, pharmacological evaluation and electrochemi-
cal studies of novel 6-nitro-3,4-methylenedioxyphenyl-
N-acylhydrazone derivatives: Discovery of LASSBio-
881, a new ligand of cannabinoid receptors. Bioorganic
and Medicinal Chemistry. 2007 Mar 15;15(6):2421-33.
PMID 17275312

[2] Tributino JL, Santos ML, Mesquita CM, Lima CK, Silva
LL, Maia RC, Duarte CD, Barreiro EJ, Fraga CA, Castro
NG, Miranda AL, Guimaraes MZ. LASSBio-881: an N-
acylhydrazone transient receptor potential vanilloid sub-
family type 1 antagonist orally effective against the hyper-
nociception induced by capsaicin or partial sciatic ligation.
British Journal of Pharmacology. 2010 Apr;159(8):1716-
23. PMID 20401963

[3] Santana P et al. NEUROACTIVE PROPERTIES OF

THE MULTIFUNCTIONAL PROTOTYPE LASSBio-
881: FOCUS ON THE CANNABINOID SYSTEM

153
Chapter 114

LBP-1 (drug)

LBP-1 is a drug originally developed by Organon
for the treatment of neuropathic pain,[1][2] and sub-
sequently further developed by Merck after they ac-
quired Organon’s patents following their merger with
Schering-Plough.[3][4][5] It acts as a potent and selec-
tive cannabinoid receptor agonist, with high potency at
both the CB1 and CB2 receptors, but low penetration
of the blood–brain barrier. This makes LBP-1 periph-
erally selective, and while it was effective in animal mod-
els of neuropathic pain and allodynia, it did not produce
cannabinoid-appropriate responding suggestive of central
effects, at any dose tested.[6]
114.1 See also
• Org 28312
• Org 28611
[5] Ratcliffe P, Adam JM, Baker J, Bursi R, Campbell R,
Clark JK, Cottney JE, Deehan M, Easson AM, Ecker D,
Edwards D, Epemolu O, Evans L, Fields R, Francis S,
Harradine P, Jeremiah F, Kiyoi T, McArthur D, Morrison
A, Passier P, Pick J, Schnabel PG, Schulz J, Steinbrede H,
Walker G, Westwood P, Wishart G, de Haes JU. Design,
synthesis and structure-activity relationships of (indo-3-
yl) heterocyclic derivatives as agonists of the CB1 recep-
tor. Discovery of a clinical candidate. Bioorganic and
Medicinal Chemistry Letters. 2011 Apr 15;21(8):2541-6.
PMID 21411321
[6] Adam JM, Clark JK, Davies K, Everett K, Fields R,
Francis S, Jeremiah F, Kiyoi T, Maidment M, Morrison
A, Ratcliffe P, Prosser A, Schulz J, Wishart G, Baker
J, Boyce S, Campbell R, Cottney JE, Deehan M, Mar-
tin I. Low brain penetrant CB1 receptor agonists for the
treatment of neuropathic pain. Bioorganic and Medici-
nal Chemistry Letters. 2012 Apr 15;22(8):2932-7. PMID
22421020

114.2 References
[1] Julia Adam. Indole Derivatives. Patent WO 2008/101995

[2] Paul David Ratcliffe, Julia Adam-Worrall, Angus John

Morrison, Stuart John Francis, Takao Kiyoi. Indole
Derivatives. Patent US 7763732

[3] Morrison AJ, Adam JM, Baker JA, Campbell RA, Clark
JK, Cottney JE, Deehan M, Easson AM, Fields R, Fran-
cis S, Jeremiah F, Keddie N, Kiyoi T, McArthur DR,
Meyer K, Ratcliffe PD, Schulz J, Wishart G, Yoshiizumi
K. Design, synthesis, and structure-activity relationships
of indole-3-heterocycles as agonists of the CB1 recep-
tor. Bioorganic and Medicinal Chemistry Letters. 2011
Jan 1;21(1):506-9. PMID 21075630

[4] Kiyoi T, Adam JM, Clark JK, Davies K, Easson AM,

Edwards D, Feilden H, Fields R, Francis S, Jeremiah
F, McArthur D, Morrison AJ, Prosser A, Ratcliffe PD,
Schulz J, Wishart G, Baker J, Campbell R, Cottney JE,
Deehan M, Epemolu O, Evans L. Discovery of potent and
orally bioavailable heterocycle-based cannabinoid CB1
receptor agonists. Bioorganic and Medicinal Chemistry
Letters. 2011 Mar 15;21(6):1748-53. PMID 21316962

154
Chapter 115

Leelamine

Leelamine is a diterpene amine that has weak affinity

for the cannabinoid receptors CB1 and CB2 , as well as
being an inhibitor of pyruvate dehydrogenase kinase.[1]
Optically active leelamine is also used as a chiral resolv-
ing agent for carboxylic acids.[2][3]

115.1 See also

• THC

• Resin acid

115.2 References
[1] “Leelamine - Dehydroabietylamine - Cayman Chemical”.
Retrieved May 20, 2013.

[2] US patent 3454626

[3] US patent 4559178

155
Chapter 116
Levonantradol
Levonantradol (CP 50,556-1) is a synthetic cannabinoid
analog of dronabinol (Marinol) developed by Pfizer in the
1980s. It is around 30x more potent than THC, and ex-
hibits antiemetic and analgesic effects via activation of
CB1 and CB2 cannabinoid receptors.[1] Levonantradol is
not currently used in medicine as dronabinol or nabilone
are felt to be more useful for most conditions, however it
is widely used in research into the potential therapeutic
applications of cannabinoids.[2][3][4]
116.1 Pharmacodynamics
Levonantradol is a full CB1 receptor agonist. Cannabi-
noid receptors belong to the superfamily of G-protein
coupled receptors (GPCRs), and endogenous cannabi-
noids naturally activate GPCRs. GPCRs modulate
the inhibition of adenylyl cyclase and accumulation of
the second messenger, cyclic adenosine monophosphate
(cAMP). The CB1 receptor is the most common GPCR
in the central nervous system. The activation of CB1 Rs
decrease calcium conductance and increase potassium
conductance in the brain. CB signaling naturally mod-
ulates synaptic transmission and mediates psychoactiv-
ity, and synthetic cannabinoids mimic these same ac-
tions. Although the efficacy of Levonantradol is depen-
dent on the level of GCPR activity, Full agonists like Lev-
onantradol have the ability to activate GPCRs and convert
Gα into a high affinity state for GTP or low affinity state
for GDP. Previous studies suggest that Levonantradol has
a higher binding affinity and efficacy than other similar
synthetic cannabinoids (e.g. Δ9 -THC).
116.2 Pharmacokinetics
Although Levonantradol has been extensively tested on
animals including cats, rodents, and non-human primates.
It has also been tested among cancer patient populations
in clinical trials. Levonantradol is most commonly ad-
ministered intramuscularly (I.M.), however it can also be
administered orally. The dosage can range from 0.25 mg-
3.0 mg every 2–4 hours, and the half-life is 1–2 hours. In
order to administer Levonantradol intramuscularly, the
156
drug must be dissolved in 5% ethanol, 5% emulphur,
and 90% sterile saline. Synthetic cannabinoids like Lev-
onantradol readily cross the blood-brain barrier because
they are highly lipophilic and have low molecular weights.
Levonantradol’s bioavailability is variable due to the first
pass metabolism.
116.3 Treatment
Levonantradol has been clinically tested in cancer pa-
tients for its pain relief and antiemetic benefits. Can-
cer patients that endure chemotherapy often develop in-
tense nausea, and Levonantradol has been tested to re-
duce these emetic symptoms. It is often used instead
of THC because it has a higher efficacy. Levonantradol
also acts on pain pathways in the central nervous sys-
tem, which enables the drug to alleviate pain. Studies
have shown an absence of emetic side effects within the
half-life of the Levonantradol administered. Other stud-
ies suggest that cannabinoid agonists can synergize opioid
anti-nociception. Cannabinoid receptors are located in
nociceptive pathways, and CBs can promote signal trans-
duction in TRP channels. Although Levonantradol re-
lieves nociceptive and postoperative pain, decreases nau-
sea, and improves spasticity in addition to being more
effective than placebos, it has yet to be approved as le-
gal medicine. Researchers have concluded that Levo-
nantradol is no more effective than Codeine, which is why
they do not recommend expansion into clinical practice.
116.4 Side effects
The side effects for Levonantradol include ptosis, seda-
tion, and ataxia in non-human primates. In rodents, the
symptoms include dysphoria, memory impairment, mo-
tor incoordination, reduced concentration, and disorien-
tation. Levonantradol also decreases startle response.
In humans, side effects include dry mouth, drowsiness,
dizziness, altered perception, mild sedation, and lack of
concentration. It can cause an increase in heart rate and
decrease in blood pressure. Euphoric symptoms rarely
occurred in subjects.
116.7. REFERENCES 157

116.5 See also

• CP 47,497

116.6 Notes
[1] Little PJ, et al. Pharmacology and stereoselectivity
of structurally novel cannabinoids in mice. Journal
of Pharmacology and Experimental Therapeutics 1988;
247:1046–1051.

[2] Tramer MR, et al. Cannabinoids for control of

chemotherapy induced nausea and vomiting: quantita-
tive systematic review. British Medical Journal 2001 Jul
7;323(7303):16-21.

[3] Campbell FA, et al. Are cannabinoids an effective and

safe treatment option in the management of pain? A qual-
itative systematic review. British Medical Journal. 2001
Jul 7;323(7303):13-6.

[4] Ben Amar M. Cannabinoids in medicine: A review of

their therapeutic potential. Journal of Ethnopharmacol-
ogy. 2006 Apr 21;105(1-2):1-25.

116.7 References
• Childers, SR (Mar 10, 2006). “Activation of G-
proteins in brain by endogenous and exogenous
cannabinoids.”. The AAPS journal 8 (1): E112–7.
doi:10.1208/aapsj080113. PMC 2751429. PMID
16584117.
• Hosking, R.D.; Zajicek, J.P. (2008). “Therapeutic
potential of cannabis in pain medicine”.
British Journal of Anaesthesia 101 (1): 59–68.
doi:10.1093/bja/aen119.
• McCarthy, LE; Borison, HL (Aug–Sep 1981).
“Antiemetic activity of N-methyllevonantradol and
nabilone in cisplatin-treated cats.”. Journal of
clinical pharmacology 21 (8–9 Suppl): 30S–37S.
doi:10.1002/j.1552-4604.1981.tb02570.x. PMID
6271834.
• Milewich, L; Gant, NF; Schwarz, BE; Chen, GT;
MacDonald, PC (Mar 15, 1979). “5 alpha-
Reductase activity in human placenta.”. American
journal of obstetrics and gynecology 133 (6): 611–
7. PMID 34324.
Chapter 117
List of AM cannabinoids
Alexandros Makriyannis is a professor in the Depart-
ment of Medicinal Chemistry at Northeastern University,
where his research group has synthesized many new com-
pounds with cannabinoid activity. Some of those are:
• AM-087 — an analgesic CB1 agonist derived from
Δ8 THC substituted with a side chain on the 3-
position, it has a Kᵢ of 0.43nM making it roughly
100x as potent as THC.
• AM-251 — an inverse agonist at the CB1
cannabinoid receptor that is structurally related to
SR141716A (rimonabant), but has a higher binding
affinity with a Kᵢ value of 7.5nM.[1]
• AM-281 — N-(morpholin-4-yl)−1-(2,4-
dichlorophenyl)−5-(4-iodophenyl)−4-methyl-
1H-pyrazole-3-carboxamide[1]
• AM-356 — a synthetically created stable chiral ana-
log of anandamide, it acts on the cannabinoid re-
ceptors with a Kᵢ of 17.9nM at CB1 and 868nM at
CB2 .[2]
• AM-374 — palmitylsulfonyl fluoride[3]
• AM-381 — stearylsulfonyl fluoride
• AM-404 — an active metabolite of paracetamol
(acetaminophen) and a likely inhibitor of fatty acid
amide hydrolase (FAAH)
• AM-411 — an adamantyl-substituted derivative of
Δ8 THC, it is a potent and fairly selective CB1 full
agonist with a Kᵢ of 6.80nM. It is also a moderately
potent CB2 agonist with a Kᵢ of 52.0nM.
• AM-630 — a potent and selective inverse agonist for
the cannabinoid receptor CB2 , with a Kᵢ of 32.1nM
at CB2 and 165x selectivity over CB1 , at which it
acts as a weak partial agonist.
• AM-661 — 1-(N-methyl-2-piperidine)methyl-2-
methyl-3-(2-iodo)benzoylindole[4]
• AM-678 — another name for JWH-018, it is a full
agonist at both cannabinoid receptors with some se-
lectivity for CB2 .
158
• AM-679 — an iodobenzoylindole which acts as a
moderately potent agonist for the cannabinoid re-
ceptors, with a Kᵢ of 13.5nM at CB1 and 49.5nM
at CB2 .
• AM-694 — an iodobenzoylindole which acts as a
potent and selective agonist for the CB1 cannabinoid
receptor, with a Kᵢ of 0.08nM at CB1 and 18x se-
lectivity over the related CB2 receptor (1.44nM).[5]
• AM-735 — 3-bornyl-Δ8-THC, a mixed CB1 / CB2
agonist with Kᵢ of 8.9nM at CB1 and 7.4nM at
CB2 .[6]
• AM-855 — an analgesic derivative of
Δ8 tetrahydrocannabinol, it is an agonist at both
CB1 and CB2 with moderate selectivity for CB1 ,
with a Kᵢ of 22.3nM at CB1 and 58.6nM at CB2 .
• AM-881 — a chlorine-substituted stereoisomer of
anandamide whose Kᵢ = 5.3nM at CB1 and 95nM at
CB2 .[2]
• AM-883 — an allyl-substituted stereoisomer of
anandamide whose Kᵢ = 9.9nM at CB1 and 226nM
at CB2 .[2]
• AM-905 — a potent and reasonably selective ago-
nist for the CB1 cannabinoid receptor, with a Kᵢ of
1.2nM at CB1 and 5.3nM at CB2 .
• AM-906 — a potent and dodecally selective ago-
nist for the CB1 cannabinoid receptor, with a Kᵢ of
0.8nM at CB1 and 9.5nM at CB2 .
• AM-919 — a potent agonist at both CB1 and CB2
with moderate selectivity for CB1 , with a Kᵢ of
2.2nM at CB1 and 3.4nM at CB2 . It is a derivative of
HU-210 and represents a hybrid structure between
the classical and nonclassical cannabinoid families.
• AM-926 — a potent agonist at both CB1 and CB2
with moderate selectivity for CB1 , with a Kᵢ of
2.2nM at CB1 and 4.3nM at CB2 . It is a derivative of
HU-210 and represents a hybrid structure between
the classical and nonclassical cannabinoid families.
• AM-938 — a potent agonist at both CB1 and CB2
with quadruple selectivity for CB2 , with a Kᵢ of
117.1. SEE ALSO
1.2nM at CB1 and 0.3nM at CB2 . It is a derivative of
HU-210 and represents a hybrid structure between
the classical and nonclassical cannabinoid families.
• AM-1116 — a dimethylated stereoisomer of anan-
damide whose Kᵢ = 7.4nM at CB1 .[2]
• AM-1172 — an endocannabinoid analog specifi-
cally designed to be a potent and selective inhibitor
of AEA uptake that is resistant to FAAH hydrolysis.
• AM-1220 — a potent and selective analgesic CB1
agonist (as racemate) with a Kᵢ of 3.88nM at CB1
and 73.4nM at CB2 , giving it 19x selectivity for
CB1 . (R) enantiomer has around 1000x higher affin-
ity for CB1 than (S) enantiomer.[7][8]
• AM-1221 — a potent and selective CB2 agonist with
a Kᵢ of 0.28nM at CB2 and 52.3nM at CB1 , giving
it a selectivity of almost 187x.
• AM-1235 — a moderately CB1 selective agonist,
with a Kᵢ of 1.5nM at CB1 and 20.4nM at CB2 , giv-
ing it a selectivity of around 13x.[9]
• AM-1241 — a potent and selective analgesic CB2
agonist with a Kᵢ of 3.4nM at CB2 and 80x selectiv-
ity over CB1 .[10]
• AM-1248 — a moderately potent agonist with
some selectivity for CB1 , containing an unusual 3-
(adamant-1-oyl) substitution on the indole ring.
• AM-1710 — a CB2 selective cannabilactone with A more complete list can be found here
54x selectivity over CB1 .[11]
• AM-1714 — a CB2 selective cannabilactone with
490x selectivity over CB1 .[11]
• AM-2201 — a potent agonist at both CB1 and CB2
with moderate selectivity for CB1 , with a Kᵢ of
1.0nM at CB1 and 2.6nM at CB2 .
• AM-2212 — a potent agonist at both CB1 and CB2
with dodecal selectivity for CB1 , with a Kᵢ of 1.4nM
at CB1 and 18.9nM at CB2 .[4]
• AM-2213 — a potent agonist at both CB1 and CB2
with 10x selectivity for CB1 , with a Kᵢ of 3.0M at
CB1 and 30nM at CB2 .[4]
• AM-2232 — a potent agonist at both CB1 and CB2 ,
with a Kᵢ of 0.28nM at CB1 and 1.48nM at CB2 .[9]
• AM-2233 — (R) enantiomer is potent and se-
lective CB1 agonist used in 131 I radiolabelled
form to map distribution of CB1 receptors in
brain.[12][13][14][15][16][17]
• AM-2389 — classical cannabinoid derivative with
26x selectivity for CB1 .
159
• AM-3102 — an analog of oleoylethanolamide, the
endogenous agonist for proliferator-activated recep-
tor α (PPARα). It also acts as a weak cannabinoid
agonist with Kᵢ values of 33µM at CB1 and 26µM at
CB2 .
• AM-4030 — a potent agonist at both CB1 and CB2 ,
it is dodecally selective for CB1 , with a Kᵢ of 0.7nM
at CB1 and 8.6nM at CB2 . It is a derivative of HU-
210 and represents a hybrid structure between the
classical and nonclassical cannabinoid families.
• AM-4054 — a potent but slow-onset agonist with
CB1 affinity of 2.2nM and a 40x selectivity for CB1
over CB2 .[18][19]
• AM-4113 — a CB1 selective neutral antagonist.[20]
• AM-6545 — a peripherally selective silent antago-
nist of CB1 receptors.
117.1 See also
• List of JWH cannabinoids
• List of HU cannabinoids
• List of CP cannabinoids
117.2 Further reading
117.3 References
[1] Lan, Ruoxi; Lu, Qian; Fan, Pusheng; Gatley, John;
Volkow, Nora D.; Fernando, Susanthi R.; Pertwee, Roger;
Makriyannis, Alexandros (1999). “Design and synthesis
of the CB1 selective cannabinoid antagonist AM281: A
potential human SPECT ligand”. AAPS PharmSci 1 (2):
39–45. doi:10.1208/ps010204.
[2] Selwood, D. (2009). “The Cannabinoid Receptors.
Edited by Patricia H. Reggio”. ChemMedChem 4: 1949.
doi:10.1002/cmdc.200900286.
[3] Pacher, P.; Bátkai, S; Kunos, G (2006). “The En-
docannabinoid System as an Emerging Target of Phar-
macotherapy”. Pharmacological Reviews 58 (3): 389–
462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID
16968947.
[4] Hongfeng Deng. Design and synthesis of selective
cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs. PhD Dissertation, University
of Connecticut, 2000.
[5] WO patent 200128557, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2001-06-
07
160 CHAPTER 117. LIST OF AM CANNABINOIDS

[6] Lu D, Guo J, Duclos RI Jr, Bowman AL, Makriyannis
A. Bornyl- and isobornyl-Delta8-tetrahydrocannabinols: a
novel class of cannabinergic ligands. Journal of Medic-
inal Chemistry. 2008 Oct 23;51(20):6393-9. PMID
18826296
[7] D'ambra, T. (1996). “C-Attached aminoalkylindoles:
potent cannabinoid mimetics”. Bioorganic & Medic-
inal Chemistry Letters 6: 17–14. doi:10.1016/0960-
894X(95)00560-G.
[16] Leung K (Dec 12, 2006). “R-2-[131I]Iodophenyl-
(1-(1-methylpiperidin-2-ylmethyl)−1H-indol-3-
yl)methanone”. Molecular Imaging and Contrast
Agent Database (MICAD) [Internet]. PMID 20641836.
[17] Pei, Y., et al. (2008). “Ligand-Binding Architecture
of Human CB2 Cannabinoid Receptor: Evidence for
Receptor Subtype-Specific Binding Motif and Model-
ing GPCR Activation”. Chemistry & Biology 15: 1207.
doi:10.1016/j.chembiol.2008.10.011.

[18] [Paronis CA, Thakur GA, Vemuri K, Makriyannis A,

[8] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D.
B.; Mukhin, A. G.; Horti, A. G. (2005). “Synthesis
and Structure−Activity Relationship of a Novel Series of
Aminoalkylindoles with Potential for Imaging the Neu-
ronal Cannabinoid Receptor by Positron Emission To-
mography”. Journal of Medicinal Chemistry 48 (18):
5813. doi:10.1021/jm0502743. PMID 16134948.
[9] US patent 7241799, Makriyannis A, Deng H,
“Cannabimimetic indole derivatives”, granted 2007-
07-10
Bergman J. Effects of a Selective Cannabinoid Ag-
onist and Antagonist on Body Temperature in Rats.
The FASEB Journal. April 2007 21 (Meeting Abstract
Supplement) A409. http://www.fasebj.org/cgi/content/
meeting_abstract/21/5/A409]
[19] Paronis, C. A.; Thakur, G. A.; Bajaj, S.; Nikas, S. P.;
Vemuri, V. K.; Makriyannis, A.; Bergman, J. (2012).
“Diuretic effects of cannabinoids”. Journal of Pharma-
cology and Experimental Therapeutics 344 (1): 8–14.
doi:10.1124/jpet.112.199331. PMID 23019138.

[10] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabi-
noid CB2 receptor: modelling and structural determinants
of CB2 selective ligands”. British Journal of Pharma-
cology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC
2219524. PMID 17982473.
[20] Seely KA, Prather PL, James LP, Moran JH. Marijuana-
based drugs: innovative therapeutics or designer drugs of
abuse? Molecular Interventions. 2011 Feb;11(1):36-51.
PMID 21441120

[11] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur

GA, Malan TP Jr, Porreca F, Veerappan V, Tian X,
George C, Parrish DA, Papahatjis DP, Makriyannis A.
Cannabilactones: a novel class of CB2 selective agonists
with peripheral analgesic activity. Journal of Medici-
nal Chemistry. 2007 Dec 27;50(26):6493-500. PMID
18038967

[12] Deng H, Gifford AN, Zvonok AM, Cui G, Li X, Fan

P, Deschamps JR, Flippen-Anderson JL, Gatley SJ,
Makriyannis A (October 2005). “Potent cannabinergic
indole analogues as radioiodinatable brain imaging agents
for the CB1 cannabinoid receptor”. Journal of Medicinal
Chemistry 48 (20): 6386–92. doi:10.1021/jm050135l.
PMID 16190764.

[13] Hanuš, L. R. O.; Mechoulam, R. (2005). “Cannabi-

noid chemistry: an overview”. “Cannabinoids as Ther-
apeutics”. Milestones in Drug Therapy MDT. p. 23.
doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6.

[14] Shen CP, Xiao JC, Armstrong H, Hagmann W, Fong

TM (February 2006). “F200A substitution in the third
transmembrane helix of human cannabinoid CB1 receptor
converts AM2233 from receptor agonist to inverse ago-
nist”. European Journal of Pharmacology 531 (1–3): 41–
6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957.

[15] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.;

Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gif-
ford, A. N. (2006). “Evaluation of the in vivo re-
ceptor occupancy for the behavioral effects of cannabi-
noids using a radiolabeled cannabinoid receptor ago-
nist, R-[125/131I]AM2233”. Synapse 60 (2): 93–101.
doi:10.1002/syn.20277. PMID 16715483.
Chapter 118
List of JWH cannabinoids
The John W. Huffman research group at Clemson Uni-
versity synthesized over 450 cannabinoids. Some of those
are:
• JWH-007 — an analgesic chemical from the
naphthoylindole family, which acts as a cannabinoid
agonist at both the CB1 receptor and CB2 receptors,
with some selectivity for CB2 with a Kᵢ of 2.9nM ±
2.6 and 9.5nM ± 4.5 at CB1 .[1]
• JWH-015 — a chemical from the naphthoylindole
family, which acts as a subtype-selective cannabi-
noid agonist. Its affinity for CB2 receptors is
13.8nM, while its affinity for CB1 is 383nM, mean-
ing that it binds almost 28x more strongly to CB2
than CB1 .[1]
• JWH-018 — an analgesic chemical from the naph-
thoylindole family, which acts as a full agonist at
both the CB1 and CB2 cannabinoid receptors, with
some selectivity for CB2 with a Kᵢ of 2.9nM ± 2.6
and 9nM ± 5 at CB1 .[1] It is found in some forms of
synthetic cannabis.
• JWH-019 — an agonist at both CB1 and CB2 re-
ceptors, it has 1.77x selectivity for CB2 with a Kᵢ of
5.55nM ± 2 and 9.8nM ± 2 at CB1 .
• JWH-030 — an analgesic chemical from the
naphthoylpyrrole family, it is a partial agonist at CB1
receptors, with a Kᵢ of 87nM, making it roughly half
the potency of THC.
• JWH-047 — a potent and selective agonist for the
CB2 receptor with a Kᵢ of 0.9 nM, and a Kᵢ of 59 ±
3 nM at CB1 , it has a 65x selectivity for CB2 .[1]
• JWH-048 — a potent and selective agonist for the
CB2 receptor with a Kᵢ of 0.49 nM ± 0.1, and a Kᵢ
of 10.7 nM ± 1.0 at CB1 , it has a 22x selectivity for
CB2 .[1]
• JWH-051 — an analgesic, it has high affinity for
the CB1 receptor, but is a much stronger agonist for
CB2 , with a Kᵢ value of 0.03nM at CB2 vs 1.20nM
at CB1 . It was one of the first CB2 -selective ligands
developed, although its selectivity for CB2 is modest
compared to newer compounds such as HU-308.
161
• JWH-057 — a 1-deoxy analog of Δ8-THC that has
very high affinity for the CB2 receptor, but also has
high affinity for the CB1 receptor.[2]
• JWH-073 — an analgesic chemical from the naph-
thoylindole family, which acts as a cannabinoid ag-
onist at both the CB1 and CB2 receptors. It is
somewhat selective for the CB1 subtype with a Kᵢ
of 8.9nM. It is found in some forms of synthetic
cannabis.
• JWH-081 — an analgesic chemical from the naph-
thoylindole family, which acts as an agonist at both
the cannabinoid receptors with a Kᵢ of 1.2nM ± 0.03
at CB1 [3] and 12.4nM ± 2.2 at the CB2 receptors. It
is fairly selective for the CB1 subtype with approxi-
mately 10x the affinity for CB2 . It is found in some
forms of synthetic cannabis.
• JWH-098 — a potent and fairly selective CB2 ag-
onist with a Kᵢ of 1.9nM ± 0.3 at CB2 and 4.5nM
± 0.1 at CB1 ,[3] giving it about 2.4x selectivity for
CB2 .
• JWH-116 — a CB1 ligand with a Kᵢ of 52 ± 5 nM[3]
• JWH-120 — a potent and 173-fold selective CB2
agonist with a Kᵢ of 6.1nM ± 0.7, it is the N-propyl
homolog of JWH-122.[2]
• JWH-122 — a potent and fairly selective CB1 ago-
nist with a Kᵢ of 0.69nM ± 0.5 at CB1 and 1.2nM ±
1.2 at CB2 . It is found in some forms of synthetic
cannabis.
• JWH-133 — a potent and highly selective CB2 re-
ceptor agonist with a Kᵢ of 3.4nM and selectivity of
around 200x for CB2 over CB1 receptors.[1]
• JWH-139 — 3-(1,1-dimethylpropyl)−6,6,9-
trimethyl-6a,7,10,10a-tetrahydro-6H-
benzo[c]chromene[4]
• JWH-147 — an analgesic drug from the naph-
thoylpyrrole family, which acts as a cannabinoid ag-
onist at both the CB1 and CB2 receptors. It is some-
what selective for the CB2 subtype, with a Kᵢ of
11.0nM at CB1 vs 7.1nM at CB2 .
162
• JWH-148 — a moderately selective ligand for the
CB2 receptor, with a binding affinity of Kᵢ = 14.0 ±
1.0 nM at this subtype, and more than 8 times selec-
tivity over the CB1 subtype.[5]
• JWH-149 — a potent and fairly selective CB2 ago-
nist with a Kᵢ of 0.73nM ± 0.03 and 5.0nM ± 2.1 at
CB1 ,[3] giving it about 6.8x selectivity for CB2 .
• JWH-161 — a CB1 ligand with Kᵢ of 19.0nM
• JWH-164 — a potent cannabinoid agonist with a Kᵢ
of 6.6nM ± 0.7 at CB1 and 6.9nM ± 0.2 at CB2 .
• JWH-166 — a potent and highly selective CB2 ag-
onist with a Kᵢ of 1.9nM ± 0.08 at CB2 and 44nM
± 10 at CB1 giving it 23x selectivity for CB2 .[1]
• JWH-167 — a weak cannabinoid agonist from the
phenylacetylindole family with 1.77x selectivity for
CB1 with a Kᵢ of 90nM ± 17 at CB1 and 159nM ±
14 at CB2 .[6]
• JWH-171 — an analgesic drug which acts as a
cannabinoid receptor agonist. Its binding affinity at
the CB1 receptor is only 51nM, making it slightly
less potent than THC itself.
• JWH-175 — (1-pentylindol-3-yl)naphthalen-1-
ylmethane, 22nM at CB1 [3]
• JWH-176 — 1-([(1E)−3-pentylinden-1-
ylidine]methyl)naphthalene, 26nM at CB1 [3]
• JWH-181 — a potent cannabinoid agonist with 2.1x
selectivity for CB2 with a Kᵢ of 0.62nM ± 0.04 and
1.3nM ± 0.1 at CB1 .
• JWH-182 — a potent cannabinoid agonist with
some selectivity for CB1 with a Kᵢ of 0.65nM ± 0.03
and 1.1nM ± 0.1 at CB2 .
• JWH-184 — 1-pentyl-1H-indol-3-yl-(4-methyl-1-
naphthyl)methane, 23nM at CB1 [3]
• JWH-185 — 1-pentyl-1H-indol-3-yl-(4-methoxy-
1-naphthyl)methane, 17nM at CB1 [3]
• JWH-192 — (1-(2-morpholin-4-ylethyl)indol-3-
yl)−4-methylnaphthalen-1-ylmethane, 41nM at
CB1 [3]
• JWH-193 — (1-(2-morpholin-4-ylethyl)indol-3-
yl)−4-methylnaphthalen-1-ylmethanone, 6nM at
CB1 [3]
• JWH-194 — 2-methyl-1-pentyl-1H-indol-3-yl-(4-
methyl-1-naphthyl)methane, 127nM at CB1 [3]
• JWH-195 — (1-(2-morpholin-4-ylethyl)indol-3-
yl)-naphthalen-1-ylmethane, 113nM at CB1 [3]
• JWH-196 — 2-methyl-3-(1-
naphthalenylmethyl)−1-pentyl-1H-Indole, 151nM
± 18 at CB1
CHAPTER 118. LIST OF JWH CANNABINOIDS
• JWH-197 — 2-methyl-1-pentyl-1H-indol-3-yl-(4-
methoxy-1-naphthyl)methane, 323nM at CB1 [3]
• JWH-198 — (1-(2-morpholin-4-ylethyl)indol-3-
yl)−4-methoxynaphthalen-1-ylmethanone, 10nM
at CB1 [3]
• JWH-199 — (1-(2-morpholin-4-ylethyl)indol-3-
yl)−4-methoxynaphthalen-1-ylmethane, 20nM at
CB1 [3]
• JWH-200 — an analgesic chemical from the
aminoalkylindole family, which acts as a cannabi-
noid receptor agonist. Its binding affinity at the CB1
receptor is 42nM, around the same as that of THC,
but interestingly, its analgesic potency in vivo was
higher than that of other analogues with stronger
CB1 binding affinity in vitro, around 3 times that of
THC but with less sedative effect, most likely re-
flecting favorable pharmacokinetic characteristics.
It is found in some forms of synthetic cannabis.
• JWH-203 — an analgesic chemical from the
phenylacetylindole family, which acts as a cannabi-
noid agonist with approximately equal affinity at
both the CB1 and CB2 receptors, having a Kᵢ of
8.0nM at CB1 and 7.0nM at CB2 . Similar to
the related 2'-methoxy compound JWH-250, JWH-
203 has a phenylacetyl group in place of the naph-
thoyl ring used in most aminoalkylindole cannabi-
noid compounds, and is the most potent compound
found in the phenylacetyl group.[6] It is found in
some forms of synthetic cannabis.
• JWH-205 — 1-(2-methyl-1-pentylindol-3-yl)−2-
phenylethanone, CB1 : 124nM ± 23 CB2 : 180nM
± 9 CB2 selectivity: 1.45x[6]
• JWH-210 — an analgesic chemical from the naph-
thoylindole family, which acts as a potent cannabi-
noid agonist at both the CB1 and CB2 receptors,
with Kᵢ values of 0.46nM at CB1 and 0.69nM at
CB2 . It is one of the most potent 4-substituted naph-
thoyl derivatives in the naphthoylindole series, hav-
ing a higher binding affinity (i.e. lower Kᵢ) at CB1
than both its 4-methyl and 4-n-propyl homologues
(JWH-122 and JWH-182 respectively), and than the
4-methoxy compound JWH-081.[1] It is found in
some forms of synthetic cannabis.
• JWH-213 — a potent and fairly selective CB2 ago-
nist with a Kᵢ of 0.42nM ± 0.05 at CB2 and 1.5nM
± 0.2 at CB1 giving it 3.6x selectivity over CB1 .[1]
• JWH-220 — 19nM at CB1
• JWH-229 — 1-methoxy-3-(1',1'-dimethylhexyl)-
Δ8 -THC, a dibenzopyran “classical” cannabinoid
drug with a Kᵢ of 4.6nM ± 2.0, it is a potent CB2
agonist.
118.1. SEE ALSO
• JWH-234 — a cannabinoid agonist that has 2.2x se-
lectivity for CB2 with a Kᵢ value of 8.4nM ± 1.8 at
CB2 and 3.8nM ± 0.6 at CB1 .
• JWH-249 — CB1 : 8.4nM ± 1.8 CB2 : 20nM ± 2
selectivity for CB1 : 2.38x[6]
• JWH-250 — an analgesic chemical from the pheny-
lacetylindole family, which acts as a cannabinoid ag-
onist at both the CB1 and CB2 receptors, with a Kᵢ
of 11nM at CB1 and 33nM at CB2 .[6] It is found in
some forms of synthetic cannabis.
• JWH-251 — (1-pentyl-3-(2-
methylphenylacetyl)indole) CB1 : 29nM ± 3
CB2 : 146nM ± 36 selectivity for CB1 : 5x[6]
• JWH-253 —
• JWH-258 — a potent and mildly selective CB1 ag-
onist with a Kᵢ of 4.6nM ± 0.6 and 10.5nM ± 1.3 at
CB2 .[1]
• JWH-300 — CB1 : 116nM CB2 : 5.3nM[2]
• JWH-302 — (1-pentyl-3-(3-
methoxyphenylacetyl)indole) CB1 : 17nM ± 2
CB2 : 89nM ± 15 selectivity for CB1 : 5.26x[6]
• JWH-307 — an analgesic drug from the naph-
thoylpyrrole family, which acts as a cannabinoid ag-
onist at both the CB1 and CB2 receptors. It is some-
what selective for the CB2 subtype, with a Kᵢ of
7.7nM at CB1 vs 3.3nM at CB2 .
• JWH-336 — CB1 : ~1.2nM CB2 : 36nM[2]
• JWH-350 — a 11-nor-1-methoxy-3-(1',1'-
dimethylheptyl)−9α-hydroxyhexahydrocannabinol
with 33-fold selectivity for the CB2 receptor and
high CB2 receptor affinity (Kᵢ=12nM ± 1) has the
desirable combination of excellent CB2 affinity
combined with little affinity for the CB1 receptor.[2]
• JWH-359 — a dibenzopyran “classical” cannabi-
noid drug with a Kᵢ of 13.0nM and selectivity of
around 220x for CB2 , it is a potent and selective CB2
receptor agonist.
• JWH-387 — 1-pentyl-3-(4-bromo-1-
naphthoyl)indole, an analgesic chemical from
the naphthoylindole family, which acts as a potent
cannabinoid agonist at both receptors with a Kᵢ of
1.2nM at CB1 and 1.1nM at CB2 .
• JWH-398 — an analgesic chemical from the naph-
thoylindole family, which acts as a potent cannabi-
noid agonist at both receptors with a Kᵢ of 2.3nM at
CB1 and 2.8nM at CB2 .[7]
• JWH-424 — a potent and moderately selective CB2
agonist with a Kᵢ of 5.44nM at CB2 and 20.9nM at
CB1 .
163
118.1 See also
• List of AM cannabinoids
• List of HU cannabinoids
• List of CP cannabinoids
• List of miscellaneous designer cannabinoids
118.2 References
[1] Huffman, JW, Zengin, G, Wu, MJ, Lu, J, Hynd, G,
Bushell, K, Tartal, C, Hurst, DP, Reggio, PH, Selley, DE,
Cassidy, MP, Wiley, JL, Martin, BR (2005). “Structure-
activity relationships for 1-alkyl-3-(1-naphthoyl)indoles
at the cannabinoid CB(1) and CB(2) receptors: steric
and electronic effects of naphthoyl substituents. New
highly selective CB(2) receptor agonists”. Bioor-
ganic & Medicinal Chemistry Letters 13 (1): 89–112.
doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
[2] Poso, A.; Huffman, J. W. (2008). “Targeting the cannabi-
noid CB2 receptor: modelling and structural determinants
of CB2 selective ligands”. British Journal of Pharma-
cology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC
2219524. PMID 17982473.
[3] Huffman, JW, Mabon, R, Wu, MJ, Lu, J, Hart, R, Hurst,
DP, Reggio, PH, Wiley, JL, Martin, BR (2003). “3-
Indolyl-1-naphthylmethanes: New Cannabimimetic In-
doles Provide Evidence for Aromatic Stacking Inter-
actions with the CB1 Cannabinoid Receptor”. Bioor-
ganic & Medicinal Chemistry Letters 11 (4): 539–549.
doi:10.1016/S0968-0896(02)00451-0. PMID 12538019.
[4] Howlett, A. C.; Barth, F; Bonner, TI; Cabral, G; Casellas,
P; Devane, WA; Felder, CC; Herkenham, M; MacKie, K
(2002). “International Union of Pharmacology. XXVII.
Classification of Cannabinoid Receptors”. Pharmacolog-
ical Reviews 54 (2): 161–202. doi:10.1124/pr.54.2.161.
PMID 12037135.
[5] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.
[6] Huffman, JW, Szklennik, PV, Almond, A, Bushell,
K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles”. Bioor-
ganic & Medicinal Chemistry Letters 15 (18): 4110–3.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
[7] “The Cannabinoid Receptors”. doi:10.1007/978-1-
59745-503-9. Retrieved 28 August 2013.
Chapter 119

LY-2183240

LY-2183240 is a drug which acts both as a po- Simmons RM, Li D, Iyengar S, Felder CC. Identification
tent inhibitor of the reuptake of the endocannabinoid of a high-affinity binding site involved in the transport of
anandamide and as an inhibitor of fatty acid amide hy- endocannabinoids. 2005 Dec; 102(49):17852-7. PMID
drolase (FAAH), the primary enzyme responsible for de- 16314570
grading anandamide. This leads to markedly elevated 2.Jump up ^ Dickason-Chesterfield AK, Kidd SR, Moore
anandamide levels in the brain, and LY-2183240 has SA, Schaus JM, Liu B, Nomikos GG, Felder CC. Phar-
been shown to produce both analgesic and anxiolytic ef- macological characterization of endocannabinoid trans-
fects in animal models.[1][2][3][4] port and fatty acid amide hydrolase inhibitors. Cellu-
lar and Molecular Neurobiology. 2006 Jul-Aug;26(4-
6):407-23. PMID 16736384 3.Jump up ^ Alexander
119.1 See also JP, Cravatt BF. The putative endocannabinoid transport
blocker LY2183240 is a potent inhibitor of FAAH and
• PF-04457845 several other brain serine hydrolases. Journal of the
American Chemical Society. 2006 Aug 2;128(30):9699-
• URB-597 704. PMID 16866524 4.Jump up ^ Maione S, Mor-
era E, Marabese I, Ligresti A, Luongo L, Ortar G, Di
Marzo V. Antinociceptive effects of tetrazole inhibitors
119.2 References of endocannabinoid inactivation: cannabinoid and non-
cannabinoid receptor-mediated mechanisms. British
[1] Dickason-Chesterfield AK, Kidd SR, Moore SA, Schaus Journal of Pharmacology. 2008 Nov;155(5):775-82.
JM, Liu B, Nomikos GG, Felder CC. Pharmacological PMID 18660824 5.Jump up ^ Powers MS, Barrenha GD,
characterization of endocannabinoid transport and fatty Mlinac NS, Barker EL, Chester JA. Effects of the novel
acid amide hydrolase inhibitors. Cellular and Molecu- endocannabinoid uptake inhibitor, LY2183240, on fear-
lar Neurobiology. 2006 Jul-Aug;26(4-6):407-23. PMID
potentiated startle and alcohol-seeking behaviors in mice
16736384
selectively bred for high alcohol preference. Psychophar-
[2] Alexander JP, Cravatt BF. The putative endocannabi- macology (Berlin). 2010 Dec;212(4):571-83. PMID
noid transport blocker LY2183240 is a potent inhibitor 20838777
of FAAH and several other brain serine hydrolases.
Journal of the American Chemical Society. 2006 Aug
2;128(30):9699-704. PMID 16866524

[3] Maione S, Morera E, Marabese I, Ligresti A, Lu-

ongo L, Ortar G, Di Marzo V. Antinociceptive ef-
fects of tetrazole inhibitors of endocannabinoid inac-
tivation: cannabinoid and non-cannabinoid receptor-
mediated mechanisms. British Journal of Pharmacology.
2008 Nov;155(5):775-82. PMID 18660824

[4] Powers MS, Barrenha GD, Mlinac NS, Barker EL,

Chester JA. Effects of the novel endocannabinoid up-
take inhibitor, LY2183240, on fear-potentiated startle and
alcohol-seeking behaviors in mice selectively bred for high
alcohol preference. Psychopharmacology (Berlin). 2010
Dec;212(4):571-83. PMID 20838777

1. Moore SA, Nomikos GG, Dickason-Chesterfield AK,

Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L,

164
Chapter 120

LY-320,135

LY-320,135 is a drug used in scientific research which

acts as a selective antagonist of the cannabinoid receptor
CB1 . It was developed by Eli Lilly and Company in the
1990s.
LY-320,135 displays fairly good selectivity, with a
binding affinity for CB1 around 70x stronger than for
CB2 ,[1] but both its potency and selectivity are modest
compared to newer agents, and at higher doses it also
binds to a range of non-cannabinoid receptors. However
LY-320,135 is still fairly widely used in research, particu-
larly for elucidating the mechanisms by which many CB1
antagonists act as inverse agonists at higher doses.[2]

120.1 References
[1] Felder CC, Joyce KE, Briley EM, Glass M, Mackie
KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW,
Chaney MO, Koppel GA, Brownstein M. LY320135, a
novel cannabinoid CB1 receptor antagonist, unmasks cou-
pling of the CB1 receptor to stimulation of cAMP ac-
cumulation. Journal of Pharmacology and Experimental
Therapeutics. 1998 Jan;284(1):291-7. PMID 9435190

[2] Pertwee RG. Inverse agonism and neutral antagonism at

cannabinoid CB1 receptors. Life Sciences. 2005 Feb
4;76(12):1307-24. PMID 15670612

165
Chapter 121

MAM-2201

MAM-2201 (4'-methyl-AM-2201, 5"-fluoro-JWH- 121.2 References

122) is a drug that presumably acts as a potent agonist
for the cannabinoid receptors. It had never previously
been reported in the scientific or patent literature, and
was first identified by laboratories in the Netherlands
and Germany in June 2011 as an ingredient in synthetic
cannabis smoking blends.[1][2][3] Like RCS-4 and AB-
001, MAM-2201 thus appears to be a novel compound
invented by "research chemical" suppliers specifically for
grey-market recreational use. Structurally, MAM-2201
is a hybrid of two known cannabinoid compounds JWH-
122 and AM-2201, both of which had previously been
used as active ingredients in synthetic cannabis blends be-
fore being banned in many countries. MAM-2201 has
been banned by being added to the temporary class drug
schedule in New Zealand, effective from 13 July 2012.[4]
[1] EMCDDA–Europol 2011 Annual Report on the imple-
mentation of Council Decision 2005/387/JHA
[2] Moosmann, B., et al. (2012). “Separation and struc-
tural characterization of the synthetic cannabinoids
JWH-412 and 1-(5-fluoropentyl)−1H-indol-3yl]-(4-
methylnaphthalen-1-yl)methanone using GC–MS,
NMR analysis and a flash chromatography system”.
Forensic Science International 220 (1–3): e17–e22.
doi:10.1016/j.forsciint.2011.12.010. PMID 22264627.
[3] Simolka, K., et al. (2012). “Analysis of synthetic cannabi-
noids in “spice-like” herbal highs: Snapshot of the Ger-
man market in summer 2011”. Analytical and Bioanalyt-
ical Chemistry 404 (1): 157–171. doi:10.1007/s00216-
012-6122-4. PMID 22710567.

[4] Temporary Class Drug Notice, 5 July 2012. NZ Depart-

121.1 Pharmacology ment of Internal Affairs.

[5] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012).

Nothing has been published on the pharmacology of
MAM-2201, though it presumably has similar properties
to the closely related AM-2201 and JWH-122, which are
both full agonists and unselectively bind to CB1 and CB2
cannabinoid receptors with low nanomolar affinity.
“The detection of the urinary metabolites of 1-(5-
fluoropentyl)−1H-indol-3-yl]-(2-iodophenyl)methanone
(AM-694), a high affinity cannabimimetic, by gas
chromatography - mass spectrometry”. Drug Testing and
Analysis 5 (2): 110–5. doi:10.1002/dta.1336. PMID
22522907.

121.1.1 Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 is
generally applicable to MAM-2201.

The pharmacokinetics of MAM-2201 has not been stud-

ied, but its metabolism likely differs only slightly from
that of JWH-018, with the main metabolic pathway
being hydroxylation at various positions, followed by
glucuronidation of the hydroxylated metabolites. N-
dealkylation is also likely to occur, producing flu-
oroalkyl metabolites and ultimately 3-fluoropropanoic
acid, though the odd-numbered alkyl chain of MAM-
2201 would not be expected to produce fluoroacetate as
a metabolite. Also metabolism of the related compound
AM-694 has shown hydrolytic defluorination of the alkyl
chain, meaning any fluoroalkyl metabolites formed are
likely to be further metabolised themselves.[5]

166
Chapter 122

MDA-19

MDA-19 is a drug that acts as a potent and selec-

tive agonist for the cannabinoid receptor CB2 , with rea-
sonable selectivity over the psychoactive CB1 receptor,
though with some variation between species. In animal
studies it was effective for the treatment of neuropathic
pain, but failed to produce cannabis-like behavioural
effects.[1][2]

122.1 See also

• AM-1221
• JTE 7-31

• JWH-019
• JWH-133

• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide

122.2 References
[1] Diaz P, et al. Design and synthesis of a novel series of
N-alkyl isatin acylhydrazone derivatives that act as selec-
tive cannabinoid receptor 2 agonists for the treatment of
neuropathic pain. Journal of Medicinal Chemistry. 2008
Aug 28;51(16):4932-47. PMID 18666769

[2] Xu JJ, et al. Pharmacological characterization of a novel

cannabinoid ligand, MDA19, for treatment of neuropathic
pain. Anesthesia and Analgesia. 2010 Jul;111(1):99-109.
PMID 20522703

167
Chapter 123

Menabitan

Menabitan (INN; SP-204), or menabitan hydrochlo-

ride (USAN), is a synthetic drug which acts as a potent
cannabinoid receptor agonist.[1][2] It is closely related to
natural cannabinoids of the tetrahydrocannabinol (THC)
group, differing mainly by its longer and branched side
chain, and the replacement of the 9-position carbon with
a nitrogen.[1] It was studied as an analgesic in the 1970s
and was found to possess antinociceptive effects in both
humans and animals but was never marketed.[1][3][4]

123.1 See also

• A-40174 (SP-1)

• Dimethylheptylpyran

123.2 References
[1] Green K, Kim K (February 1977). “Acute dose re-
sponse of intraocular pressure to topical and oral cannabi-
noids”. Proceedings of the Society for Experimental
Biology and Medicine. Society for Experimental Biol-
ogy and Medicine (New York, N.Y.) 154 (2): 228–31.
doi:10.3181/00379727-154-39643. PMID 402656.

[2] David J. Triggle (1996). Dictionary of Pharmacological

Agents. Boca Raton: Chapman & Hall/CRC. p. 1271.
ISBN 978-0-412-46630-4.

[3] Reggio PH (1987). “Molecular determinants for cannabi-

noid activity: refinement of a molecular reactivity tem-
plate”. NIDA Research Monograph 79: 82–95. PMID
2830539.

[4] Gabriel G. Nahas (5 April 1999). Marihuana and

Medicine. Humana Press. p. 46. ISBN 978-0-89603-
593-5. Retrieved 9 May 2012.

168
Chapter 124

Methanandamide

Methanandamide (AM-356) is a synthetically cre-

ated stable chiral analog of anandamide.[1] Its effects
have been observed to act on the cannabinoid receptors
(specifically on CB1 receptors, which are part of the
central nervous system) found in different organisms such
as mammals, fish, and certain invertebrates (e.g. Hydra).

124.1 References
[1] Abadji, V, et al. (1994). "(R)-methanandamide: A
chiral novel anandamide possessing higher potency and
metabolic stability”. Journal of Medical Chemistry 37
(12): 1889–93. doi:10.1021/jm00038a020. PMID
8021930.

169
Chapter 125

MK-9470

MK-9470 is a synthetic compound, which binds to the

CB1 cannabinoid receptor and functions as an inverse ag-
onist.[1]

125.1 References
[1] Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill
TG, Bormans G, Eng WS, Gibson R, Ryan C, Con-
nolly B, Patel S, Krause S, Vanko A, Van Hecken A,
Dupont P, De Lepeleire I, Rothenberg P, Stoch SA,
Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet
MT, Gottesdiener K, Wagner JA, de Hoon J, Mortel-
mans L, Fong TM, Hargreaves RJ (2007). "[18 F]MK-
9470, a positron emission tomography (PET) tracer for
in vivo human PET brain imaging of the cannabinoid-
1 receptor”. Proc. Natl. Acad. Sci. U.S.A.
104 (23): 9800–5. Bibcode:2007PNAS..104.9800B.
doi:10.1073/pnas.0703472104. PMC 1877985. PMID
17535893.

170
Chapter 126

N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide

7-methoxy-1-(2-morpholinoethyl)-N-((1S,4R)−1,3,3-
trimethylbicyclo[2.2.1]heptan-2-yl)−1H-indole-3-
carboxamide (N-[(S)-fenchyl]−1-[2-(morpholin-4-
yl)ethyl]−7-methoxyindole-3-carboxamide, UR-12,
MN-25) is a drug invented by Bristol-Myers Squibb,[1]
that acts as a reasonably selective agonist of peripheral
cannabinoid receptors.[2] It has moderate affinity for
CB2 receptors with a Kᵢ of 11nM, but 22x lower
affinity for the psychoactive CB1 receptors with a Kᵢ of
245nM. The indole 2-methyl derivative has the ratio of
affinities reversed however, with a Kᵢ of 8nM at CB1
and 29nM at CB2 ,[3][4] which contrasts with the usual
trend of 2-methyl derivatives having increased selectivity
for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs
JWH-098).[5][6]
Chemically, it is closely related to another indole-3-
carboxamide synthetic cannabinoid, Org 28611, but with
a different cycloalkyl substitution on the carboxam-
ide, and the cyclohexylmethyl group replaced by mor-
pholinylethyl, as in JWH-200 or A-796,260. Early
compounds such as these have subsequently led to the
development of a large number of related indole-3-
carboxamide cannabinoid ligands.[7][8][9][10]

126.1 See also

• A-834,735
2-methyl derivative
• AB-001

• AM-1221 126.2 References

• JTE 7-31
[1] CANNABINOID RECEPTOR MODULATORS,
THEIR PROCESSES OF PREPARATION, AND
• JWH-203 USE OF CANNABINOID RECEPTOR MODU-
LATORS IN TREATING RESPIRATORY AND
• MDA-19 NON-RESPIRATORY DISEASES. WO 2001/58869

• SR-144,528 [2] Rulin Zhao, et al. Improved procedure for the prepara-
tion of 7-methoxy-2-methyl-1-(2-morpholinoethyl)−1H-
• UR-144 indole-3-carboxylic acid, key intermediate in the synthesis

171
172 CHAPTER 126. N-(S)-FENCHYL-1-(2-MORPHOLINOETHYL)−7-METHOXYINDOLE-3-CARBOXAMIDE

of novel 3-amidoindole and indolopyridone cannabinoid 3. Chin CL, et al. (January 2008). “Differential ef-
ligands. ARKIVOC 2010 (vi):89-95. fects of cannabinoid receptor agonists on regional brain
activity using pharmacological MRI”. British Journal of
[3] Hynes, J., et al. (2002). “C-3 Amido-Indole cannabinoid
receptor modulators”. Bioorganic & Medicinal Chem-
Pharmacology 153 (2): 367–79. doi :10.1038/ sj.bjp
istry Letters 12 (17): 2399–402. doi:10.1016/S0960- .0707506. PMC 2219521. PMID 17965748
894X(02)00466-3. PMID 12161142.

[4] Wrobleski, Stephen T., et al. (2003). “Rational

Design and Synthesis of an Orally Active Indolopyri-
done as a Novel Conformationally Constrained Cannabi-
noid Ligand Possessing Antiinflammatory Properties”.
Journal of Medicinal Chemistry 46 (11): 2110–6.
doi:10.1021/jm020329q. PMID 12747783.

[5] Huffman, J. W.; Padgett, L. W. (2005). “Re-

cent Developments in the Medicinal Chemistry of
Cannabimimetic Indoles, Pyrroles and Indenes”.
Current Medicinal Chemistry 12 (12): 1395–1411.
doi:10.2174/0929867054020864. PMID 15974991.

[6] Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). “In-

doles and Related Compounds as Cannabinoid Ligands”.
Mini Reviews in Medicinal Chemistry 8 (4): 370–387.
doi:10.2174/138955708783955935. PMID 18473928.

[7] Adam, J. M., et al. (2010). “Design, synthesis, and

structure–activity relationships of indole-3-carboxamides
as novel water soluble cannabinoid CB1 receptor ago-
nists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.

[8] Kiyoi T, et al. (August 2010). “Design, synthe-

sis, and structure-activity relationship study of confor-
mationally constrained analogs of indole-3-carboxamides
as novel CB1 cannabinoid receptor agonists”. Bioor-
ganic & Medicinal Chemistry Letters 20 (16): 4918–21.
doi:10.1016/j.bmcl.2010.06.067. PMID 20634067.

[9] Moir EM, et al. (December 2010). “Design, syn-

thesis, and structure-activity relationship study of bi-
cyclic piperazine analogs of indole-3-carboxamides as
novel cannabinoid CB1 receptor agonists”. Bioor-
ganic & Medicinal Chemistry Letters 20 (24): 7327–30.
doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.

[10] Blaazer, A. R. et al. (2011). “Novel indole and azaindole

(pyrrolopyridine) cannabinoid (CB) receptor agonists:
Design, synthesis, structure–activity relationships, physic-
ochemical properties and biological activity”. European
Journal of Medicinal Chemistry 46 (10): 5086–5098.
doi:10.1016/j.ejmech.2011.08.021. PMID 21885167.

126.3 Further reading

1. John Hynes., et al. C3 AMIDO-INDOLE CANNABI-
NOID RECEPTOR MODULATORS. Bioorganic and
Medical Chemistry Letters. Volume 12 issue 17, 2
September 2002 pages 2399-2402
2. Frost, J. M., et al. (2010). “Indol −3-ylcycloalkyl Ke-
tones: Effects of N1 Substituted Indole Side Chain Vari-
ations on CB2 Cannabinoid Receptor Activity”. Jour-
nal of Medicinal Chemistry 53 (1): 295. doi :10.1021/
jm901214q. PMID 19921781
Chapter 127

Nabazenil

Nabazenil (SP-175) is a synthetic cannabinoid receptor

agonist, which has anticonvulsant properties.[1]

127.1 References
[1] Concise dictionary of pharmacological agents: properties
and synonyms. p188. ISBN 0-7514-0499-3

173
Chapter 128

Nabilone

Main article: Medical cannabis vealed that patients taking cisplatin chemotherapy pre-
ferred metoclopramide, while patients taking carboplatin
chemotherapy preferred nabilone to control nausea and
Nabilone is a synthetic cannabinoid with therapeutic [5]
use as an antiemetic and as an adjunct analgesic for vomiting.
neuropathic pain. It mimics the main chemical com- One study compared the efficacy and tolerability of
pound of cannabis (THC), the active ingredient found in nabilone with that of dihydrocodeine in the treatment of
naturally occurring Cannabis sativa L.[1] neuropathic pain.[6] The authors found that nabilone was
In Canada, the United States, the United Kingdom and not as effective as dihydrocodeine in controlling pain, and
Mexico, nabilone is marketed as Cesamet. It was ap- caused a higher incidence of minor adverse drug reactions
proved in 1985 by the U.S. Food and Drug Adminis- than did dihydrocodeine. One critic of the study has sug-
tration (FDA) for treatment of chemotherapy-induced gested that nabilone might be best suited for the treatment
nausea and vomiting (CINV) that has not responded to of patients suffering from central and spasticity-related
conventional antiemetics. Though it was approved by pain, for which there is stronger evidence for the bene-
the FDA in 1985, the drug only began marketing in the fits of cannabinoid therapy; however, these patients made
United States in 2006. In Austria Nabilone is marketed up only a small fraction of the study’s population, and
as Canemes and got its approval for CINV in 2013.[2] the study was not designed to identify subgroups which
might have responded more favorably to treatment than
Although it doesn't have any indication officially (except others.[7]
in Mexico), nabilone is widely used as an adjunct ther-
apy for chronic pain management. Numerous trials and A clinical trial performed in Canada reviewed the use
of nabilone to treat nightmares in individuals suffering
case studies have demonstrated modest effectiveness for
[3]
relieving fibromyalgia and multiple sclerosis. [4] from post-traumatic stress syndrome.[8] The study found
that nighttime administration of nabilone reduced the
Nabilone is a racemic mixture consisting of the (S,S) and frequency and/or intensity of nightmares in 34 out of
the (R,R) isomers ("trans"). 47 (72%) of patients, with 28 reporting complete ces-
sation of nightmares.[8] This study is limited to the ex-
tent that there was no placebo control, but warrants fu-
ture investigation into the use of cannabinoid therapy
128.1 Medical uses in the treatment of post-traumatic stress syndrome and
other disorders involving recurrent nightmares. As en-
Nabilone has shown modest effectiveness in relieving docannabinoids play a significant role in regulating long-
fibromyalgia.[3] term depression, perhaps downregulating the CB1 sys-
The main settings that have seen published clinical tem can help remove the highly potentiated, hippocam-
trials of nabilone include movement disorders such pal/amydygalia memories of the fear. At the very least,
as Parkinson’s syndrome, chronic pain, dystonia and CB1 agonists make one less likely to remember a dream,
spasticity neurological disorders, multiple sclerosis, and or even make REM sleep happen without significant in-
the nausea of cancer chemotherapy. Nabilone is also ef- volvement of the limbic system.
fective in the treatment of inflammatory bowel disease,
especially ulcerative colitis. Medical marijuana patients
report that nabilone is more similar in effect to CBD than 128.2 Adverse effects
THC, indicating that it has more of a therapeutic effect
on the body than a “high” effect on the mind. Nabilone can increase, rather than decrease, post-
A study comparing nabilone with metoclopramide, operative pain; in the treatment of fibromyalgia, ad-
conducted before the development of modern 5- verse effects limits the useful dose.[3] Adverse effects of
HT3 antagonist anti-emetics such as ondansetron, re- nabilone include, but are not limited to dizziness/vertigo,

174
128.4. REFERENCES 175

euphoria, drowsiness, dry mouth, ataxia, sleep distur-

bance, dysphoria, headache, nausea, disorientation, de-
personalization, asthenia and increased appetite.[9]

128.3 See also

• Dronabinol

128.4 References
[1] “How to use Cesamet”. Artek LLC. 2008.

[2] “Canemes (nabilone)".

[3] Fine PG, Rosenfeld MJ (2013). “The endocannabi-

noid system, cannabinoids, and pain”. Ram-
bam Maimonides Med J (Review) 4 (4): e0022.
doi:10.5041/RMMJ.10129. PMC 3820295. PMID
24228165.

[4] Wissel J, et al. (2006). “Low dose treatment with

the synthetic cannabinoid Nabilone significantly reduces
spasticity-related pain : a double-blind placebo-controlled
cross-over trial”. J Neurol. (Research article) 253
(10): 1337–41. doi:10.1007/s00415-006-0218-8. PMID
16988792.

[5] Cunningham D, et al. (1988). “A randomized trial of oral

nabilone and prochlorperazine compared to intravenous
metoclopramide and dexamethasone in the treatment of
nausea and vomiting induced by chemotherapy regimens
containing cisplatin or cisplatin analogues”. Eur J Cancer
Clin Oncol (Randomized controlled trial) 24 (4): 685–9.
doi:10.1016/0277-5379(88)90300-8. PMID 2838294.

[6] Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D

(January 2008). “Comparison of analgesic effects and
patient tolerability of nabilone and dihydrocodeine for
chronic neuropathic pain: randomised, crossover, dou-
ble blind study”. BMJ (Randomized controlled trial) 336
(7637): 199–201. doi:10.1136/bmj.39429.619653.80.
PMC 2213874. PMID 18182416.

[7] Cohen SP (January 2008). “Cannabinoids for chronic

pain”. BMJ (Research article) 336 (7637): 167–
8. doi:10.1136/bmj.39434.444583.80. PMC 2213791.
PMID 18182415.

[8] Fraser, GA (2009). “The Use of a Synthetic Cannabinoid

in the Management of Treatment-Resistant Nightmares
in Posttraumatic Stress Disorder (PTSD)". CNS Neurosci
Ther (Trial report) 15 (1): 84–88. doi:10.1111/j.1755-
5949.2008.00071.x. PMID 19228182.

[9] “Cesamet (nabilone) Prescribing Information”. http://

www.cesamet.com/pdf/Cesamet_PI_50_count.pdf. Meda
Pharmaceuticals Inc. Retrieved 16 July 2014.
Chapter 129

Nabitan

Nabitan (Nabutam, Benzopyranoperidine, SP-106,

Abbott 40656) is a synthetic cannabinoid analog
of dronabinol (Marinol).[1] It exhibits antiemetic and
analgesic effects, most likely by binding to and activat-
ing the CB1 and CB2 cannabinoid receptors, and reduced
intraocular pressure in animal tests, making it potentially
useful in the treatment of glaucoma.[2]
Nabitan has the advantage of being water soluble un-
like most cannabinoid derivatives, and was researched
for potential use as an analgesic or sedative,[3] although
it was never developed for clinical use and is not cur-
rently used in medicine, as dronabinol or nabilone were
felt to be more useful. However it is sometimes used
in research into the potential therapeutic applications of
cannabinoids.

129.1 References
[1] Razdan RK. The Total Synthesis of Cannabinoids. Wiley-
Interscience 1980

[2] Razdan RK, Howes JF. “Drugs related to tetrahydro-

cannabinol.” Medicinal Research Reviews 1983; 3(2):119-
146. PMID 6134882

[3] Archer RA. “The cannabinoids: therapeutic potentials.”

Annual Reports in Medicinal Chemistry 1974; 9: 253-259.
PMID 12307093

176
Chapter 130
Nabiximols
Canadian packaging of a case of Sativex vials
Nabiximols (USAN,[1] trade name Sativex) is a patented
cannabinoid oromucosal mouth spray developed by
the UK company GW Pharmaceuticals for multiple
sclerosis (MS) patients, who can use it to alleviate
neuropathic pain, spasticity, overactive bladder, and other
symptoms.[2] Nabiximols is distinct from all other phar-
maceutically produced cannabinoids currently available
because it is a mixture of compounds derived from
Cannabis plants, rather than a mono-molecular synthetic
product. The drug is a pharmaceutical product standard-
ised in composition, formulation, and dose, although it is
still effectively a tincture of the cannabis plant. Its princi-
pal active cannabinoid components are the cannabinoids:
tetrahydrocannabinol (THC) and cannabidiol (CBD).
The product is formulated as an oromucosal spray which
is administered by spraying into the mouth. Each spray
delivers a near 1:1 ratio of CBD to THC, with a fixed dose
of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also be-
ing developed in Phase III trials as a potential treatment to
alleviate pain due to cancer. It has also been researched
in various models of peripheral and central neuropathic
pain.
In May 2003 GW Pharmaceuticals and Bayer en-
tered into an exclusive marketing agreement for GW’s
cannabis-based medicinal extract product, to be mar-
keted under the brand name Sativex. “Bayer has obtained
exclusive rights to market Sativex in the UK. In addition,
Bayer has the option for a limited period of time to nego-
177
tiate the marketing rights in other countries in European
Union and selected other countries around the world.”
In April 2011, GW licensed to Novartis the rights to
commercialise nabiximols in Asia (excluding China and
Japan), Africa and the Middle East (excluding Israel). [3]
130.1 Availability
In June 2010, the Medicines and Healthcare products
Regulatory Agency of the United Kingdom licensed
nabiximols as a prescription-only medicine for the treat-
ment of spasticity due to multiple sclerosis. This regula-
tory authorization represents the world’s first full regula-
tory approval for the medicine. The spray is being mar-
keted in the UK by Bayer Schering Pharma. Many MS
patients cannot receive nabiximols due to local National
Health Service (NHS) resistance to its funding.[4][5] but,
in August 2014, the NHS in Wales agreed to fund Sativex
for people with multiple sclerosis.[6]
Nabiximols was also approved in Spain for MS spasticity
in the second half of 2010 and was launched in that coun-
try in March 2011. It was approved in the Czech Repub-
lic in April 2011, in Germany in May 2011, in Denmark
in June 2011 and in Sweden in January 2012 to MS pa-
tients who have not responded adequately to other medi-
cation for spasticity.[7] It has also been recommended for
approval in Italy and Austria with formal approvals ex-
pected in these countries during 2011. In Spain and other
European markets (excluding the UK), nabiximols will be
marketed by Almirall.
In Canada, nabiximols has been approved by Health
Canada for the treatment of MS spasticity. It has also
received a licence with conditions (NOC/c) for two addi-
tional uses: as adjunctive treatment for the symptomatic
relief of neuropathic pain in multiple sclerosis,[8] and also
for pain due to cancer.[9][10]
Nabiximols is available in a number of countries as an
unlicensed medicine, which enables doctors to prescribe
the product to individual patients who they consider may
benefit. The product has been exported from the UK to a
total of 28 countries to date.
In February 2007, GW and Otsuka Pharmaceutical an-
178
nounced an exclusive agreement for Otsuka to develop
and market the drug in the United States. The first large
scale US Phase IIb trial, Spray Trial, for cancer patients
reported positive results in March 2010. GW and Ot-
suka have now commenced the Phase III development of
nabiximols in cancer pain.
In 2013, France legalized the use of cannabinoids in
medicine, Sativex is the first one to be sold under pre-
scription.
130.2 Effectiveness
Of the two preliminary Phase III studies investigating the
treatment of MS patients, one showed a reduction of spas-
ticity of 1.2 points on the 0–10 points rating scale (versus
0.6 points under placebo), the other showed a reduction
of 1.0 versus 0.8 points. Only the first study reached sta-
tistical significance. The Phase III approval study con-
sisted of a run-in phase where the response of individuals
to the drug was determined. The responders (42% of pa-
tients) showed a significant effect in the second, placebo
controlled, phase of the trial.[11] A 2009 meta-analysis of
six studies found large variations of effectiveness, with a
– statistically non-significant – trend towards a reduction
of spasticity.[12]
130.3 Side effects
In early clinical trials, nabiximols has generally been well
tolerated.[13][14][15] The most common adverse effects in
Phase III trials were dizziness (25%), drowsiness (8.2%)
and disorientation (4%). 12% of patients stopped taking [11] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel
the drug because of the side effects. No investigations
regarding the potential for dependence are available, but
such a potential is unlikely considering the pharmacolog- [12] Lakhan, Shaheen E; Rowland, Marie (2009). “Whole
ical properties of the two components.[11]
130.4 Controversy
GW Pharmaceuticals were issued a unique license to cul-
tivate cannabis for the manufacturing of Sativex in the
UK, granting them the sole legal right to research in
aerosolized cannabis derived therapeutics, which in April
2013 became commercially viable when the UK Govern-
[14] Wade D, Makela P, House H, Bateman C, Robson P
ment scheduled the Sativex formulation to part IV of the
UK Drugs Act.[16]
130.5 See also
• Medical cannabis
• Nabilone
CHAPTER 130. NABIXIMOLS
• Dronabinol
• GW Pharmaceuticals
• Hortapharm B.V.
130.6 References
[1] United States Adopted Names Coincil: Statement on a
nonproprietary name
[2] http://www.gwpharm.com/SPC.aspx
[3] “GW signs Sativex cannabis-based drug deal with Novar-
tis”. The Telegraph. 11 April 2011. Retrieved 12 July
2012.
[4] Ryan, Siobhan (4 June 2011). “Sussex MS sufferers call
for drug funding”. Argus (Sussex,UK). Retrieved 8 June
2011.
[5] “Sativex rejected by healthcare provider”. Lincolnshire.
20 June 2011. Retrieved 20 June 2011.
[6] “Wales NHS to offer MS cannabis drug Sativex”. 15 Au-
gust 2014. Retrieved 18 August 2014.
[7] Sativex (nabiximols), Swedish Medical Products Agency
[8] GW Pharmaceuticals. "Multiple Sclerosis". Accessed 24
July 2011.
[9] GW Pharmaceuticals. "Cancer Pain" Accessed 24 July
2011.
[10] “Sativex - Investigational Cannabis-Based Treatment for
Pain and Multiple Sclerosis Drug Development Tech-
nology”. www.drugdevelopment-technology.com. Re-
trieved 2008-08-08.
2011/2012 (German)
plant cannabis extracts in the treatment of spasticity in
multiple sclerosis: a systematic review”. BMC Neurol
9: 59. doi:10.1186/1471-2377-9-59. PMC 2793241.
PMID 19961570.
[13] Wade D, Makela P, Robson P, House H, Bateman C
(2004). “Do cannabis-based medicinal extracts have gen-
eral or specific effects on symptoms in multiple scle-
rosis? A double-blind, randomized, placebo-controlled
study on 160 patients”. Mult Scler 10 (4): 434–41.
doi:10.1191/1352458504ms1082oa. PMID 15327042.
(2006). “Long-term use of a cannabis-based medicine
in the treatment of spasticity and other symptoms
in multiple sclerosis”. Mult Scler 12 (5): 639–45.
doi:10.1177/1352458505070618. PMID 17086911.
[15] Wade D, Robson P, House H, Makela P, Aram J (2003).
“A preliminary controlled study to determine whether
whole-plant cannabis extracts can improve intractable
neurogenic symptoms”. Clin Rehabil 17 (1): 21–9.
doi:10.1191/0269215503cr581oa. PMID 12617376.
130.7. EXTERNAL LINKS 179

[16] http://www.gwpharm.com/GW%20Pharmaceuticals%
20cannabinoid-medicine%20Sativex%20moved%
20to%20Schedule%204%20of%20UK%20Drugs%
20Act.aspx

130.7 External links

• GW Pharmaceuticals Website
Chapter 131

Naboctate

Naboctate (SP-325) is a synthetic cannabinoid recep-

tor agonist, which has antiemetic, sedative, anxiolytic and
anti-glaucoma properties.[1]

131.1 References
[1] Concise dictionary of pharmacological agents: properties
and synonyms. p188. ISBN 0-7514-0499-3

180
Chapter 132

NESS-0327

NESS-0327 is a drug used in scientific research which

acts as an extremely potent and selective antagonist of
the cannabinoid receptor CB1 . It is much more potent an
antagonist, and more selective for the CB1 receptor over
CB2 , than the more commonly used ligand rimonabant,
with a Kᵢ at CB1 of 350fM (i.e. 0.00035nM) and a
selectivity of over 60,000x for CB1 over CB2 .[1] Inde-
pendently, two other groups have described only modest
nanomolar CB1 affinity for this compound (125nM[2] and
18.4nM[3] ). Also unlike rimonabant, NESS-0327 does
not appear to act as an inverse agonist at higher doses, in-
stead being a purely neutral antagonist which blocks the
CB1 receptor but does not produce any physiological ef-
fect of its own.[4]

132.1 See also

• Discovery and development of Cannabinoid Recep-
tor 1 Antagonists
• NESS-040C5

132.2 References
[1] Ruiu S, Pinna GA, Marchese G, Mussinu JM, Saba P,
Tambaro S, Casti P, Vargiu R, Pani L. Synthesis and char-
acterization of NESS 0327: a novel putative antagonist of
the CB1 cannabinoid receptor. Journal of Pharmacology
and Experimental Therapeutics. 2003 Jul;306(1):363-70.
PMID 12663689

[2] A.R. Stoit, J.H.M. Lange, A.P. den Hartog, E. Ronken,

K. Tipker, H.H. van Stuivenberg, J.A.R. Dijksman, H.C.
Wals, C.G. Kruse, Chem. Pharm. Bull. 50 (2002) 1109-
1113

[3] Y. Zhang, J.P. Burgess, M. Brackeen, A. Gilliam, S.W.

Mascarella, K. Page, H.H. Seltzman, B.F. Thomas, J.
Med. Chem. 51 (2008) 3526-3539

[4] Tambaro S, Mongeau R, Dessi C, Pani L, Ruiu S. Modu-

lation of ATP-mediated contractions of the rat vas defer-
ens through presynaptic cannabinoid receptors. European
Journal of Pharmacology. 2005 Nov 21;525(1-3):150-3.
PMID 16271359

181
Chapter 133

NESS-040C5

NESS-040C5 is a potent cannabinoid agonist which was

developed for the treatment of glaucoma.[1] It has rea-
sonable selectivity for the CB2 receptor subtype, having
a CB2 affinity of 0.4nM, and 25x selectivity over the re-
lated CB1 receptor.[2]

133.1 See also

• AB-FUBINACA
• NESS-0327

• SR-144,528

133.2 References
[1] Paolo Lazzari et al. Pharmaceutical Compounds. US
Patent 8106218

[2] Hanus LO, Mechoulam R. Novel natural and synthetic lig-

ands of the endocannabinoid system. Current Medicinal
Chemistry. 2010;17(14):1341-59. PMID 20166928

182
Chapter 134

NMP-7

NMP-7 is a drug which acts as both a non-selective

agonist of the CB1 and CB2 cannabinoid receptors, and
also as a blocker of T-type calcium channels, the target
of anticonvulsant drugs such as ethosuximide. NMP-7
has an agonist EC50 of 96.9nM at CB1 and 10.5nM at
CB2 , and an IC50 of 1.84μM for blocking Cav3.2 T-type
calcium channels. In animal studies it produces potent
analgesic effects in a variety of different tests.[1]

134.1 References
[1] You H, Gadotti VM, Petrov RR, Zamponi GW, Diaz P.
Functional characterization and analgesic effects of mixed
cannabinoid receptor/T-type channel ligands. Molecular
Pain. 2011 Nov 17;7:89. PMID 22093952

183
Chapter 135

Nonabine

Nonabine (BRL-4664) is a drug which is a cannabinoid

derivative, which was developed for the preven-
tion of nausea and vomiting associated with cancer
chemotherapy.[1] It has strong antiemetic effects equiv-
alent to those of chlorpromazine, and also produces
some mild sedative effects, along with dry mouth and
EEG changes typical of cannabinoid agonists, but with
minimal changes in mood or perception, suggesting the
abuse potential is likely to be low.[2][3]

135.1 References
[1] Staquet M, Bron D, Rozencweig M, Kenis Y. Clinical
studies with a THC analog (BRL-4664) in the prevention
of cisplatin-induced vomiting. Journal of Clinical Phar-
macology. 1981 Aug-Sep;21(8-9 Suppl):60S-63S. PMID
7197692

[2] Archer CB, Amlot PL, Trounce JR. Antiemetic effect

of nonabine in cancer chemotherapy: a double blind
study comparing nonabine and chlorpromazine. British
Medical Journal (Clinical Research Edition). 1983 Jan
29;286(6362):350-1. PMID 6402096

[3] McClelland GR, Sutton JA. Pilot investigation of the

quantitative EEG and clinical effects of ketazolam and
the novel antiemetic nonabine in normal subjects. Psy-
chopharmacology (Berlin). 1985;85(3):306-8. PMID
2860687

184
Chapter 136
11-nor-9-Carboxy-THC
Not to be confused with Tetrahydrocannabinolic acid.
11-nor−9-Carboxy-THC, also known as 11-nor−9-
carboxy-delta-9-tetrahydrocannabinol, 11-nor-
9-carboxy-delta-9-THC, 11-COOH-THC, THC-
COOH, and THC-11-oic acid, is the main secondary
metabolite of THC which is formed in the body after
Cannabis is consumed.
11-COOH-THC is formed in the body by oxidation of the
active metabolite 11-Hydroxy-THC (also known as 11-
OH-THC) by liver enzymes. It is then metabolized fur-
ther by conjugation with glucuronide,[2] forming a water-
soluble congener which can be more easily excreted by
the body.[3]
11-COOH-THC is not psychoactive itself, but has a long
half-life in the body of up to several days (or even weeks
in very heavy users),[4][5][6] making it the main metabo-
lite tested for when blood or urine testing for cannabis
use. More selective tests are able to distinguish between
11-OH-THC and 11-COOH-THC, which can help deter-
mine how recently cannabis was consumed;[7][8] if only
11-COOH-THC is present then the cannabis was used
some time ago and any impairment in cognitive ability
or motor function will have dissipated, whereas if both
11-OH-THC and 11-COOH-THC are present then the
cannabis was consumed more recently and motor impair-
ment may still be present.
Some jurisdictions where cannabis use is decriminalized
or permitted under some circumstances use such tests
when determining whether drivers were legally intoxi-
cated and therefore unfit to drive, with the compara-
tive levels of THC, 11-OH-THC and 11-COOH-THC
being used to derive a “blood cannabis level” analo-
gous to the blood alcohol level used in prosecuting im-
paired drivers.[9] On the other hand in jurisdictions where
cannabis is completely illegal, any detectable levels of 11-
COOH-THC may be deemed to constitute driving while
intoxicated, even though this approach has been criticized
as tantamount to prohibition of “driving whilst being a
recent user of cannabis” regardless of the presence or ab-
sence of any actual impairment that might impact on driv-
ing performance.
185
While 11-COOH-THC does not have any psychoac-
tive effects in its own right, it may still have a
role in the analgesic and antiinflammatory effects of
cannabis,[10][11][12] and has also been shown to moderate
the effects of THC itself which may help explain the dif-
ference in subjective effects seen between occasional and
regular users of cannabis.[13][14]
136.1 References
[1] http://www.clinchem.org/cgi/content/full/55/12/2180
[2] Skopp, G; Pötsch, L (2002). “Stability of 11-nor-delta(9)-
carboxy-tetrahydrocannabinol glucuronide in plasma and
urine assessed by liquid chromatography-tandem mass
spectrometry”. Clinical chemistry 48 (2): 301–6. PMID
11805011.
[3] Law, B; Mason, PA; Moffat, AC; King, LJ (1984). “Con-
firmation of cannabis use by the analysis of delta 9-
tetrahydrocannabinol metabolites in blood and urine by
combined HPLC and RIA”. Journal of analytical tox-
icology 8 (1): 19–22. doi:10.1093/jat/8.1.19. PMID
6323852.
[4] Huestis, MA; Mitchell, JM; Cone, EJ (1995). “Detection
times of marijuana metabolites in urine by immunoas-
say and GC-MS”. Journal of analytical toxicology 19 (6):
443–9. doi:10.1093/jat/19.6.443. PMID 8926739.
[5] Pope Jr, HG; Gruber, AJ; Hudson, JI; Huestis,
MA; Yurgelun-Todd, D (2001). “Neuropsycho-
logical performance in long-term cannabis users”.
Archives of General Psychiatry 58 (10): 909–15.
doi:10.1001/archpsyc.58.10.909. PMID 11576028.
[6] Dietz, L; Glaz-Sandberg, A; Nguyen, H; Skopp,
G; Mikus, G; Aderjan, R (2007). “The urinary
disposition of intravenously administered 11-nor-9-
carboxy-delta-9-tetrahydrocannabinol in humans”.
Therapeutic drug monitoring 29 (3): 368–72.
doi:10.1097/FTD.0b013e31805ba6fd. PMID 17529896.
[7] Huestis, MA; Henningfield, JE; Cone, EJ (1992).
“Blood cannabinoids. II. Models for the prediction
of time of marijuana exposure from plasma concentra-
tions of delta 9-tetrahydrocannabinol (THC) and 11-nor-
9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)".
186 CHAPTER 136. 11-NOR-9-CARBOXY-THC

Journal of analytical toxicology 16 (5): 283–90.

doi:10.1093/jat/16.5.283. PMID 1338216.

[8] Huestis, MA; Elsohly, M; Nebro, W; Barnes, A;

Gustafson, RA; Smith, ML (2006). “Estimating time
of last oral ingestion of cannabis from plasma THC and
THCCOOH concentrations”. Therapeutic drug monitor-
ing 28 (4): 540–4. doi:10.1097/00007691-200608000-
00009. PMID 16885722.

[9] Ménétrey, A; Augsburger, M; Favrat, B; Pin, MA;

Rothuizen, LE; Appenzeller, M; Buclin, T; Mangin, P;
Giroud, C (2005). “Assessment of driving capability
through the use of clinical and psychomotor tests in re-
lation to blood cannabinoids levels following oral admin-
istration of 20 mg dronabinol or of a cannabis decoction
made with 20 or 60 mg Delta9-THC”. Journal of analyt-
ical toxicology 29 (5): 327–38. doi:10.1093/jat/29.5.327.
PMID 16105257.

[10] Burstein, SH; Hull, K; Hunter, SA; Latham, V (1988).

“Cannabinoids and pain responses: a possible role for
prostaglandins”. The FASEB journal : official publication
of the Federation of American Societies for Experimental
Biology 2 (14): 3022–6. PMID 2846397.

[11] Doyle, SA; Burstein, SH; Dewey, WL; Welch, SP (1990).

“Further studies on the antinociceptive effects of delta 6-
THC-7-oic acid”. Agents and actions 31 (1–2): 157–63.
doi:10.1007/bf02003237. PMID 2178317.

[12] Ujváry, I; Grotenhermen, F (2014). “11-Nor-9-carboxy-

Δ9-tetrahydrocannabinol – a ubiquitous yet underre-
searched cannabinoid. A review of the literature”.
Cannabinoids 9 (1): 1–8.

[13] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1987).

“A major metabolite of delta 1-tetrahydrocannabinol re-
duces its cataleptic effect in mice”. Experientia 43 (4):
402–3. doi:10.1007/BF01940427. PMID 3032669.

[14] Burstein, S; Hunter, SA; Latham, V; Renzulli, L

(1986). “Prostaglandins and cannabis--XVI. Antagonism
of delta 1-tetrahydrocannabinol action by its metabo-
lites”. Biochemical pharmacology 35 (15): 2553–8.
doi:10.1016/0006-2952(86)90053-5. PMID 3017356.
Chapter 137

O-1057

O-1057 is an analgesic cannabinoid derivative created

by Organix Inc. for use in scientific research. Unlike
most cannabinoids discovered to date, it is water solu-
ble, which gives it considerable advantages over many re-
lated cannabinoids. It has moderate affinity for both CB1
and CB2 receptors, with Kᵢ values of 8.36nM at CB1 and
7.95nM at CB2 .[1]

137.1 See also

• AM-2232
• O-774

• O-1812
• O-2694

137.2 References
[1] Pertwee RG, et al. O-1057, a potent water-soluble
cannabinoid receptor agonist with antinociceptive prop-
erties. British Journal of Pharmacology. 2000
Apr;129(8):1577-84. PMID 10780961

187
Chapter 138

O-1125

O-1125 (3-(1,1-dimethylhexyl-6-
dimethylcarboxamide)-Δ8-tetrahydrocannabinol) is
a drug which is a cannabinoid derivative. It has analgesic
effects and is used in scientific research. It is a potent
CB1 full agonist with a Ki of 1.16nM.[1]

138.1 References
[1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid
agonists and antagonists discriminated by receptor bind-
ing in rat cerebellum. British Journal of Pharmacology.
1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806
PMID 10516649

188
Chapter 139

O-1238

O-1238 is a drug which is a cannabinoid derivative that

is used in scientific research. It is a partial agonist at the
cannabinoid receptor CB1 ,[1] producing a maximal stim-
ulation of 58.3%[2] with a Ki of 8.45nM.[3]

139.1 References
[1] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid
agonists and antagonists discriminated by receptor bind-
ing in rat cerebellum. British Journal of Pharmacology.
1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806
PMID 10516649

[2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ,
Saha B, Razdan RK, Martin BR, Abood ME. An investi-
gation into the structural determinants of cannabinoid re-
ceptor ligand efficacy. British Journal of Pharmacology.
1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469
PMID 10323589

[3] Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker

P, Razdan RK, Pertwee RG. Structural determinants
of the partial agonist-inverse agonist properties of 6'-
azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabi-
noid receptors. British Journal of Pharmacology. 1999
Oct;128(3):735-43. PMID 10516656

189
Chapter 140

O-1269

O-1269 is a drug that is a diarylpyrazole derivative, [5] Wiley, J. L.; Selley, D. E.; Wang, P.; Kottani, R.;
related to potent cannabinoid antagonist drugs such as Gadthula, S.; Mahadeven, A. (2011). “3-Substituted
rimonabant and surinabant. However O-1269 and sev- Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Re-
eral related drugs were unexpectedly found to act as full ceptor Antagonist Rimonabant: Cannabinoid Agonist-
or partial agonists at the cannabinoid receptors rather than Like Effects in Mice via Non-CB1, Non-CB2 Mecha-
nism”. Journal of Pharmacology and Experimental Thera-
antagonists, and so produce the usual effects expected
peutics 340 (2): 433–444. doi:10.1124/jpet.111.187815.
of cannabinoid agonists in animal tests, such as sedation PMC 3263966. PMID 22085649.
and analgesic effects. The N-heptyl homologue O-1270
and the N-propyl homologue O-1399 also act as cannabi-
noid agonists with similar potency in vivo, despite weaker
binding affinity at cannabinoid receptors compared to the
pentyl homologue O-1269.[1][2][3] Agonist-like and atyp-
ical cannabinoid activity has also been observed with a
number of related compounds.[4][5]

140.1 References
[1] Billy R. Martin, Raj K. Razdan, Anu Mahadevan. Pyra-
zole cannabinoid agonist and antagonists. US Patent
6509367, filed Sep 22, 2001, issued Jan 21, 2003.

[2] Shim JY, Welsh WJ, Cartier E, Edwards JL, Howlett AC.
Molecular interaction of the antagonist N-(piperidin-
1-yl)−5-(4-chlorophenyl)−1- (2,4-dichlorophenyl)−4-
methyl-1H-pyrazole-3-carboxamide with the CB1
cannabinoid receptor. Journal of Medicinal Chemistry.
2002 Mar 28;45(7):1447-59. PMID 11906286

[3] Francisco ME, Seltzman HH, Gilliam AF, Mitchell RA,

Rider SL, Pertwee RG, Stevenson LA, Thomas BF. Syn-
thesis and structure-activity relationships of amide and
hydrazide analogues of the cannabinoid CB(1) receptor
antagonist N-(piperidinyl)- 5-(4-chlorophenyl)−1-(2,4-
dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide
(SR141716). Journal of Medicinal Chemistry. 2002 Jun
20;45(13):2708-19. PMID 12061874

[4] Thomas, B. F.; Francisco, M. E. Y.; Seltzman,

H. H.; Thomas, J. B.; Fix, S. E.; Schulz, A. K.;
Gilliam, A. F.; Pertwee, R. G.; Stevenson, L. A.
(2005). “Synthesis of long-chain amide analogs of the
cannabinoid CB1 receptor antagonist N-(piperidinyl)−5-
(4-chlorophenyl)−1-(2,4-dichlorophenyl)−4-methyl-
1H-pyrazole-3-carboxamide (SR141716) with unique
binding selectivities and pharmacological activities”.
Bioorganic & Medicinal Chemistry 13 (18): 5463–5474.
doi:10.1016/j.bmc.2005.06.005. PMID 15994087.

190
Chapter 141

O-1602

O-1602 is a synthetic compound most closely related to 17 (8): 1651–1664. doi:10.1002/ibd.21538. PMC
abnormal cannabidiol, and more distantly related in struc- 3116968. PMID 21744421.
ture to cannabinoid drugs such as THC. O-1602 does
[4] Díaz-Arteaga, A.; Vázquez, M. J.; Vazquez-Martínez,
not bind to the classical cannabinoid receptors CB1 or
R.; Pulido, M. R.; Suarez, J.; Velásquez, D. A.; López,
CB2 with any significant affinity, but instead is an ag- M.; Ross, R. A.; De Fonseca, F. R.; Bermudez-Silva,
onist at several other receptors which appear to be re- F. J.; Malagón, M. M.; Diéguez, C.; Nogueiras, R.
lated to the cannabinoid receptors, particularly GPR18 (2012). “The atypical cannabinoid O-1602 stimulates
and GPR55. These previously orphan receptors have food intake and adiposity in rats”. Diabetes, Obesity
been found to be targets for a number of endogenous and and Metabolism 14 (3): 234–243. doi:10.1111/j.1463-
synthetic cannabinoid compounds, and are thought to be 1326.2011.01515.x. PMID 21981246.
responsible for most of the non-CB1 , non-CB2 mediated
[5] Kargl, J.; Haybaeck, J.; Stančić, A.; Andersen, L.;
effects that have become evident in the course of cannabi- Marsche, G.; Heinemann, A.; Schicho, R. (2012). “O-
noid research. O-1602 produces some effects shared with 1602, an atypical cannabinoid, inhibits tumor growth in
classical cannabinoid compounds such as analgesic and colitis-associated colon cancer through multiple mecha-
antiinflammatory effects and appetite stimulation, but it nisms”. Journal of Molecular Medicine 91 (4): 449–58.
does not produce sedation or psychoactive effects, and doi:10.1007/s00109-012-0957-1. PMC 3529923. PMID
has several actions in the gut and brain that are not shared 22965195.
with typical cannabinoid agonists.[1][2][3][4][5][6][7]
[6] McHugh, D.; Wager-Miller, J.; Page, J.; Bradshaw, H. B.
(2012). “SiRNA knockdown of GPR18 receptors in BV-
2 microglia attenuates N-arachidonoyl glycine-induced
141.1 See also cell migration”. Journal of Molecular Signaling 7 (1): 10.
doi:10.1186/1750-2187-7-10. PMC 3493281. PMID
• Cannabidiol 22834922.

[7] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Brad-

• O-1918
shaw, H.; Kelly, M. E.; Straiker, A. (2013). “A
GPR18-based signaling system regulates IOP in murine
eye”. British Journal of Pharmacology 169 (4): 834–
141.2 References 43. doi:10.1111/bph.12136. PMC 3687663. PMID
23461720.
[1] Ashton, J. C. (2012). “The atypical cannabinoid o-1602:
Targets, actions, and the central nervous system”. Cen-
tral nervous system agents in medicinal chemistry 12 (3):
233–239. doi:10.2174/187152412802430156. PMID
22831390.

[2] Schuelert, N.; McDougall, J. J. (2011). “The abnormal

cannabidiol analogue O-1602 reduces nociception in a rat
model of acute arthritis via the putative cannabinoid re-
ceptor GPR55”. Neuroscience Letters 500 (1): 72–76.
doi:10.1016/j.neulet.2011.06.004. PMID 21683763.

[3] Schicho, R.; Bashashati, M.; Bawa, M.; McHugh, D.;

Saur, D.; Hu, H. M.; Zimmer, A.; Lutz, B.; MacKie,
K.; Bradshaw, H. B.; McCafferty, D. M.; Sharkey, K.
A.; Storr, M. (2011). “The atypical cannabinoid O-
1602 protects against experimental colitis and inhibits
neutrophil recruitment”. Inflammatory Bowel Diseases

191
Chapter 142

O-1812

O-1812 is an eicosanoid derivative related to anandamide
that acts as a potent and highly selective agonist for the
cannabinoid receptor CB1 , with a Kᵢ of 3.4nM at CB1
and 3870nM at CB2 .[1] Unlike most related compounds,
O-1812 is metabolically stable against rapid breakdown
by enzymes, and produces a cannabinoid-like discrim-
inative effect in rats, which is similar but not identical
to that produced by cannabinoid drugs of other chemical
classes.[2][3][4][5]
142.1 See also
• AM-1235
[4] Wiley JL, Smith FL, Razdan RK, Dewey WL (March
2005). “Task specificity of cross-tolerance between
Delta9-tetrahydrocannabinol and anandamide analogs in
mice”. European Journal of Pharmacology 510 (1-
2): 59–68. doi:10.1016/j.ejphar.2005.01.006. PMID
15740725.
[5] Breivogel CS, et al. (July 2008). “Sensitivity to delta9-
tetrahydrocannabinol is selectively enhanced in beta-
arrestin2 -/- mice”. Behavioural Pharmacology 19 (4):
298–307. doi:10.1097/FBP.0b013e328308f1e6. PMC
2751575. PMID 18622177.

• AM-2232

• AM-2389

• Methanandamide

• O-774

• O-1057

142.2 References
[1] Di Marzo V, et al. (February 2001). “Highly se-
lective CB(1) cannabinoid receptor ligands and novel
CB(1)/VR(1) vanilloid receptor “hybrid” ligands”. Bio-
chemical and Biophysical Research Communications 281
(2): 444–51. doi:10.1006/bbrc.2001.4354. PMID
11181068.

[2] Baskfield CY, Martin BR, Wiley JL (April 2004).

“Differential effects of delta9-tetrahydrocannabinol and
methanandamide in CB1 knockout and wild-type mice”.
The Journal of Pharmacology and Experimental Thera-
peutics 309 (1): 86–91. doi:10.1124/jpet.103.055376.
PMID 14718593.

[3] Wiley JL, et al. (August 2004). “A compari-

son of the discriminative stimulus effects of delta(9)-
tetrahydrocannabinol and O-1812, a potent and metabol-
ically stable anandamide analog, in rats”. Experimen-
tal and Clinical Psychopharmacology 12 (3): 173–9.
doi:10.1037/1064-1297.12.3.173. PMID 15301634.

192
Chapter 143

O-1871

O-1871 is a potent cannabinoid agonist which was in-

vented by Billy R Martin and Raj K Razdan in 2002.
It has a CB1 receptor affinity of 2.0nM and a CB2 re-
ceptor affinity of 0.3nM.[1] Structurally, O-1871 is a
cyclohexylphenol derivative related to CP 47,497, and
so is illegal in most jurisdictions where CP 47,497
and its derivatives are banned. However the 3,3-
dimethylcyclohexyl substituent of O-1871 can be re-
placed by various other groups, producing other potent
compounds such as the cycloheptyl derivative O-1656
and the 2-adamantyl derivative O-1660, as well as the
corresponding 3,5-dichlorophenyl derivative,[2] which are
not cyclohexylphenol derivatives.

143.1 See also

• CP 55,940
• Cannabidiol

• Cannabicyclohexanol

143.2 References
[1] Billy R Martin, Raj K Razdan. CANNABINOIDS. Patent
WO 2003/091189

[2] Xin-Zhong Lai, Dai Lu, Alexandros Makriyannis. Novel

biphenyl and biphenyl-like cannabinoids. Patent US
2004/0087590

193
Chapter 144

O-1918

O-1918 is a synthetic compound related to cannabidiol,
which is an antagonist at two former orphan receptors
GPR18 and GPR55, that appear to be related to the
cannabinoid receptors. O-1918 is used in the study of
these receptors, which have been found to be targets for
a number of endogenous and synthetic cannabinoid com-
pounds, and are thought to be responsible for most of the
non-CB1 , non-CB2 mediated effects that have become
evident in the course of cannabinoid research.[1][2][3][4][5]
[5] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Brad-
shaw, H.; Kelly, M. E.; Straiker, A. (2013). “A
GPR18-based signaling system regulates IOP in murine
eye”. British Journal of Pharmacology 169 (4): 834–
43. doi:10.1111/bph.12136. PMC 3687663. PMID
23461720.

144.1 See also

• Abnormal cannabidiol

• O-1602

144.2 References
[1] Offertáler, L.; Mo, F. M.; Bátkai, S.; Liu, J.; Begg,
M.; Razdan, R. K.; Martin, B. R.; Bukoski, R. D.;
Kunos, G. (2003). “Selective ligands and cellular ef-
fectors of a G protein-coupled endothelial cannabinoid
receptor”. Molecular Pharmacology 63 (3): 699–705.
doi:10.1124/mol.63.3.699. PMID 12606780.

[2] Zakrzeska, A.; Schlicker, E.; Baranowska, M.;

Kozłowska, H.; Kwolek, G.; Malinowska, B. (2010). “A
cannabinoid receptor, sensitive to O-1918, is involved
in the delayed hypotension induced by anandamide in
anaesthetized rats”. British Journal of Pharmacology 160
(3): 574–584. doi:10.1111/j.1476-5381.2009.00579.x.
PMC 2931558. PMID 20105178.

[3] Schuelert, N.; McDougall, J. J. (2011). “The abnormal

cannabidiol analogue O-1602 reduces nociception in a rat
model of acute arthritis via the putative cannabinoid re-
ceptor GPR55”. Neuroscience Letters 500 (1): 72–76.
doi:10.1016/j.neulet.2011.06.004. PMID 21683763.

[4] Szczesniak, A. M.; Maor, Y.; Robertson, H.; Hung,

O.; Kelly, M. E. M. (2011). “Nonpsychotropic
Cannabinoids, Abnormal Cannabidiol and Canabigerol-
Dimethyl Heptyl, Act at Novel Cannabinoid Recep-
tors to Reduce Intraocular Pressure”. Journal of Oc-
ular Pharmacology and Therapeutics 27 (5): 427–435.
doi:10.1089/jop.2011.0041. PMID 21770780.

194
Chapter 145

O-2050

O-2050 is a drug that is a classical cannabinoid derivative, RE, Razdan RK, Martin BR. Structural and pharmaco-
which acts as a silent antagonist for the CB1 receptor. logical analysis of O-2050, a putative neutral cannabinoid
This gives it an advantage in research over many com- CB(1) receptor antagonist. European Journal of Pharma-
monly used cannabinoid antagonists such as rimonabant, cology. 2011 Jan 25;651(1-3):96-105. PMID 21114999
which at higher doses act as inverse agonists at CB1 as
well as showing off-target effects. However while O-
2050 acts as a silent antagonist in vitro, some tests in vivo
have suggested it may show agonist activity under certain
circumstances.[1][2][3][4][5][6]

145.1 See also

• O-2113

145.2 References
[1] Martin B, et al. Agonists and silent antagonists in a series
of cannabinoid sulfonamides. 12th Annual Symposium
on the Cannabinoids, 2002

[2] Martin et al. SULFONAMIDE CANNABINOID AGO-

NISTS AND ANTAGONISTS. US Patent 7279500, Oct
9 2007

[3] Gardner A, Mallet PE. Suppression of feeding, drinking,

and locomotion by a putative cannabinoid receptor 'silent
antagonist'. European Journal of Pharmacology. 2006
Jan 13;530(1-2):103-6. PMID 16380113

[4] Higuchi S, Irie K, Mishima S, Araki M, Ohji M,

Shirakawa A, Akitake Y, Matsuyama K, Mishima K,
Mishima K, Iwasaki K, Fujiwara M. The cannabinoid 1-
receptor silent antagonist O-2050 attenuates preference
for high-fat diet and activated astrocytes in mice. Jour-
nal of Pharmacological Sciences. 2010;112(3):369-72.
PMID 20168044

[5] Higuchi S, Ohji M, Araki M, Furuta R, Katsuki M, Ya-

maguchi R, Akitake Y, Matsuyama K, Irie K, Mishima
K, Mishima K, Iwasaki K, Fujiwara M. Increment of
hypothalamic 2-arachidonoylglycerol induces the prefer-
ence for a high-fat diet via activation of cannabinoid
1 receptors. Behavioural Brain Research. 2011 Jan
1;216(1):477-80. PMID 20817042

[6] Wiley JL, Breivogel CS, Mahadevan A, Pertwee RG, Cas-

cio MG, Bolognini D, Huffman JW, Walentiny DM, Vann

195
Chapter 146

O-2113

O-2113 is a drug that is a classical cannabinoid derivative,

which acts as a potent agonist for cannabinoid receptors,
producing sedation, hypothermia and analgesia in animal
studies.[1]

146.1 See also

• O-2050

• O-2372
• O-2545

146.2 References
[1] Martin, et al. SULFONAMIDE CANNABINOID AGO-
NISTS AND ANTAGONISTS. US Patent 7279500, Oct
9 2007

196
Chapter 147

O-2372

O-2372 is an analgesic cannabinoid derivative created by

Organix Inc. for use in scientific research. It has high
affinity for both CB1 and CB2 receptors, with Kᵢ values of
1.3nM at CB1 and 0.57nM at CB2 , but is only moderately
soluble in water compared to other related compounds
such as O-2694, which it is a metabolite of.[1]

147.1 See also

• O-2113

• O-2545
• O-2694

147.2 References
[1] Martin BR, et al. Pharmacological characteriza-
tion of novel water-soluble cannabinoids. Journal of
Pharmacology and Experimental Therapeutics. 2006
Sep;318(3):1230-9. PMID 16757541

197
Chapter 148

O-2545

O-2545 is an analgesic cannabinoid derivative created

by Organix Inc. for use in scientific research. Unlike
most cannabinoids discovered to date, it is water soluble,
which gives it considerable advantages over many related
cannabinoids. It has high affinity for both CB1 and CB2
receptors, with Kᵢ values of 1.5nM at CB1 and 0.32nM
at CB2 .[1]

148.1 See also

• O-2113
• O-2372

• Tropoxane

148.2 References
[1] Martin BR, et al. Pharmacological characteriza-
tion of novel water-soluble cannabinoids. Journal of
Pharmacology and Experimental Therapeutics. 2006
Sep;318(3):1230-9. PMID 16757541

198
Chapter 149

O-2694

O-2694 is a drug that is a cannabinoid derivative. It has

analgesic effects and is used in scientific research. Unlike
most cannabinoids discovered to date, it is highly water-
soluble, which gives it considerable advantages over many
related drugs. It has high affinity for both CB1 and CB2
receptors, with Kᵢ values of 3.7nM at CB1 and 2.8nM at
CB2 . However, it has complex pharmacokinetics as most
of the administered dose is metabolised by hydrolysis of
the ester link to the water-insoluble compound O-2372,
thus producing a biphasic effects profile that is less suit-
able for research purposes than the related compound O-
2545.[1]

149.1 See also

• O-1057

• O-2372

149.2 References
[1] Martin BR, et al. Pharmacological characteriza-
tion of novel water-soluble cannabinoids. Journal of
Pharmacology and Experimental Therapeutics. 2006
Sep;318(3):1230-9. PMID 16757541

199
Chapter 150

O-774

O-774 is a classical cannabinoid derivative which acts as

a potent agonist for the cannabinoid receptors, with a Kᵢ
of 0.6 nM at CB1 , and very potent cannabinoid effects in
animal studies.[1][2]

150.1 See also

• AM-2232

• O-1057
• O-1812

150.2 References
[1] Singer M, et al. Potent cyano and carboxam-
ido side-chain analogues of 1', 1'-dimethyl-delta8-
tetrahydrocannabinol. Journal of Medicinal Chemistry.
1998 Oct 22;41(22):4400-7. PMID 9784115

[2] The Cannabinoid Receptors. Part I. Cannabinoid Recep-

tor Ligands and Structure-Activity Relationships. pp 6-9.
Edited by Patricia H Reggio. Humana Press 2009. ISBN
978-1-58829-712-9

200
Chapter 151

O-806

O-806 is a drug which is a cannabinoid derivative that is

used in scientific research. It is described as a mixed ago-
nist/antagonist at the cannabinoid receptor CB1 , meaning
that it acts as an antagonist when co-administered along-
side a more potent CB1 agonist, but exhibits weak partial
agonist effects when administered by itself.[1][2]

151.1 References
[1] Griffin, G.; Wray, E.; Rorrer, W.; Crocker, P.; Ryan, W.;
Saha, B.; Razdan, R.; Martin, B.; Abood, M. (1999). “An
investigation into the structural determinants of cannabi-
noid receptor ligand efficacy”. British Journal of Pharma-
cology 126 (7): 1575–1584. doi:10.1038/sj.bjp.0702469.
PMC 1565939. PMID 10323589.

[2] Griffin, G.; Wray, E.; Martin, B.; Abood, M.

(1999). “Cannabinoid agonists and antagonists dis-
criminated by receptor binding in rat cerebellum”.
British Journal of Pharmacology 128 (3): 684–688.
doi:10.1038/sj.bjp.0702806. PMC 1571656. PMID
10516649.

201
Chapter 152

O-823

O-823 is a drug which is a cannabinoid derivative that is

used in scientific research. It is described as a mixed ago-
nist/antagonist at the cannabinoid receptor CB1 , meaning
that it acts as an antagonist when co-administered along-
side a more potent CB1 agonist, but exhibits weak partial
agonist effects when administered by itself.[1][2][3]

152.1 References
[1] Pertwee RG, Fernando SR, Griffin G, Ryan W,
Razdan RK, Compton DR, Martin BR. Agonist-
antagonist characterization of 6'-cyanohex-2'-yne-delta
8-tetrahydrocannabinol in two isolated tissue prepara-
tions. European Journal of Pharmacology. 1996 Nov
14;315(2):195-201. PMID 8960884

[2] Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ,
Saha B, Razdan RK, Martin BR, Abood ME. An investi-
gation into the structural determinants of cannabinoid re-
ceptor ligand efficacy. British Journal of Pharmacology.
1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469
PMID 10323589

[3] Griffin G, Wray EJ, Martin BR, Abood ME. Cannabinoid

agonists and antagonists discriminated by receptor bind-
ing in rat cerebellum. British Journal of Pharmacology.
1999 Oct;128(3):684-8. doi:10.1038/sj.bjp.0702806
PMID 10516649

202
Chapter 153

Org 27569

Org 27569 is a drug which acts as a potent and selective

allosteric modulator of the cannabinoid CB1 receptor.
Studies in vitro suggest that it binds to a regulatory site on
the CB1 receptor target, causing a conformational change
that increases the binding affinity of CB1 agonists such as
CP 55,940, while decreasing the binding affinity of CB1
antagonists or inverse agonists such as rimonabant. How-
ever while Org 27569 increases the ability of CB1 ago-
nists to bind to the receptor, it decreases their efficacy at
stimulating second messenger signalling once bound, and
so in practice behaves as an insurmountable antagonist of
CB1 receptor function.[1]

153.1 References
[1] Price MR, Baillie GL, Thomas A, Stevenson LA, Eas-
son M, Goodwin R, McLean A, McIntosh L, Goodwin
G, Walker G, Westwood P, Marrs J, Thomson F, Cowley
P, Christopoulos A, Pertwee RG, Ross RA (November
2005). “Allosteric modulation of the cannabinoid CB1
receptor”. Molecular Pharmacology 68 (5): 1484–95.
doi:10.1124/mol.105.016162. PMID 16113085.

203
Chapter 154

Org 28312

Org 28312 is a drug developed by Organon International

which acts as a potent cannabinoid receptor full agonist at
both the CB1 and CB2 receptors. It was developed with
the aim of finding a water soluble cannabinoid agonist
suitable for intravenous use as an analgesic, but did not
proceed to human trials, with the related compound Org
28611 chosen instead due to its better penetration into
the brain.[1] The structure-activity relationships of these
compounds have subsequently been investigated further
leading to the development of a number of more potent
analogues, derived by cyclisation around the indole or
piperazine rings.[2][3]

154.1 See also

• LBP-1
• Org 28611

154.2 References
[1] Adam, J. M., et al. (2010). “Design, synthesis, and
structure–activity relationships of indole-3-carboxamides
as novel water soluble cannabinoid CB1 receptor ago-
nists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.

[2] Kiyoi T, York M, Francis S, Edwards D, Walker G,

Houghton AK, Cottney JE, Baker J, Adam JM (August
2010). “Design, synthesis, and structure-activity rela-
tionship study of conformationally constrained analogs
of indole-3-carboxamides as novel CB1 cannabinoid re-
ceptor agonists”. Bioorganic & Medicinal Chemistry Let-
ters 20 (16): 4918–21. doi:10.1016/j.bmcl.2010.06.067.
PMID 20634067.

[3] Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson

M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G,
York M, Baker J, Cottney JE, Houghton AK, McPhail P,
Osprey A, Walker G, Adam JM (December 2010). “De-
sign, synthesis, and structure-activity relationship study
of bicyclic piperazine analogs of indole-3-carboxamides
as novel cannabinoid CB1 receptor agonists”. Bioor-
ganic & Medicinal Chemistry Letters 20 (24): 7327–30.
doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.

204
Chapter 155

Org 28611

Org 28611 (SCH-900,111) is a drug developed by

Organon International which acts as a potent cannabinoid
receptor full agonist at both the CB1 and CB2 receptors.
It was developed with the aim of finding a water solu-
ble cannabinoid agonist suitable for intravenous use as an
analgesic,[1] and while it achieved this aim and has pro-
gressed as far as Phase II clinical trials in humans as both
a sedative and an analgesic, results against the compari-
son drugs (midazolam and morphine respectively) were
not particularly favourable in initial testing.[2][3]

155.1 See also

• LBP-1
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide
• Org 28312

155.2 References
[1] Adam, J. M., et al. (2010). “Design, synthesis, and
structure–activity relationships of indole-3-carboxamides
as novel water soluble cannabinoid CB1 receptor ago-
nists”. MedChemComm 1: 54. doi:10.1039/c0md00022a.

[2] Zuurman L, Passier PC, de Kam M, Kleijn HJ, Cohen

AF, van Gerven JM (August 2009). “Pharmacodynamic
and pharmacokinetic effects of the intravenously adminis-
tered CB1 receptor agonist Org 28611 in healthy male vol-
unteers”. Journal of Psychopharmacology (Oxford, Eng-
land) 23 (6): 633–44. doi:10.1177/0269881108091551.
PMID 18635703.

[3] A Comparison of Analgesic Efficacy Between a Single

Dose of ORG 28611, Morphine, and Placebo After Den-
tal Impaction Surgery

205
Chapter 156

Otenabant

Otenabant (CP-945,598) is a drug which acts as a po-

tent and highly selective CB1 antagonist.[1] It was devel-
oped by Pfizer for the treatment of obesity,[2] but develop-
ment for this application has been discontinued following
the problems seen during clinical use of the similar drug
rimonabant.[3]

156.1 See also

• Cannabinoid receptor antagonist

156.2 References
[1] Kim, M., et al. (2008), Design, chemical synthe-
sis, and biological evaluation of novel triazolyl ana-
logues of taranabant (MK-0364), a cannabinoid-1 recep-
tor inverse agonist, Tetrahedron 64 (48): 10802–10809,
doi:10.1016/j.tet.2008.09.057

[2] Woods SC. The endocannabinoid system: novel path-

way for cardiometabolic Risk-factor reduction. Journal
of the American Academy of Physician Assistants. 2007
Nov;Suppl Endocannabinoid:7-10. PMID 18047036

[3] http://www.pfizer.com

206
Chapter 157

Parahexyl

Parahexyl (Synhexyl, n-hexyl-Δ3 THC) is a synthetic 157.2 See also

homologue of THC, which was invented in 1949 during
attempts to elucidate the structure of Δ9 -THC, one of the
active components of cannabis. [1][2]
Parahexyl is similar in both structure and activity to THC,
differing only in the position of one double bond, and the
lengthening of the 3-pentyl chain by one CH2 group to
n-hexyl. [3] Parahexyl produces classic cannabis agonist
effects in animals. It has a somewhat higher oral bioavail-
ability than THC itself but is otherwise very similar. [4]
Presumably it acts as a CB1 agonist in the same way as
THC but as there has been no research published using
Parahexyl since the discovery of the CB1 receptor this
has not been definitively confirmed.
Parahexyl was made illegal under UN convention in 1982
on the basis of its structural similarity and similar effects
profile to THC, despite never having had any recorded
instances of abuse by humans or illicit sale. Parahexyl was
placed into the most restrictive Schedule 1 as a compound
with no medical use.
157.1 Isomerism
• Tetrahydrocannabivarin
• Tetrahydrocannabinol-C4
157.3 References
[1] Adams R, Harfenist M, Loewe S (1949). “New Analogs
of Tetrahydrocannabinol. XIX”. J. Am. Chem. Soc. 71
(5): 1624–1628. doi:10.1021/ja01173a023.
[2] Ask Dr. Shulgin Online March 7, 2001
[3] Ono M, Shimamine M, Takahashi K, Inoue T (1974).
"[Studies on hallucinogens. VII Synthesis of parahexyl]".
Eisei Shikenjo hōkoku. Bulletin of National Institute of
Hygienic Sciences (in Japanese) 49 (92): 46–50. PMID
4477495.
[4] Fairchild MD, Jenden DJ, Mickey MR, Yale C (1980).
“EEG effects of hallucinogens and cannabinoids us-
ing sleep-waking behavior as baseline”. Pharmacol.
Biochem. Behav. 12 (1): 99–105. doi:10.1016/0091-
3057(80)90422-0. PMID 6102770.

Dibenzopyran and monoterpenoid numbering of tetrahydro-

cannabinol derivatives

Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-

benzo[c]chromen-1-ol.
See also: Tetrahydrocannabinol#Isomerism.

207
Chapter 158
UR-144
UR-144 (TMCP-018, KM-X1, MN-001, YX-17) is a
drug invented by Abbott Laboratories,[1] that acts as a se-
lective full agonist of the peripheral cannabinoid receptor
CB2 , but with much lower affinity for the psychoactive
CB1 receptor.
158.1 Pharmacology
UR-144 has high affinity for the CB2 receptor with a Kᵢ
of 1.8 nM but 83x lower affinity for the CB1 receptor with
a Kᵢ of 150 nM.[2] Although a later study found its CB1
affinity to be much higher than previously expected, with
a Kᵢ of 28.9nM and an EC50 of 1295nM. Chemically it
is closely related to other 2,2,3,3-tetramethylcyclopropyl
synthetic cannabinoids like A-796,260 and A-834,735
but with a different substitution on the 1-position of the
indole core, in these compounds its 1-pentyl group is re-
placed with alkylheterocycles like 1-(2-morpholinoethyl)
and 1-(tetrahydropyran-4-ylmethyl).
158.2 History of use
UR-144 has been detected as an ingredient of synthetic
cannabis smoking blends in New Zealand, and subse-
quently banned from sale as a temporary class drug on
6 April 2012.[3] It has also been encountered in smoking
blends and subsequently banned in Russia.[4]
The chemical UR-144 has also been banned in the UK in
2013 along with RCS-4 and AM-2201. This is due to two
people in Glasgow being admitted to hospital after tak-
ing a legal high with the chemicals in it. Another person
was admitted to Brighton hospital after overdosing on the
drug.
158.3 Detection
A forensic standard of UR-144 is available, and the com-
pound has been posted on the Forendex website of po-
tential drugs of abuse.[5] An ELISA immunoassay tech-
nique for detecting UR-144 in urine as part of general
208
drug screens has been developed by Tulip Biolabs, Inc.
An Homogeneous Immunoassay that runs on most Clin-
ical Chemistry Analyzers and detects several UR and
XLR synthetic cannabinoids has been developed and in-
troduced by Immunalysis Inc. Pomona USA.
158.4 See also
• AB-001
• AM-1221
• 4-HTMPIPO
• JTE 7-31
• JWH-018
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide
• XLR-11
158.5 References
[1] WO application 2006069196, Pace JM, Tietje K,
Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as
cannabinoid receptor ligands”, published 2006-06-29, as-
signed to Abbott Laboratories
[2] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson
GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai
M, Zhu CZ, Chandran P, Meyer MD (January 2010).
“Indol-3-ylcycloalkyl ketones: effects of N1 substituted
indole side chain variations on CB(2) cannabinoid re-
ceptor activity”. J. Med. Chem. 53 (1): 295–315.
doi:10.1021/jm901214q. PMID 19921781.
[3] Temporary Class Drug Notices. New Zealand Ministry of
Health
[4] Sobolevsky T, Prasolov I, Rodchenkov G (October 2012).
“Detection of urinary metabolites of AM-2201 and UR-
144, two novel synthetic cannabinoids”. Drug Test Anal.
doi:10.1002/dta.1418. PMID 23042760.
[5] Southern Association of Forensic Scientists
http://forendex.southernforensic.org/index.php/detail/
index/1218
158.6. FURTHER READING 209

158.6 Further reading

• Poso A, Huffman JW (January 2008). “Targeting
the cannabinoid CB2 receptor: modelling and
structural determinants of CB2 selective lig-
ands”. Br. J. Pharmacol. 153 (2): 335–46.
doi:10.1038/sj.bjp.0707567. PMC 2219524.
PMID 17982473.

• Chin CL, Tovcimak AE, Hradil VP, Seifert TR,

Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D,
Pai M, Wetter J, Hsieh GC, Honore P, Frost JM,
Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB
(January 2008). “Differential effects of cannabi-
noid receptor agonists on regional brain activity us-
ing pharmacological MRI”. Br. J. Pharmacol. 153
(2): 367–79. doi:10.1038/sj.bjp.0707506. PMC
2219521. PMID 17965748.
• Frost JM, Dart MJ, Tietje KR, Garrison TR,
Grayson GK, Daza AV, El-Kouhen OF, Miller
LN, Li L, Yao BB, Hsieh GC, Pai M, Zhu CZ,
Chandran P, Meyer MD (March 2008). “Indol-
3-yl-tetramethylcyclopropyl ketones: effects of in-
dole ring substitution on CB2 cannabinoid recep-
tor activity”. J. Med. Chem. 51 (6): 1904–12.
doi:10.1021/jm7011613. PMID 18311894.
Chapter 159

Perrottetinene

Perrottetinene is a naturally occurring cannabinoid com-

pound found in the New Zealand liverwort plant Radula
marginata and other species from the Radula genus,[1]
along with a number of similar compounds. Its chem-
ical structure closely resembles that of THC, the main
active component of marijuana, and it is thought that
perrottetinene may also be an active cannabinoid ago-
nist although detailed pharmacological investigation of
the compound has yet to be reported.[2][3] Stereoselec-
tive synthesis of perrottinene has also been carried out to
investigate the activity of its different enantiomers.[4]

159.1 References
[1] Cullmann F, Becker H. Prenylated bibenzyls from the liv-
erwort Radula laxiramea. Zeitschrift Fur Naturforschung.
1999; 54(3-4): 147-150. ISSN 09395075

[2] Toyota M, Kinugawa T, Asakawa Y. Bibenzyl Cannabi-

noid and Bisbibenzyl Derivative from the Liverwort
Radula perrottetii. Phytochemistry 1994; 37(3):859-862.

[3] Toyota M, Shimamura T, Ishii H, Renner M, Braggins

J, Asakawa Y. New bibenzyl cannabinoid from the New
Zealand liverwort Radula marginata. Chemical and Phar-
maceutical Bulletin (Tokyo). 2002 Oct;50(10):1390-2.
PMID 12372871

[4] Song Y, Hwang S, Gong P, Kim D, Kim S. Stereoselec-

tive total synthesis of (-)-perrottetinene and assignment
of its absolute configuration. Organic Letters. 2008 Jan
17;10(2):269-71. PMID 18085788

210
Chapter 160

PF-03550096

PF-03550096 is a drug that acts as a potent agonist for

the CB2 cannabinoid receptor, with good selectivity over
CB1 having Kᵢ values of 7nM at CB2 and 1500nM at
CB1 . It was originally developed by Pfizer in 2008 as a
medication for irritable bowel syndrome,[1] but has only
progressed to animal studies.[2]

160.1 See also

• AB-FUBINACA
• AB-PINACA

160.2 References
[1] Ando K et al, BENZIMIDAZOLONE DERIVATIVES.
WO 2008/032164

[2] Kikuchi, A.; Ohashi, K.; Sugie, Y.; Sugimoto, H.;

Omura, H. (2008). “Pharmacological evaluation of a
novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro
and in vivo by using a rat model of visceral hypersensitiv-
ity”. Journal of pharmacological sciences 106 (2): 219–
224. doi:10.1254/jphs.FP0071599. PMID 18270474.

211
Chapter 161

PF-514273

PF-514273 is a drug developed by Pfizer, which acts as

an extremely selective antagonist for the CB1 receptor,
with approximately 10,000x selectivity over the closely
related CB2 receptor. This very high selectivity makes
it useful for scientific research into these receptors, as
many commonly used cannabinoid receptor antagonists
also block the CB2 receptor to some extent.[1]

161.1 References
[1] Dow RL, Carpino PA, Hadcock JR, Black SC, Iredale
PA, DaSilva-Jardine P, Schneider SR, Paight ES, Griffith
DA, Scott DO, O'Connor RE, Nduaka CI. Discov-
ery of 2-(2-chlorophenyl)−3-(4-chlorophenyl)−7-
(2,2-difluoropropyl)−6,7-dihydro-2H-pyrazolo[3,4-
f][1,4]oxazepin-8(5H)-one (PF-514273), a novel,
bicyclic lactam-based cannabinoid-1 receptor antago-
nist for the treatment of obesity. Journal of Medicinal
Chemistry. 2009 May 14;52(9):2652-5. PMID 19351113

212
Chapter 162

PipISB

PipISB is a drug used in scientific research which acts as

a potent and selective inverse agonist of the cannabinoid
receptor CB1 . It is highly selective for the CB1 receptor
over CB2 , with a K at CB1 of 1.5nM vs over 7000nM
at CB2 , has good blood-brain barrier penetration, and
can be conveniently radiolabelled with either 11 C or 18 F,
making it useful for mapping the distribution of CB1 re-
ceptors in the brain.[1][2]

162.1 References
[1] Donohue, Sean R.; Halldin, Christer; Schou, Mag-
nus; Hong, Jinsoo; Phebus, Lee; Chernet, Eyassu;
Hitchcock, Stephen A.; Gardinier, Kevin M.; Ru-
ley, Kevin M.; Krushinski, Joseph H.; Schaus, John;
Pike, Victor W. (2008). “Radiolabeling of a high
potency cannabinoid subtype-1 receptor inverse ago-
nist, N-(4-fluoro-benzyl)−4-(3-(piperidin-1-yl-indole-1-
sulfonyl)benzamide (PipISB), with carbon-11 or fluorine-
18”. Journal of Labelled Compounds and Radiopharma-
ceuticals 51 (3): 146. doi:10.1002/jlcr.1491.

[2] Finnema, S. J.; Donohue, S. R.; Zoghbi, S. S.; Brown,

A. K.; Gulyás, B. Z.; Innis, R. B.; Halldin, C.; Pike, V.
W. (2009). “Evaluation of \11C]PipISB and \18F]PipISB
in monkey as candidate radioligands for imaging brain
cannabinoid type-1 receptors in vivo”. Synapse 63 (1):
22–30. doi:10.1002/syn.20578. PMC 2587077. PMID
18925657.

213
Chapter 163

Pirnabine

Pirnabine (SP-304) is a synthetic cannabinoid recep-

tor ligand, which was developed for the treatment of
glaucoma.[1]

163.1 References
[1]

214
Chapter 164

PSB-SB-1202

PSB-SB-1202 is a coumarin derivative which is an ag-

onist at the cannabinoid receptors CB1 and CB2 , with a
CB1 Ki of 32nM and a CB2 Ki of 49nM.[1] It is also
a weak antagonist at the related receptor GPR55, with
an IC50 of 6350nM, but has no significant affinity for
GPR18.[2]

164.1 See also

• PSB-SB-487

164.2 References
[1] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I,
Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3-
benzylcoumarins: a versatile scaffold for the development
of potent and selective cannabinoid receptor agonists and
antagonists. Journal of Medicinal Chemistry. 2012 Sep
27;55(18):7967-77. PMID 22916707

[2] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse,
S.; Müller, C. E. (2013). “Antagonists for the orphan
G protein-coupled receptor GPR55 based on a coumarin
scaffold”. Journal of Medicinal Chemistry 56 (11):
130516144836005. doi:10.1021/jm4005175. PMID
23679955.

215
Chapter 165

PSB-SB-487

PSB-SB-487 is a coumarin derivative which is an antag-

onist at the former orphan receptor GPR55. Unlike older
GPR55 antagonists such as O-1918, PSB-SB-487 has
good selectivity over the related receptor GPR18, with
an IC50 of 113nM at GPR55 vs 12500nM at GPR18.[1]
However it has poorer selectivity over other related re-
ceptors, acting as a weak antagonist at CB1 with a Ki
of 1170nM, and a partial agonist at CB2 with a Ki of
292nM.[2]

165.1 See also

• PSB-SB-1202

165.2 References
[1] Rempel, V.; Volz, N.; Gläser, F.; Nieger, M.; Bräse,
S.; Müller, C. E. (2013). “Antagonists for the orphan
G protein-coupled receptor GPR55 based on a coumarin
scaffold”. Journal of Medicinal Chemistry 56 (11):
130516144836005. doi:10.1021/jm4005175. PMID
23679955.

[2] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I,

Nieger M, Wenzel W, Bräse S, Müller CE. 7-Alkyl-3-
benzylcoumarins: a versatile scaffold for the development
of potent and selective cannabinoid receptor agonists and
antagonists. Journal of Medicinal Chemistry. 2012 Sep
27;55(18):7967-77. PMID 22916707

216
Chapter 166

QUCHIC

QUCHIC (BB-22 or 1-(cyclohexylmethyl)−1H-

indole-3-carboxylic acid 8-quinolinyl ester) is
a designer drug offered by online vendors as a
cannabimimetic agent, and was first detected being
sold in synthetic cannabis products in Japan in early
2013,[1] and subsequently also in New Zealand.[2] The
structure of QUCHIC appears to utilise an understanding
of structure-activity relationships within the indole class
of cannabimimetics, although its design origins are
unclear. QUCHIC, along with QUPIC, represents a
structurally unique synthetic cannabinoid chemotype
since it contains an ester linker at the indole 3-position
rather than the precedented ketone of JWH-018 and its
analogues, or the amide of SDB-001 and its analogues.
No information regarding the in vitro or in vivo activity
of QUCHIC has been published, and only anecdotal
reports are known of its pharmacology in humans or
other animals.

166.1 See also

• 5F-PB-22
• JWH-018
• PB-22
• QUPIC
• SDB-001

166.2 References
[1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; Kikura-
Hanajiri, R.; Goda, Y. (2013). “Two new-type
cannabimimetic quinolinyl carboxylates, QUPIC and
QUCHIC, two new cannabimimetic carboxamide deriva-
tives, ADB-FUBINACA and ADBICA, and five synthetic
cannabinoids detected with a thiophene derivative α-PVT
and an opioid receptor agonist AH-7921 identified in ille-
gal products”. Forensic Toxicology. doi:10.1007/s11419-
013-0182-9.
[2] Dunne bans further two substances found in K2. Press
Release: New Zealand Government. Tuesday, 30 April
2013

217
Chapter 167
QUPIC
QUPIC (PB-22 or 1-pentyl-1H-indole-3-carboxylic
acid 8-quinolinyl ester) is a designer drug offered by
online vendors as a cannabimimetic agent, and detected
being sold in synthetic cannabis products in Japan in
2013.[1] The structure of QUPIC appears to use an un-
derstanding of structure-activity relationships within the
indole class of cannabimimetics, although its design ori-
gins are unclear. QUPIC represents a structurally unique
synthetic cannabinoid chemotype, since it contains an es-
ter linker at the indole 3-position, rather than the prece-
dented ketone of JWH-018 and its analogs, or the amide
of SDB-001 and its analogs. No information regarding
the in vitro activity of QUPIC has been published, how-
ever one in vivo study found PB-22 to cause seizures in
humans and dogs.[2] QUPIC is an analog of JWH-018
which differs by having 8-hydroxyquinoline replacing the
naphthalene group of JWH-018. QUPIC is now found in
many herbal incense and potpourri products.
167.1 Detection
A forensic standard of PB-22 is available, and the com-
pound has been posted on the Forendex website of poten-
tial drugs of abuse.[3]
167.2 Legal status
As of 9 May 2014, PB-22 is no longer legal in New
Zealand.
In January 2014, QUPIC was designated as a Schedule I
controlled substance in the United States.[4][5]
In Ohio, QUPIC is illegal.[6]
Florida also has banned QUPIC/P-22.[7]
167.3 See also
• 5F-PB-22
• QUCHIC
218
• SDB-001
167.4 References
[1] Uchiyama, N.; Matsuda, S.; Kawamura, M.; Kikura-
Hanajiri, R.; Goda, Y. (2013). “Two new-type
cannabimimetic quinolinyl carboxylates, QUPIC and
QUCHIC, two new cannabimimetic carboxamide deriva-
tives, ADB-FUBINACA and ADBICA, and five synthetic
cannabinoids detected with a thiophene derivative α-PVT
and an opioid receptor agonist AH-7921 identified in ille-
gal products”. Forensic Toxicology. doi:10.1007/s11419-
013-0182-9.
[2] Gugelmann, H; Gerona, R; Li, C; Tsutaoka, B; Olson, KR;
Lung, D (2014). "'Crazy Monkey' Poisons Man and Dog:
Human and canine seizures due to PB-22, a novel syn-
thetic cannabinoid.”. Clinical Toxicology 52 (6): 635–8.
doi:10.3109/15563650.2014.925562. PMID 24905571.
[3] Forendex entry, Southern Association of Forensic Scien-
tists
[4] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G;
Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C
(2014). “Four Postmortem Case Reports with Quantita-
tive Detection of the Synthetic Cannabinoid, 5F-PB-22”.
Journal of analytical toxicology. doi:10.1093/jat/bku048.
PMID 24876364.
[5] “PB-22 and 5F-PB-22”. Drug Enforcement Administra-
tion, Office of Diversion Control.
[6] Jeremy Pelzer (April 17, 2014). “Ohio bans two synthetic
marijuana drugs sold as “herbal incense"". cleveland.com.
[7] “Statutes & Constitution :View Statutes : Online Sun-
shine”. Leg.state.fl.us. 1997-05-06. Retrieved 2014-07-
12.
Chapter 168

Rimonabant

Rimonabant (also known as SR141716; trade name the anti-obesity treatment for approval.[2] Subsequently,
Acomplia) is an anorectic antiobesity drug that has been Sanofi-Aventis announced it was suspending the new drug
withdrawn from the market due to potentially serious side application (NDA) for rimonabant, and that it would re-
effects. It was approved for use in Europe and other coun- submit an application at some point in the future.
tries, but never approved in the United States. Rimona- The EU’s approval was not a blanket approval, nor did it
bant is an inverse agonist for the cannabinoid receptor approve Acomplia for nonobesity-related problems, such
CB1.[3] Its main effect is reduction in appetite. as smoking cessation, although off-label use of the drug
was still possible. The approval was, in combination
with diet and exercise, for the treatment of obese patients
(BMI greater than or equal to 30), or overweight patients
168.1 History (BMI greater than 27) with associated risk factors, such
as type 2 diabetes or dyslipidaemia.
See also: Discovery and development of Cannabinoid
In October 2008, the European Medicines Agency's
Receptor 1 Antagonists
Committee for Medicinal Products for Human Use
(CHMP) had determined that the risks of Acomplia out-
Rimonabant was the first selective CB1 receptor blocker weighed its benefits. The Agency subsequently recom-
to be approved for use anywhere in the world. In Europe, mended that the product be suspended from the UK mar-
it was indicated for use in conjunction with diet and ex- ket, and that doctors not prescribe the drug due to the risk
ercise for patients with a body mass index (BMI) greater of serious psychiatric problems, and even suicide. Sanofi-
than 30 kg/m², or patients with a BMI greater than 27 Aventis then suspended sale of the drug.[1][6][7] Approval
kg/m² with associated risk factors, such as type 2 diabetes of the drug was officially withdrawn by the European
or dyslipidaemia. In the UK, it was available beginning Medicines Agency on 16 January 2009.[8]
in July 2006. As of 2008, the drug was available in 56
India has prohibited the manufacture and sale of the
countries.
drug.[9]
On 21 June 2006, the European Commission approved
the sale of rimonabant in the then-25-member European
Union. Pharmaceutical company Sanofi-Aventis, (which
changed its name to Sanofi in 2011) announced the first
country in which Acomplia would be sold was the United
Kingdom as a prescription drug. Sales began in July
2006. Sanofi-Aventis also projected that the drug would 168.2 Uses/potential uses
be sold shortly thereafter in Denmark, Ireland, Germany,
Finland, and Norway. It was expected in Belgium[4] and
Sweden in 2007. Ordinary obesity would, according to 168.2.1 Obesity
official medical recommendations, not be enough to ac-
quire the prescription in Sweden; there would be ad- In a 2006 (2 year) study reported in JAMA, “Compared
ditional requirements concerning abnormal blood lipid with the placebo group, the 20 mg of rimonabant group
levels.[5] produced greater mean (SEM) reductions in weight (−6.3
Rimonabant was submitted to the Food and Drug Admin- [0.2] kg vs −1.6 [0.2] kg; P<.001), waist circumference
istration (FDA) for approval in the United States. How- (−6.1 [0.2] cm vs −2.5 [0.3] cm; P<.001), and level of
ever, in 2007, the FDA’s Endocrine and Metabolic Drugs triglycerides (percentage change, −5.3 [1.2] vs 7.9 [2.0];
Advisory Committee (EMDAC) concluded the French P<.001) and a greater increase in level of high-density
manufacturer Sanofi-Aventis failed to demonstrate the lipoprotein cholesterol (percentage change, 12.6 [0.5] vs
safety of rimonabant and voted against recommending 5.4 [0.7]; P<.001).” [10]

219
220 CHAPTER 168. RIMONABANT

168.2.2 Smoking cessation 168.4 Negative side effects

Rimonabant may also be found to be effective in assisting
some smokers to quit smoking. Sanofi is currently con-
ducting studies to determine the possible value of rimon-
abant in smoking-cessation therapy. The Studies with
Rimonabant and Tobacco Use (STRATUS) program in-
volves more than 6,000 subjects. STRATUS is designed
to explore two smoking-related therapies: first, to use ri-
monabant directly to aid in smoking cessation; second, to
help prevent weight gain in former smokers. Initial re-
sults apparently suggest rimonabant is effective for both
uses. However, the FDA has explicitly stated to Sanofi
that, without additional studies, rimonabant cannot be ap-
proved in the United States for smoking cessation therapy.
According to a Cochrane Collaboration review in 2007,
rimonabant “may increase the odds of quitting approxi-
mately 11/2-fold”.[11]
Shortly after market introduction, press reports and inde-
pendent studies suggested that side effects occurred more
intensely and more commonly than had been found by the
manufacturer in their clinical studies. Reports of severe
depression and suicidal thoughts were frequent.[18] As the
drug’s target CB1 receptors are fairly ubiquitous through-
out the central nervous system, it is not currently under-
stood where the inverse agonist is acting to cause these
side-effects.
In 2007, it was reported that the committee advising the
U.S. FDA had voted not to recommend the drug’s ap-
proval because of concerns over suicidality, depression,
and other related side effects associated with use of the
drug.[19]

168.5 Preparation
168.2.3 Addiction behaviors
The chemical synthesis of rimonabant is described as
follows:[20]
Rimonabant reduced resumption of cocaine-seeking re-
sponses triggered by two of the three most common trig-
gers of relapse in humans: priming and cues. It may also
reduce ethanol- and opiate-seeking behavior.[12]

168.2.4 Short-term memory

Tetrahydrocannabinol (THC) is known to impair short-

term memory. It was therefore hypothesised that ri-
monabant may reduce or inhibit the atrophic effects of
cannabinoids. Indeed, in animal studies, it significantly
improved the ability of rats to encode information into
short-term memory.[13]

168.2.5 Blockage of cannabis effects

Rimonabant blocks the psychoactive and some of the

cardiovascular effects of Δ9 -tetrahydrocannabinol (THC)
in humans without affecting the pharmacokinetics.[14]
Rimonabant has been described colloquially as “re-
verse marijuana”, having a depressing effect on ap- 168.6 Brand names
petite inverse to the increased appetite created by
cannabinoids.[15]
Brand names for rimonabant include Acomplia, Bethin,
Monaslim, Remonabent, Riobant, Slimona, and Ri-
moslim. The proposed brand name if it had been ap-
proved for use in the United States was Zimulti.
168.3 Other effects

Rimonabant reduces voluntary wheel running in labora- 168.7 References

tory mice.[16]
Rimonabant significantly increased human sperm motil- [1] “Anti-obesity drug use suspended”. BBC News. 23 Octo-
ity and viability in vitro.[17] ber 2008. Retrieved 4 March 2010.
168.7. REFERENCES 221

[2] “Zimulti Acomplia Report - Diet Drug Acomplia / Zi-
multi Gets Thumbs Down From FDA Panel”. Acompli-
areport.com. 2007-06-13. Retrieved 2010-03-19.
[3] Fong TM, Heymsfield SB (September 2009).
“Cannabinoid-1 receptor inverse agonists: current
understanding of mechanism of action and unan-
swered questions”. Int J Obes (Lond) 33 (9): 947–55.
doi:10.1038/ijo.2009.132. PMID 19597516.
[4] Auteur: Femke Gebruers. “Article from the Belgian
newspaper De Standaard”. Standaard.be. Retrieved
2010-03-19.
[16] Keeney BK, et al. (2008). “Differential response
to a selective cannabinoid receptor antagonist
(SR141716: rimonabant) in female mice from lines
selectively bred for high voluntary wheel-running
behavior”. Behavioural Pharmacology 19 (8): 812–
820. doi:10.1097/FBP.0b013e32831c3b6b. PMID
19020416.
[17] Aguila S, et al. (2010). “Rimonabant (SR141716) in-
duces metabolism and acquisition of fertilizing ability
in human sperm”. Br J Pharmacol 159 (4): 831–41.
doi:10.1111/j.1476-5381.2009.00570.x. PMC 2829209.
PMID 20067470.

[5] “Article from the Swedish TV station TV 4 website”. [18] “Kassen müssen nicht für “Acomplia” zahlen”. tagess-
Tv4.se. 2008-03-06. Retrieved 2010-03-19. chau.de. 2006-10-17. Retrieved 2007-06-13.

[6] “European Medicines Agency”. Ema.europa.eu/ema/. [19] “Suicide risk fears over diet pill”. BBC News. 15 June
2010-02-15. Retrieved 2010-03-19. 2007. Retrieved 4 March 2010.

[7] “Sanofi-aventis - A diversified healthcare company, fo-
cused on patients’ needs”. En.sanofi-aventis.com. Re-
trieved 2010-03-19.
[8] “Microsoft Word - Zimulti _Rimonabant_ Public State-
ment” (PDF). Retrieved 2010-03-19.
[20] Yoshioka, T., et al. (1989). “Studies on hindered
phenols and analogs. 1. Hypolipidemic and hypo-
glycemic agents with ability to inhibit lipid peroxida-
tion”. Journal of Medicinal Chemistry 32 (2): 421.
doi:10.1021/jm00122a022. PMID 2913302.

[9] “Drugs banned in India”. Central Drugs Standard Control

Organization, Dte.GHS, Ministry of Health and Family
Welfare, Government of India. Retrieved 2013-09-17.

[10] JAMA. 2006 Feb 15;295(7):761-75. Effect of rimon-

abant, a cannabinoid-1 receptor blocker, on weight and
cardiometabolic risk factors in overweight or obese pa-
tients: RIO-North America: a randomized controlled
trial. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J,
Rosenstock J; RIO-North America Study Group. PMID
16478899

[11] Cahill K, Ussher M (2007). Cahill, Kate, ed.

“Cannabinoid type 1 receptor antagonists (rimon-
abant) for smoking cessation”. Cochrane database
of systematic reviews (Online) (4): CD005353.
doi:10.1002/14651858.CD005353.pub3. PMID
17943852.

[12] Maldonado R, Valverde O, Berrendero F (2006). “In-

volvement of the endocannabinoid system in drug
addiction”. Trends Neurosci. 29 (4): 225–32.
doi:10.1016/j.tins.2006.01.008. PMID 16483675.

[13] Deadwyler SA, Goonawardena AV, Hampson RE (2007).

“Short-term memory is modulated by the spontaneous re-
lease of endocannabinoids: evidence from hippocampal
population codes”. Behavioural Pharmacology 18 (5–6):
571–80. doi:10.1097/FBP.0b013e3282ee2adb. PMID
17762525.

[14] Huestis MA, et al. (2001). “Blockade of effects of

smoked marijuana by the CB1-selective cannabinoid re-
ceptor antagonist SR141716”. Arch. Gen. Psychiatry
58 (4): 322–8. doi:10.1001/archpsyc.58.4.322. PMID
11296091.

[15] Stephan Guyenet, PhD (9 March 2012) Seduced by Food:

Obesity and the Human Brain Boing Boing
Chapter 169

Rosonabant

Rosonabant (INN; E-6776) is a drug acting as a CB1

receptor antagonist/inverse agonist that was under inves-
tigation by Esteve as an appetite suppressant for the treat-
ment of obesity.[1][2] Development of the drug for clinical
use was apparently halted shortly after the related CB1
antagonist rimonabant was discontinued, likely due to
the reports of severe psychiatric adverse effects such as
anxiety, depression, and suicidal ideation associated with
it and with similarly-acting agents.[3][4]

169.1 See also

• Cannabinoid receptor antagonist

169.2 References
[1] Janero DR, Makriyannis A (March 2009). “Cannabinoid
receptor antagonists: pharmacological opportunities,
clinical experience, and translational prognosis”. Ex-
pert Opinion on Emerging Drugs 14 (1): 43–65.
doi:10.1517/14728210902736568. PMID 19249987.

[2] Tim C. Kirkham; S. J. Cooper (2007). Appetite and Body

Weight: Integrative Systems and the Development of Anti-
Obesity Drugs. Academic Press. p. 325. ISBN 978-0-12-
370633-1. Retrieved 12 May 2012.

[3] Heal DJ, Gosden J, Smith SL (December 2009).

“Regulatory challenges for new drugs to treat obesity and
comorbid metabolic disorders”. British Journal of Clini-
cal Pharmacology 68 (6): 861–74. doi:10.1111/j.1365-
2125.2009.03549.x. PMC 2810797. PMID 20002080.

[4] Lee HK, Choi EB, Pak CS (2009). “The current sta-
tus and future perspectives of studies of cannabinoid
receptor 1 antagonists as anti-obesity agents”. Cur-
rent Topics in Medicinal Chemistry 9 (6): 482–503.
doi:10.2174/156802609788897844. PMID 19689362.

222
Chapter 170

S-444,823

S-444,823 is a drug developed by Shionogi which

is a cannabinoid agonist.[1] It was developed as an
antipruritic, and has moderate selectivity for the CB2
subtype, having a CB2 affinity of 18nM, and 32x se-
lectivity over the CB1 receptor. In animal studies it
showed analgesic effects and strongly reduced itching
responses, but without producing side effects such as
sedation and catalepsy that are seen with centrally acting
CB1 agonists.[2]

170.1 See also

• JTE 7-31

170.2 References
[1] Arimura A. Novel Use of Cannabinoid Receptor Agonist.
Patent WO 2005/016351

[2] Odan M, et al. Discovery of S-444823, a potent CB1/CB2

dual agonist as an antipruritic agent. Bioorganic and
Medicinal Chemistry Letters. 2012 Apr 15;22(8):2898-
901. PMID 22421019

223
Chapter 171

SDB-001

This article is about the cannabinoid drug. For the South
Korean girl band, see 2NE1. For the metabotropic
glutamate receptor antagonist, see APICA (drug).
SDB-001 (2NE1, APICA, N-(1-adamantyl)−1-
pentyl-1H-indole-3-carboxamide) is a drug that acts
as a potent agonist for the cannabinoid receptors. It
had never previously been reported in the scientific or
patent literature, and was first identified by laboratories
in Japan in March 2012 as an ingredient in synthetic
cannabis smoking blends, along with a related compound
APINACA (sold as “AKB48”).[1] Structurally it closely
resembles cannabinoid compounds from patent WO
2003/035005 but with an indole core instead of indazole,
and a simple pentyl chain on the indole 1-position.
Pharmacological testing determined SDB-001 to have
an IC50 of 175nM at CB1 , only slightly less potent than
JWH-018 which had an IC50 of 169nM, but over four
times more tightly binding than AKB48, which had an
IC50 of 824nM.[2] The first published synthesis and
pharmacological evaluation of SDB-001 revealed that it
acts as a full agonist at CB1 (EC50 = 34 nM) and CB2
receptors (EC50 = 29 nM).[3] Furthermore, SDB-001
possesses cannabis-like effects in rats, and appears to be
less potent than JWH-018 but more potent than THC.[3]
adamantyl)−1-pentyl-1H-indazole-3-carboxamide (AP-
INACA), and detection of five synthetic cannabinoids,
AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and
AM-1248, as designer drugs in illegal products”. Forensic
Toxicology 30 (2): 114. doi:10.1007/s11419-012-0136-
7.
[2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri, R.;
Goda, Y. (2012). “URB-754: A new class of de-
signer drug and 12 synthetic cannabinoids detected in il-
legal products”. Forensic Science International 227 (1–
3): 21–32. doi:10.1016/j.forsciint.2012.08.047. PMID
23063179.
[3] Banister, S. D.; Wilkinson, S. M.; Longworth, M.;
Stuart, J.; Apetz, N.; English, K.; Brooker, L.;
Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.;
McGregor, I. S.; Kassiou, M. (2013). “The syn-
thesis and pharmacological evaluation of adamantane-
derived indoles: Novel cannabimimetic drugs of abuse”.
ACS Chemical Neuroscience 4 (7): 130403084729007.
doi:10.1021/cn400035r.

171.1 See also

• AB-001

• QUCHIC

• JWH-018

• SDB-006

• STS-135 (drug)

171.2 References
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri,
R.; Goda, Y. (2012). “Identification of two new-
type synthetic cannabinoids, N-(1-adamantyl)−1-
pentyl-1H-indole-3-carboxamide (APICA) and N-(1-

224
Chapter 172

SDB-006

SDB-006 is a drug that acts as a potent agonist for the

cannabinoid receptors, with an EC50 for CB1 activation
of 19nM, and 7x selectivity for CB1 over CB2 . It was dis-
covered during research into the related compound SDB-
001 which had been sold illicitly as “2NE1”.[1]

172.1 See also

• APINACA
• SDB-001

• STS-135_(drug)

172.2 References
[1] Banister, S. D.; Wilkinson, S. M.; Longworth, M.;
Stuart, J.; Apetz, N.; English, K.; Brooker, L.;
Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.;
McGregor, I. S.; Kassiou, M. (2013). “The syn-
thesis and pharmacological evaluation of adamantane-
derived indoles: Novel cannabimimetic drugs of abuse”.
ACS Chemical Neuroscience 4 (7): 130403084729007.
doi:10.1021/cn400035r.

225
Chapter 173

SER-601

SER-601 (COR-167) is a drug which acts as a potent

and selective cannabinoid CB2 receptor agonist, based
on a quinolone−3-carboxylic acid core structure, with
190x selectivity for CB2 over the related CB1 recep-
tor. It has analgesic effects in animal studies, as well as
neuroprotective effects,[1] but without cannabis-like be-
havioural effects due to its low affinity for CB1 .[2] A num-
ber of related compounds are known, almost all of which
have high selectivity for CB2 .[3]

173.1 See also

• A-836,339
• CBS-0550

173.2 References
[1] Contartese, A.; Valoti, M.; Corelli, F.; Pasquini, S.; Mug-
naini, C.; Pessina, F.; Aldinucci, C.; Sgaragli, G.; Frosini,
M. (2012). “A novel CB2 agonist, COR167, potently pro-
tects rat brain cortical slices against OGD and reperfu-
sion injury”. Pharmacological Research 66 (6): 555–563.
doi:10.1016/j.phrs.2012.08.003. PMID 23036353.

[2] Pasquini S,et al. (August 2008). “Investigations on

the 4-quinolone-3-carboxylic acid motif. 2. Synthesis
and structure-activity relationship of potent and selective
cannabinoid-2 receptor agonists endowed with analgesic
activity in vivo”. Journal of Medicinal Chemistry 51 (16):
5075–84. doi:10.1021/jm800552f. PMID 18680276.

[3] Pasquini S,et al. (August 2010). “Investigations on

the 4-quinolone-3-carboxylic acid motif. 3. Syn-
thesis, structure-affinity relationships, and pharmaco-
logical characterization of 6-substituted 4-quinolone-3-
carboxamides as highly selective cannabinoid-2 receptor
ligands”. Journal of Medicinal Chemistry 53 (16): 5915–
28. doi:10.1021/jm100123x. PMID 20718492.

226
Chapter 174

Serinolamide A

Serinolamide A is a naturally occurring eicosanoid

derivative related to anandamide, which has been isolated
from the marine cyanobacteria Lyngbya majuscula and
related species in the Oscillatoria family. Testing estab-
lished that serinolamide A is an active cannabinoid ago-
nist with moderate potency, having a Ki of 1300nM at
CB1 and 5x selectivity over the related CB2 receptor.[1]

174.1 See also

• Methanandamide
• O-1812

• Perrottetinene

174.2 References
[1] Gutiérrez, M.; Pereira, A. R.; Debonsi, H. M.; Li-
gresti, A.; Di Marzo, V.; Gerwick, W. H. (2011).
“Cannabinomimetic Lipid from a Marine Cyanobac-
terium”. Journal of Natural Products 74 (10): 2313–
2317. doi:10.1021/np200610t. PMC 3325759. PMID
21999614.

227
Chapter 175

SR-144,528

SR144528 is a drug that acts as a potent and highly se-
lective CB2 receptor inverse agonist, with a Kᵢ of 0.6nM
at CB2 and 400nM at the related CB1 receptor.[1][2] It
is used in scientific research for investigating the func-
tion of the CB2 receptor,[3][4][5] as well as for studying
the effects of CB1 receptors in isolation, as few CB1 ag-
onists that do not also show significant activity as CB2 ag-
onists are available.[6][7][8] It has also been found to be an
inhibitor of acyl-coenzymeA:cholesterol acyltransferase,
an effect that appears to be independent from its action
on CB2 receptors.[9]
175.1 See also
• NESS-040C5
• SR141716
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-
methoxyindole-3-carboxamide
175.2 References
[1] Rinaldi-Carmona M, et al. (February 1998). “SR
144528, the first potent and selective antagonist of the
CB2 cannabinoid receptor”. The Journal of Pharma-
cology and Experimental Therapeutics 284 (2): 644–50.
PMID 9454810.
[2] Portier M, et al. (February 1999). “SR 144528, an an-
tagonist for the peripheral cannabinoid receptor that be-
haves as an inverse agonist”. The Journal of Pharma-
cology and Experimental Therapeutics 288 (2): 582–9.
PMID 9918562.
747–57. doi:10.1016/S0306-4522(03)00126-X. PMID
12809695.
[5] Páldy E, et al. (December 2008). “CB(2) cannabinoid re-
ceptor antagonist SR144528 decreases mu-opioid recep-
tor expression and activation in mouse brainstem: role
of CB(2) receptor in pain”. Neurochemistry International
53 (6-8): 309–16. doi:10.1016/j.neuint.2008.08.005.
PMID 18804501.
[6] Lay L, Angus JA, Wright CE (March 2000). “Pharmaco-
logical characterisation of cannabinoid CB(1) receptors in
the rat and mouse”. European Journal of Pharmacology
391 (1-2): 151–61. doi:10.1016/S0014-2999(00)00062-
5. PMID 10720647.
[7] Germanò MP, et al. (February 2001). “Cannabinoid
CB1-mediated inhibition of stress-induced gastric ulcers
in rats”. Naunyn-Schmiedeberg’s Archives of Pharma-
cology 363 (2): 241–4. doi:10.1007/s002100000360.
PMID 11218077.
[8] Abalo R, et al. (June 2010). “The cannabinoid an-
tagonist SR144528 enhances the acute effect of WIN
55,212-2 on gastrointestinal motility in the rat”. Neuro-
gastroenterology and Motility : the Official Journal of the
European Gastrointestinal Motility Society 22 (6): 694–
e206. doi:10.1111/j.1365-2982.2009.01466.x. PMID
20132133.
[9] Thewke D, et al. (April 2009). “AM-251 and SR144528
are acyl CoA:cholesterol acyltransferase inhibitors”. Bio-
chemical and Biophysical Research Communications 381
(2): 181–6. doi:10.1016/j.bbrc.2009.02.020. PMC
2665256. PMID 19338772.

[3] Gouldson P, et al. (July 2000). “Mutational analysis

and molecular modelling of the antagonist SR 144528
binding site on the human cannabinoid CB(2) recep-
tor”. European Journal of Pharmacology 401 (1): 17–25.
doi:10.1016/S0014-2999(00)00439-8. PMID 10915832.

[4] Nackley AG, Makriyannis A, Hohmann AG (2003). “Se-

lective activation of cannabinoid CB(2) receptors sup-
presses spinal fos protein expression and pain behavior
in a rat model of inflammation”. Neuroscience 119 (3):

228
Chapter 176

Stearoylethanolamide

Stearoylethanolamide (SEA) is an endocannabinoid

neurotransmitter.

176.1 References
Binding, degradation and apoptotic activity of
stearoylethanolamide in rat C6 glioma cells

229
Chapter 177

STS-135 (drug)

STS-135 (N-(adamantan-1-yl)−1-(5-
fluoropentyl)−1H-indole-3-carboxamide) is a
designer drug offered by online vendors as a
cannabimimetic agent. The structure of STS-135
appears to utilise an understanding of structure-activity
relationships within the indole class of cannabimimetics,
although its design origins are unclear. STS-135 is
the terminally-fluorinated analogue of SDB-001, just
as AM-2201 is the terminally-fluorinated analogue of
JWH-018, and XLR-11 is the terminally-fluorinated ana-
logue of UR-144. No information regarding the in vitro
or in vivo activity of STS-135 has been published, and
only anecdotal reports are known of its pharmacology in
humans or other animals.

177.1 Detection
A forensic standard of STS-135 is available, and the com-
pound has been posted on the Forendex website of poten-
tial drugs of abuse.[1]

177.2 See also

• AB-001

• APINACA
• AM-2201

• JWH-018
• SDB-001

177.3 References
[1] Southern Association of Forensic Scientists

230
Chapter 178

Surinabant

Surinabant (SR147778) is a cannabinoid receptor type
1 antagonist developed by Sanofi-Aventis.[1] It is being in-
vestigated as a potential treatment for nicotine addiction,
to assist smoking cessation. It may also be developed
as an anorectic drug to assist with weight loss, how-
ever there are already several CB1 antagonists or inverse
agonists on the market or under development for this
application,[2] so surinabant is at present mainly being de-
veloped as an anti-smoking drug,[3] with possible appli-
cation in the treatment of other addictive disorders such
as alcoholism.[4][5] Other potential applications such as
treatment of ADHD have also been proposed.[6]
erties of alcohol in alcohol-preferring sP rats. Alcohol and
Alcoholism. 2005 Jan-Feb;40(1):46-53. PMID 15582988
[5] Lallemand F, De Witte P. SR147778, a CB1 cannabi-
noid receptor antagonist, suppresses ethanol preference
in chronically alcoholized Wistar rats. Alcohol. 2006
Jul;39(3):125-34. PMID 17127132
[6] Louis C, Terranova JP, Decobert M, Bizot JC, Francon D,
Alonso R, Cohen C, Griebel G. Surinabant, a new CB1 re-
ceptor antagonist, displays efficacy in animal models of at-
tention deficit/hyperactivity disorder. Behavioural Phar-
macology 2005; 16:S42.

178.1 See also

• Cannabinoid receptor antagonist
• O-1269

178.2 References
[1] Rinaldi-Carmona M, Barth F, Congy C, Martinez S,
Oustric D, Pério A, Poncelet M, Maruani J, Arnone
M, Finance O, Soubrié P, Le Fur G. SR147778
[5-(4-bromophenyl)−1-(2,4-dichlorophenyl)−4-ethyl-
N-(1-piperidinyl)−1H-pyrazole-3-carboxamide], a new
potent and selective antagonist of the CB1 cannabinoid
receptor: biochemical and pharmacological charac-
terization. Journal of Pharmacology and Experimental
Therapeutics. 2004 Sep;310(3):905-14. PMID 15131245

[2] Doggrell SA. Will the new CB1 cannabinoid recep-

tor antagonist SR-147778 have advantages over rimon-
abant? Expert Opinion on Investigational Drugs. 2005
Mar;14(3):339-42. PMID 15833065

[3] Lamota L, Bermudez-Silva FJ, Marco EM, Llorente R,

Gallego A, Rodríguez de Fonseca F, Viveros MP. Ef-
fects of adolescent nicotine and SR 147778 (Surina-
bant) administration on food intake, somatic growth and
metabolic parameters in rats. Neuropharmacology. 2008
Jan;54(1):194-205. PMID 17720206

[4] Gessa GL, Serra S, Vacca G, Carai MA, Colombo G. Sup-

pressing effect of the cannabinoid CB1 receptor antago-
nist, SR147778, on alcohol intake and motivational prop-

231
Chapter 179

Taranabant

Taranabant (codenamed MK-0364) is a cannabinoid
receptor type 1 inverse agonist being investigated as
a potential treatment for obesity due to its anorectic
effects.[1][2] It was discovered by Merck & Co.
In October 2008, Merck has stopped its phase III clinical
trials with the drugs due to high level of central side ef-
fects, mainly depression and anxiety.[3][4][5][6]
179.1 See also
• Cannabinoid receptor antagonist
to assess the safety and efficacy of the CB1R inverse ag-
onist taranabant in overweight and obese patients with
type 2 diabetes”. Diabetes, Obesity & Metabolism 12 (6):
517–31. doi:10.1111/j.1463-1326.2009.01188.x. PMID
20518807.
[6] Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q,
Suryawanshi S, Jones ME, Johnson-Levonas AO, Heyms-
field SB, Kaufman KD, Amatruda JM (August 2010). “A
clinical trial assessing the safety and efficacy of the CB1R
inverse agonist taranabant in obese and overweight pa-
tients: low-dose study”. International Journal of Obe-
sity (2005) 34 (8): 1243–54. doi:10.1038/ijo.2010.38.
PMID 20212496.

179.2 References
[1] Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP,
Shah SK, et al. “Substituted acyclic sulfonamides as hu-
man cannabinoid-1 receptor inverse agonists.” Bioorganic
& Medicinal Chemistry Letters. 2007 Apr 15;17(8):2184-
7. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087

[2] Fong TM, Guan XM, Marsh DJ, Shen CP, Strib-
ling DS, Rosko KM, et al. “Antiobesity efficacy
of a novel cannabinoid-1 receptor inverse agonist,
N-[(1S,2S)−3-(4-chlorophenyl)−2-(3-cyanophenyl)−1-
methylpropyl]−2-methyl-2-[[5-(trifluoromethyl)pyridin-
2-yl]oxy]propanamide (MK-0364), in rodents.”
Journal of Pharmacology and Experimental Thera-
peutics. 2007 Jun;321(3):1013-22. PMID 17327489.
doi:10.1124/jpet.106.118737

[3] “Press release by Merck”. Retrieved October 2008.

[4] Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N,

Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan
AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda
JM (May 2010). “A clinical trial assessing the safety
and efficacy of taranabant, a CB1R inverse agonist, in
obese and overweight patients: a high-dose study”. In-
ternational Journal of Obesity (2005) 34 (5): 919–35.
doi:10.1038/ijo.2010.21. PMID 20157323.

[5] Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T,

Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M,
Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kauf-
man KD, Amatruda JM (June 2010). “A one-year study

232
Chapter 180

Tedalinab

Tedalinab (GRC-10693) is a drug developed by

Glenmark Pharmaceuticals for the treatment of
osteoarthritis and neuropathic pain, which acts as a
potent and selective cannabinoid CB2 receptor agonist.
It has a very high selectivity of 4700x for CB2 over
the related CB1 receptor, has good oral bioavailability
and has shown promising safety results and effective
analgesic and antiinflammatory actions in early clinical
trials.[1] A large number of related compounds are
known, most of which also show high CB2 selectivity.[2]

180.1 See also

• CBS-0550
• SER-601

180.2 References
[1] Glenmark’s Molecule for Neuropathic Pain, Osteoarthri-
tis - GRC 10693, Successfully Completes Phase I Trials.
April 13, 2009.

[2] Glenmark Pharmaceuticals. NOVEL CANNABINOID

RECEPTOR LIGANDS, PHARMACEUTICAL COM-
POSITIONS CONTAINING THEM, AND PROCESS
FOR THEIR PREPARATION, Filed June 1st, 2006.
WO 2006/129178.

233
Chapter 181

Tetrad test

The tetrad test is a series of behavioral paradigms in 181.1 References

which rodents treated with cannabinoids such as THC
show effects.[1] It is widely used for screening drugs that [1] Little, P.J.; Compton, D.R.; Johnson, M.R.; Melvin, L.S.;
induce cannabinoid receptor-mediated effects in rodents. Martin, B.R. (1988). Pharmacology and stereoselectivity
The four behavioral components of the tetrad are spon- of structurally novel cannabinoids in mice. J Pharmacol
taneous activity, catalepsy, hypothermia, and analgesia. Exp Ther 247: 1046–51.
Common assays for these behavioral paradigms are as fol-
lows:

• Spontaneous activity (or hypomotility) is deter-

mined by an open field test, in which a mouse is
placed in a cage with perpendicular grid lines, usu-
ally spaced by approx. 1 inch. An experimenter
counts the number of line crossings by the mouse
in a given amount of time.

• Catalepsy is determined by the bar test. The mouse

is placed on a bar oriented parallel to and approx-
imately 1 inch off of the ground. If the mouse re-
mains immobile on the bar for typically more than
20 seconds, it is considered cataleptic.

• Hypothermia is determined by using a rectal probe

to measure the rectal temperature.

• Analgesia is usually determined by the hot plate or

tail immersion test. In the hot plate test, the mouse is
placed on a heated plate, typically between 54 and
58°C. An experimenter measures the time it takes
for the mouse to jump off of the hot plate. In the
tail immersion test, the mouse is immobilized and its
tail is placed into a warm water bath, typically also
between 54 and 58°C. An experimenter measures
the time it takes for the mouse to remove its tail from
the water bath.

Direct CB1 agonists, such as THC (the psychoactive

component of marijuana), or WIN 55,212-2, have ef-
fects in all components of the tetrad and induce hypo-
motility, catalepsy, hypothermia, and analgesia in ro-
dents. Accordingly, all true “tetrad effects” are not ob-
served following treatment with antagonists of CB1 such
as rimonabant.

234
Chapter 182

Tetrahydrocannabinol

“THC” redirects here. For other uses, see THC (disam- the periaqueductal gray.[16] Other effects include relax-
biguation). ation, alteration of visual, auditory, and olfactory senses,
fatigue, and appetite stimulation. THC has marked
antiemetic properties. It may acutely reduce aggression
Tetrahydrocannabinol (THC), or more precisely
9
its main isomer (−)-trans-Δ -tetrahydrocannabinol and increase aggression during withdrawal.[17]
( (6aR,10aR)-delta-9-tetrahydrocannabinol), is the Due to its partial agonistic activity, THC appears to re-
principal psychoactive constituent (or cannabinoid) of sult in greater downregulation of cannabinoid receptors
the cannabis plant. First isolated in 1964 by Israeli than endocannabinoids, further limiting its efficacy over
scientists Raphael Mechoulam and Yechiel Gaoni at the other cannabinoids. While tolerance may limit the maxi-
Weizmann Institute of Science[8][9][10] it is a water-clear mal effects of certain drugs, evidence suggests that toler-
glassy solid when cold, which becomes viscous and ance develops irregularly for different effects with greater
sticky if warmed. A pharmaceutical formulation of resistance for primary over side-effects, and may actu-
(−)-trans-Δ9 -tetrahydrocannabinol, known by its INN ally serve to enhance the drug’s therapeutic window.[18]
dronabinol, is available by prescription in the U.S. and However, this form of tolerance appears to be irregu-
Canada under the brand name Marinol. An aromatic lar throughout mouse brain areas. THC, as well as other
terpenoid, THC has a very low solubility in water, but cannabinoids that contain a phenol group, possesses mild
good solubility in most organic solvents, specifically antioxidant activity sufficient to protect neurons against
lipids and alcohols.[7] Along with CBD, CBN, CBC, oxidative stress, such as that produced by glutamate-
CBG and other 80 molecules make up the phytocannabi- induced excitotoxicity.[19]
noid family, found in different quantities in Cannabis
Sativa plants.[11]
Like most pharmacologically-active secondary metabo- 182.1.1 Appetite and taste
lites of plants, THC in cannabis is assumed to be involved
in self-defense, perhaps against herbivores.[12] THC also It has long been known that, in humans, cannabis in-
possesses high UV-B (280–315 nm) absorption proper- creases appetite and consumption of food. The mecha-
ties, which, it has been speculated, could protect the plant nism for appetite stimulation in subjects is believed to re-
from harmful UV radiation exposure.[13][14][15] sult from activity in the gastro-hypothalamic axis. CB1
Tetrahydrocannabinol with double bond isomers and their activity in the hunger centers in the hypothalamus in-
stereoisomers is one of only three cannabinoids scheduled creases the palatability of food when levels of a hunger
by Convention on Psychotropic Substances (the other two hormone ghrelin increase prior to consuming a meal.
are dimethylheptylpyran and parahexyl). Cannabis as a After chyme is passed into the duodenum, signaling
plant is scheduled by the Single Convention on Narcotic hormones such as cholecystokinin and leptin are released,
Drugs (Schedule I and IV). causing reduction in gastric emptying and transmission of
satiety signals to the hypothalamus. Cannabinoid activity
is reduced through the satiety signals induced by leptin
release.
182.1 Effects
A study in mice suggested that based on the connec-
tion between palatable food and stimulation of dopamine
See also: Effects of cannabis, Long-term effects of (DA) transmission in the shell of the nucleus accumbens
cannabis and Cannabis in pregnancy (NAc), cannabis may not only stimulate taste, but pos-
sibly the hedonic (pleasure) value of food as well. The
THC has mild to moderate analgesic effects, and cannabis study later demonstrates habitual use of THC lessening
can be used to treat pain by altering transmitter re- this heightened pleasure response, indicating a possible
lease on dorsal root ganglion of the spinal cord and in similarity in humans.[20] The inconsistency between DA

235
236 CHAPTER 182. TETRAHYDROCANNABINOL

habituation and enduring appetite observed after THC

application suggests that cannabis-induced appetite stim-
ulation is not only mediated by enhanced pleasure from
palatable food, but through THC stimulation of another
appetitive response as well.

182.2 Chemistry

182.2.1 Discovery and structure identifica-

tion
The discovery of THC by team of researchers from
Hebrew University Pharmacy School was first described
in “Isolation, structure and partial synthesis of an ac-
tive constituent of hashish”, published in the Journal of
the American Chemical Society in 1964.[8] Research
was also published in the academic journal Science, with
“Marijuana chemistry” by Raphael Mechoulam in June 3D rendering of the THC molecule
1970,[21] In the latter, the team of researchers from He-
brew University and Tel Aviv University experimented
on monkeys to isolate the active compounds in hashish.
Their results provided evidence that, except for tetrahy-
drocannabinol, no other major active compounds were
present in hashish.

182.2.2 Isomerism

A hybrid Cannabis strain (White Widow) flower coated with

trichomes, which contain more THC than any other part of the
plant

Dibenzopyran and monoterpenoid numbering of tetrahydro-

cannabinol derivatives

Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-

benzo[c]chromen-1-ol.

• Further reading on cannabanoid isomerism: John C.

Leffingwell (May 2003). “Chirality & Bioactivity
I.: Pharmacology” 3 (1). pp. 18–20. Retrieved 12
January 2014.

Closeup of THC-filled trichomes on a Cannabis sativa leaf

182.3 Medical uses
medical marijuana and marijuana-derived products in
In April 2014 the American Academy of Neurology pub- certain neurological disorders.[22] The review identified
lished a systematic review of the efficacy and safety of 34 studies meeting inclusion criteria, of which 8 were
182.4. ADVERSE EFFECTS 237

rated as Class I quality.[22] The study found evidence sup-
porting the effectiveness of cannabis extracts and THC in
treating certain symptoms of multiple sclerosis, but found
insufficient evidence to determine the effectiveness of
cannabis products in treating several other neurological
diseases.[22]
• Epilepsy. Data was considered insufficient to judge
the utility of cannabis products in reducing seizure
frequency or severity.[22]
182.3.4 Other studies in humans

Evidence suggests that THC helps alleviate symptoms

182.3.1 Multiple sclerosis symptoms
• Spasticity. Based on the results of 3 high quality
trials and 5 of lower quality, oral cannabis extract
was rated as effective, and THC as probably effec-
tive, for improving patient’s subjective experience
of spasticity. Oral cannabis extract and THC both
were rated as possibly effective for improving ob-
jective measures of spasticity.[22]
• Centrally mediated pain and painful spasms. Based
on the results of 4 high quality trials and 4 low qual-
ity trials, oral cannabis extract was rated as effec-
tive, and THC as probably effective in treating cen-
tral pain and painful spasms.[22]
• Bladder dysfunction. Based on a single high qual-
ity study, oral cannabis extract and THC were rated
as probably ineffective for controlling bladder com-
plaints in multiple sclerosis[22]
suffered both by AIDS patients, and by cancer patients
undergoing chemotherapy, by increasing appetite and de-
creasing nausea.[24][25][26][27] It has also been shown to as-
sist some glaucoma patients by reducing pressure within
the eye, and is used in the form of cannabis by a num-
ber of multiple sclerosis patients, who use it to alleviate
neuropathic pain and spasticity. The National Multiple
Sclerosis Society is currently supporting further research
into these uses.[28] Studies in humans have been limited
by federal and state laws criminalizing marijuana.
In August 2009 a phase IV clinical trial by the Hadassah
Medical Center in Jerusalem, Israel started to investigate
the effects of THC on post-traumatic stress disorders.[29]
Studies have been conducted with spinal injury patients
and THC.[30]
182.4 Adverse effects

182.4.1 Acute toxicity

182.3.2 Neurodegenerative disorders
There has never been a documented human fatality solely
• Huntington disease. No reliable conclusions could from overdosing on tetrahydrocannabinol or cannabis in
be drawn regarding the effectiveness of THC or oral its natural form.[31] However, numerous reports have sug-
cannabis extract in treating the symptoms of Hunt- gested an association of cannabis smoking with an in-
ington disease as the available trials were too small
creased risk of myocardial infarction.[32][33] Information
to reliably detect any difference[22] about the toxicity of THC is primarily based on results
from animal studies. The toxicity depends on the route
• Parkinson disease. Based on a single study, oral of administration and the laboratory animal.
cannabis extract was rated probably ineffective in
The estimated lethal dose of intravenous dronabinol in
treating levodopa-induced dyskinesia in Parkinson
humans is 30 mg/kg,[34] meaning lethality is unlikely.
disease.[22]
The typical medicinal dosage administered is two 2.5 mg
capsules daily; for an 80 kg man (~170 lb). A lethal dose
• Alzheimer’s disease. A 2011 Cochrane Review for such a person would be 960 of those capsules infused
found insufficient evidence to conclude whether intravenously. Non-fatal overdoses have occurred: “Sig-
cannabis products have any utility in the treatment nificant CNS symptoms in antiemetic studies followed
of Alzheimer’s disease.[23] oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol
capsules.”[34]
182.3.3 Other neurological disorders
A meta analysis of cannabis and
• Tourette syndrome. The available data was deter- THC clinical trials conducted by
mined to be insufficient to allow reliable conclu- the American Academy of Neu-
sions to be drawn regarding the effectiveness of oral rology found that of 1619 persons
cannabis extract or THC in controlling tics.[22] treated with cannabis products (in-
cluding some treated with smoked
• Cervical dystonia. Insufficient data was available to cannabis and nabiximols), 6.9%
assess the effectiveness of oral cannabis extract of discontinued due to side effects,
THC in treating cervical dystonia.[22] compared to 2.2% of 1,118 treated
238 CHAPTER 182. TETRAHYDROCANNABINOL

with placebo. Detailed informa-
tion regarding side effects was not
available from all trials, but nau-
sea, increased weakness, behavioral
or mood changes, suicidal ideation,
hallucinations, dizziness, and vaso-
vagal symptoms, fatigue, and feel-
ings of intoxication were each de-
scribed as side effects in at least
2 trials. There was a single death
rated by the investigator as “possi-
bly related” to treatment. This per-
son had a seizure followed by aspi-
ration pneumonia. The paper does
not describe whether this was one
of the patients from the epilepsy
trials.[22]
182.4.2 Cognitive effects
cannabis use is associated with a two-fold increase in the
risk of psychosis, but that cannabis use is “neither neces-
sary nor sufficient” to cause psychosis.[41] A French re-
view from 2009 came to a conclusion that cannabis use,
particularly that before age 15, was a factor in the devel-
opment of schizophrenic disorders.[42]
Some studies have suggested that cannabis users have
a greater risk of developing psychosis than non-users.
This risk is most pronounced in cases with an existing
risk of psychotic disorder.[43][44] A 2005 paper from the
Dunedin study suggested an increased risk in the develop-
ment of psychosis linked to polymorphisms in the COMT
gene.[45] However, a more recent study cast doubt on the
proposed connection between this gene and the effects of
cannabis on the development of psychosis.[46]
A 2008 German review reported that cannabis was a
causal factor in some cases of schizophrenia and stressed
the need for better education among the public due to in-
creasingly relaxed access to cannabis.[47]

Its status as an illegal drug in most countries can make

research difficult; for instance in the United States where 182.4.4 Other potential long-term effects
the National Institute on Drug Abuse was the only legal
source of cannabis for researchers until it recently became A 2008 National Institutes of Health study of 19 chronic
legalized in Colorado and Washington state.[35] heavy marijuana users with cardiac and cerebral abnor-
A 2011 systematic review evaluated published studies of malities (averaging 28 g to 272 g (1 to 9+ oz) weekly)
the acute and long-term cognitive effects of cannabis. and 24 controls found elevated levels of apolipoprotein
[48]
THC intoxication is well established to impair cognitive C-III (apoC-III) in the chronic smokers. An in-
functioning on an acute basis, including effects on the crease in apoC-III levels induces the development of
ability to plan, organize, solve problems, make decisions, hypertriglyceridemia.
and control impulses. The extent of this impact may be
greater in novice users, and paradoxically, those habitu-
ated to high level ingestion may have reduced cognition Detection in body fluids
during withdrawal. Studies of long-term effects on cogni-
tion have provided conflicting results, with some studies THC, 11-OH-THC and THC-COOH can be detected and
finding no difference between long-term abstainers and quantitated in blood, urine, hair, oral fluid or sweat us-
never-users and others finding long term deficits. The dis- ing a combination of immunoassay and chromatographic
crepancies between studies may reflect greater long term techniques as part of a drug use testing program or in a
effects among heavier users relative to occasional users, forensic investigation of a traffic or other criminal offense
and greater duration of effect among those with heavy or suspicious death.[49][50][51]
use as adolescents compared to later in life.[36] A sec-
ond systematic review focused on neuroimaging studies
found little evidence supporting an effect of cannabis use
on brain structure and function.[37] A 2003 meta analysis
182.4.5 Interactions
concluded that any long term cognitive effects were rela-
tively modest in magnitude and limited to certain aspects The effects of the drug can be reduced by the CB1 re-
of learning and memory.[38] ceptor inverse agonist rimonabant (SR141716A) as well
as opioid receptor antagonists (opioid blockers) naloxone
and naloxonazine.[20][52] The α7 nicotinic receptor antag-
182.4.3 Impact on psychosis onist methyllycaconitine can block self-administration of
THC in rates comparable to the effects of varenicline on
A 2007 meta analysis concluded that cannabis use re- nicotine administration.[53]
duced the average age of onset of psychosis by 2.7 years Cannabidiol, the second most abundant cannabinoid
relative to non-cannabis use.[39] A 2005 meta analysis found in cannabis, is an indirect antagonist against
concluded that adolescent use of cannabis increases the cannabinoid agonists; thus reducing the effects of
risk of psychosis, and that the risk is dose-related.[40] anandamide and THC agonism on the CB1 and CB2 re-
A 2004 literature review on the subject concluded that ceptors.
182.7. CHEMICAL SYNTHESIS 239

182.5 Mechanism of action

For a review of the mechanisms behind endocannabinoid
synaptic transmission, see Endocannabinoid system.

The pharmacological actions of THC result from its

partial agonist activity at the cannabinoid receptor CB1
(Kᵢ=10nM[54] ), located mainly in the central nervous sys-
tem, and the CB2 receptor (Kᵢ=24nM[54] ), mainly ex-
pressed in cells of the immune system.[19] The psychoac-
tive effects of THC are primarily mediated by its acti-
vation of CB1 G-protein coupled receptors, which result
in a decrease in the concentration of the second messen-
ger molecule cAMP through inhibition of adenylate cy-
Biosynthesis of THC
clase.[16]
The presence of these specialized cannabinoid re-
ceptors in the brain led researchers to the discov- is decarboxylated, producing THC. The pathway for
ery of endocannabinoids, such as anandamide and 2- THCA biosynthesis is similar to that which produces the
arachidonoyl glyceride (2-AG). THC targets receptors bitter acid humulone in hops.[62][63]
in a manner far less selective than endocannabinoid
molecules released during retrograde signaling, as the
drug has a relatively low cannabinoid receptor efficacy 182.7 Chemical synthesis
and affinity. In populations of low cannabinoid recep-
tor density, THC may act to antagonize endogenous ag-
Total chemical syntheses largely depend on care-
onists that possess greater receptor efficacy.[18] THC is a
fully controlled acid catalyzed condensation of selected
lipophilic molecule[55] and may bind non-specifically to a
monoterpenes with olivetol. If citral is used as start ma-
variety of entities in the brain and body, such as adipose
terial only the racemic product is formed. The conden-
tissue (fat).[56][57]
sation is acid catalyzed, but 0.0005 N hydrogen chloride
THC, similarly to cannabidiol, albeit less potently, is an only affords a 12% yield. ∴ 1% boron trifluoride is used
allosteric modulator of the μ- and δ-opioid receptors.[58] as the catalyst.
Since isomerization of Δ1 THC to virtually inactive
Δ6 THC takes place readily in acid or upon heating, the
182.5.1 Pharmacokinetics cyclizations must be carefully controlled.
THC is metabolized mainly to 11-OH-THC by the body. Optically active verbenol can be used instead of citral.
This metabolite is still psychoactive and is further oxi- Please note the attached citations:[64][65][66]
dized to 11-nor-9-carboxy-THC (THC-COOH). In hu-
mans and animals, more than 100 metabolites could
be identified, but 11-OH-THC and THC-COOH are
the dominating metabolites. Metabolism occurs mainly
182.8 Marinol
in the liver by cytochrome P450 enzymes CYP2C9,
CYP2C19, and CYP3A4.[59] More than 55% of THC is Dronabinol is the INN for a pure isomer of THC, (–)-
excreted in the feces and ~20% in the urine. The main trans-Δ9 -tetrahydrocannabinol,[67] which is the main iso-
metabolite in urine is the ester of glucuronic acid and mer found in cannabis. It is sold as Marinol (a regis-
THC-COOH and free THC-COOH. In the feces, mainly tered trademark of Solvay Pharmaceuticals). Dronabi-
11-OH-THC was detected.[60] nol is also marketed, sold, and distributed by PAR Phar-
maceutical Companies under the terms of a license and
distribution agreement with SVC pharma LP, an affili-
ate of Rhodes Technologies. Synthesized THC may be
182.6 Biosynthesis generally referred to as dronabinol. It is available as a
prescription drug (under Marinol[68] ) in several countries
In the cannabis plant, THC occurs mainly as including the United States and Germany. In the United
tetrahydrocannabinolic acid (THCA, 2-COOH-THC). States, Marinol is a Schedule III drug, available by pre-
Geranyl pyrophosphate and olivetolic acid react, catal- scription, considered to be non-narcotic and to have a
ysed by an enzyme to produce cannabigerolic acid,[61] low risk of physical or mental dependence. Efforts to
which is cyclized by the enzyme THC acid synthase get cannabis rescheduled as analogous to Marinol have
to give THCA. Over time, or when heated, THCA not succeeded thus far, though a 2002 petition has been
240 CHAPTER 182. TETRAHYDROCANNABINOL

accepted by the DEA. As a result of the rescheduling ics like nabilone.[79]

of Marinol from Schedule II to Schedule III, refills are
now permitted for this substance. Marinol has been ap-
proved by the U.S. Food and Drug Administration (FDA)
in the treatment of anorexia in AIDS patients, as well as
for refractory nausea and vomiting of patients undergoing
chemotherapy, which has raised much controversy[69] as
to why natural THC is still a schedule I drug.[70]
182.9 Regulatory history
An overdose usually presents with lethargy, decreased
motor coordination, slurred speech, and postural hy- For more details on this topic, see Removal of cannabis
potension. The FDA estimates the lethal human dose from Schedule I of the Controlled Substances Act.
of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70
kg).[71]
Since at least 1986, the trend has been for THC in gen-
An analog of dronabinol, nabilone, is available commer- eral, and especially the Marinol preparation, to be down-
cially in Canada under the trade name Cesamet, manu- graded to less and less stringently-controlled schedules of
factured by Valeant Pharmaceuticals. Cesamet has also controlled substances, in the U.S. and throughout the rest
received FDA approval and began marketing in the U.S. of the world.
in 2006. Nabilone is a Schedule II drug.[72]
On May 13, 1986, the Drug Enforcement Administra-
tion (DEA) issued a Final Rule and Statement of Pol-
182.8.1 Comparisons with medical mari- icy authorizing the “Rescheduling of Synthetic Dron-
abinol in Sesame Oil and Encapsulated in Soft Gelatin
juana
Capsules From Schedule I to Schedule II” (DEA 51 FR
Further information: Medical cannabis 17476-78). This permitted medical use of Marinol, al-
beit with the severe restrictions associated with Sched-
ule II status.[80] For instance, refills of Marinol prescrip-
Female cannabis plants contain more than 60 cannabi- tions were not permitted. At its 1045th meeting, on
noids, including cannabidiol (CBD), thought to be April 29, 1991, the Commission on Narcotic Drugs, in
the major anticonvulsant that helps multiple sclero- accordance with article 2, paragraphs 5 and 6, of the
sis patients;[73] and cannabichromene (CBC), an anti- Convention on Psychotropic Substances, decided that Δ9 -
inflammatory which may contribute to the pain-killing tetrahydrocannabinol (also referred to as Δ9 -THC) and
effect of cannabis.[74] its stereochemical variants should be transferred from
It takes over one hour for Marinol to reach full systemic Schedule I to Schedule II of that Convention. This re-
effect,[75] compared to seconds or minutes for smoked leased Marinol from the restrictions imposed by Article
or vaporized cannabis.[76] Some patients accustomed to 7 of the Convention (See also United Nations Convention
inhaling just enough cannabis smoke to manage symp- Against Illicit Traffic in Narcotic Drugs and Psychotropic
toms have complained of too-intense intoxication from Substances).
Marinol’s predetermined dosages. Many patients have An article published in the April–June 1998 issue of the
said that Marinol produces a more acute psychedelic ef- Journal of Psychoactive Drugs found that “Healthcare
fect than cannabis, and it has been speculated that this professionals have detected no indication of scrip-chasing
disparity can be explained by the moderating effect of or doctor-shopping among the patients for whom they
the many non-THC cannabinoids present in cannabis. have prescribed dronabinol”. The authors state that Mari-
For that reason, alternative THC-containing medications nol has a low potential for abuse.[81]
based on botanical extracts of the cannabis plant such
as nabiximols are being developed. Mark Kleiman, di- In 1999, Marinol was rescheduled from Schedule II to III
rector of the Drug Policy Analysis Program at UCLA’s of the Controlled Substances Act, reflecting a finding that
School of Public Affairs said of Marinol, “It wasn't any THC had a potential for abuse less than that of cocaine
fun and made the user feel bad, so it could be approved and heroin. This rescheduling constituted part of the ar-
without any fear that it would penetrate the recreational gument for a 2002 petition for removal of cannabis from
market, and then used as a club with which to beat back Schedule I of the Controlled Substances Act, in which pe-
the advocates of whole cannabis as a medicine.”[77] Mr. titioner Jon Gettman noted, “Cannabis is a natural source
Kleiman’s opinion notwithstanding, clinical trials com- of dronabinol (THC), the ingredient of Marinol, a Sched-
paring the use of cannabis extracts with Marinol in the ule III drug. There are no grounds to schedule [82]
cannabis
treatment of cancer cachexia have demonstrated equal in a more restrictive schedule than Marinol”.
efficacy and well-being among patients in the two treat- At its 33rd meeting, in 2003, the World Health Organi-
ment arms.[78] United States federal law currently regis- zation Expert Committee on Drug Dependence recom-
ters dronabinol as a Schedule III controlled substance, but mended transferring THC to Schedule IV of the Conven-
all other cannabinoids remain Schedule I, except synthet- tion, citing its medical uses and low abuse potential.[83]
182.11. REFERENCES
182.10 See also
• Anandamide
• Cannabis (drug)
• Psychoactive drug
• Cannabinoids
• 11-Hydroxy-THC, metabolite of THC
• Anandamide, 2-Arachidonoylglycerol, en-
dogenous cannabinoid agonists
• Cannabidiol (CBD), an isomer of THC
• Cannabinol (CBN), a metabolite of THC
• Dimethylheptylpyran
• Parahexyl
• Tetrahydrocannabinolic acid, the biosynthetic
precursor for THC
• HU-210, WIN 55,212-2, JWH-133, synthetic
cannabinoid agonists
• Medical cannabis
• War on Drugs
• Cannabis rescheduling in the United States
• Health issues and the effects of cannabis
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[47] Kawohl W, Rössler W (2008). “Cannabis and
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Darwin WD, Kelly DL, Goodwin RS, Gorelick DA,
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11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma
Pharmacokinetics during and after Continuous High-
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doi:10.1373/clinchem.2008.122119. PMC 3196989.
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[50] Röhrich J, Schimmel I, Zörntlein S, Becker J, Drob-
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and cannabinoid regulation of brain reward circuits”.
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[55] Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R,
Duetz WA (November 2009). “Hydroxylation and Fur-
ther Oxidation of Δ9-Tetrahydrocannabinol by Alkane-
Degrading Bacteria” (PDF). Appl Environ Microbiol 75
(22): 7135–7141. doi:10.1128/AEM.01277-09. PMC
2786519. PMID 19767471. "Δ9-THC and many of its
derivatives are highly lipophilic and poorly water soluble.
Calculations of the n-octanol/water partition coefficient
(Ko/w) of Δ9-THC at neutral pH vary between 6,000, us-
ing the shake flask method, and 9.44 × 106, by reverse-
phase high-performance liquid chromatography estima-
tion.”
[56] Ashton CH (February 2001). “Pharmacology and effects
of cannabis: a brief review”. Br J Psychiatry 178: 101–
106. doi:10.1192/bjp.178.2.101. PMID 11157422. “Be-
cause they are extremely lipid soluble, cannabinoids ac-
cumulate in fatty tissues, reaching peak concentrations in
4–5 days. They are then slowly released back into other
body compartments, including the brain. ... Within the
brain, THC and other cannabinoids are differentially dis-
tributed. High concentrations are reached in neocortical,
limbic, sensory and motor areas.”
[57] Huestis MA (August 2007). “Human cannabinoid
pharmacokinetics”. Chem Biodivers 4 (8): 1770–804.
doi:10.1002/cbdv.200790152. PMC 2689518. PMID
17712819. “THC is highly lipophilic and initially taken
up by tissues that are highly perfused, such as the lung,
heart, brain, and liver.”
[58] Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker
E (February 2006). “Cannabidiol is an allosteric mod-
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doi:10.1007/s00210-006-0033-x. PMID 16489449.
[59] Watanabe K, Yamaori S, Funahashi T, Kimura T, Ya-
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involved in the metabolism of tetrahydrocannabinols and
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244
[60] Huestis MA (2005). “Pharmacokinetics and Metabolism
of the Plant Cannabinoids, Δ9 -Tetrahydrocannabinol,
Cannabidiol and Cannabinol”. Cannabinoids. Hand-
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PMID 16596792.
[61] Fellermeier M, Zenk MH (1998). “Prenylation of oliveto-
late by a hemp transferase yields cannabigerolic acid, the
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9607329.
[62] Marks MD, Tian L, Wenger JP, Omburo SN, Soto-
Fuentes W, He J, Gang DR, Weiblen GD, Dixon
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ing Δ9-tetrahydrocannabinol biosynthesis in Cannabis
sativa”. Journal of Experimental Botany 60 (13): 3715–
26. doi:10.1093/jxb/erp21. PMC 2736886. PMID
19581347.
[63] Baker PB, Taylor BJ, Gough TA (June 1981). “The
tetrahydrocannabinol and tetrahydrocannabinolic acid
content of cannabis products”. J Pharm Pharmacol. 33
(6): 369–72. doi:10.1111/j.2042-7158.1981.tb13806.x.
PMID 6115009.
[64] Razdan RK (1970). “Hashish. V. A stereospecific
synthesis of (-)−.DELTA.1-and (-).DELTA.1(6)-
tetrahydrocannabinols”. Journal of the Amer-
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doi:10.1021/ja00723a044.
[65] Petrzilka T (1969). “Synthese von Haschisch-
Inhaltsstoffen. 4. Mitteilung”. Helvetica Chimica Acta 52
(4): 1102–1134. doi:10.1002/hlca.19690520427.
[66] Jen T (1967). “Total synthesis of .DELTA.8-
(.DELTA.1(6)-tetrahydrocannabinol, a biologically
active constituent of hashish (marijuana)". Journal of
the American Chemical Society 89 (17): 4551–4552.
doi:10.1021/ja00993a071.
[67] “List of psychotropic substances under international con-
trol” (PDF). International Narcotics Control Board. p. 5.
Archived from the original on 7 September 2005. Re-
trieved 20 April 2011. “This international non-proprietary
name refers to only one of the stereochemical variants
of delta-9-tetrahydrocannabinol, namely (-)-trans-delta-9-
tetrahydrocannabinol”
[68] “Marinol – the Legal Medical Use for the Marijuana
Plant”. Drug Enforcement Administration. Archived
from the original on 21 October 2002. Retrieved 20 April
2011.
[69] Downs, David (21 October 2014). “War on marijuana
unconstitutional, doctors testify in federal court Monday”.
sfgate.com. Retrieved 21 October 2014.
[70] Eustice, Carol (12 August 1997). “Medicinal Marijuana:
A Continuing Controversy”. About.com. Retrieved 20
April 2011.
[71] “Marinol”. FDA.gov. Retrieved 14 March 2014.
CHAPTER 182. TETRAHYDROCANNABINOL
[72] “Title 21 of the Code of Federal Regulations – PART
1308 — SCHEDULES OF CONTROLLED SUB-
STANCES”. US Department of Justice. DEA Office of
Diversion Control. Retrieved 12 January 2014. With
changes through 77 F.R. 4235 (January 27, 2012).
[73] Pickens JT (1981). “Sedative activity of cannabis
in relation to its delta'-trans-tetrahydrocannabinol and
cannabidiol content”. British Journal of Pharmacology 72
(4): 649–56. doi:10.1111/j.1476-5381.1981.tb09145.x.
PMC 2071638. PMID 6269680.
[74] Burns TL, Ineck JR (2006). “Cannabinoid Analgesia as
a Potential New Therapeutic Option in the Treatment of
Chronic Pain”. Annals of Pharmacotherapy 40 (2): 251–
260. doi:10.1345/aph.1G217. PMID 16449552.
[75] MARINOL (dronabinol) capsule drug label/data at Daily
Med from U.S. National Library of Medicine, National
Institutes of Health.
[76] McKim, William A (2002). Drugs and Behavior: An In-
troduction to Behavioral Pharmacology (5th ed.). Prentice
Hall. p. 400. ISBN 0-13-048118-1.
[77] Greenberg, Gary (1 November 2005). “Respectable
Reefer”. Mother Jones. Retrieved 8 April 2010.
[78] “Cannabis and Cannabinoids (PDQ®)". Cancer Topics.
National Cancer Institute, U.S. Department of Health and
Human Services.
[79] “Government eases restrictions on pot derivative”. Online
Athens. Retrieved 12 January 2014.
[80] 51 Fed. Reg. 17476 (1986), Tuesday, May 13, 1986,
pages 17476-17478
[81] Calhoun SR, Galloway GP, Smith DE (1998).
“Abuse potential of dronabinol (Marinol)". Jour-
nal of Psychoactive Drugs 30 (2): 187–96.
doi:10.1080/02791072.1998.10399689. PMID
9692381.
[82] “Petition to Reschedule Cannabis (Marijuana)". Coalition
for Rescheduling Cannabis. 9 October 2002.
[83] “WHO Expert Committee on Drug Dependence”. World
Health Organization. Retrieved 12 January 2014.
182.12 Further reading
• Calhoun SR, Galloway GP, Smith DE (1998).
“Abuse potential of dronabinol (Mari-
nol)". J Psychoactive Drugs 30 (2): 187–96.
doi:10.1080/02791072.1998.10399689. PMID
9692381.
• DEA Moves Marinol To Schedule Three, But
Leaves Marijuana in Schedule One. The Magic of
Sesame Oil, Richard Cowan, MarijuanaNews.com.
182.13. EXTERNAL LINKS 245

• Petition to Reschedule Cannabis (Marijuana) per

21 CFR § 1308.44(b) at the Wayback Machine
(archived December 6, 2002), Filed October 9,
2002 with the DEA by the Coalition for Reschedul-
ing Cannabis.

182.13 External links

• U.S. National Library of Medicine: Drug Informa-
tion Portal – Tetrahydrocannabinol
Chapter 183

Tetrahydrocannabinol-C4

Tetrahydrocannabinol-C4, also known as THC-C4 and

butyl-THC, is a homologue of tetrahydrocannabinol
(THC), the active component of cannabis. They are
only different by the pentyl side chain being replaced
by a butyl side chain. It is unknown whether THC-
C4 is an agonist, partial agonist, or antagonist at the
cannabinoid receptors. The propyl analog, THCV, is a
cannabinoid receptor type 1 and cannabinoid receptor
type 2 antagonist,[1] while THC is a CB1 agonist. THC-
C4 has rarely been isolated from cannabis samples,[2] but
appears to be less commonly present than THC or THCV.
It is metabolised in a similar manner to THC.[3] Similarly
to THC, it has 7 double bond isomers and 30 stereoiso-
mers.
It is not scheduled by Convention on Psychotropic Sub-
stances.

183.1 See also

• Cannabinoids
• Cannabis
• Parahexyl

183.2 References
[1] Thomas, Adèle; Stevenson, Lesley A; Wease, Ker-
rie N; Price, Martin R; Baillie, Gemma; Ross, Ruth
A; Pertwee, Roger G (December 2005). “Evidence
that the plant cannabinoid Δ9-tetrahydrocannabivarin
is a cannabinoid CB1 and CB2 receptor antagonist”.
British Journal of Pharmacology 146 (7): 917–926.
doi:10.1038/sj.bjp.0706414. PMID 16205722.
[2] Harvey DJ. Characterization of the butyl homologues of
delta1-tetrahydrocannabinol, cannabinol and cannabidiol
in samples of cannabis by combined gas chromatography
and mass spectrometry. Journal of Pharmacy and Phar-
macology. 1976 Apr;28(4):280-5. PMID 6715
[3] Brown NK, Harvey DJ. In vivo metabolism of the n-butyl-
homologues of delta 9-tetrahydrocannabinol and delta 8-
tetrahydrocannabinol by the mouse. Xenobiotica. 1988
Apr;18(4):417-27. PMID 2840781

246
Chapter 184
Tetrahydrocannabinolic acid
Not to be confused with 11-nor-9-Carboxy-THC.
Tetrahydrocannabinolic acid (THCA, 2-
COOH-THC), is a biosynthetic precursor of
tetrahydrocannabinol (THC), the active component
of Cannabis.[1][2][3][4] THCA is found in variable quan-
tities in fresh, undried cannabis, but is progressively
decarboxylated to THC with drying, and especially un-
der intense heating such as when cannabis is smoked.[5]
While THCA does not have psychoactive effects
in its own right, it does have antiinflammatory and
neuroprotective effects.[6][7] Despite the ready decar-
boxylation by drying or heating ex vivo, conversion
of THCA to THC in vivo appears to be very limited,
giving it only very slight efficacy as a prodrug for
THC.[8] Consequently it is believed to be important
in less-psychoactive preparations of cannabis used for
medical use, such as cannabis tea.[9] It is also commonly
used as a biomarker in drug testing along with THCV,
to distinguish between prescribed synthetic Delta-9-
tetrahydrocannabinol, such as Marinol, and cannabis
plant material which may also be used by patients.[10]
184.1 See also
• Cannabinoids
• Cannabidiol
184.2 References
[1] Baker PB, Taylor BJ, Gough TA. (Jun 1981), The
tetrahydrocannabinol and tetrahydrocannabinolic acid
content of cannabis products, Journal of Pharmacy and
Pharmacology 33 (6): 369–72, doi:10.1111/j.2042-
7158.1981.tb13806.x, PMID 6115009
[2] Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa
Y, Wada Y, Shoyama Y, Taura F. (2004-09-17), The
gene controlling marijuana psychoactivity: molecu-
lar cloning and heterologous expression of Delta1-
tetrahydrocannabinolic acid synthase from Cannabis
sativa L., Journal of Biological Chemistry 279 (38):
247
39767–74, doi:10.1074/jbc.M403693200, PMID
15190053
[3] Moore C, Rana S, Coulter C. (2007-06-01), Simultaneous
identification of 2-carboxy-tetrahydrocannabinol, tetrahy-
drocannabinol, cannabinol and cannabidiol in oral fluid,
J Chromatogr B Analyt Technol Biomed Life Sci. 852 (1-
2): 459–64, doi:10.1016/j.jchromb.2007.02.016, PMID
17321807
[4] Taura F. (Jun 2009), Studies on tetrahydrocannabinolic
acid synthase that produces the acidic precursor of tetrahy-
drocannabinol, the pharmacologically active cannabinoid
in marijuana, Drug Discoveries and Therapeutics 3 (3):
83–7, PMID 22495534
[5] Dussy FE, Hamberg C, Luginbühl M, Schwerzmann
T, Briellmann TA. (2005-04-20), Isolation of Delta9-
THCA-A from hemp and analytical aspects concern-
ing the determination of Delta9-THC in cannabis prod-
ucts, Forensic Science International 149 (1): 3–10,
doi:10.1016/j.forsciint.2004.05.015, PMID 15734104
[6] Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Ver-
poorte R, Bohlin L. (2011), Evaluation of the cyclooxy-
genase inhibiting effects of six major cannabinoids iso-
lated from Cannabis sativa, Biological and Pharmaceutical
Bulletin 34 (5): 774–8, doi:10.1248/bpb.34.774, PMID
21532172
[7] Moldzio R, Pacher T, Krewenka C, Kranner B, No-
vak J, Duvigneau JC, Rausch WD. (2012-05-07), Ef-
fects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-
tetrahydrocannabinolic acid and cannabidiol in MPP(+)
affected murine mesencephalic cultures, Phytomedicine
19 (8-9): 819–24, doi:10.1016/j.phymed.2012.04.002,
PMID 22571976
[8] Jung J, Meyer MR, Maurer HH, Neusüss C, Wein-
mann W, Auwärter V. (Oct 2009), Studies on the
metabolism of the Delta-9-tetrahydrocannabinol precursor
delta-9-tetrahydrocannabinolic acid A (Delta9-THCA-A)
in rat using LC-MS/MS, LC-QTOF MS and GC-MS tech-
niques, Journal of Mass Spectrometry 44 (10): 1423–33,
doi:10.1002/jms.1624, PMID 19728318
[9] Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte
R. (2007-07-15), Cannabis tea revisited: a systematic
evaluation of the cannabinoid composition of cannabis
tea, Journal of Ethnopharmacology 113 (1): 85–90,
doi:10.1016/j.jep.2007.05.019, PMID 17604926
248 CHAPTER 184. TETRAHYDROCANNABINOLIC ACID

[10] Radünz L, Westphal F, Maser E, Rochholz G. (2012-

02-10), THCVA-A - a new additional marker for ille-
gal cannabis consumption, Forensic Science International
215 (1-3): 171–4, doi:10.1016/j.forsciint.2011.03.001,
PMID 21454026
Chapter 185
Tetrahydrocannabivarin
Tetrahydrocannabivarin (THCV, THV) is a
homologue of tetrahydrocannabinol (THC) having
a propyl (3-carbon) side chain. This terpeno-phenolic
compound is found naturally in Cannabis, sometimes in
significant amounts. The psychoactive effects of THCV
in Cannabis preparations are not well characterized.
Similarly to THC, it has 7 double bond isomers and 30
stereoisomers (see: Tetrahydrocannabinol#Isomerism).
It is not scheduled by Convention on Psychotropic Sub-
stances.
185.1 Description
Plants with elevated levels of propyl cannabinoids (in-
cluding THCV) have been found in populations of
Cannabis sativa L. ssp. indica (= Cannabis indica Lam.)
from China, India, Nepal, Thailand, Afghanistan, and
Pakistan, as well as southern and western Africa. THCV
levels up to 53.7% of total cannabinoids have been re-
ported. [1] [2]
THCV is a cannabinoid receptor type 1 antagonist and
cannabinoid receptor type 2 partial agonist.[3] Δ8-THCV
has also been shown to be a CB1 antagonist.[4] Both pa-
pers describing the antagonistic properties of THCV were
demonstrated in murine models.
185.2 Biosynthesis
Unlike THC, cannabidiol (CBD), and cannabichromene
(CBC), THCV doesn’t begin as cannabigerolic acid
(CBGA). Instead of combining with olivetolic acid to cre-
ate CBGA, geranyl pyrophosphate joins with divarinolic
acid, which has 2 less carbon molecules. The result is
cannabigerovarin acid (CBGVA). Once CBGVA is cre-
ated, the process continues exactly same as it would for
THC. CBGVA is broken down to tetrahydrocannabivarin
carboxylic acid (THCVA) by the enzyme THCV syn-
thase. At that point, THCVA can be decarboxylated with
heat or UV light to create THCV.[5]
249
185.3 See also
• Cannabinoids
• Cannabis
• Medical marijuana
• Rimonabant (synthetic CB1 antagonist)
• Tetrahydrocannabinol-C4
• Parahexyl
185.4 References
[1] Turner, C.E., Hadley, K.W., and Fetterman, P. 1973.
Constituents of Cannabis Sativa L., VI: Propyl Homo-
logues in Samples of Known Geographical Origin. J.
Pharm. Sci. 62(10):1739-1741
[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemo-
taxonomic analysis of cannabinoid variation in Cannabis
(Cannabaceae). American Journal of Botany 91(6): 966-
975.
[3] Pertwee, Roger G (September 2007). “The diverse CB1
and CB2 receptor pharmacology of three plant cannabi-
noids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-
tetrahydrocannabivarin”. British Journal of Pharmacol-
ogy 153 (2): 199–215. doi:10.1038/sj.bjp.0707617.
[4] Pertwee RG, Thomas A, Stevenson LA, et al.
2007. The psychoactive plant cannabinoid, Δ9-
tetrahydrocannabinol, is antagonized by Δ8- and
Δ9-tetrahydrocannabivarin in mice in vivo. Br. J.
Pharmacol. 150(5): 586–94.
[5] MedicalJane. “What is Tetrahydrocannabivarin?".
185.5 External links
• Erowid Compounds found in Cannabis sativa
• www.tetrahydrocannabivarin.com Article on
THCV
Chapter 186

THC-O-acetate

THC acetate ester is a derivative of THC which has been

found by the DEA as an apparent controlled substance
analogue of THC. It was apparently made by extracting
and purifying THC from cannabis plant material using
a soxhlet extractor, followed by reaction with acetic an-
hydride in an analogous manner to how heroin is made
from morphine.[1] A similar case was reported in June
1995 in the UK and THC-O-acetate was ruled to be a
Class A drug.[2] THC acetate was also reported to have
been found by New Zealand police in 1995, again made
by acetylation of purified cannabis extracts with acetic
anhydride.[3] The acetylation of THC does not change the
properties of the compound to the same extent as with
other acetate esters (e.g. morphine vs heroin), as the par-
ent compound is already highly lipophilic, but potency is
nonetheless increased to some extent. This derivative of
THC is interesting as one of the few analogues of THC
to have been encountered as a recreational drug sold and
used in a highly pure smokable form.
THC acetate ester was also investigated as a possible non-
lethal incapacitating agent, as part of the Edgewood Ar-
senal experiments.[4]

186.1 References
[1] Donald A. Cooper. Future Synthetic Drugs of Abuse.
Drug Enforcement Administration, McLean, Virginia

[2] David T. Brown. Cannabis: The Genus Cannabis. p82

ISBN 90-5702-291-5

[3] Valentine MD. Δ9-THC acetate from acetylation of

cannabis oil. Science and Justice 1995; 36(3):195–197.

[4] Possible Long-Term Health Effects of Short-Term Ex-

posure To Chemical Agents, Volume 2: Cholinesterase
Reactivators, Psychochemicals and Irritants and Vesi-
cants (1984) Commission on Life Sciences. The National
Academies Press. pp79-99.

250
Chapter 187

THC-O-phosphate

THC-O-phosphate is a water-soluble phosphate ester

derivative of THC, invented in 1978 in an attempt to get
around the poor water solubility of THC and make it eas-
ier to inject for the purposes of animal research into its
pharmacology and mechanism of action. The main dis-
advantage of THC phosphate ester is the slow rate of hy-
drolysis of the ester link, resulting in delayed onset of
action and lower potency than the parent drug.
THC phosphate ester is made by reacting THC with
phosphoryl chloride using pyridine as a solvent, follow-
ing by quenching with water to produce THC phosphate
ester. In the original research the less active but more
stable isomer Δ8THC was used, but the same reaction
scheme could be used to make the phosphate ester of the
more active isomer Δ9THC. [1]

187.1 References
[1] Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S.
Synthesis and pharmacological activity of a phosphate es-
ter of delta8-tetrahydrocannabinol. Journal of Medicinal
Chemistry. 1978 Oct;21(10):1079-81.

251
Chapter 188

Tinabinol

Tinabinol (INN; SP-119) is a synthetic cannabinoid drug

and analogue of dronabinol which was patented as an
antihypertensive but was never marketed.[1][2]

188.1 See also

• Dronabinol

• Nabitan

188.2 References
[1] David T. Brown (19 November 1998). Cannabis: The
Genus Cannabis. CRC Press. p. 80. ISBN 978-90-5702-
291-3. Retrieved 27 April 2012.

[2] Martin Negwer (1994). Organic-chemical drugs and their

synonyms: an international survey. Indices. Akad.-Verl.
p. 2242. ISBN 978-3-05-501629-5. Retrieved 27 April
2012.

252
Chapter 189

URB602

URB602 ([1,1'-biphenyl]−3-yl-carbamic acid, cyclo-

hexyl ester) is a compound that has been found to in-
hibit hydrolysis of monoacyl glycerol compounds, such
as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol
(2-OG). It was first described in 2003.[1] A study per-
formed in 2005 found that the compound had speci-
ficity for metabolizing 2-AG over anandamide (another
cannabinoid ligand) in rat brain presumably by inhibit-
ing the enzyme monoacylglycerol lipase (MAGL), which
is the primary metabolic enzyme of 2-AG.[2] However,
subsequent studies have shown that URB602 lacks speci-
ficity for MAGL inhibition in vitro.[3]

189.1 References
[1] Tarzia, G; Duranti, A; Tontini, A; Piersanti, G; Mor, M;
Rivara, S; Plazzi, PV; Park, C et al. (2003). “Design,
synthesis, and structure-activity relationships of alkylcar-
bamic acid aryl esters, a new class of fatty acid amide hy-
drolase inhibitors”. Journal of Medical Chemistry 46 (12):
2352–60. doi:10.1021/jm021119g. PMID 12773040.

[2] Hohmann, Andrea G.; Suplita, Richard L.; Bolton,

Nathan M.; Neely, Mark H.; Fegley, Darren; Mang-
ieri, Regina; Krey, Jocelyn F.; Michael Walker,
J. et al. (2005). “An endocannabinoid mech-
anism for stress-induced analgesia”. Nature 435
(7045): 1108–12. Bibcode:2005Natur.435.1108H.
doi:10.1038/nature03658. PMID 15973410.

[3] Vandevoorde, S; Jonsson, K-O; Labar, G; Persson, E;

Lambert, D M; Fowler, C J (2007). “Lack of selectiv-
ity of URB602 for 2-oleoylglycerol compared to anan-
damide hydrolysisin vitro”. British Journal of Pharmacol-
ogy 150 (2): 186–91. doi:10.1038/sj.bjp.0706971. PMC
2042901. PMID 17143303.

253
Chapter 190

URB754

URB754 was originally reported by Piomelli et al. to be

a potent, noncompetitive inhibitor of monoacylglycerol
lipase.[1] However, recent studies have shown that
URB754 failed to inhibit recombinant MGL, and brain
FAAH activity was also resistant to URB754.[2] In a later
study by Piomelli et al. showed that the MGL-inhibitory
activity attributed to URB754 is in fact due to a chemical
impurity present in the commercial sample, identified as
bis(methylthio)mercurane.[3]

190.1 References
[1] Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S,
Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S,
Freund TF, Piomelli D (2005). “Selective inhibition
of 2-AG hydrolysis enhances endocannabinoid signaling
in hippocampus”. Nat. Neurosci. 8 (9): 1139–41.
doi:10.1038/nn1521. PMID 16116451.

[2] Saario SM, Palomäki V, Lehtonen M, Nevalainen T,

Järvinen T, Laitinen JT (2006). “URB754 has no ef-
fect on the hydrolysis or signaling capacity of 2-AG
in the rat brain”. Chem. Biol. 13 (8): 811–4.
doi:10.1016/j.chembiol.2006.07.008. PMID 16931330.

[3] Tarzia, G; et al. (2007). “Identification of a bioac-

tive impurity in a commercial sample of 6-methyl-2-p-
tolylaminobenzo[d][1,3]oxazin-4-one (URB754.”. Ann
Chim. 97 (9): 887–94.

254
Chapter 191

VCHSR

VCHSR is a drug used in scientific research which acts

as a selective antagonist of the cannabinoid receptor
CB1 . It is derived from the widely used CB1 antago-
nist rimonabant, and has similar potency and selectivity
for the CB1 receptor, but has been modified to remove
the hydrogen bonding capability in the C-3 substituent
region, which removes the inverse agonist effect that ri-
monabant produces at high doses, so that VCHSR instead
acts as a neutral antagonist, blocking the receptor but pro-
ducing no physiological effect of its own.[1][2]

191.1 References
[1] Hurst, DP; Lynch, DL; Barnett-Norris, J; Hyatt, SM;
Seltzman, HH; Zhong, M; Song, ZH; Nie, J et al. (2002).
“N-(piperidin-1-yl)−5-(4-chlorophenyl)−1-(2,4-
dichlorophenyl)−4-methyl-1H-pyrazole-3-carboxamide
(SR141716A) interaction with LYS 3.28(192) is cru-
cial for its inverse agonism at the cannabinoid CB1
receptor”. Molecular Pharmacology 62 (6): 1274–87.
doi:10.1124/mol.62.6.1274. PMID 12435794.

[2] Hurst, D; Umejiego, U; Lynch, D; Seltzman, H; Hy-

att, S; Roche, M; McAllister, S; Fleischer, D et al.
(2006). “Biarylpyrazole inverse agonists at the cannabi-
noid CB1 receptor: importance of the C-3 carboxamide
oxygen/lysine3.28(192) interaction”. Journal of Medical
Chemistry 49 (20): 5969–87. doi:10.1021/jm060446b.
PMID 17004712.

255
Chapter 192

VDM-11

VDM-11 is a potent cannabinoid reuptake inhibitor. It

is light-sensitive and therefore must be stored within an
inert gas such as argon, in a dark place and at an ideal
temperature of −20°C.[1] This gold-colored substance is
rarely found outside research laboratories.

192.1 See also

• AM-404

192.2 References
[1] VDM 11 at Sigma-Aldrich

256
Chapter 193

WIN 54,461

WIN 54,461 (6-Bromopravadoline) is a drug that

acts as a potent and selective inverse agonist for the
cannabinoid receptor CB2 .[1]

193.1 See also

• AM-630 (6-Iodopravadoline)
• WIN 48,098 (Pravadoline)

• WIN 55,212-2

193.2 References
[1] Howlett AC, Berglund B, Melvin LS (October 1995).
“Cannabinoid Receptor Agonists and Antagonists”. Cur-
rent Pharmaceutical Design 1 (3): 343–352.

257
Chapter 194
WIN 55,212-2
Pancreatic stellate cells. The cells in the lower frame are under
the action of WIN 55,212-2. They are thought to assume a more
"quiescent" phenotype. From Michalski et al., 2008.[1]
WIN 55,212-2 is a chemical described as an
aminoalkylindole derivative, which produces effects sim-
ilar to those of cannabinoids such as tetrahydrocannabinol
(THC) but has an entirely different chemical struc-
ture.[2][3][4]
WIN 55,212-2 is a potent cannabinoid receptor agonist[5]
that has been found to be a potent analgesic[6] in a rat
model of neuropathic pain.[7] It activates p42 and p44
MAP kinase via receptor-mediated signaling.[8]
At 5 µM WIN 55,212-2 inhibit ATP production in sperm
in a CB1 receptor-dependent fashion.[9]
258
WIN 55,212-2, along with HU-210 and JWH-133, may
prevent the inflammation caused by amyloid beta proteins
involved in Alzheimer’s disease, in addition to preventing
cognitive impairment and loss of neuronal markers. This
anti-inflammatory action is induced through agonist ac-
tion at cannabinoid receptors, which prevents microglial
activation that elicits the inflammation. Additionally,
cannabinoids completely abolish neurotoxicity related to
microglial activation in rat models.
WIN 55,212-2 is a full agonist at the CB1 cannabinoid
receptor (Kᵢ = 1.9 nM) and has much higher affinity than
THC (Kᵢ = 41 nM) for this receptor.[10]
WIN 55,212-2 reduces voluntary wheel running in labo-
ratory mice, but with effects that depend on both genetic
background and sex.[11]
194.1 See also
• WIN 48,098
• WIN 54,461
• WIN 55,225
• WIN 56,098
194.2 References
[1] Michalski, C., et al. (2008). Gluud, Christian,
ed. “Cannabinoids Reduce Markers of Inflamma-
tion and Fibrosis in Pancreatic Stellate Cells”. PLoS
ONE 3 (2): e1701. Bibcode:2008PLoSO...3.1701M.
doi:10.1371/journal.pone.0001701. PMC 2253501.
PMID 18301776.
[2] Compton DR, et al. Aminoalkylindole Analogs:
Cannabimimetic Activity of a Class of Compounds Struc-
turally Distinct from Δ9 -Tetrahydrocannabinol. Journal
of Pharmacology and Experimental Therapeutics. 1992;
263(3):1118-1126.
[3] Ferraro, L.; Tomasini, M. C.; Gessa, G. L.; Bebe, B.
W.; Tanganelli, S.; Antonelli, T. (2001). “The Cannabi-
noid Receptor Agonist WIN 55,212-2 Regulates Gluta-
mate Transmission in Rat Cerebral Cortex: An in Vivo
194.3. EXTERNAL LINKS 259

and in Vitro Study”. Cerebral Cortex 11 (8): 728–733. • JNeurosci.org Prevention of Alzheimer’s Disease
doi:10.1093/cercor/11.8.728. PMID 11459762. Pathology by Cannabinoids: Neuroprotection Me-
diated by Blockade of Microglial Activation
[4] Zhang, Q., et al. (2002). “In vitro
metabolism of R(+)−2,3-dihydro-5-methyl-3- • New Scientist: Hope for cannabis-based drug for
(morpholinyl)methylpyrrolo 1,2,3-de1,4-benzoxazinyl- Alzheimer’s
(1-naphthalenyl) methanone mesylate, a cannabinoid
receptor agonist”. Drug metabolism and disposition:
the biological fate of chemicals 30 (10): 1077–1086.
doi:10.1124/dmd.30.10.1077. PMID 12228183.

[5] Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.;

MacKie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R.
L. (1995). “Comparison of the pharmacology and sig-
nal transduction of the human cannabinoid CB1 and CB2
receptors”. Molecular pharmacology 48 (3): 443–450.
PMID 7565624.

[6] Meng, I. D.; Manning, B. H.; Martin, W. J.; Fields, H. L.

(1998). “An analgesia circuit activated by cannabinoids”.
Nature 395 (6700): 381–383. doi:10.1038/26481. PMID
9759727.

[7] Herzberg, U.; Eliav, E.; Bennett, G. J.; Kopin, I. J. (1997).

“The analgesic effects of R(+)-WIN 55,212–2 mesylate,
a high affinity cannabinoid agonist, in a rat model of neu-
ropathic pain”. Neuroscience Letters 221 (2–3): 157–160.
doi:10.1016/S0304-3940(96)13308-5. PMID 9121688.

[8] Bouaboula, M.; Poinot-Chazel, C.; Bourrié, B.; Canat, X.;

Calandra, B.; Rinaldi-Carmona, M.; Le Fur, G.; Casellas,
P. (1995). “Activation of mitogen-activated protein ki-
nases by stimulation of the central cannabinoid receptor
CB1”. The Biochemical journal. 312 ( Pt 2) (Pt 2): 637–
641. PMC 1136308. PMID 8526880.

[9] Morgan, D. J.; Muller, C. H.; Murataeva, N. A.; Davis, B.

J.; MacKie, K. (2012). "Δ9-Tetrahydrocannabinol (Δ9-
THC) attenuates mouse sperm motility and male fecun-
dity”. British Journal of Pharmacology 165 (8): 2575–
2583. doi:10.1111/j.1476-5381.2011.01506.x. PMC
3423255. PMID 21615727.

[10] Kuster, J. E., et al. (1993). “Aminoalkylindole binding in

rat cerebellum: selective displacement by natural and syn-
thetic cannabinoids”. The Journal of Pharmacology and
Experimental Therapeutics 264 (3): 1352–1363. PMID
8450470.

[11] Keeney BK, et al. (2012). “Sex differences in cannabi-

noid receptor-1 (CB1) pharmacology in mice selectively
bred for high voluntary wheel-running behavior”. Phar-
macology, Biochemistry and Behavior 101: 528–537.
doi:10.1016/j.pbb.2012.02.017.

194.3 External links

• Enzo Life Sciences Win 55,212-2 Data Sheet

• The cannabinoid WIN 55,212-2 inhibits transient

receptor potential vanilloid 1 (TRPV1) and evokes
peripheral antihyperalgesia via calcineurin. 2006
Jul 18; PubMed 16849427
Chapter 195

WIN 56,098

WIN 56,098 is a chemical that is considered to be an

aminoalkylindole derivative. It is a tricyclic aryl deriva-
tive that acts as a competitive antagonist at the CB2
cannabinoid receptor. Its activity at CB1 was significantly
less effective. WIN 56,098 failed to antagonize any of the
in vivo effects of THC.[1]

195.1 See also

• WIN 55,212-2

• WIN 55,225

195.2 References
[1] Howlett AC, Berglund B, Melvin LS (October 1995).
“Cannabinoid Receptor Agonists and Antagonists”. Cur-
rent Pharmaceutical Design 1 (3): 343–352.

260
Chapter 196
XLR-11 (drug)
Not to be confused with Reaction Motors XLR11.
XLR-11 (5"-fluoro-UR-144) is a drug that acts as a po-
tent agonist for the cannabinoid receptors CB1 and CB2
with a Kᵢ of 24.2nM and a EC50 of 359nM at CB1 .
It is a 3-(tetramethylcyclopropylmethanoyl)indole deriva-
tive related to compounds such as UR-144, A-796,260
and A-834,735, but it is not specifically listed in the
patent or scientific literature alongside these other sim-
ilar compounds,[2][3] and appears to have not previously
been made by Abbott Laboratories, despite falling within
the claims of patent WO 2006/069196.
196.1 Detection
A forensic standard for this compound is available, and
a representative mass spectrum has been posted on
Forendex.[4] An ELISA immunoassay technique for de-
tecting XLR-11 and UR-144 in blood and urine as part
of general drug screens has been developed by Randox
Laboratories and Tulip Biolabs, Inc.[5]
196.2 Recreational use
XLR-11 was instead first identified by laboratories in
2012 as an ingredient in synthetic cannabis smoking
blends, and appears to be a novel compound invented
specifically for grey-market recreational use. It was
banned in New Zealand by being added to the temporary
class drug schedule, effective from 13 July 2012.[6] It has
also been banned in Florida as of 11 December 2012.[7]
Arizona banned XLR-11 on April 3, 2013.[8]
196.3 Toxicity
XLR-11 has been linked to acute kidney injury in some
users,[9] along with AM-2201.[10][11]
261
196.4 See also
• JWH-018
• STS-135
• UR-144
196.5 References
[1] SD HB1024
[2] WO application 2006069196, Pace JM, Tietje K,
Dart MJ, Meyer MD, “3-Cycloalkylcarbonyl indoles as
cannabinoid receptor ligands”, published 2006-06-29, as-
signed to Abbott Laboratories
[3] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson
GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai
M, Zhu CZ, Chandran P, Meyer MD (January 2010).
“Indol-3-ylcycloalkyl ketones: effects of N1 substituted
indole side chain variations on CB(2) cannabinoid re-
ceptor activity”. J. Med. Chem. 53 (1): 295–315.
doi:10.1021/jm901214q. PMID 19921781.
[4] “XLR-11”. Structural, chemical, and analytical data on
controlled substances. Southern Association of Forensic
Scientists (SAFS).
[5] “Randox Toxicology launches ELISA for the detection of
new generation Synthetic Cannabinoids (Spice) drugs UR-
144 and XLR-11”. Press Release. Randox Laboratories
Ltd. 2013-04-29.
[6] “CB-13, MAM-2201, AKB48, and XLR11 are classified
as temporary class drugs”. Temporary Class Drug No-
tice. The Department of Internal Affairs: New Zealand
Gazette. 2012-07-05.
[7] “News Release - Attorney General Pam Bondi Outlaws
Additional Synthetic Drugs”. News Release. State of
Florida. 2012-12-11.
[8] State of Arizona, Office of the Governor. azgover-
nor.gov http://azgovernor.gov/dms/upload/PR_040313_
SyntheticDrugs.pdf |url= missing title (help). Retrieved
2014-08-27.
262 CHAPTER 196. XLR-11 (DRUG)

[9] “Alphabet Soup, or the newer synthetic cannabinoids...”.

The Dose Makes The Poison Blog. 11 December 2013.
Retrieved 18 September 2014.

[10] Bhanushali GK, Jain G, Fatima H, Leisch LJ, Thornley-

Brown D (April 2013). “AKI associated with synthetic
cannabinoids: a case series”. Clin J Am Soc Nephrol 8 (4):
523–6. doi:10.2215/CJN.05690612. PMID 23243266.

[11] “Acute Kidney Injury Associated with Synthetic Cannabi-

noid Use — Multiple States, 2012”. Morbidity and Mor-
tality Weekly Report. U.S. Centers for Disease Control and
Prevention (CDC). 2013-92-13. Retrieved 2013-02-15.
Check date values in: |date= (help)
Chapter 197

AM251

AM-251 is an inverse agonist at the CB1 cannabinoid re-

ceptor. AM-251 is structurally very close to SR141716A
(rimonabant); both are biarylpyrazole cannabinoid recep-
tor antagonists. In AM-251 the p-chloro group attached
to the phenyl substituent at C-5 of the pyrazole ring is re-
placed with a p-iodo group. The resulting compound ex-
hibits slightly better binding affinity for the CB1 receptor
(with a Kᵢ value of 7.5nM) than SR141716A, which has
a Kᵢ value of 11.5nM, AM-251 is, however, about two-
fold more selective for the CB1 receptor when compared
to SR141716A.[1]

197.1 See also

• Discovery and development of Cannabinoid Recep-
tor 1 Antagonists

197.2 References
[1] Lan, R., Liu, Q., Fan, P., et al. Structure-activity rela-
tionships of pyrazole derivatives as cannabinoid receptor
antagonists. J Med Chem 42 769-776 (1999). PubMed
10052983

263
Chapter 198

Aminoalkylindole

Aminoalkylindoles (AAIs) are a family of

cannabinergic compound that act as a cannabinoid
receptor agonist. They were invented by pharmaceu-
tical company Sterling-Winthrop in the early 1990s as
potential non-steroidal anti-inflammatory agents.[1]

198.1 Legality
Aminoalkylindole are now commonly found in synthetic
cannabis designer drugs.[2]
In the United States, the DEA added the aminoalkylin-
dole JWH-200 to Schedule I of the Controlled Substances
Act on 1 March 2011 for 12 months.[2][3]

198.2 References
[1] Emmanuel S. Onaivi (2006). Marijuana and Cannabinoid
Research: Methods and Protocols. Springer. pp. 128–.
ISBN 978-1-59259-999-8.

[2] “Synthetic Cannabinoids”. American Association for

Clinical Chemistry. 2013-02-01. Retrieved 2013-11-17.

[3] “Schedules of Controlled Substances: Temporary Place-

ment of Five Synthetic Cannabinoids Into Schedule I”.
Federal Register. 2011-03-01. Retrieved 2013-11-17.

198.3 External links

• Aminoalkylindoles, ChEBI

264
Chapter 199

Cannabipiperidiethanone

Cannabipiperidiethanone, (CPE, or 1-
(N-methylpiperidin-2-ylmethyl)−3-(2-
methoxyphenylacetyl)indole), is a synthetic cannabi-
noid that has been found as an ingredient of “herbal”
synthetic cannabis blends sold in Japan, alongside JWH-
122 and JWH-081. Its binding affinity was measured at
the CB1 and CB2 receptors and it was found to have an
IC50 of 591nM at CB1 and 968nM at CB2 , making it
2.3x and 9.4x weaker than JWH-250 at these two targets
respectively.[1]

199.1 See also

• AM-1220

• AM-1248
• AM-2233

• JWH-203
• RCS-8

199.2 References
[1] Uchiyama N, Kikura-Hanajiri R, Goda Y (2011). “Iden-
tification of a novel cannabimimetic phenylacetylindole,
cannabipiperidiethanone, as a designer drug in a herbal
product and its affinity for cannabinoid CB₁ and CB₂ re-
ceptors”. Chemical & Pharmaceutical Bulletin 59 (9):
1203–5. doi:10.1248/cpb.59.1203. PMID 21881274.

265
Chapter 200
JWH-193
JWH-193 is a drug from the aminoalkylindole family
which acts as a cannabinoid receptor agonist. It was in-
vented by the pharmaceutical company Sanofi-Winthrop
in the early 1990s. JWH-193 has a binding affinity at the
CB1 receptor of 6nM, binding around seven times more
tightly than the parent compound JWH-200,[1] though
with closer to twice the potency of JWH-200 in activity
tests. A structural isomer of JWH-193 with the methyl
group on the indole ring instead of the naphthoyl ring,
was also found to be of similarly increased potency over
JWH-200.[2][3]
6-Methyl-JWH-200
200.1 See also
• JWH-122
266
• JWH-198
200.2 References
[1] Huffman JW, Padgett LW. Recent Developments in
the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.
[2] Eissenstat MA, et al. (August 1995). “Aminoalkylin-
doles: structure-activity relationships of novel cannabi-
noid mimetics”. Journal of Medicinal Chemistry 38 (16):
3094–105. doi:10.1021/jm00016a013. PMID 7636873.
[3] Shim JY, et al. (November 1998). “Three-dimensional
quantitative structure-activity relationship study of the
cannabimimetic (aminoalkyl)indoles using comparative
molecular field analysis”. Journal of Medicinal Chem-
istry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID
9804691.
Chapter 201

JWH-198

JWH-198 is a drug from the aminoalkylindole family

which acts as a cannabinoid receptor agonist. It was in-
vented by the pharmaceutical company Sanofi-Winthrop
in the early 1990s. JWH-198 has a binding affinity at
the CB1 receptor of 10nM, binding around four times
more tightly than the parent compound JWH-200, which
has no substitution on the naphthoyl ring.[1] It has been
used mainly in molecular modelling of the cannabinoid
receptors.[2][3]

201.1 See also

• JWH-081
• JWH-193

201.2 References
[1] Huffman JW, Padgett LW. Recent Developments in
the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.

[2] Eissenstat MA, et al. (August 1995). “Aminoalkylin-

doles: structure-activity relationships of novel cannabi-
noid mimetics”. Journal of Medicinal Chemistry 38 (16):
3094–105. doi:10.1021/jm00016a013. PMID 7636873.

[3] Shim JY, et al. (November 1998). “Three-dimensional

quantitative structure-activity relationship study of the
cannabimimetic (aminoalkyl)indoles using comparative
molecular field analysis”. Journal of Medicinal Chem-
istry 41 (23): 4521–32. doi:10.1021/jm980305c. PMID
9804691.

267
Chapter 202

JWH-200

JWH-200 (WIN 55,225)[1] is an analgesic chemi-
cal from the aminoalkylindole family that acts as a
cannabinoid receptor agonist. Its binding affinity at
the CB1 receptor is 42nM, around the same as that of
THC,[2] but its analgesic potency in vivo was higher than
that of other analogues with stronger CB1 binding affin-
ity in vitro,[3] around 3 times that of THC but with
less sedative effect,[4] most likely reflecting favourable
pharmacokinetic characteristics. It was discovered by,
and named after, Dr. John W. Huffman.
The US DEA temporarily declared JWH-200 a schedule
I controlled substance on 1 March 2011 through 76 FR
11075, and permanently instated the same schedule on 9
July 2012 in the Section 1152 of the Food and Drug Ad-
ministration Safety and Innovation Act.[5] As of 26 June
2011, the drug is legal in Canada.[6]
[3] Bell, MR, et al.. “Antinociceptive (aminoalkyl)indoles”.
Journal of Medicinal Chemistry 34 (3): 1099–1110.
doi:10.1021/jm00107a034. PMID 1900533.
[4] Compton, DR, et al. (1992). “Aminoalkylindole analogs:
cannabimimetic activity of a class of compounds struc-
turally distinct from delta 9-tetrahydrocannabinol”. Jour-
nal of Pharmacology and Experimental Therapeutics 263
(3): 1118–26. PMID 1335057.
[5] “Schedules of Controlled Substances: Temporary Place-
ment of Four Synthetic Cannabinoids Into Schedule I”.
DEA Office of Diversion Control. Retrieved 11 March
2014.
[6] http://laws.justice.gc.ca/en/C-38.8/

202.1 See also

• JWH-018

• JWH-073

• CP-47,497

• HU-210

• A-796,260

• WIN 55,212-2

202.2 References
[1] Dutta, A. K. , E. A. ; Ryan, W.; Thomas, B. F.;
Singer, M.; Compton, D. R.; Martin, B. R.; Razdan,
R. K. (1997). “Synthesis, pharmacology, and molecu-
lar modeling of novel 4-alkyloxy indole derivatives re-
lated to cannabimimetic aminoalkyl indoles (AAIs)".
Bioorganic & Medicinal Chemistry 5 (8): 1591–1600.
doi:10.1016/S0968-0896(97)00111-9. PMID 9313864.

[2] Huffman JW, Padgett LW. Recent Developments in

the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.

268
Chapter 203
Pravadoline
Pravadoline (WIN 48,098) is an antiinflammatory and
analgesic drug with an IC50 of 4.9 µM and a Kᵢ of
2511nM at CB1 , related in structure to non-steroidal
antinflammtory drugs (NSAIDs) such as indometacin. It
was developed in the 1980s as a new antiinflammatory
and prostaglandin synthesis inhibitor, acting through in-
hibition of the enzyme cyclooxygenase (COX).
However, pravadoline was found to exhibit unexpect-
edly strong analgesic effects, which appeared at doses
ten times smaller than the effective anti-inflammatory
dose and so could not be explained by its action as a
COX inhibitor. These effects were not blocked by opi-
oid antagonists such as naloxone,[1] and it was eventu-
ally discovered that pravadoline represented the first com-
pound from a novel class of cannabinoid agonists, the
aminoalkylindoles.[2]
Pravadoline was never developed for use as an analgesic,
partly due to toxicity concerns (although these were later
shown to be a result of the salt form that the drug had been
prepared in rather than from the pravadoline itself),[3]
however the discovery of cannabinoid activity in this
structurally novel family of drugs led to the discovery
of several new cannabinoid agonists, including the drug
WIN 55,212-2, which is now widely used in scientific
research.[4][5]
203.1 Animal studies
Administration of pravadoline on rats showed:[1]
• Prolonged the response latency induced by tail im-
mersion in hot water at a temperature of 55 degrees
Celsius (minimum effective dose, 100 mg/kg s.c.)
• Prevented hyperalgesia in rats with Brewer’s Yeast
injections during (Randall-Selitto test) (minimum
effective dose, 1 mg/kg, p.o.)
• Prevented the nociceptive response induced by paw
flexion in the adjuvant-arthritic rat (ED50,41 mg/kg,
p.o.)
• Prevented the nociceptive response of bradykinin-
induced head and forepaw flexion (ED50, 78 mg/kg,
p.o.)
269
The antinociceptive activity of pravadoline cannot be ex-
plained by an opioid mechanism, because pravadoline-
induced antinociception was not antagonized by naloxone
(1 mg/kg, s.c.) and pravadoline did not bind to the opioid
receptors at concentrations up to 10μM.[1]
203.2 See also
• AM-630 (6-iodopravadoline)
• WIN 54,461 (6-bromopravadoline)
• WIN 55,212-2
• RCS-4 (1-pentyl-3-(4-methoxybenzoyl)indole)
203.3 References
[1] Haubrich DR, et al. (1990). “Pharmacology of pravado-
line: a new analgesic agent”. J. Pharmacol. Exp. Ther.
255 (2): 511–22. PMID 2243340.
[2] Bell MR, et al. (1991). “Antinociceptive
(aminoalkyl)indoles”. J. Med. Chem. 34 (3): 1099–110.
doi:10.1021/jm00107a034. PMID 1900533.
[3] Everett RM, et al. (1993). “Nephrotoxicity of pravado-
line maleate (WIN 48098-6) in dogs: evidence of maleic
acid-induced acute tubular necrosis”. Fundam Appl Tox-
icol 21 (1): 59–65. doi:10.1006/faat.1993.1072. PMID
8365586.
[4] D'Ambra TE, et al. (1992). “Conformationally restrained
analogues of pravadoline: nanomolar potent, enantios-
elective, (aminoalkyl)indole agonists of the cannabi-
noid receptor”. J. Med. Chem. 35 (1): 124–35.
doi:10.1021/jm00079a016. PMID 1732519.
[5] Compton DR, et al. (1992). “Aminoalkylindole analogs:
cannabimimetic activity of a class of compounds struc-
turally distinct from delta 9-tetrahydrocannabinol”. J.
Pharmacol. Exp. Ther. 263 (3): 1118–26. PMID
1335057.
Chapter 204
RCS-4
RCS-4, or 1-pentyl-3-(4-methoxybenzoyl)indole, is a
synthetic cannabinoid drug sold under the names SR-19,
BTM-4, or Eric-4 (later shortened to E-4), but originally,
OBT-199.
204.1 Legality
RCS-4 was banned in Sweden on 1 October 2010 as
a hazardous good harmful to health, after being iden-
tified as an ingredient in “herbal” synthetic cannabis
products.[2][3] It was outlawed in Denmark on 11 March
2011.[4] In August 2011, New Zealand added not only
RCS-4 but also its 1-butyl homologue, and the 2-
methoxybenzoyl isomers of both these compounds, to a
temporary class drug schedule (i.e. equivalent to Class
C but reviewed after 12 months, and with personal pos-
session and use of small amounts decriminalised), which
was newly created under the Misuse of Drugs Amend-
ment Act 2011 passed a week earlier.[5][6][7]
RCS-4 and related analogues detected in synthetic cannabis
blends
270
204.2 See also
• AM-630
• AM-679
• RCS-8
• Pravadoline (WIN 48,098)
204.3 References
[1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r.
o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U.
2011 nr 105 poz. 614 )". Internetowy System Aktów
Prawnych. Retrieved 12 June 2011.
[2] Swedish Code of Statutes Regulation (2010:1086).
[3] Swedish Code of Statutes Regulation (2010:1086). (pdf)
[4] http://laegemiddelstyrelsen.dk/~{}/media/
AC4F04EB48F74523A76BA84DAB9B6067.ashx
[5] “Kronic ban passed by Parliament”. The New Zealand
Herald. NZPA. 4 August 2011. Retrieved 4 November
2011.
[6] “Synthetic cannabis off shelves by Wednesday”. The New
Zealand Herald. NZPA. 9 August 2011. Retrieved 4
November 2011.
[7] New Zealand Gazette. Tuesday 9 August 2011. Issue No
122, pp 3365-3366. Departmental Notices. Health. Mis-
use of Drugs Act 1975. Temporary Class Drug Notice.
Chapter 205

Anandamide

Anandamide, also known as N- uterus. Therefore cannabinoids such as Δ9 -THC might

arachidonoylethanolamine or AEA, is an endogenous influence processes during the earliest stages of hu-
cannabinoid neurotransmitter. The name is taken man pregnancy.[9] Peak plasma anandamide occurs at
from the Sanskrit word (and Hinduistic religious ovulation and positively correlates with peak estradiol
term) ananda, which means “joy, bliss, delight", and and gonadotrophin levels, suggesting that these may
amide.[1][2] It is synthesized from N-arachidonoyl be involved in the regulation of AEA (anandamide)
phosphatidylethanolamine by multiple pathways.[3] It is levels.[10] Subsequently, anandamide has been proposed
degraded primarily by the fatty acid amide hydrolase as a biomarker of infertility, but so far lacks any predictive
(FAAH) enzyme, which converts anandamide into values in order to be used clinically.[11]
ethanolamine and arachidonic acid. As such, inhibitors Anandamide plays a role in the regulation of feeding
of FAAH lead to elevated anandamide levels and are behavior, and the neural generation of motivation and
being pursued for therapeutic use.[4][5] pleasure. In addition, anandamide injected directly into
the forebrain reward-related brain structure nucleus ac-
cumbens enhances the pleasurable responses of rats to
205.1 History a rewarding sucrose taste, and enhances food intake as
well.[7][12]
It was isolated and its structure first described in 1992 A study published in 1998 shows that anandamide in-
by W. A. Devane, Lumír Hanuš et al. who were work- hibits human breast cancer cell proliferation.[13] Some
ing in a team led by Raphael Mechoulam at the Hebrew studies have linked anandamide release as a mechanism
University of Jerusalem.[6] of analgesic effects induced by exercise, particularly by
running.[14]
In 1996, researchers discovered anandamide in choco-
205.2 Physiological functions late. They also detected the presence of two sub-
stances that might mimic the effects of anandamide, N-
oleoylethanolamine and N-linoleoylethanolamine.[15]
Anandamide’s effects can be either central, in the brain,
or peripheral, in other parts of the body. These distinct
effects are mediated primarily by CB1 cannabinoid re-
ceptors in the central nervous system, and CB2 cannabi- 205.3 Synthesis and degradation
noid receptors in the periphery.[7] The latter are mainly
involved in functions of the immune system. Cannabi- The human body synthesizes anandamide from N-
noid receptors were originally discovered as being sen- arachidonoyl phosphatidylethanolamine (NAPE), which
sitive to Δ9 -tetrahydrocannabinol (Δ9 -THC, commonly is itself made by transferring arachidonic acid from
called THC), which is the primary psychoactive cannabi- lecithin to the free amine of cephalin through an
noid found in cannabis. The discovery of anandamide N-acyltransferase enzyme.[16][17] Anandamide synthesis
came from research into CB1 and CB2, as it was in- from NAPE occurs via multiple pathways and includes
evitable that a naturally occurring (endogenous) chemical enzymes such as phospholipase A2, phospholipase C and
would be found to affect these receptors. NAPE-PLD.[3]
Anandamide has been shown to impair working memory Endogenous anandamide is present at very low levels and
in rats.[8] Studies are under way to explore what role anan-
has a very short half-life due to the action of the en-
damide plays in human behavior, such as eating and sleep
zyme fatty acid amide hydrolase (FAAH), which breaks it
patterns, and pain relief. down into free arachidonic acid and ethanolamine. Stud-
Anandamide is also important for implantation of the ies of piglets show that dietary levels of arachidonic acid
early stage embryo in its blastocyst form into the and other essential fatty acids affect the levels of anan-

271
272
damide and other endocannabinoids in the brain.[18] High
fat diet feeding in mice increases levels of anandamide in
the liver and increases lipogenesis.[19] This suggests that
anandamide may play a role in the development of obe-
sity, at least in rodents.
Paracetamol (or acetaminophen in the U.S.A.) is
metabolically combined with arachidonic acid by FAAH
to form AM404.[20] This metabolite of paracetamol is a
potent agonist at the TRPV1 vanilloid receptor, a weak
agonist at both CB1 and CB2 receptors, and an inhibitor
of anandamide reuptake. As a result, anandamide levels
in the body and brain are elevated. In this fashion, parac-
etamol acts as a pro-drug for a cannabimimetic metabo-
lite. This action may be partially or fully responsible for
the analgesic effects of paracetamol.[21][22]
There have been identified transport proteins for anan-
damide and its sister molecule 2-arachidonoylglycerol.
These include the heat shock proteins (Hsp70s) and fatty
acid binding proteins (FABPs).[23][24]
205.4 Medical benefits
The Royal Society of Chemistry have stated that research
indicates that AM1172 could potentially be developed
into a drug that would increase the brain’s anandamide
levels to help treat anxiety and depression.[25]
205.5 See also
• Cannabinoids
• Virodhamine
• Tetrahydrocannabinol (THC)
• 2-Arachidonoylglycerol
• Fatty acid amide hydrolase
• Endocannabinoid transporters
• Raphael Mechoulam
205.6 References
[1] Devane WA et al. (December 1992). “Isolation
and structure of a brain constituent that binds to the
cannabinoid receptor”. Science 258 (5090): 1946–9.
doi:10.1126/science.1470919. PMID 1470919. |first3=
missing |last3= in Authors list (help); |first4= missing
|last4= in Authors list (help); |first5= missing |last5= in
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list (help); |first7= missing |last7= in Authors list (help);
|first8= missing |last8= in Authors list (help); |first9= miss-
ing |last9= in Authors list (help); |first10= missing |last10=
in Authors list (help)
CHAPTER 205. ANANDAMIDE
[2] Mechoulam R, Fride E (1995). “The unpaved road to the
endogenous brain cannabinoid ligands, the anandamides”.
In Pertwee RG. Cannabinoid receptors. Boston: Aca-
demic Press. pp. 233–258. ISBN 0-12-551460-3.
[3] Wang, J.; Ueda, N. (2009). “Biology of endo-
cannabinoid synthesis system”. Prostaglandins
& Other Lipid Mediators 89 (3–4): 112–119.
doi:10.1016/j.prostaglandins.2008.12.002. PMID
19126434.
[4] Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.;
Cassano, T.; Piomelli, D.; Cuomo, V. (2009). “Chap-
ter 5 The Endocannabinoid System as A Target for Novel
Anxiolytic and Antidepressant Drugs”. “International
Review of Neurobiology - 85”. International Review
of Neurobiology 85. pp. 57–13. doi:10.1016/S0074-
7742(09)85005-8. ISBN 9780123748935.
[5] Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.;
Makriyannis, A.; Bahr, B. A. (2009). “Enhancement
of endocannabinoid signaling by fatty acid amide
hydrolase inhibition: A neuroprotective therapeutic
modality”. Life Sciences 86 (15–16): 615–623.
doi:10.1016/j.lfs.2009.06.003. PMC 2848893. PMID
19527737.
[6] Mechoulam, WA; Hanus L; Breuer A; Pertwee RG;
Stevenson LA; Griffin G; Gibson D; Mandelbaum
A; Etinger A; Mechoulam R (December 1992).
“Isolation and structure of a brain constituent that
binds to the cannabinoid receptor”. Science 258
(5090): 1946–9. Bibcode:1992Sci...258.1946D.
doi:10.1126/science.1470919. PMID 1470919.
[7] Pacher P, Batkai S, Kunos G; Bátkai; Kunos (2006).
“The Endocannabinoid System as an Emerging Target
of Pharmacotherapy”. Pharmacol Rev. 58 (3): 389–
462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID
16968947.
[8] allet PE, Beninger RJ; Beninger (1996). “The endogenous
cannabinoid receptor agonist anandamide impairs mem-
ory in rats”. Behavioural Pharmacology 7 (3): 276–284.
doi:10.1097/00008877-199605000-00008.
[9] Piomelli D (January 2004). “THC: moderation dur-
ing implantation”. Nat. Med. 10 (1): 19–20.
doi:10.1038/nm0104-19. PMID 14702623.
[10] El-Talatini MR, Taylor AH, Konje JC; Taylor; Konje
(April 2010). “The relationship between plasma levels of
the endocannabinoid, anandamide, sex steroids, and go-
nadotrophins during the menstrual cycle”. Fertil. Steril.
93 (6): 1989–96. doi:10.1016/j.fertnstert.2008.12.033.
PMID 19200965.
[11] Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M.
(2014). “Endocannabinoids as biomarkers of human re-
production”. Human Reproduction Update 20 (4): 501–
516. doi:10.1093/humupd/dmu004. ISSN 1355-4786.
PMID 24516083.
[12] Mahler SV, Smith KS, Berridge KC; Smith; Berridge
(November 2007). “Endocannabinoid hedonic
hotspot for sensory pleasure: anandamide in nu-
cleus accumbens shell enhances 'liking' of a sweet
205.7. EXTERNAL LINKS 273

reward”. Neuropsychopharmacology 32 (11): 2267–78.
doi:10.1038/sj.npp.1301376. PMID 17406653.
[13] De Petrocellis L et al. (July 1998). “The endogenous
cannabinoid anandamide inhibits human breast cancer cell
proliferation”. Proc. Natl. Acad. Sci. U.S.A. 95 (14):
8375–80. doi:10.1073/pnas.95.14.8375. PMC 20983.
PMID 9653194. |first3= missing |last3= in Authors list
(help); |first4= missing |last4= in Authors list (help);
|first5= missing |last5= in Authors list (help); |first6= miss-
ing |last6= in Authors list (help); |first7= missing |last7= in
Authors list (help)
[14] http://www.harford.de/arne/articles/NeuroReport.pdf
[15] di Tomaso E, Beltramo M, Piomelli D.; Beltramo; Pi-
omelli (Aug 1996). “Brain cannabinoids in chocolate”.
Nature 382 (6593): 677–8. doi:10.1038/382677a0.
PMID 8751435.
[16] Natarajan V, Reddy PV, Schmid PC, Schmid HH;
Reddy; Schmid; Schmid (August 1982). “N-
Acylation of ethanolamine phospholipids in canine
myocardium”. Biochim. Biophys. Acta 712 (2): 342–55.
doi:10.1016/0005-2760(82)90352-6. PMID 7126608.
[17] Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli
(February 1997). “Occurrence and biosynthesis of en-
dogenous cannabinoid precursor, N-arachidonoyl phos-
phatidylethanolamine, in rat brain”. J. Neurosci. 17 (4):
1226–42. PMID 9006968.
[21] Bertolini A et al. (2006). “Paracetamol: new vis-
tas of an old drug”. CNS Drug Rev 12 (3–4): 250–
75. doi:10.1111/j.1527-3458.2006.00250.x. PMID
17227290. |first3= missing |last3= in Authors list (help);
|first4= missing |last4= in Authors list (help); |first5= miss-
ing |last5= in Authors list (help); |first6= missing |last6= in
Authors list (help)
[22] Sinning C et al. (December 2008). “New analgesics
synthetically derived from the paracetamol metabolite
N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-
5,8,11,14-enamide”. J. Med. Chem. 51 (24): 7800–5.
doi:10.1021/jm800807k. PMID 19053765. |first3=
missing |last3= in Authors list (help); |first4= missing
|last4= in Authors list (help); |first5= missing |last5= in
Authors list (help); |first6= missing |last6= in Authors
list (help); |first7= missing |last7= in Authors list (help);
|first8= missing |last8= in Authors list (help)
[23] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009).
“Identification of intracellular carriers for the endo-
cannabinoid anandamide”. Proceedings of the National
Academy of Sciences of the United States of America 106
(15): 6375–6380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[24] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-
Agro, A.; Maccarrone, M. (2009). “Molecular identifi-
cation of albumin and Hsp70 as cytosolic anandamide-
binding proteins”. Chemistry & Biology 16 (6): 624–632.
doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.

[18] Berger A et al. (May 2001). “Anandamide and diet: [25] http://www.rsc.org/chemistryworld/Issues/2004/July/
Inclusion of dietary arachidonate and docosahexaenoate anandamide.asp
leads to increased brain levels of the corresponding N-
acylethanolamines in piglets”. Proc. Natl. Acad. Sci.
U.S.A. 98 (11): 6402–6. doi:10.1073/pnas.101119098.
PMC 33480. PMID 11353819. |first3= missing |last3= 205.7 External links
in Authors list (help); |first4= missing |last4= in Authors
list (help); |first5= missing |last5= in Authors list (help); • Could anandamide be the missing link to “runner’s
|first6= missing |last6= in Authors list (help) high"? Accessed 2008-10-18

[19] Osei-Hyiaman D et al. (May 2005). “Endocannabinoid

activation at hepatic CB1 receptors stimulates fatty acid
synthesis and contributes to diet-induced obesity”. J. Clin.
Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMC
1087161. PMID 15864349. |first3= missing |last3= in
Authors list (help); |first4= missing |last4= in Authors
list (help); |first5= missing |last5= in Authors list (help);
|first6= missing |last6= in Authors list (help); |first7= miss-
ing |last7= in Authors list (help); |first8= missing |last8=
in Authors list (help); |first9= missing |last9= in Authors
list (help); |first10= missing |last10= in Authors list (help);
|first11= missing |last11= in Authors list (help)

[20] Högestätt, E. D.; Jönsson, B. A.; Ermund, A.; Anders-

son, D. A.; Björk, H.; Alexander, J. P.; Cravatt, B. F.;
Basbaum, A. I.; Zygmunt, P. M. (2005). “Conversion
of Acetaminophen to the Bioactive N-Acylphenolamine
AM404 via Fatty Acid Amide Hydrolase-dependent
Arachidonic Acid Conjugation in the Nervous Sys-
tem” (pdf). Journal of Biological Chemistry 280 (36):
31405–31412. doi:10.1074/jbc.M501489200. PMID
15987694.
Chapter 206

N-Arachidonoyl dopamine

N-Arachidonoyl dopamine (NADA) is an

endocannabinoid that acts as an agonist of the CB1
receptor[1] and the transient receptor potential V1
(TRPV1) ion channel. Its discovery was described in
2002 by an academic research group from Italy and the
USA. It was found in the brain of rats, with especially
high concentrations in the hippocampus, cerebellum, and
striatum. It activates the TRPV1 channel with an EC50
of approximately of 50nM. The high potency makes it
the putative endogenous TRPV1 agonist.[2]

206.1 See also

• Endocannabinoid

206.2 References
[1] Ralevic V (July 2003). “Cannabinoid modulation of
peripheral autonomic and sensory neurotransmission”.
European Journal of Pharmacology 472 (1–2): 1–21.
doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.

[2] Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De

Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF,
Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM,
Di Marzo V (June 2002). “An endogenous capsaicin-
like substance with high potency at recombinant and na-
tive vanilloid VR1 receptors”. Proceedings of the Na-
tional Academy of Sciences of the United States of America
99 (12): 8400–5. doi:10.1073/pnas.122196999. PMC
123079. PMID 12060783.

206.3 External links

• General information about NADA.

274
Chapter 207

2-Arachidonoylglycerol

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, 207.3 Pharmacology

an endogenous agonist of the CB1 receptor.[1][2] It is an
ester formed from the omega-6 fatty acid arachidonic Unlike anandamide, formation of 2-AG is calcium-
acid and glycerol. It is present at relatively high levels dependent and is mediated by the activities of
in the central nervous system, with cannabinoid neuro- phospholipase C (PLC) and diacylglycerol lipase
modulatory effects. It has been found in maternal bovine (DAGL).[2] 2-AG acts as a full agonist at the CB1
and human milk. The chemical was first described in receptor.[10] At a concentration of 0.3nM, 2-AG induces
1994-1995, although had been discovered some time a rapid, transient increase in intracellular free calcium in
before that. The activities of Phospholipase C (PLC) NG108-15 neuroblastoma X glioma cells through a CB1
and diacylglycerol lipase (DAGL) mediate its formation. receptor-dependent mechanism.[2] 2-AG is hydrolyzed
2-AG is synthesized from arachidonic acid-containing in vitro by monoacylglycerol lipase (MAGL), fatty acid
diacylglycerol (DAG). amide hydrolase (FAAH), and the uncharacterized
serine hydrolase enzymes ABHD6 and ABHD12.[11]
The exact contribution of each of these enzymes to
the termination of 2-AG signaling in vivo is unknown,
207.1 Occurrence though it is estimated that MAGL is responsible for
~85% of this activity in the brain.[12] There have been
2-AG, unlike anandamide (another endocannabinoid), is identified transport proteins for 2-arachidonoylglycerol
present at relatively high levels in the central nervous sys- and anandamide. These include the heat shock proteins
tem; it is the most abundant molecular species of monoa- (Hsp70s) and fatty acid binding proteins (FABPs).[13][14]
cylglycerol found in mouse and rat brain (~5-10 nmol/g
tissue).[2][3] Detection of 2-AG in brain tissue is compli-
cated by the relative ease of its isomerization to 1-AG
during standard lipid extraction conditions. It has been
207.4 Biosynthesis
found in maternal bovine and human milk.[4]
2-Arachidonoylglycerol is synthesized from arachidonic
acid-containing diacylglycerol (DAG), which is derived
from the increase of inositol phospholipid metabolism
207.2 Discovery by the action of diacylglycerol lipase. The molecule
can also be formed from pathways like the hydrolysis
Shimon Ben-Shabat, of Ben-Gurion University, discov- derived (by diglyceride) from both phosphatidylcholine
ered the chemical.[5] 2-AG was a known chemical com- (PC) and phosphatidic acid (PAs) by the action of DAG
pound but its occurrence in mammals and its affinity for lipase and the hydrolysis of arachidonic acid-containing [15]
the cannabinoid receptors were first described in 1994- lysophosphatidic acid by the action of a phosphatase.
1995. A research group at Teikyo University reported
the affinity of 2-AG for the cannabinoid receptors in
1994-1995,[6][7] but the isolation of 2-AG in the canine 207.5 See also
gut was first reported in 1995 by the research group
of Raphael Mechoulam at the Hebrew University of • 2-Arachidonoyl glyceryl ether
Jerusalem, which additionally characterized its pharma-
cological properties in vivo.[8] 2-Arachidonoylglycerol, • Endocannabinoid transporters
next with Anandamide, was the second endocannabinoid
discovered. The cannabinoid established the existence
of a cannabinoid neuromodulatory system in the nervous 207.6 References
system.[9]

275
276
207.6.1 Notes
[1] Stella N, Schweitzer P, Piomelli D (August 1997). “A
second endogenous cannabinoid that modulates long-
term potentiation”. Nature 388 (6644): 773–8.
doi:10.1038/42015. PMID 9285589.
[2] Sugiura T, Kodaka T, Nakane S, et al. (January 1999).
“Evidence that the cannabinoid CB1 receptor is a 2-
arachidonoylglycerol receptor. Structure-activity relation-
ship of 2-arachidonoylglycerol, ether-linked analogues,
and related compounds”. The Journal of Biological Chem-
istry 274 (5): 2794–801. doi:10.1074/jbc.274.5.2794.
PMID 9915812.
[3] Kondo S, Kondo H, Nakane S, et al. (June 1998). “2-
Arachidonoylglycerol, an endogenous cannabinoid recep-
tor agonist: identification as one of the major species
of monoacylglycerols in various rat tissues, and evi-
dence for its generation through Ca2+-dependent and -
independent mechanisms”. FEBS Letters 429 (2): 152–6.
doi:10.1016/S0014-5793(98)00581-X. PMID 9650580.
[4] Fride E, Bregman T, Kirkham TC. (April 2005).
“Endocannabinoids and food intake: newborn suckling
and appetite regulation in adulthood”. Experimental Bi-
ology and Medicine 230 (4): 225–234. PMID 15792943.
[5] Pizzorno, Lara; MDiv; MA; LMT. “New Developments
in Cannabinoid-Based Medicine: An Interview with Dr.
Raphael Mechoulam”. Longevity Medicine Review. Re-
trieved 2011-05-26.
[6] Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Pro-
ceedings of Japanese conference on the Biochemistry of
Lipids, 36, 71-74 (in Japanese)
[7] Sugiura T, Kondo S, Sukagawa A, et al. (October 1995).
“2-Arachidonoylglycerol: a possible endogenous cannabi-
noid receptor ligand in brain”. Biochem. Biophys. Res.
Commun. 215 (1): 89–97. doi:10.1006/bbrc.1995.2437.
PMID 7575630. Retrieved 2009-01-27.
[8] Mechoulam R, Ben-Shabat S, Hanuš L, et al. (June
1995). “Identification of an endogenous 2-monoglyceride,
present in canine gut, that binds to cannabinoid re-
ceptors”. Biochemical pharmacology 50 (1): 83–90.
doi:10.1016/0006-2952(95)00109-D. PMID 7605349.
[9] Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience
Intelligence Unit) (1st ed.). Georgetown, Texas: Springer.
pp. 99, 181. ISBN 978-0-306-48228-1.
[10] Savinainen JR, Järvinen T, Laine K, Laitinen JT (Oc-
tober 2001). “Despite substantial degradation, 2-
arachidonoylglycerol is a potent full efficacy agonist me-
diating CB(1) receptor-dependent G-protein activation in
rat cerebellar membranes”. British Journal of Pharmacol-
ogy 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC
1572991. PMID 11588122.
[11] Blankman JL, Simon GM, Cravatt BF (Decem-
ber 2007). “A comprehensive profile of brain
enzymes that hydrolyze the endocannabinoid 2-
arachidonoylglycerol”. Chemistry & biology 14 (12):
1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC
2692834. PMID 18096503.
CHAPTER 207. 2-ARACHIDONOYLGLYCEROL
[12] Savinainen, JR; Saario, SM; Laitinen, JT (2012). “The
serine hydrolases MAGL, ABHD6 and ABHD12 as
guardians of 2-arachidonoylglycerol signalling through
cannabinoid receptors”. Acta physiologica (Oxford,
England) 204 (2): 267–76. doi:10.1111/j.1748-
1716.2011.02280.x. PMC 3320662. PMID 21418147.
[13] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009).
“Identification of intracellular carriers for the endo-
cannabinoid anandamide”. Proceedings of the National
Academy of Sciences of the United States of America 106
(15): 6375–6380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[14] Oddi, S.; Fezza, F.; Pasquariello, N.; d'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-
Agrò, A.; MacCarrone, M. (2009). “Molecular identi-
fication of albumin and Hsp70 as cytosolic anandamide-
binding proteins”. Chemistry & Biology 16 (6): 624–632.
doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
[15] Köfalvi, Attila (2008). Cannabinoids and the Brain. New
York City: Axel Springer AG. p. 15. ISBN 978-0-387-
74348-6. “2-Arachidonoylglycerol can be synthesized
from arachidonic acid-containing diacylglycerol derived
from increaded inositol phospholid metabolism by the ac-
tion of a diacylglycerol lipase. 2-Arachidonoylglycerol
can also be formed via other pathways such as the hydrol-
ysis of the diaclygly derived from PC and phosphatidic
acid by the action of a diacyglycerol lipase and the hy-
drolysis of arachidonic acid-containing lysophosphatidic
acid by the action of a phosphatase. The relative impor-
tance of these pathways may depend on the types of cells
and stimuli.”
207.6.2 General references
• Dinh TP, Carpenter D, Leslie FM, et al. (Au-
gust 2002). “Brain monoglyceride lipase partic-
ipating in endocannabinoid inactivation”. Pro-
ceedings of the National Academy of Sciences of
the United States of America 99 (16): 10819–
24. doi:10.1073/pnas.152334899. PMC 125056.
PMID 12136125.
Chapter 208
2-Arachidonyl glyceryl ether
2-Arachidonyl glyceryl ether (2-AGE, Noladin ether)
is a putative endocannabinoid discovered by Lumír Hanuš
and colleagues at the Hebrew University of Jerusalem, Is-
rael. Its isolation from porcine brain and its structural
elucidation and synthesis were described in 2001.[1]
208.1 Discovery
Lumír Hanuš, Saleh Abu-Lafi, Ester Fride, Aviva Breuer,
Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and
Raphael Mechoulam found the endogenous agonist of the
cannabinoid receptor type 1 (CB1) in 2000. The dis-
covery was 100 gram of porcine brain, (approximately
a single brain) was added to a mixture of 200 mL of
chloroform and 200 mL of methanol and mixed in a
laboratory blender for 2 minutes. 100 mL of Water was
then added, and the mixing process continued for an-
other minute. After this, the mixture was filtered. Two
layers then formed and the layer of water-methanol was
separated and evaporated when pressure was reduced.
Synaptosomal membranes were prepared from 250g of
the brains of Sabra male rats. A Hewlett Packard G
1800B GCD system that has a HP-5971 GC with electron
ionization detector was used.[1]
208.2 Production
The production of the endocannabinoid is enhanced in
normal, but not in endothelium-denuded rat aorta on re-
acting with carbachol, an parasympathomimetic drug. It
potently reduces blood pressure in rats and may represent
an endothelium-derived hypotension factor.[1]
2-Arachidonyl glyceryl ether’s structure can be deter-
mined by mass spectrometry and Rutherford backscatter-
ing spectrometry. It was confirmed by comparison with a
synthetic sample of the endocannabinoid. It binds to the
Cannabinoid receptor type 1 (Ki = 21.2 ± 0.5 nM), which
causes sedation, hypothermia, intestinal immobility, and
mild antinociception in mice.[1] The endocannabinoid ex-
hibits Ki values of 21.2 nM and >3 µM at the Cannabi-
noid receptor type 1 and the peripheral cannabinoid
277
receptors.[2]
The presence of 2-AGE in body tissue is disputed.
Although a research group from Teikyo University,
Kanagawa, Japan could not detect it in the brains of
mice, hamsters, guinea-pigs or pigs,[3] two other research
groups successfully detected it in animal tissues.[4][5]
208.3 Pharmacology
2-AGE binds with a Kᵢ of 21 nM to the CB1 receptor[1]
and 480 nM to the CB2 receptor.[6] It shows agonistic
behaviour on both receptors and is a partial agonist for
the TRPV1 channel.[7] After binding to CB2 receptors
it inhibits adenylate cyclase and stimulates ERK-MAPK
and regulates calcium transients.[8] In comparison to 2-
arachidonoyl glycerol, noladin is metabolically more sta-
ble resulting in a longer half-life.[9] It lowers Intraocular
pressure,[9] increases the uptake of GABA in the globus
pallidus of rats[10] and is neuroprotective by binding to
and activation of PPARα.[11]
208.4 See also
• 2-Arachidonoylglycerol
208.5 References
[1] Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vo-
gel, Z.; Shalev, D.; Kustanovich, I.; Mechoulam, R.
(2001). “2-Arachidonyl glyceryl ether, an endogenous ag-
onist of the cannabinoid CB1 receptor”. Proceedings of
the National Academy of Sciences 98 (7): 3662–3665.
doi:10.1073/pnas.061029898. PMC 31108. PMID
11259648.
[2] “2-Arachidonyl Glycerol ether · Noladin; 2-AG ether
(CAS 222723-55-9) || Cayman Chemical”. Cayman
Chemical. Retrieved 2011-05-29.
[3] Oka S, Tsuchie A, Tokumura A et al. (2003).
“Ether-linked analogue of 2-arachidonoylglycerol (no-
ladin ether) was not detected in the brains of various
278 CHAPTER 208. 2-ARACHIDONYL GLYCERYL ETHER

mammalian species”. J. Neurochem. 85 (6): 1374–

81. doi:10.1046/j.1471-4159.2003.01804.x. PMID
12787057.

[4] Fezza F, Bisogno T, Minassi A, Appendino G, Me-

choulam R, Di Marzo V (2002). “Noladin ether, a pu-
tative novel endocannabinoid: inactivation mechanisms
and a sensitive method for its quantification in rat tis-
sues”. FEBS Lett. 513 (2–3): 294–8. doi:10.1016/S0014-
5793(02)02341-4. PMID 11904167.

[5] Richardson D, Ortori CA, Chapman V, Kendall DA,

Barrett DA (2007). “Quantitative profiling of endo-
cannabinoids and related compounds in rat brain using liq-
uid chromatography-tandem electrospray ionization mass
spectrometry”. Anal. Biochem. 360 (2): 216–26.
doi:10.1016/j.ab.2006.10.039. PMID 17141174.

[6] Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR,

Prather PL (2005). “The endocannabinoid noladin ether
acts as a full agonist at human CB2 cannabinoid recep-
tors”. J. Pharmacol. Exp. Ther. 314 (2): 868–75.
doi:10.1124/jpet.105.085282. PMID 15901805.

[7] Duncan M, Millns P, Smart D, Wright JE, Kendall DA,

Ralevic V (2004). “Noladin ether, a putative endo-
cannabinoid, attenuates sensory neurotransmission in the
rat isolated mesenteric arterial bed via a non-CB1/CB2
Gi/o linked receptor”. Br. J. Pharmacol. 142 (3): 509–
18. doi:10.1038/sj.bjp.0705789. PMC 1574960. PMID
15148262.

[8] Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL

(2005). “Agonist-directed trafficking of response
by endocannabinoids acting at CB2 receptors”. J.
Pharmacol. Exp. Ther. 315 (2): 828–38.
doi:10.1124/jpet.105.089474. PMID 16081674.

[9] Laine K, Järvinen K, Mechoulam R, Breuer A, Järvi-

nen T (2002). “Comparison of the enzymatic stability
and intraocular pressure effects of 2-arachidonylglycerol
and noladin ether, a novel putative endocannabinoid”. In-
vest. Ophthalmol. Vis. Sci. 43 (10): 3216–22. PMID
12356827.

[10] Venderova K, Brown TM, Brotchie JM (2005). “Differ-

ential effects of endocannabinoids on [(3)H]-GABA up-
take in the rat globus pallidus”. Exp. Neurol. 194 (1):
284–7. doi:10.1016/j.expneurol.2005.02.012. PMID
15899265.

[11] Sun Y, Alexander SP, Garle MJ et al. (2007).

“Cannabinoid activation of PPARα; a novel neuropro-
tective mechanism”. Br. J. Pharmacol. 152 (5): 734–
43. doi:10.1038/sj.bjp.0707478. PMC 2190030. PMID
17906680.

208.6 External links

• Commercial supplier of Noladin ether
Chapter 209
Oleamide
Oleamide is an amide of the fatty acid oleic acid. It
is an endogenous substance: it occurs naturally in the
body of animals. It accumulates in the cerebrospinal
fluid during sleep deprivation and induces sleep in ani-
mals.[4] It is being studied as a potential medical treat-
ment for mood and sleep disorders, and cannabinoid-
regulated depression.[5][6]
The mechanism of action of oleamide’s sleep induc-
ing effects is an area of current research. It is likely
that oleamide interacts with multiple neurotransmitter
systems.[7] Oleamide is structurally related to the endoge-
nous cannabinoid anandamide, and has the ability to bind
to the CB1 receptor as a full agonist.
Synthetically produced oleamide has a variety of indus-
trial uses including as a slip agent, a lubricant, and a cor-
rosion inhibitor.[8]
Oleamide was originally characterized as an endogenous
bioactive substance, isolated from the cerebrospinal fluid
of sleep deprived cats. It was characterised in 1995 by
Benjamin Cravatt III and Richard Lerner at The Scripps
Research Institute in La Jolla, CA.[9]
Oleamide was found by researchers to be leaking out of
polypropylene plastics used in laboratory experiments,
affecting experimental results.[10] Since polypropylene is
used in a wide number of food containers such as those
for yogurt, the problem is being studied.[11]
A chemical analysis of 44 products containing synthetic
cannabinoid drugs marketed as “herbal incense” revealed
oleamide in 7 of the products tested.[12] [10] McDonald, RG. et al. (2008). “Bioactive Contaminants
209.1 See also
[11] Mittelstaedt, Martin (6 November 2008). “Researchers
• Anandamide
• Fatty acid amide hydrolase
[12] Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Ogata, Jun;
• Virodhamine
209.2 References
[1] Oleamide at chemicalland21.com
279
[2] http://www.chemicalbook.com/
ProductChemicalPropertiesCB3238286_EN.htm
[3] http://www.chemspider.com/Chemical-Structure.
4446508.html
[4] Salvador Huitron-Resendiz, Lhys Gombart, Benjamin
F. Cravatt, and Steven J. Henriksen (2001). “Effect
of Oleamide on Sleep and Its Relationship to Blood
Pressure, Body Temperature, and Locomotor Activity
in Rats”. Experimental Neurology 172 (1): 235–243.
doi:10.1006/exnr.2001.7792. PMID 11681856.
[5] Methods of treating anxiety and mood disorders with
oleamide - US Patent 6359010
[6] Raphael Mechoulam, Ester Fride, Lumír Ondřej Hanuš,
Tzviel Sheskin, Tiziana Bisogno, Vincenzo Di Marzo,
Michael Bayewitch and Zvi Vogel (1997). “Anandamide
may mediate sleep induction”. Nature 389 (6646): 25–26.
doi:10.1038/37891. PMID 9288961.
[7] Fedorova I, Hashimoto A, Fecik RA et al. (2001). “Be-
havioral evidence for the interaction of oleamide with
multiple neurotransmitter systems”. J. Pharmacol. Exp.
Ther. 299 (1): 332–42. PMID 11561096.
[8] Surfactants : Westco Oleamide a Slip Agent In Polyethy-
lene Films
[9] Cravatt BF, et al. (June 1995). “Chemical characteriza-
tion of a family of brain lipids that induce sleep”. Sci-
ence 268 (5216): 1506–9. doi:10.1126/science.7770779.
PMID 7770779.
Leach from Disposable Laboratory Plasticware”. Science
322 (5903): 917. doi:10.1126/science.1162395. PMID
18988846.
Raise Alarm After Chemical Leak Found In Common
Plastic”. Globe and Mail. Retrieved 10 June 2013.
Goda, Yukihiro (2010). “Chemical analysis of syn-
thetic cannabinoids as designer drugs in herbal prod-
ucts”. Forensic Science International 198 (1–3): 31–8.
doi:10.1016/j.forsciint.2010.01.004. PMID 20117892.
Chapter 210

RVD-Hpα

RVD-Hpα is an endogenous neuropeptide found in Journal of Biological Chemistry 287 (44): 36944–36967.
human and mammalian brain, which was originally doi:10.1074/jbc.M112.382481. PMC 3481297. PMID
proposed to act as a selective agonist for the CB1 22952224.
cannabinoid receptor. It is a 12-amino acid polypeptide
having the amino acid sequence Arg-Val-Asp-Pro-Val-
Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal ex-
tended form of hemopressin, a 9-AA polypeptide de-
rived from the α1 subunit of hemoglobin which has pre-
viously been shown to act as a CB1 inverse agonist.[1]
All three polypeptides have been isolated from vari-
ous mammalian species, with RVD-Hpα being one of
the more abundant neuropeptides expressed in mouse
brain, and these neuropeptides represent a new avenue for
cannabinoid research distinct from the previously known
endogenous lipid-derived cannabinoid agonists such as
anandamide.[2] Recently it was shown that RVD-Hpα
(also called Pepcan-12) is an potent negative allosteric
modulator at CB1 receptors, together with other newly
described N-terminally extended peptides (pepcans) [3]

210.1 References
[1] Heimann, A.; Gomes, I.; Dale, C.; Pagano, R.;
Gupta, A.; De Souza, L.; Luchessi, A.; Castro, L.;
Giorgi, R.; Rioli, V.; Ferro, E. S.; Devi, L. A.
(2007). “Hemopressin is an inverse agonist of CB1
cannabinoid receptors”. Proceedings of the National
Academy of Sciences of the United States of America 104
(51): 20588–20593. Bibcode:2007PNAS..10420588H.
doi:10.1073/pnas.0706980105. PMC 2154475. PMID
18077343.

[2] Gomes, I.; Grushko, J.; Golebiewska, U.; Hoogendoorn,

S.; Gupta, A.; Heimann, A.; Ferro, E.; Scarlata, S.;
Fricker, L.; Devi, L. A. (2009). “Novel endogenous
peptide agonists of cannabinoid receptors”. The FASEB
journal : official publication of the Federation of Amer-
ican Societies for Experimental Biology 23 (9): 3020–
3029. doi:10.1096/fj.09-132142. PMC 2735371. PMID
19380512.

[3] Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.;

Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch,
J. (2012). “Identification and Quantification of a New
Family of Peptide Endocannabinoids (Pepcans) Show-
ing Negative Allosteric Modulation at CB1 Receptors”.

280
Chapter 211

Virodhamine

Virodhamine (O-arachidonoyl ethanolamine) is an

endocannabinoid and a nonclassic eicosanoid, derived
from arachidonic acid. O-Arachidonoyl ethanolamine is
arachidonic acid and ethanolamine joined by an ester
linkage, the opposite of the amide linkage found in
anandamide. Based on this opposite orientation, the
molecule was named virodhamine from the Sanskrit word
virodha, which means opposition. It acts as an antagonist
of the CB1 receptor and agonist of the CB2 receptor.
Concentrations of virodhamine in the human hippocam-
pus are similar to those of anandamide, but they are 2-
to 9-fold higher in peripheral tissues that express CB2 .
Virodhamine lowers body temperature in mice, demon-
strating cannabinoid activity in vivo.[1]

211.1 See also

• Anandamide
• Oleamide

211.2 References
[1] Porter AC, Sauer JM, Knierman MD et al. (2002).
“Characterization of a novel endocannabinoid, virod-
hamine, with antagonist activity at the CB1 recep-
tor”. J. Pharmacol. Exp. Ther. 301 (3): 1020–
4. doi:10.1124/jpet.301.3.1020. PMID 12023533. Re-
trieved 2007-10-31.

281
Chapter 212

HU-320

HU-320 is a drug related to cannabidiol, which has

strong antiinflammatory and immunosuppressive proper-
ties while demonstrating no psychoactive effects.[1]

212.1 See also

• HU-210
• HU-308

• HU-331

212.2 References
[1] Sumariwalla PF, et al. (2004). “A novel synthetic,
nonpsychoactive cannabinoid acid (HU-320) with an-
tiinflammatory properties in murine collagen-induced
arthritis”. Arthritis Rheum. 50 (3): 985–998.
doi:10.1002/art.20050. PMID 15022343.

282
Chapter 213

HU-336

HU-336 is a strongly antiangiogenic compound, signif-

icantly inhibiting angiogenesis at concentrations as low
as 300nM. It inhibits angiogenesis by directly inducing
apoptosis of vascular endothelial cells without changing
the expression of pro- and antiangiogenic cytokines and
their receptors. HU-336 is highly effective against tumor
xenografts in nude mice.[1]

213.1 See also

• HU-210
• HU-331

• HU-345

213.2 References
[1] Natalya M. Kogan, et al. (2006). “A Cannabinoid
Quinone Inhibits Angiogenesis by Targeting Vascular En-
dothelial Cells”. Molecular Pharmacology 70 (1): 51–59.
doi:10.1124/mol.105.021089. PMID 16571653.

283
Chapter 214

HU-345

HU-345 (cannabinol quinone) is a drug that is able to

inhibit aortic ring angiogenesis more potently than its par-
ent compound cannabinol.[1][2]

214.1 See also

• HU-210
• HU-336

214.2 References
[1] Natalya M. Kogan, et al. (2006). “A Cannabinoid
Quinone Inhibits Angiogenesis by Targeting Vascular En-
dothelial Cells”. Molecular Pharmacology 70 (1): 51–59.
doi:10.1124/mol.105.021089. PMID 16571653.

[2] US patent 0092584, Mechoulam R, Kogan NM, Rabi-

nowitz R, Schlesinger M, “Therapeutic Use of Quinonoid
Derivatives of Cannabinoids”, granted 2011-04-21

284
Chapter 215

Raphael Mechoulam

Raphael Mechoulam (Hebrew: ‫( )רפאל משולם‬born 215.2 Research

1930) is an Israeli organic chemist and professor
of Medicinal Chemistry at the Hebrew University
of Jerusalem in Israel. Mechoulam is best known
for his work (together with Y. Gaoni) in the iso-
lation, structure elucidation and total synthesis of
Δ9 -tetrahydrocannabinol, the main active principle of
cannabis and for the isolation and the identification of the
endogenous cannabinoids anandamide from the brain and
2-arachidonoyl glycerol (2-AG) from peripheral organs
together with his students, postdocs and collaborators.
Raphael Mechoulam’s major scientific interest is the
chemistry and pharmacology of cannabinoids. He and
his research group succeeded in the total synthesis of
the major plant cannabinoids Δ9 -tetrahydrocannabinol,
cannabidiol, cannabigerol and various others. Another
research project initiated by him led to the isolation of
the first described endocannabinoid anandamide which
was isolated and characterized by two of his postdoctoral
researchers, Lumír Ondřej Hanuš and William Devane.
Another endogenous cannabinoid, 2-AG, was soon dis-
covered by Shimon Ben-Shabat, one of his PhD students.
He published more than 350 scientific articles.

215.1 Biography
215.3 References
Raphael Mechoulam was born in Sofia, Bulgaria on
November 5, 1930. His father was a physician and head [1] http://www.nndb.com/people/699/000210069/
of a local hospital, while his mother “who had studied in [2] Conversation with Raphael Mechoulam, Addiction (Wi-
Berlin, enjoyed the life of a well-to-do Jewish family”. ley) 102 (6), 2007: 887–893, doi:10.1111/j.1360-
He attended an “American Grade School” until his par- 0443.2007.01795.x, PMID 17523982
ents were forced to leave their hometown because of anti-
semitic laws and his father was subsequently sent to a con- [3] Michael Denman (2007), “MECHOULAM,
centration camp, from which he survived. After the com- RAPHAEL”, Encyclopaedia Judaica 13 (2nd ed.),
Thomson Gale, pp. 711–712
munist takeover of hitherto pro-German Bulgaria in 1944
he studied chemical engineering, which he “disliked.” In
1949 his family immigrated to Israel where he later stud-
ied chemistry. He gained his first research experience in 215.4 Podcasts
the Israeli Army working on insecticides.[2]
He received his M.Sc. in biochemistry from the He- • A podcast (open access) of an interview with
brew University of Jerusalem (1952), and his Ph.D. at the Raphael Mechoulam, recorded by Steve Alexander
Weizmann Institute, Reḥovot (1958), with a thesis on the for the British Journal of Pharmacology on the oc-
chemistry of steroids. After postdoctoral studies at the casion of his 80th Birthday in November 2010.
Rockefeller Institute, New York (1959–60), he was on
the scientific staff of the Weizmann Institute (1960–65),
before moving to the Hebrew University of Jerusalem,
where he became professor (1972) and Lionel Jacobson
Professor of Medicinal Chemistry from 1975. He was
rector (1979–82) and pro-rector (1983–85). In 1994 he
was elected a member of the Israel Academy of Sciences.
His honors include the Kolthof Prize in chemistry from
the Haifa Technion (1994) and the Israel Prize in chem-
istry (2000).[3]

285
Chapter 216

John W. Huffman

John William Huffman (born 1932) is a professor 216.2 See also

emeritus of organic chemistry at Clemson University
who first synthesised many novel cannabinoids.[1] His re- • List of JWH cannabinoids
search, funded by the National Institute on Drug Abuse,
was focused on making a drug to target endocannabinoid
receptors in the body.[2]
216.3 References
Beginning in 1984, Huffman and his team of researchers
began developing cannabinoid compounds to aid in re- [1] “Clemson University :: Department of Chemistry”.
search of multiple sclerosis, HIV/AIDS, and chemother- Clemson.edu. Retrieved 2010-08-24.
apy. Over the course of twenty years, Huffman and his
[2] Brownstein, Joseph (March 17, 2010), K2 Giving People
team developed 450 synthetic cannabinoid compounds
Another Dangerous Way to Get High, ABC News
which were used to test the effect of cannabinoid re-
ceptors in the brain and other organs. Ultimately, the [3] Wang, Linda (June 28, 2010). “C&EN Talks With John
cannabinoid research provided understanding of diseases W. Huffman”. Chemical & Engineering News 88 (26): 43.
and information for medication development. In the late Retrieved October 8, 2011.
2000s, two of Huffman’s cannabinoid compounds began
being sold in Germany as marijuana alternatives known
as K2 and Spice. “I figured once it got started in Germany
it was going to spread. I'm concerned that it could hurt
people,” Huffman said. “I think this was something that
was more or less inevitable. It bothers me that people are
so stupid as to use this stuff”. Huffman may have devel-
oped these compounds for scientific research, but now he
gets blamed for its abuse. As JWH-018 is more potent
and easy to make, Huffman believes it is a more widely
used synthetic cannabinoid of the JWH series.[3]

216.1 Law enforcement

More than half a dozen countries have banned herbal

blends containing synthetic cannabinoids since 2008.
Many countries also consider banning these mixtures. In
the US, the states of Kansas, Georgia, Alabama, Ten-
nessee, Missouri, Louisiana, Mississippi, Arkansas, and
New York banned K2, herbal incense. JWH-018 is cur-
rently banned by controlled substances act. [3]
Law enforcement officials in Canada asked Huffman to
serve as a consultant and expert witness. He received
numerous media queries and requests for analytical help
from law enforcement officials.[3]

286
Chapter 217
JWH-007
JWH-007 is an analgesic chemical from the
naphthoylindole family, which acts as a cannabinoid
agonist at both the CB1 and CB2 receptors. It was the
most active of the first group of N-alkyl naphoylindoles
discovered by the team led by John W Huffman, several
years after the family was initially described with
the discovery of the N-morpholinylethyl compounds
pravadoline (WIN 48,098), WIN 55,225 (JWH-200)
and WIN 55,212-2 by the Sterling Winthrop group.[1]
Several other N-alkyl substituents were found to be
active by Huffman’s team including the n-butyl, n-hexyl,
2-heptyl and cyclohexylethyl groups,[2] but it was sub-
sequently determined that the 2-methyl group on the
indole ring is not required for CB1 binding, and tends
to increase affinity for CB2 instead.[3][4] Consequently
the 2-desmethyl derivative of JWH-007, JWH-018 has
slightly higher binding affinity for CB1 , with an optimum
binding of 9.00nM at CB1 and 2.94nM at CB2 , and
JWH-007 displayed optimum binding of 9.50nM at CB1
and 2.94nM at CB2 .[5]
217.1 Law
Sweden: JWH-007 was banned in Sweden on 1 Oc-
tober 2010 as a hazardous good harmful to health, af-
ter being identified as an ingredient in “herbal” synthetic
cannabis products.[6][7] Poland: JWH-007 is illegal in
Poland since 08.06.2010 on the basis of 'Ustawa z dnia
15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu
narkomanii' published in Dz.U. 2011 nr 105 poz. 614[8]
217.2 See also
• JWH-015
• JWH-018
• JWH-019
• JWH-073
287
217.3 References
[1] Compton, D. R., et al. (1992). “Aminoalkylindole
analogs: cannabimimetic activity of a class of compounds
structurally distinct from delta 9-tetrahydrocannabinol”.
The Journal of Pharmacology and Experimental Thera-
peutics 263 (3): 1118–1126. PMID 1335057.
[2] Huffman JW, Dong D. Design, Synthesis and Pharmacol-
ogy of Cannabimimetic Indoles. Bioorganic and Medici-
nal Chemistry Letters. 1994;4(4):563-566.
[3] Huffman, J., et al. (2005). “Structure-activity relation-
ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.
[4] Huffman, J. W.; Padgett, L. W. (2005). “Recent develop-
ments in the medicinal chemistry of cannabimimetic in-
doles, pyrroles and indenes”. Current medicinal chemistry
12 (12): 1395–1411. doi:10.2174/0929867054020864.
PMID 15974991.
[5] Aung, M. M., et al. (2000). “Influence of the N-1 alkyl
chain length of cannabimimetic indoles upon CB(1) and
CB(2) receptor binding”. Drug and alcohol dependence
60 (2): 133–140. doi:10.1016/S0376-8716(99)00152-0.
PMID 10940540.
[6] Swedish Code of Statutes Regulation (2010:1086).
[7] Swedish Code of Statutes Regulation (2010:1086). (pdf)
[8] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o
przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz.
614 )". ISAP. Retrieved 12 June 2011.
Chapter 218

Naphthoylindole

JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM- 218.2.1 Pharmacokinetics

678[1] is an analgesic chemical from the naphthoylin-
dole family that acts as a full agonist at both the CB1 JWH-018 administered to rats resulted in the excretion
and CB2 cannabinoid receptors, with some selectivity for of an indole-N-desalkyl metabolite as well as several hy-
CB2 . It produces effects in animals similar to those of droxylated metabolites in urine. The highest signals were
THC, a cannabinoid naturally present in cannabis, lead- observed for the hydroxylated N-desalkyl metabolites.
ing to its use in synthetic cannabis products such as “le- Hydroxylation took place on the side chain and in both
gal cannabis herbal incense blends” which in some coun- aromatic systems, the naphthalene and the indole rings,
tries are sold legally as “incense”, labeled “not for human as could be shown by mass shift of the corresponding
consumption”.[2][3][4][5][6] fragments and by MS3 experiments.[13] Human metabo-
lites were similar although most metabolism took place
on the indole ring and pentyl side chain, and the hy-
droxylated metabolites were extensively conjugated with
glucuronide.[14]
218.1 History
218.3 Usage
John W. Huffman, an organic chemist at Clemson Uni-
versity, synthesized analogues and metabolites of Δ9 -
At least one case of JWH-018 dependence has been re-
tetrahydrocannabinol (THC), the principal active com-
ported by the media.[2] The user consumed JWH-018
ponent of cannabis. JWH-018 is one of these analogues,
daily for eight months. Withdrawal symptoms were sim-
with studies showing an affinity for the cannabinoid (CB1 )
ilar to those experienced as a result of cannabis depen-
receptor five times greater than that of THC. Cannabinoid
dence. JWH-018 has been shown to cause profound
receptors are found in mammalian brain and spleen tis-
changes in CB1 receptor density following administra-
sue; however, the structural details of the active sites are
tion, causing desensitization to its effects more rapidly
currently unknown.[7][8]
than related cannabinoids.[6]
On December 15, 2008, it was reported by the German
On October 15, 2011, Anderson County coroner Greg
pharmaceutical company THC Pharm that JWH-018 was
Shore attributed the death of a South Carolina college
found as one of the active components in at least three
basketball player to “drug toxicity and organ failure”
versions of the herbal blend Spice, which has been sold
caused by JWH-018.[15] An email dated Nov 4, 2011
as an incense in a number of countries around the world
concerning the case was finally released by the city of
since 2002.[9][10][11] An analysis of samples acquired four
Anderson S.C. on Dec 16, 2011 under the Freedom of
weeks after the German prohibition of JWH-018 took
Information Act after multiple requests by media to see
place found that the compound had been replaced with
the information had been denied.[16]
JWH-073.[12]
Compared to THC, which is a partial agonist at CB1
receptors, JWH-018 (and many of its analogues) are
full agonists. THC has been shown to inhibit GABA
receptor neurotransmission in the brain via several
218.2 Pharmacology pathways.[17][18] JWH-018 may cause intense anxiety, ag-
itation, and, in rare cases (generally with non-regular
JWH users), has been assumed to have been the cause of
JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotrans-
cannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep-
9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the user

288
218.6. SYNTHESIS 289

when used to excess.[19]

Various physical and psychological adverse effects have
been reported from JWH-018 use. One study re-
ported psychotic relapses and anxiety symptoms in well-
treated patients with mental illness following JWH-018
inhalation.[20] Due to concerns about the potential of
JWH-018 and other synthetic cannabinoids to cause psy-
chosis in vulnerable individuals, it has been recom-
mended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51]
nesses (like a past or family history of psychosis) not use
these substances.[21]
218.6 Synthesis

218.7 See also

218.4 Detection in biological fluids
• AM-2201

JWH-018 usage is readily detected in urine using “spice” • BB-22 (drug)

screening immunoassays from several manufacturers fo-
• JWH-073
cused on both the parent drug and its omega-hydroxy and
carboxyl metabolites.[22] JWH-018 will not be detected • JWH-250
by older methods employed for detecting THC and other
cannabis terpenoids. Determination of the parent drug in • JWH-200
serum or its metabolites in urine has been accomplished
by GC-MS or LC-MS. Serum JWH-018 concentrations • PB-22
are generally in the 1–10 μg/L range during the first
• SDB-001
few hours after recreational usage. The major urinary
metabolite is a compound that is monohydroxylated on
the omega minus one carbon atom of the alkyl side chain.
A lesser metabolite monohydroxylated on the omega (ter- 218.8 References
minal) position was present in the urine of 6 users of the
drug at concentrations of 6–50 μg/L, primarily as a glu- [1] “Department of Justice :: Drug Enforcement Administra-
curonide conjugate.[23][24][25][26][27][28][29][30][31] tion”. 2011-03-01. Retrieved 2011-03-02.

[2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees

JA, Spanagel R, Schulz K (2009). “Withdrawal Phenom-
ena and Dependence Syndrome After the Consumption
of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467.
218.5 Legal status doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID
19652769.

[3] Aung MM, Griffin G, Huffman JW, Wu M, Keel

C, Yang B, Showalter VM, Abood ME, Martin BR
(2000). “Influence of the N-1 alkyl chain length of
cannabimimetic indoles upon CB1 and CB2 receptor
binding”. Drug and Alcohol Dependence 60 (2): 133–140.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.

[4] US patent 6900236, Alexandros Makriyannis, Hongfeng

Deng, “Cannabimimetic indole derivatives”, issued 2005-
05-31

[5] US patent 7241799, Alexandros Makriyannis, Hongfeng

Deng, “Cannabimimetic indole derivatives”, issued 2007-
07-10

[6] Atwood, B.K., et al., “JWH018, a common constituent of

JWH-018 powder as it was commonly sold online 'Spice' herbal blends, is a potent and efficacious cannabi-
noid CB1 receptor agonist.” British Journal of Pharma-
cology, Vol. 160, No. 3. 585-593. 2010.
290
[7] “Clemson University :: Department of Chemistry”.
Clemson.edu. Retrieved 2010-08-23.
[8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23.
[9] Gefährlicher Kick mit Spice (German)
[10] Erstmals Bestandteile der Modedroge “Spice”
nachgewiesen (German)
[11] Spice enthält chemischen Wirkstoff (German)
[12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wig-
germann M, Ernst L, Beuerle T (30 October 2009).
“Spice: A never ending story?". Forensic Science Inter-
national (Forensic Science International) 191 (1): 58–63.
doi:10.1016/j.forsciint.2009.06.008. PMID 19589652.
[13] T. Kraemer, et al. Studies on the metabolism of JWH-
018 and of a homologue of CP 47,497, pharmacolog-
ically active ingredients of different misused incense
(“Spice”) using GC-MS and LC-MSn techniques (In-
stitute of Legal Medicine, Saarland University, 66421
Homburg, Germany http://www.gtfch.org/cms/images/
stories/media/tk/tk76_2/abstractsvortraege.pdf
[14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010).
“Detection of JWH-018 metabolites in smoking mixture
post-administration urine”. Forensic Science International
200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[15] wyff4.com, Coroner: Synthetic Pot Killed College Ath-
lete, posted 10/14/11, accessed 12/22/11, http://www.
wyff4.com/news/29497549/detail.html,
[16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”,
independentmail.com, posted Dec 16, 2011, accessed
12/22/11, http://www.independentmail.com/news/2011/
dec/16/city-releases-email-lamar-jack-case/
[17] Laaris N, Good CH, Lupica CR (July–August 2010).
"Δ9-tetrahydrocannabinol is a full agonist at CB1 re-
ceptors on GABA neuron axon terminals in the hip-
pocampus”. Neuropharmacology 59 (1–2): 121–127.
doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293.
PMID 20417220.
[18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of
cannabinoid inhibition of GABAA synaptic transmission
in the hippocampus”. The Journal of Neuroscience 20 (7):
2470–2479. ISSN 0270-6474. PMID 10729327. Re-
trieved 2011-07-26.
[19] European Monitoring Centre for Drugs and Drug Ad-
diction. “Understanding the Spice Phenomenon.” 2009.
ISBN 978-92-9168-411-3.
[20] Every-Palmer, S. Synthetic cannabinoid use and psy-
chosis: an explorative study. Journal of Drug and Alcohol
Dependence 2011. [Epub ahead of print].
[21] Every-Palmer S (2010). “WARNING: LEGAL SYN-
THETIC CANNABINOID-RECEPTOR AGONISTS
SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS
IN VULNERABLE INDIVIDUALS”. Addiction 105:
1859–1860. doi:10.1111/j.1360-0443.2010.03119.x.
PMID 20840203.
CHAPTER 218. NAPHTHOYLINDOLE
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/
content/37/5/284.abstract, https://www.caymanchem.
com/app/template/Product.vm/catalog/580210;
http://www.randoxtoxicology.com/Products/Elisa-p-50,
http://tulipbiolabs.com/our-product-areas/
synthetic-cannabinoids and others.
[23] Möller I, et al. Screening for the synthetic cannabinoid
JWH-018 and its major metabolites in human doping con-
trols. Drug Test. Anal. Sep 24, 2010. [Epub ahead of
print]
[24] Teske J, et al. Sensitive and rapid quantification
of the cannabinoid receptor agonist naphthalen-1-yl-(1-
pentylindol-3-yl)methanone (JWH-018) in human serum
by liquid chromatography-tandem mass spectrometry. J
Chrom. B 878: 2659-2663, 2010.
[25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz
M, Ferreirós N (2009). "'Spice' and other herbal blends:
harmless incense or cannabinoid designer drugs?". Jour-
nal of mass spectrometry : JMS 44 (5): 832–837.
doi:10.1002/jms.1558. PMID 19189348. Free version
[26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees
JA, Spanagel R, Schulz K (2009). “Withdrawal phe-
nomena and dependence syndrome after the consumption
of “spice gold"". Deutsches Arzteblatt international 106
(27): 464–467. doi:10.3238/arztebl.2009.0464. PMC
2719097. PMID 19652769.
[27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “De-
tection of JWH-018 metabolites in smoking mixture post-
administration urine”. Forensic Science International 200
(1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[28] Beuck S, Möller I, Thomas A, Klose A, Schlörer
N, Schänzer W, Thevis M (August 2011). “Struc-
ture characterisation of urinary metabolites of the
cannabimimetic JWH-018 using chemically synthesised
reference material for the support of LC-MS/MS-based
drug testing”. Anal Bioanal Chem 401 (2): 493–505.
doi:10.1007/s00216-011-4931-5. PMID 21455647.
[29] Moran CL, Le VH, Chimalakonda KC, Smedley AL,
Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske
FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski
PJ, Wessinger WD, Fantegrossi WE, Prather PL, James
LP, Radominska-Pandya A, Moran JH (June 2011).
“Quantitative measurement of JWH-018 and JWH-073
metabolites excreted in human urine”. Anal. Chem.
83 (11): 4228–36. doi:10.1021/ac2005636. PMID
21506519.
[30] Logan BK, et al. Identification of primary JWH-
018 and JWH-073 metabolites in human urine.
NMS Labs Technical Bulletin, May 25, 2011.
http://toxwiki.wikispaces.com/file/view/JWH_
metabolites_Technical_Bulletin_Final_v1.1.pdf
[31] R. Baselt, Disposition of Toxic Drugs and Chemicals in
Man, 10th edition, Biomedical Publications, Seal Beach,
CA, 2014, p. 1863.
[32] <http://www.legislation.qld.gov.au/LEGISLTN/
CURRENT/D/DrugsMisuseR87.pdf>
218.9. EXTERNAL LINKS 291

[33] “Controlled Drugs and Substances Act”. 218.9 External links

Laws.justice.gc.ca. 2010-08-16. Retrieved 2010-
08-23. • JWH-018 Report Psychonaut Web Mapping Re-
[34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VAL- search Project
TIONEUVOSTON YLEISISTUNTO 1.3.2012 ***
• User of legal high
(Finnish)

[35] “EMCDDA | Drug profile: Synthetic cannabinoids and

'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved
2010-08-23.

[36] http://www.afssaps.fr/var/afssaps_site/storage/original/
application/d23d05edc58479d91c803b496017f073.pdf

[37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19.

Januar 2009, S. 49–50.

[38] Many head shop products banned - Irish Times.

[39] http://www.politicheantidroga.it/
comunicazione/comunicati/2010/luglio/spice,
-n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian)

[40] https://www.drugfoundation.org.nz/
synthetic-cannabinoids/what-they-are

[41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465.
html

[42] (2 July 2009). “1 ‘5- - ’ ".

. Retrieved 18 February 2010.

[43] http://www.regeringen.se/sb/d/12102/a/130038
(Swedish)

[44] “Illicit Drug Report of Turkey 2010”. Department of

Anti-smuggling and Organised Crime. Retrieved 2012-
05-03.(Turkish)

[45] “Decision of the Council of Ministers, Enactment

2011/1310”. General Directorate of Legislation Develop-
ment and Publication. Retrieved 2012-05-03.(Turkish)

[46] “Attachment to Enactment 2012/2861”. General Direc-

torate of Legislation Development and Publication. Re-
trieved 2012-05-03.(Turkish)

[47] “Decision of the Council of Ministers, Enactment

2012/2861”. General Directorate of Legislation Develop-
ment and Publication. Retrieved 2012-05-03.(Turkish)

[48] Ford, Richard (2009-12-23). “Three legal highs banned

after deaths linked to the drugs”. The Times (London).
Retrieved 2010-05-07.

[49] “Schedules of Controlled Substances: Temporary Place-

ment of Four Synthetic Cannabinoids Into Schedule I”.
DEA Office of Diversion Control. Retrieved 11 March
2014.

[50] <http://www.antinarcotics.psd.gov.jo>

[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014).

“Recreational drug discovery: natural products as lead
structures for the synthesis of smart drugs”. Natural Prod-
uct Reports 31 (7): 880–904. doi:10.1039/c4np00010b.
Chapter 219

JWH-019

JWH-019 is an analgesic chemical from the 219.2 See also

naphthoylindole family that acts as a cannabinoid
agonist at both the CB1 and CB2 receptors. It is the • JWH-007
N1-hexyl homologue of the more common synthetic
cannabinoid compound JWH-018. Unlike the butyl • JWH-018
homologue JWH-073, which is several times weaker
• JWH-073
than JWH-018, the hexyl homologue is only slightly less
potent, although extending the chain one carbon longer • JWH-200
to the heptyl homologue JWH-020 results in dramatic
loss of activity. These results show that the optimum
side chain length for CB1 binding in the naphthoylindole
series is the five-carbon pentyl chain, shorter than in the
219.3 References
classical cannabinoids where a seven-carbon heptyl chain
[1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r.
produces the most potent compounds. This difference
o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U.
is thought to reflect a slightly different binding confor- 2011 nr 105 poz. 614 )". Internetowy System Aktów
mation adopted by the naphthoylindole compounds as Prawnych. Retrieved 12 June 2011.
compared to the classical cannabinoids, and may be
useful in characterising the active site of the CB1 and [2] Aung MM, et al. (August 2000). “Influence of the
CB2 receptors.[2][3][4] N-1 alkyl chain length of cannabimimetic indoles upon
CB(1) and CB(2) receptor binding”. Drug and Alco-
hol Dependence 60 (2): 133–40. doi:10.1016/S0376-
8716(99)00152-0. PMID 10940540.
219.1 Legal Status
[3] Poso A, Huffman JW (January 2008). “Targeting
the cannabinoid CB2 receptor: modelling and
219.1.1 Poland structural determinants of CB2 selective ligands”.
British Journal of Pharmacology 153 (2): 335–46.
In Poland, JWH-019 is I-N (Poland)[1] doi:10.1038/sj.bjp.0707567. PMC 2219524. PMID
17982473.

219.1.2 Sweden [4] Ashton JC, Wright JL, McPartland JM, Tyndall JD
(2008). “Cannabinoid CB1 and CB2 receptor ligand
JWH-019 is illegal in Sweden specificity and the development of CB2-selective ago-
nists”. Current Medicinal Chemistry 15 (14): 1428–43.
doi:10.2174/092986708784567716. PMID 18537620.
219.1.3 UK [5] http://crimlaw.blogspot.com/2011/04/
no-more-synthetic-cannabinoid.html
JWH-019 is Class B in the United Kingdom.

219.1.4 USA
JWH-019 is not controlled federally in the United States,
however if intended for human consumption, possession
or sales could possibly be prosecuted under the Federal
Analog Act.
JWH-019 is illegal in Virginia.[5]

292
Chapter 220

JWH-030

JWH-030 is a research chemical which is a cannabinoid

receptor agonist.[1] It has analgesic effects and is used in
scientific research.[2] It is a partial agonist at CB1 recep-
tors, with a Ki of 87nM, making it roughly half the po-
tency of THC.[3] It was discovered and named after Dr.
John W. Huffman.

220.1 See also

• JWH-147

220.2 References
[1] Lainton JAH, Huffman JW, Martin BR, Compton DR.
Tetrahedron Letters. 1995; 36:1401.

[2] Pertwee RG, Griffin, G, Lainton JAH, Huffman JW. Eu-

ropean Journal of Pharmacology. 1995; 284:241.

[3] Griffin, G.; Atkinson, P. J.; Showalter, V. M.; Martin,

B. R.; Abood, M. E. (1998). “Evaluation of cannabinoid
receptor agonists and antagonists using the guanosine-5'-
O-(3-35Sthio)-triphosphate binding assay in rat cerebellar
membranes”. The Journal of Pharmacology and Experi-
mental Therapeutics 285 (2): 553–560. PMID 9580597.

293
Chapter 221

JWH-047

JWH-047 is a selective cannabinoid ligand, with a bin-

dining affinity of Kᵢ = 0.9 nM for the CB2 subtype, and
more than 65 times selectivity over the CB1 .[1]

221.1 See also

• JWH-015

• JWH-018
• JWH-019

• JWH-073

221.2 References
[1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel
C, Yang B, Showalter VM, Abood ME, Martin BR
(2000). “Influence of the N-1 alkyl chain length of
cannabimimetic indoles upon CB1 and CB2 receptor
binding”. Drug and Alcohol Dependence 60 (2): 133–40.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.

294
Chapter 222

JWH-048

JWH-048 is a selective cannabinoid ligand, with a bin-

dining affinity of Kᵢ = 0.5 ± 0.1 nM for the CB2 subtype,
and more than 22 times selectivity over the CB1 .[1]

222.1 See also

• JWH-015

• JWH-018
• JWH-019

• JWH-073

222.2 References
[1] Aung MM, Griffin G, Huffman JW, Wu M-J, Keel
C, Yang B, Showalter VM, Abood ME, Martin BR
(2000). “Influence of the N-1 alkyl chain length of
cannabimimetic indoles upon CB1 and CB2 receptor
binding”. Drug and Alcohol Dependence 60 (2): 133–40.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.

295
Chapter 223

JWH-073

JWH-073 is an analgesic chemical from the synthetic cannabis smoking blends.

naphthoylindole family that acts as a partial agonist
at both the CB1 and CB2 cannabinoid receptors. It is
somewhat selective for the CB1 subtype, with affinity at
this subtype approximately 5x the affinity at CB2 .[2] The
abbreviation JWH stands for John W. Huffman, one of
the inventors of the compound.
On 20 April 2009, JWH-073 was claimed by researchers
at the University of Freiburg to have been found in a
“fertiliser” product called “Forest Humus”, along with
another synthetic cannabinoid (C8)-CP 47,497.[3] These
claims were confirmed in July 2009 when tests of Spice
product, seized after the legal ban on JWH-018 had gone
into effect in Germany, were shown to contain the unreg-
ulated compound JWH-073 instead.[4]

223.1 Pharmacology
JWH-073 has been shown to produce behavioral effects
very similar to THC in animals.[5]
Its effects are produced by binding and acting as an ago-
4'-Methyl-JWH-073
nist to the CB1 and CB2 cannabinoid receptors. The CB1
receptor is found in the brain. JWH-073 bind to CB1 with
a higher affinity than THC, suggesting that taking more
too soon after the initial dose could lead to diminished 223.3 Legal status
effects. CB2 is found outside the brain, mostly in the im-
mune system. The binding with CB2 receptors has been
shown to be similar between JWH-073 and THC.[5] 223.3.1 United States
A search in the literature yielded no published studies of See also: JWH-018
the effects of JWH-073 in humans, but these studies in The US DEA temporarily declared JWH-073 a schedule
animals suggest with high probability that JWH-073 pro- I controlled substance on 1 March 2011 through 76 FR
duces effects very similar to those of THC in humans.[5] 11075, and permanently instated the same schedule on
9 July 2012 in the Section 1152 of the Food and Drug
Administration Safety and Innovation Act.[7]
223.2 Derivatives
The 4'-methyl derivative of JWH-073 has been encoun- 223.3.2 Australia
tered as an ingredient of synthetic cannabis blends in Ger-
many and several other European countries since 2010.[6] See also: JWH-018
The 4'-methoxy derivative JWH-080 is also known to be a
potent cannabinoid agonist and has been banned in some On 8 July 2011 the AUS government banned the sale of
countries, though it is unclear if it has also been used in JWH-073.[8]

296
223.5. REFERENCES 297

[9] https://www.drugfoundation.org.nz/
synthetic-cannabinoids/what-they-are

1 g of JWH-073

223.3.3 New Zealand

On 8 May 2014 the New Zealand government banned the
sale of JWH-073. [9]

223.4 See also

• JWH-081
• JWH-018
• JWH-019
• HU-210

223.5 References
[1] http://www.likumi.lv/doc.php?id=201101&from=off

[2] Aung MM, et al. (August 2000). “Influence of the N-1

alkyl chain length of cannabimimetic indoles upon CB(1)
and CB(2) receptor binding”. Drug Alcohol Depend
60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0.
PMID 10940540.

[3] Forest Humus - Enthält synthetische Cannabinoide (in

German)

[4] Lindigkeit R, et al. (July 2009). “Spice: A never ending

story?". Forensic Science International 191 (1–3): 58–63.
doi:10.1016/j.forsciint.2009.06.008. PMID 19589652.

[5] http://www.deadiversion.usdoj.gov/drugs_concern/
spice/spice_jwh073.html

[6] EMCDDA Annual Report 2010

[7] “Schedules of Controlled Substances: Temporary Place-

ment of Four Synthetic Cannabinoids Into Schedule I”.
DEA Office of Diversion Control. Retrieved 11 March
2014.

[8] http://www.tga.gov.au/pdf/scheduling/
scheduling-decisions-1107-final.pdf
Chapter 224

JWH-081

JWH-081 is an analgesic chemical from the

naphthoylindole family, which acts as a cannabinoid
agonist at both the CB1 and CB2 receptors.[2] With a Kᵢ
of 1.2nM it is fairly selective for the CB1 subtype, its
affinity at this subtype approximately 10x the affinity at
CB2 .[3] It was discovered by and named after Dr. John
W. Huffman.

224.1 See also

• JWH-018

• JWH-098

• JWH-164
• JWH-198

• JWH-210

224.2 References
[1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy
o przeciwdziałaniu narkomanii (Dz.U. 2011 nr 105 poz.
614)". Internetowy System Aktów Prawnych. Retrieved
12 June 2011.

[2] Aung MM, et al. Influence of the N-1 alkyl chain length
of cannabimimetic indoles upon CB1 and CB2 receptor
binding. Drug and Alcohol Dependence 2000; 60:133-
140.

[3] Huffman JW, et al. Structure–activity relationships for 1-

alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and
CB2 receptors: steric and electronic effects of naphthoyl
substituents. New highly selective CB2 receptor agonists.
Bioorganic and Medicinal Chemistry. 2005; 13:89-112.

298
Chapter 225

JWH-098

JWH-098 is a synthetic cannabinoid receptor agonist

from the naphthoylindole family. It is the indole 2-methyl
derivative of a closely related compound JWH-081, but
has markedly different affinity for the CB1 and CB2 re-
ceptors. While JWH-081 is around 10x selective for CB1
over CB2 , in JWH-098 this is reversed, and it is around
4 times weaker than JWH-081 at CB1 while being six
times more potent at CB2 , giving it a slight selectivity
for CB2 overall. This makes JWH-098 a good example
of how methylation of the indole 2-position in the naph-
thoylindole series tends to increase CB2 affinity, but often
at the expense of CB1 binding.[1] JWH-098 is illegal in
Russia,[2] Sweden,[3] and the UK,[4] although it is unclear
whether it has any history of human use.

225.1 See also

• JWH-007

• JWH-081

225.2 References
[1] Huffman JW, et al. Structure–activity relationships for 1-
alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and
CB2 receptors: steric and electronic effects of naphthoyl
substituents. New highly selective CB2 receptor agonists.
Bioorganic and Medicinal Chemistry. 2005; 13:89-112.
PMID 15582455

[2] "Постановление от 31 декабря 2009 г. № 1186

О внесении изменений в некоторые постановления
Правительства Российской Федерации по вопросам,
связанным с оборотом наркотических средств". Gov-
ernment.ru. Retrieved 2010-09-09.

[3] Svensk författningssamling

[4] The Misuse of Drugs Act 1971 (Amendment) Order 2009

299
Chapter 226

JWH-116

JWH-116 is a synthetic cannabinoid receptor ligand from

the naphthoylindole family. It is the indole 2-ethyl deriva-
tive of related compound JWH-018. The binding affinity
of JWH-116 for the CB1 receptor is reported as Kᵢ = 52
± 5 nM.[1]

226.1 See also

• JWH-018

• JWH-081

226.2 References
[1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP,
Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1-
naphthylmethanes: new cannabimimetic indoles provide
evidence for aromatic stacking interactions with the CB1
cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539–
549. doi:10.1016/s0968-0896(02)00451-0.

300
Chapter 227

JWH-147

JWH-147 is an analgesic drug used in scientific research,

which acts as a cannabinoid agonist at both the CB1 and
CB2 receptors. It is somewhat selective for the CB2 sub-
type, with a Ki of 11.0nM at CB1 vs 7.1nM at CB2 .[1]
It was discovered and named after Dr. John W. Huff-
man. JWH-147 was banned in Sweden on 1 October
2010 as a hazardous good harmful to health, after being
identified as an ingredient in “herbal” synthetic cannabis
products.[2][3]

227.1 See also

• JWH-030
• JWH-307

227.2 References
[1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL,
Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New
high affinity ligands for the cannabinoid CB1 and CB2 re-
ceptors. Bioorganic & Medicinal Chemistry Letters 2006;
16:5432-5435.

[2] Swedish Code of Statutes Regulation (2010:1086).

[3] Swedish Code of Statutes Regulation (2010:1086). (pdf)

301
Chapter 228

JWH-164

JWH-164 is a synthetic cannabinoid receptor agonist

from the naphthoylindole family. It has approximately
equal affinity for the CB1 and CB2 receptors, with a Kᵢ
of 6.6nM at CB1 and 6.9nM at CB2 . JWH-164 is a
positional isomer of the related compound JWH-081, but
with a methoxy group at the 7-position of the naphthyl
ring, rather than the 4-position as in JWH-081. Its po-
tency is intermediate between that of JWH-081 and its
ring unsubstituted derivative JWH-018, demonstrating
that substitution of the naphthyl 7-position can also result
in increased cannabinoid receptor binding affinity.[1][2]

228.1 References
[1] Huffman JW, et al. Structure–activity relationships for 1-
alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and
CB2 receptors: steric and electronic effects of naphthoyl
substituents. New highly selective CB2 receptor agonists.
Bioorganic and Medicinal Chemistry. 2005; 13:89-112.
PMID 15582455

[2] Huffman JW, Padgett LW. Recent Developments in

the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411. PMID 15974991

302
Chapter 229

Phenylacetylindole

JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a
synthetic cannabinoid from the phenylacetylindole
family, which acts as a cannabinoid agonist with about
1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and
159nM ± 14 at CB2 . Similar to the related 2'-methoxy
compound JWH-250, and the 2'-chloro compound
JWH-203, JWH-167 has a phenylacetyl group in place
of the naphthoyl ring used in most aminoalkylindole
cannabinoid compounds.[1][2]

229.1 References
[1] Huffman, JW, Szklennik, PV, Almond, A, Bushell,
K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles”. Bioor-
ganic & Medicinal Chemistry Letters 15 (18): 4110–3.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.

[2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

303
Chapter 230

JWH-175

JWH-175 is a drug from the naphthylmethylindole fam-

ily which acts as a cannabinoid receptor agonist. It was
invented by the scientist John W. Huffman and colleagues
at Clemson University. JWH-175 is closely related to
the widely used cannabinoid designer drug JWH-018, but
with the ketone bridge replaced by a simpler methylene
bridge. It is several times weaker than JWH-018, having
a binding affinity at the CB1 receptor of 22nM, though
some derivatives substituted at the 4-position of the naph-
thyl ring have potency more closely approaching that of
the equivalent naphthoylindoles.[1] This makes JWH-175
considerably less potent than most synthetic cannabinoid
drugs used in synthetic cannabis blends, and it is unclear if
JWH-175 has ever been used for this purpose. However
it has still been explicitly banned in several jurisdictions
including Russia and some Australian states, in order to
stop its potential use as an ingredient in such products.

230.1 See also

• JWH-176
• JWH-184

• JWH-185

230.2 References
[1] Huffman JW, Padgett LW. Recent Developments in
the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.

304
Chapter 231

JWH-184

JWH-184 is a synthetic cannabinoid receptor ligand from

the naphthoylindole family. It is the carbonyl-reduced
derivative of related compound JWH-122. The binding
affinity of JWH-184 for the CB1 receptor is reported as
Kᵢ = 23 ± 6 nM.[1]

231.1 See also

• JWH-018

• JWH-122
• JWH-185

231.2 References
[1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP,
Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1-
naphthylmethanes: new cannabimimetic indoles provide
evidence for aromatic stacking interactions with the CB1
cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539–
549. doi:10.1016/s0968-0896(02)00451-0.

305
Chapter 232

JWH-185

JWH-185 is a synthetic cannabinoid receptor ligand from

the naphthoylindole family. It is the carbonyl-reduced
derivative of related compound JWH-081. The binding
affinity of JWH-185 for the CB1 receptor is reported as
Kᵢ = 17 ± 3 nM.[1]

232.1 See also

• JWH-081

• JWH-184

232.2 References
[1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP,
Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1-
naphthylmethanes: new cannabimimetic indoles provide
evidence for aromatic stacking interactions with the CB1
cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539–
549. doi:10.1016/s0968-0896(02)00451-0.

306
Chapter 233

JWH-196

JWH-196 is a synthetic cannabinoid receptor ligand from

the naphthoylindole family. It is the indole 2-methyl
derivative of related compound JWH-175, and the car-
bonyl reduced analog of JWH-007. The binding affinity
of JWH-196 for the CB1 receptor is reported as Kᵢ = 151
± 18 nM.[1]

233.1 See also

• JWH-007
• JWH-175

233.2 References
[1] Huffman JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP,
Reggio PH, Wiley JL, Martin BR (2003). “3-Indolyl-1-
naphthylmethanes: new cannabimimetic indoles provide
evidence for aromatic stacking interactions with the CB1
cannabinoid receptor”. Bioorg. Med. Chem. 11 (4): 539–
549. doi:10.1016/s0968-0896(02)00451-0.

307
Chapter 234

JWH-203

JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole)
is an analgesic chemical from the phenylacetylindole
family that acts as a cannabinoid agonist with ap-
proximately equal affinity at both the CB1 and CB2
receptors, having a Kᵢ of 8.0nM at CB1 and 7.0nM
at CB2 . It was originally discovered by, and named
after, Dr. John W. Huffman, but has subsequently
been sold without his permission as an ingredient of
synthetic cannabis smoking blends.[2] Similar to the
related 2'-methoxy compound JWH-250, the 2'-bromo
compound JWH-249, and the 2'-methyl compound
JWH-251, JWH-203 has a phenylacetyl group in place
of the naphthoyl ring used in most aminoalkylindole
cannabinoid compounds, and has the strongest in vitro
binding affinity for the cannabinoid receptors of any
compound in the phenylacetyl group.[3][4][5]
Unexpectedly despite its weaker CB1 Kᵢ in vitro, the 2-
methylindole derivative JWH-204 is actually more potent
than JWH-203 in animal tests for cannabinoid activity,
though it is still weaker than JWH-249.[6]

234.1 See also

• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7- JWH-204
methoxyindole-3-carboxamide
[4] Manera, C; Tuccinardi, T; Martinelli, A (2008). “In-
doles and related compounds as cannabinoid ligands”.
234.2 References Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

[1] = WDU20111050614 “Ustawa z dnia 15 kwietnia 2011 r. [5] Bononi M, Belgi P, Tateo F (2011). “Analytical data for
o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. identification of the Cannabimimetic Phenylacetylindole
2011 nr 105 poz. 614 )". Internetowy System Aktów JWH-203”. Journal of Analytical Toxicology 35 (6): 360–
Prawnych. Retrieved 17 June 2011. 3. doi:10.1093/anatox/35.6.360. PMID 21740693.

[2] “Analytical data for identification of the Cannabimimetic [6] “1-Pentyl-3-phenylacetylindoles and JWH-018 share in
Phenylacetylindole JWH-203”. J Anal Toxicol 35 (6): vivo cannabinoid profiles in mice”. Drug Alcohol Depend.
360–3. July 2011. doi:10.1093/anatox/35.6.360. PMID November 2011. doi:10.1016/j.drugalcdep.2011.11.001.
21740693. PMID 22127210.

[3] Huffman, JW, et al. (2005). “1-Pentyl-3-

phenylacetylindoles, a new class of cannabimimetic
indoles”. Bioorganic & Medicinal Chemistry Letters 15
(18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.

308
Chapter 235

JWH-210

JWH-210 is an analgesic chemical from the [5] LVFS 2011:8

naphthoylindole family, which acts as a potent
cannabinoid agonist at both the CB1 and CB2 re-
ceptors, with Kᵢ values of 0.46nM at CB1 and 0.69nM at
CB2 . It is one of the most potent 4-substituted naphthoyl
derivatives in the naphthoylindole series, having a higher
binding affinity (i.e. lower Kᵢ) at CB1 than both its
4-methyl and 4-n-propyl homologues JWH-122 (CB1 Kᵢ
0.69nM) and JWH-182 (CB1 Kᵢ 0.65nM) respectively,
and than the 4-methoxy compound JWH-081 (CB1
Kᵢ 1.2nM).[2] It was discovered by and named after
Dr. John W. Huffman. JWH-210 and JWH-122 were
banned in Sweden on 1 October 2010 as hazardous
goods harmful to health, after being identified as ingre-
dients in “herbal” synthetic cannabis products.[3][4] The
substances JWH-210, JWH-122 and JWH-203 were
classified as illegal drugs by the Swedish government as
of 1 September 2011.[5]

235.1 See also

• JWH-081

• JWH-193

• JWH-398

235.2 References
[1] “Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o
przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz.
614 )". Internetowy System Aktów Prawnych. Retrieved
12 June 2011.

[2] Huffman, J., et al. (2005). “Structure-activity relation-

ships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabi-
noid CB(1) and CB(2) receptors: steric and electronic
effects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.”. Bioorganic & Medicinal Chem-
istry 13 (1): 89–112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.

[3] Swedish Code of Statutes Regulation (2010:1086).

[4] Swedish Code of Statutes Regulation (2010:1086). (pdf)

309
Chapter 236

JWH-249

JWH-249 (1-pentyl-3-(2-bromophenylacetyl)indole)
is a synthetic cannabinoid from the phenylacetylindole
family, which acts as a cannabinoid agonist with about
2.4x selectivity for CB1 with a Kᵢ of 8.4nM ± 1.8 and
20nM ± 2 at CB2 . Similar to the related 2'-methoxy
compound JWH-250, the 2'-chloro compound JWH-203,
and the 2'-methyl compound JWH-251, JWH-249 has a
phenylacetyl group in place of the naphthoyl ring used in
most aminoalkylindole cannabinoid compounds. [1][2]

236.1 See also

• AM-679

236.2 References
[1] Huffman, JW, Szklennik, PV, Almond, A, Bushell,
K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles”. Bioor-
ganic & Medicinal Chemistry Letters 15 (18): 4110–3.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.

[2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

310
Chapter 237

JWH-250

JWH-250 or (1-pentyl-3-(2- [5] Understanding the ‘Spice’ phenomenon. EMCDDA, Lis-

methoxyphenylacetyl)indole) is an analgesic chemical bon, November 2009
from the phenylacetylindole family that acts as a
[6] Arntson et al (2013) http://jat.oxfordjournals.org/
cannabinoid agonist at both the CB1 and CB2 recep- content/37/5/284.abstract
tors, with a Kᵢ of 11nM at CB1 and 33nM at CB2 .
Unlike many of the older JWH series compounds, this
compound does not have a naphthalene ring, instead
occupying this position with a 2'-methoxy-phenylacetyl
group, making JWH-250 a representative member
of a new class of cannabinoid ligands.[2] Other 2'-
substituted analogues such as the methyl, chloro and
bromo compounds are also active and somewhat more
potent.[3][4]

237.1 History
JWH-250 was discovered by, and named after the re-
searcher Dr. John W. Huffman. He created JWH-
250 and a number of other compounds to research the
structure and function of the endocannabinoid system of
mammals. Samples of JWH-250 were first identified in
May 2009 by the German Federal Criminal Police, as
an ingredient in new generation "herbal smoking blends"
that had been released since the banning of the original
ingredients (C8)-CP 47,497 and JWH-018.[5] An ELISA
immunoassay technique for detecting JWH-250 in urine
has been reported.[6]

237.2 References
[1] Legal article in Latvian (www.likumi.lv)
[2] Huffman, JW, et al. (2005). “1-Pentyl-3-
phenylacetylindoles, a new class of cannabimimetic
indoles”. Bioorganic & Medicinal Chemistry Letters 15
(18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.
[3] Manera, C; Tuccinardi, T; Martinelli, A (2008). “In-
doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.
[4] The Cannabinoid Receptors. Edited by Patricia H Reggio.
Humana Press 2009. ISBN 978-1-58829-712-9

311
Chapter 238

JWH-251

JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole)
is a synthetic cannabinoid from the phenylacetylindole
family, which acts as a cannabinoid agonist with about
5x selectivity for CB1 with a Kᵢ of 29nM and 146nM
at CB2 . Similar to the related 2'-methoxy com-
pound JWH-250, the 2'-chloro compound JWH-203,
and the 2'-bromo compound JWH-249, JWH-251 has a
phenylacetyl group in place of the naphthoyl ring used in
most aminoalkylindole cannabinoid compounds. [1][2]

238.1 References
[1] Huffman, JW, Szklennik, PV, Almond, A, Bushell,
K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles”. Bioor-
ganic & Medicinal Chemistry Letters 15 (18): 4110–3.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.

[2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

312
Chapter 239

JWH-302

JWH-302 or (1-pentyl-3-(3-
methoxyphenylacetyl)indole) is an analgesic chemical
from the phenylacetylindole family, which acts as a
cannabinoid agonist with moderate affinity at both the
CB1 and CB2 receptors. It is a positional isomer of the
more common drug JWH-250, though it is slightly less
potent with a Kᵢ of 17nM at CB1 , compared to 11nM
for JWH-250.[1][2] Because of their identical molecular
weight and similar fragmentation patterns, JWH-302 and
JWH-250 can be very difficult to distinguish by GC-MS
testing.[3]

239.1 References
[1] Huffman, JW. et al. (2005). “1-Pentyl-3-
phenylacetylindoles, a new class of cannabimimetic
indoles”. Bioorganic & Medicinal Chemistry Letters 15
(18): 4110–3. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.

[2] Manera, C; Tuccinardi, T; Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

[3] 'Herbal High' synthetic Cannabinoid composition, re-

leased by ESR July 2011

313
Chapter 240

JWH-307

JWH-307 is an analgesic drug used in scientific research,

which acts as a cannabinoid agonist at both the CB1 and
CB2 receptors. It is somewhat selective for the CB2 sub-
type, with a Ki of 7.7nM at CB1 vs 3.3nM at CB2 .[1]
It was discovered by, and named after, Dr. John W.
Huffman. JWH-307 was detected as an ingredient in
synthetic cannabis smoking blends in 2012, initially in
Germany.[2][3]

240.1 See also

• JWH-147

240.2 References
[1] Huffman JW, Padgett LW, Isherwood ML, Wiley JL,
Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New
high affinity ligands for the cannabinoid CB1 and CB2 re-
ceptors. Bioorganic & Medicinal Chemistry Letters 2006;
16:5432-5435.

[2] Ernst, L.; Krüger, K.; Lindigkeit, R.; Schiebel, H.

M.; Beuerle, T. (2012). “Synthetic cannabinoids in
“spice-like” herbal blends: First appearance of JWH-
307 and recurrence of JWH-018 on the German mar-
ket”. Forensic Science International 222 (1–3): 216–22.
doi:10.1016/j.forsciint.2012.05.027. PMID 22748479.

[3] Kneisel, S.; Auwärter, V. (2012). “Analysis of 30 syn-

thetic cannabinoids in serum by liquid chromatography-
electrospray ionization tandem mass spectrometry after
liquid-liquid extraction”. Journal of Mass Spectrometry 47
(7): 825–835. doi:10.1002/jms.3020. PMID 22791249.

314
Chapter 241

JWH-398

JWH-398 is an analgesic chemical from the

naphthoylindole family, which acts as a cannabinoid
agonist at both the CB1 and CB2 receptors. It has
mild selectivity for CB1 with a Kᵢ of 2.3nM and 2.8nM
at CB2 .[2] It was identified by the EMCDDA as an
ingredient in three separate "herbal incense" products
purchased from online shops between February to June
2009.[3] It was discovered by, and named after, Dr. John
W. Huffman.[4]

241.1 See also

• JWH-122
• JWH-424

241.2 References
[1]

[2] Huffman JW (2009) Cannabimimetic indoles, pyrroles,

and indenes: structure-activity relationships and receptor
interactions. Cited in: The cannabinoid receptors, Reg-
gio PH (Ed), Humana Press. ISBN 978-1-58829-712-9
doi:10.1007/978-1-59745-503-9

[3] Understanding the ‘Spice’ phenomenon. EMCDDA, Lis-

bon, November 2009

[4] John W. Huffman, et al. STRUCTURE-ACTIVITY

RELATIONSHIPS AT THE CB1 AND CB2 RECEP-
TORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8-
HALOGEN SUBSTITUTED) INDOLES (2009) 19th
Annual Symposium on the Cannabinoids, Burlington,
Vermont, International Cannabinoid Research Society,
Page 2.

315
Chapter 242

JWH-424

JWH-424 is a drug from the naphthoylindole family,

which acts as a cannabinoid agonist at both the CB1 and
CB2 receptors, but with moderate selectivity for CB2 ,
having a Kᵢ of 5.44nM at CB2 vs 20.9nM at CB1 . The
heavier 8-iodo analogue is even more CB2 selective, with
its 2-methyl derivative having 40x selectivity for CB2 .
However the 1-propyl homologues in this series showed
much lower affinity at both receptors, reflecting a gen-
erally reduced affinity for the 8-substituted naphthoylin-
doles overall.[1][2]

242.1 See also

• JWH-018

• JWH-398

242.2 References
[1] Valerie Smith, John Huffman, Jenny Wiley and
Billy Martin. EFFECTS OF HALOGEN SUB-
STITUENTS UPON CB1 AND CB2 RECEPTOR
AFFINITIES IN THE SERIES OF N-ALKYL-3-(8-
HALO-1-NAPTHOYL)INDOLES. (2007) 17th Annual
Symposium on the Cannabinoids, Burlington, Vermont,
International Cannabinoid Research Society, Page 72.

[2] John W. Huffman, et al. STRUCTURE-ACTIVITY

RELATIONSHIPS AT THE CB1 AND CB2 RECEP-
TORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8-
HALOGEN SUBSTITUTED) INDOLES (2009) 19th
Annual Symposium on the Cannabinoids, Burlington,
Vermont, International Cannabinoid Research Society,
Page 2.

316
Chapter 243

Naphthoylindole

JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM- 243.2.1 Pharmacokinetics

678[1] is an analgesic chemical from the naphthoylin-
dole family that acts as a full agonist at both the CB1 JWH-018 administered to rats resulted in the excretion
and CB2 cannabinoid receptors, with some selectivity for of an indole-N-desalkyl metabolite as well as several hy-
CB2 . It produces effects in animals similar to those of droxylated metabolites in urine. The highest signals were
THC, a cannabinoid naturally present in cannabis, lead- observed for the hydroxylated N-desalkyl metabolites.
ing to its use in synthetic cannabis products such as “le- Hydroxylation took place on the side chain and in both
gal cannabis herbal incense blends” which in some coun- aromatic systems, the naphthalene and the indole rings,
tries are sold legally as “incense”, labeled “not for human as could be shown by mass shift of the corresponding
consumption”.[2][3][4][5][6] fragments and by MS3 experiments.[13] Human metabo-
lites were similar although most metabolism took place
on the indole ring and pentyl side chain, and the hy-
droxylated metabolites were extensively conjugated with
glucuronide.[14]
243.1 History
243.3 Usage
John W. Huffman, an organic chemist at Clemson Uni-
versity, synthesized analogues and metabolites of Δ9 -
At least one case of JWH-018 dependence has been re-
tetrahydrocannabinol (THC), the principal active com-
ported by the media.[2] The user consumed JWH-018
ponent of cannabis. JWH-018 is one of these analogues,
daily for eight months. Withdrawal symptoms were sim-
with studies showing an affinity for the cannabinoid (CB1 )
ilar to those experienced as a result of cannabis depen-
receptor five times greater than that of THC. Cannabinoid
dence. JWH-018 has been shown to cause profound
receptors are found in mammalian brain and spleen tis-
changes in CB1 receptor density following administra-
sue; however, the structural details of the active sites are
tion, causing desensitization to its effects more rapidly
currently unknown.[7][8]
than related cannabinoids.[6]
On December 15, 2008, it was reported by the German
On October 15, 2011, Anderson County coroner Greg
pharmaceutical company THC Pharm that JWH-018 was
Shore attributed the death of a South Carolina college
found as one of the active components in at least three
basketball player to “drug toxicity and organ failure”
versions of the herbal blend Spice, which has been sold
caused by JWH-018.[15] An email dated Nov 4, 2011
as an incense in a number of countries around the world
concerning the case was finally released by the city of
since 2002.[9][10][11] An analysis of samples acquired four
Anderson S.C. on Dec 16, 2011 under the Freedom of
weeks after the German prohibition of JWH-018 took
Information Act after multiple requests by media to see
place found that the compound had been replaced with
the information had been denied.[16]
JWH-073.[12]
Compared to THC, which is a partial agonist at CB1
receptors, JWH-018 (and many of its analogues) are
full agonists. THC has been shown to inhibit GABA
receptor neurotransmission in the brain via several
243.2 Pharmacology pathways.[17][18] JWH-018 may cause intense anxiety, ag-
itation, and, in rare cases (generally with non-regular
JWH users), has been assumed to have been the cause of
JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotrans-
cannabinoid receptors, with a reported binding affinity of mission more effectively than THC. Cannabinoid recep-
9.00 ± 5.00 nM at CB1 and 2.94 ± 2.65 nM at CB2 .[3] tor full agonists may present serious dangers to the user

317
318 CHAPTER 243. NAPHTHOYLINDOLE

when used to excess.[19]

Various physical and psychological adverse effects have
been reported from JWH-018 use. One study re-
ported psychotic relapses and anxiety symptoms in well-
treated patients with mental illness following JWH-018
inhalation.[20] Due to concerns about the potential of
JWH-018 and other synthetic cannabinoids to cause psy-
chosis in vulnerable individuals, it has been recom-
mended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51]
nesses (like a past or family history of psychosis) not use
these substances.[21]
243.6 Synthesis

243.7 See also

243.4 Detection in biological fluids
• AM-2201

JWH-018 usage is readily detected in urine using “spice” • BB-22 (drug)

screening immunoassays from several manufacturers fo-
• JWH-073
cused on both the parent drug and its omega-hydroxy and
carboxyl metabolites.[22] JWH-018 will not be detected • JWH-250
by older methods employed for detecting THC and other
cannabis terpenoids. Determination of the parent drug in • JWH-200
serum or its metabolites in urine has been accomplished
by GC-MS or LC-MS. Serum JWH-018 concentrations • PB-22
are generally in the 1–10 μg/L range during the first
• SDB-001
few hours after recreational usage. The major urinary
metabolite is a compound that is monohydroxylated on
the omega minus one carbon atom of the alkyl side chain.
A lesser metabolite monohydroxylated on the omega (ter- 243.8 References
minal) position was present in the urine of 6 users of the
drug at concentrations of 6–50 μg/L, primarily as a glu- [1] “Department of Justice :: Drug Enforcement Administra-
curonide conjugate.[23][24][25][26][27][28][29][30][31] tion”. 2011-03-01. Retrieved 2011-03-02.

[2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees

JA, Spanagel R, Schulz K (2009). “Withdrawal Phenom-
ena and Dependence Syndrome After the Consumption
of “Spice Gold"". Dtsch Arztebl Int 106 (27): 464–467.
243.5 Legal status doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID
19652769.

[3] Aung MM, Griffin G, Huffman JW, Wu M, Keel

C, Yang B, Showalter VM, Abood ME, Martin BR
(2000). “Influence of the N-1 alkyl chain length of
cannabimimetic indoles upon CB1 and CB2 receptor
binding”. Drug and Alcohol Dependence 60 (2): 133–140.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.

[4] US patent 6900236, Alexandros Makriyannis, Hongfeng

Deng, “Cannabimimetic indole derivatives”, issued 2005-
05-31

[5] US patent 7241799, Alexandros Makriyannis, Hongfeng

Deng, “Cannabimimetic indole derivatives”, issued 2007-
07-10

[6] Atwood, B.K., et al., “JWH018, a common constituent of

JWH-018 powder as it was commonly sold online 'Spice' herbal blends, is a potent and efficacious cannabi-
noid CB1 receptor agonist.” British Journal of Pharma-
cology, Vol. 160, No. 3. 585-593. 2010.
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[7] “Clemson University :: Department of Chemistry”.
Clemson.edu. Retrieved 2010-08-23.
[8] “Drugs Forum”. Drugs Forum. Retrieved 2010-08-23.
[9] Gefährlicher Kick mit Spice (German)
[10] Erstmals Bestandteile der Modedroge “Spice”
nachgewiesen (German)
[11] Spice enthält chemischen Wirkstoff (German)
[12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wig-
germann M, Ernst L, Beuerle T (30 October 2009).
“Spice: A never ending story?". Forensic Science Inter-
national (Forensic Science International) 191 (1): 58–63.
doi:10.1016/j.forsciint.2009.06.008. PMID 19589652.
[13] T. Kraemer, et al. Studies on the metabolism of JWH-
018 and of a homologue of CP 47,497, pharmacolog-
ically active ingredients of different misused incense
(“Spice”) using GC-MS and LC-MSn techniques (In-
stitute of Legal Medicine, Saarland University, 66421
Homburg, Germany http://www.gtfch.org/cms/images/
stories/media/tk/tk76_2/abstractsvortraege.pdf
[14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010).
“Detection of JWH-018 metabolites in smoking mixture
post-administration urine”. Forensic Science International
200 (1–3): 141–7. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[15] wyff4.com, Coroner: Synthetic Pot Killed College Ath-
lete, posted 10/14/11, accessed 12/22/11, http://www.
wyff4.com/news/29497549/detail.html,
[16] Mayo, Nikie, “City Releases Email in Lamar Jacks Case”,
independentmail.com, posted Dec 16, 2011, accessed
12/22/11, http://www.independentmail.com/news/2011/
dec/16/city-releases-email-lamar-jack-case/
[17] Laaris N, Good CH, Lupica CR (July–August 2010).
"Δ9-tetrahydrocannabinol is a full agonist at CB1 re-
ceptors on GABA neuron axon terminals in the hip-
pocampus”. Neuropharmacology 59 (1–2): 121–127.
doi:10.1016/j.neuropharm.2010.04.013. PMC 2882293.
PMID 20417220.
[18] Hoffman AF, Lupica CR (2000-04-01). “Mechanisms of
cannabinoid inhibition of GABAA synaptic transmission
in the hippocampus”. The Journal of Neuroscience 20 (7):
2470–2479. ISSN 0270-6474. PMID 10729327. Re-
trieved 2011-07-26.
[19] European Monitoring Centre for Drugs and Drug Ad-
diction. “Understanding the Spice Phenomenon.” 2009.
ISBN 978-92-9168-411-3.
[20] Every-Palmer, S. Synthetic cannabinoid use and psy-
chosis: an explorative study. Journal of Drug and Alcohol
Dependence 2011. [Epub ahead of print].
[21] Every-Palmer S (2010). “WARNING: LEGAL SYN-
THETIC CANNABINOID-RECEPTOR AGONISTS
SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS
IN VULNERABLE INDIVIDUALS”. Addiction 105:
1859–1860. doi:10.1111/j.1360-0443.2010.03119.x.
PMID 20840203.
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[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/
content/37/5/284.abstract, https://www.caymanchem.
com/app/template/Product.vm/catalog/580210;
http://www.randoxtoxicology.com/Products/Elisa-p-50,
http://tulipbiolabs.com/our-product-areas/
synthetic-cannabinoids and others.
[23] Möller I, et al. Screening for the synthetic cannabinoid
JWH-018 and its major metabolites in human doping con-
trols. Drug Test. Anal. Sep 24, 2010. [Epub ahead of
print]
[24] Teske J, et al. Sensitive and rapid quantification
of the cannabinoid receptor agonist naphthalen-1-yl-(1-
pentylindol-3-yl)methanone (JWH-018) in human serum
by liquid chromatography-tandem mass spectrometry. J
Chrom. B 878: 2659-2663, 2010.
[25] Auwärter V, Dresen S, Weinmann W, Müller M, Pütz
M, Ferreirós N (2009). "'Spice' and other herbal blends:
harmless incense or cannabinoid designer drugs?". Jour-
nal of mass spectrometry : JMS 44 (5): 832–837.
doi:10.1002/jms.1558. PMID 19189348. Free version
[26] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees
JA, Spanagel R, Schulz K (2009). “Withdrawal phe-
nomena and dependence syndrome after the consumption
of “spice gold"". Deutsches Arzteblatt international 106
(27): 464–467. doi:10.3238/arztebl.2009.0464. PMC
2719097. PMID 19652769.
[27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). “De-
tection of JWH-018 metabolites in smoking mixture post-
administration urine”. Forensic Science International 200
(1–3): 141–147. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[28] Beuck S, Möller I, Thomas A, Klose A, Schlörer
N, Schänzer W, Thevis M (August 2011). “Struc-
ture characterisation of urinary metabolites of the
cannabimimetic JWH-018 using chemically synthesised
reference material for the support of LC-MS/MS-based
drug testing”. Anal Bioanal Chem 401 (2): 493–505.
doi:10.1007/s00216-011-4931-5. PMID 21455647.
[29] Moran CL, Le VH, Chimalakonda KC, Smedley AL,
Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske
FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski
PJ, Wessinger WD, Fantegrossi WE, Prather PL, James
LP, Radominska-Pandya A, Moran JH (June 2011).
“Quantitative measurement of JWH-018 and JWH-073
metabolites excreted in human urine”. Anal. Chem.
83 (11): 4228–36. doi:10.1021/ac2005636. PMID
21506519.
[30] Logan BK, et al. Identification of primary JWH-
018 and JWH-073 metabolites in human urine.
NMS Labs Technical Bulletin, May 25, 2011.
http://toxwiki.wikispaces.com/file/view/JWH_
metabolites_Technical_Bulletin_Final_v1.1.pdf
[31] R. Baselt, Disposition of Toxic Drugs and Chemicals in
Man, 10th edition, Biomedical Publications, Seal Beach,
CA, 2014, p. 1863.
[32] <http://www.legislation.qld.gov.au/LEGISLTN/
CURRENT/D/DrugsMisuseR87.pdf>
320 CHAPTER 243. NAPHTHOYLINDOLE

[33] “Controlled Drugs and Substances Act”. 243.9 External links

Laws.justice.gc.ca. 2010-08-16. Retrieved 2010-
08-23. • JWH-018 Report Psychonaut Web Mapping Re-
[34] *** Tiedote/Valtioneuvoston viestintäyksikkö: VAL- search Project
TIONEUVOSTON YLEISISTUNTO 1.3.2012 ***
• User of legal high
(Finnish)

[35] “EMCDDA | Drug profile: Synthetic cannabinoids and

'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved
2010-08-23.

[36] http://www.afssaps.fr/var/afssaps_site/storage/original/
application/d23d05edc58479d91c803b496017f073.pdf

[37] BGBl I Nr. 3 vom 21.01.2009, 22. BtMÄndV vom 19.

Januar 2009, S. 49–50.

[38] Many head shop products banned - Irish Times.

[39] http://www.politicheantidroga.it/
comunicazione/comunicati/2010/luglio/spice,
-n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian)

[40] https://www.drugfoundation.org.nz/
synthetic-cannabinoids/what-they-are

[41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465.
html

[42] (2 July 2009). “1 ‘5- - ’ ".

. Retrieved 18 February 2010.

[43] http://www.regeringen.se/sb/d/12102/a/130038
(Swedish)

[44] “Illicit Drug Report of Turkey 2010”. Department of

Anti-smuggling and Organised Crime. Retrieved 2012-
05-03.(Turkish)

[45] “Decision of the Council of Ministers, Enactment

2011/1310”. General Directorate of Legislation Develop-
ment and Publication. Retrieved 2012-05-03.(Turkish)

[46] “Attachment to Enactment 2012/2861”. General Direc-

torate of Legislation Development and Publication. Re-
trieved 2012-05-03.(Turkish)

[47] “Decision of the Council of Ministers, Enactment

2012/2861”. General Directorate of Legislation Develop-
ment and Publication. Retrieved 2012-05-03.(Turkish)

[48] Ford, Richard (2009-12-23). “Three legal highs banned

after deaths linked to the drugs”. The Times (London).
Retrieved 2010-05-07.

[49] “Schedules of Controlled Substances: Temporary Place-

ment of Four Synthetic Cannabinoids Into Schedule I”.
DEA Office of Diversion Control. Retrieved 11 March
2014.

[50] <http://www.antinarcotics.psd.gov.jo>

[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014).

“Recreational drug discovery: natural products as lead
structures for the synthesis of smart drugs”. Natural Prod-
uct Reports 31 (7): 880–904. doi:10.1039/c4np00010b.
Chapter 244

Phenylacetylindole

JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a
synthetic cannabinoid from the phenylacetylindole
family, which acts as a cannabinoid agonist with about
1.75x selectivity for CB1 with a Kᵢ of 90nM ± 17 and
159nM ± 14 at CB2 . Similar to the related 2'-methoxy
compound JWH-250, and the 2'-chloro compound
JWH-203, JWH-167 has a phenylacetyl group in place
of the naphthoyl ring used in most aminoalkylindole
cannabinoid compounds.[1][2]

244.1 References
[1] Huffman, JW, Szklennik, PV, Almond, A, Bushell,
K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). “1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles”. Bioor-
ganic & Medicinal Chemistry Letters 15 (18): 4110–3.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.

[2] Manera, C, Tuccinardi, T, Martinelli, A (2008). “In-

doles and related compounds as cannabinoid ligands”.
Mini reviews in medicinal chemistry 8 (4): 370–87.
doi:10.2174/138955708783955935. PMID 18473928.

321
Chapter 245

RCS-8

RCS-8, or 1-(2-cyclohexylethyl)−3-(2-
methoxyphenylacetyl)indole, is a synthetic cannabinoid
also known as SR-18 or BTM-8 that has been found as
an ingredient of “herbal” synthetic cannabis blends. It
can be described as an analogue of JWH-250 with the
1-pentyl group replaced by 1-(2-cyclohexylethyl), and
can be expected to be less potent than JWH-250 (cf.
JWH-007 and its cyclohexylethyl analogue).[1] Despite
not having been reported in the scientific or patent
literature as yet, reputed recreational use of RCS-8 in the
United States has led to it being specifically listed in a
proposed 2011 amendment to the Controlled Substances
Act, aiming to add a number of synthetic drugs into
Schedule I.[2]

245.1 See also

• Cannabipiperidiethanone

• JWH-250
• RCS-4

245.2 References
[1] Huffman, J. W.; Dai, D.; Martin, B. R.; Compton,
D. R. (1994). “Design, Synthesis and Pharmacology
of Cannabimimetic Indoles”. Bioorganic & Medici-
nal Chemistry Letters 4 (4): 563. doi:10.1016/S0960-
894X(01)80155-4.

[2] Synthetic Drug Control Act of 2011

322
Chapter 246

Intravenous Marijuana Syndrome

Intravenous Marijuana Syndrome is a distinct short-

term clinical syndrome related to the intravenous injec-
tion of boiled cannabis broth, which had been filtered
through a cotton cloth. The syndrome has at least 25
known cases in the English language literature, but all of
them prior to 1983.[1]
It is postulated that contamination, perhaps from the cot-
ton used to strain the liquid of the broth or from partic-
ulate plant matter getting through the straining method,
could be cause for the cases of illnesses.[1]

246.1 References
[1] Daniel Brandenburg; Richard Wernick (July 1986).
“Intravenous Marijuana Syndrome”. wjm 145 (1): 94–96.
PMC 1306836. PMID 3489321. Retrieved 2008-06-21.

323
Chapter 247

Mellow Yellow coffeeshop

Mellow Yellow is the oldest cannabis coffee shop in 247.3 External links
Amsterdam. The coffee shop was founded in 1972 by
Wernard Bruinin in Weesperzijde, Amsterdam, on the • Mellow Yellow Lounge
premises of a former bakery. The shop is named after
"Mellow Yellow", a song by Donovan which describes the • Stichting Mediwiet
singer trying to become intoxicated through smoking the
peel of banana.[1]
The intent of the shop is to sell cannabis, despite this be-
ing illegal at the time of its creation.[1] Sales were origi-
nally disguised by drug dealers seated at the bar posing as
customers. Mellow Yellow was unsuccessfully raided by
police several times. Unpackaged cannabis, bought from
wholesalers including drug lord Klaas Bruinsma, was hid-
den behind secret doors and shutters.
In 1975, the concept was adopted by a shop named Russia
situated on the same street as Mellow Yellow and was fol-
lowed by another coffee shop called The Bulldog. Now
there are 223[2] such coffee shops in Amsterdam.
Bruining also runs Stichting Mediwiet (Medi Cannabis
Foundation), a group that supports the legalization of
growing marijuana for medicinal uses.

247.1 Citations

[1] “De eerste coffeeshop ter wereld” (in Dutch). November

2008. Retrieved December 2012.

[2] “FAQ Coffeeshops in Amsterdam”. I Amsterdam. Re-

trieved 2013-03-24.

247.2 References

• “Hasj” (in Dutch). Geschiedenis 24.

• Schoof, Rob (1 May 2008). “De achterdeur van de

coffeeshop” (in Dutch). NRC Handelsblad.

• van Schaik, Nol (7 October 2009). “Dutch Cannabis

Coffeeshop History”.

324
Chapter 248

The Night Train Seizure

The Night Train Drug Seizure was a 1978 seizure of 54
tons of marijuana by the United States Coast Guard off
the southeastern coast of Florida which marked the be-
ginning of Operation Stopgap, a United States federal law
enforcement inter-agency drug interdiction operation fo-
cusing on interdicting drugs from Colombian cartels and
other illicit Central and South American drug sources.[1]
The Night Train seizure was the largest single drug seizure
in history at the time it occurred, and it remains one of the
largest marijuana seizures made in the territorial waters
of the United States.[2]
Operation Stopgap was one of the first inter-agency law
enforcement efforts focused on the interdiction of illegal
drugs from Central and South America, and it featured
personnel of the Coast Guard, DEA and US Federal Mar-
shals Service working together,[3] as well as the resources
of the Intelligence Section of the Drug Enforcement Ad-
ministration and Coast Guard Intelligence (CGI).[4]
The Night Train was a 189 foot coastal cargo vessel that
had become legendary in the law enforcement commu-
nity and smuggling circles due to its repeated ability to
elude US law enforcement for almost two years before
they were finally captured off of West Palm Beach as the
first seizure of Stopgap. Operation Stopgap was but the
first of a number of highly successful inter-agency intel-
ligence and interdiction operations[5] that led to a large
number of successful seizures and prosecutions in the late
1970s and early 1980s, garnering the U.S. Coast Guard
considerable press coverage during this period as seizure
records continued to be broken.[6] Stopgap was also one
of the earliest interdiction operations to effectively use
satellite technology in the pursuit and interdiction of drug
smugglers.[7]
• List of United States Coast Guard cutters
• List of United States Coast Guard stations
• Maritime Law Enforcement Academy
• MARSEC
• National Data Buoy Center
• National Ice Center
• Patrol Forces Southwest Asia
• United States Coast Guard Legal Division
• United States Coast Guard officer rank insignia
• United States Coast Guard Research & Develop-
ment Center
248.2 References
[1] Name Of Pot-Laden Ship Sounded Familiar To Coast
Guard Miami News, December 11, 1977
[2] Marijuana Seizure Was Largest Haul On Record Lakeland
(Florida) Ledger, April 20, 1978
[3] “The Battle Against Drugs Takes to the Seas: High Seas
Drama When the Night Train was Seized by the Coast
Guard.” U.S. News and World Report LXXXIV (Mar 27,
1978), pp. 69–71.
[4] DEA and Coast Guard Could Almost Track Drug Ship By
The Smell St. Petersburg Times, July 11, 1978
[5] Operation Stopgap The Spokesman Review, September
16, 1978

[6] Operation Stopgap Nails The Legendary Night Train, St.

248.1 See also Petersburg Times, July 11, 1978

[7] Satellites Aiding In Pot Seizures Sarasota Herald-Tribune,

• Coast Guard Investigative Service
July 11, 1978
• Go-fast boat

• Joint Maritime Training Center

• List of active United States military aircraft

325
Chapter 249

PSN-375,963

PSN-375,963 is a selective ligand for the suggested novel

cannabinoid receptor GPR119.[1]

249.1 See also

• AR-231,453

• PSN-632,408

249.2 References
[1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner
LS, Griffin G, Jackson HC, Procter MJ, Rasamison
CM, Tang-Christensen M, Widdowson PS, Williams
GM, Reynet C. (2006). “Deorphanization of a G
protein-coupled receptor for oleoylethanolamide
and its use in the discovery of small-molecule hy-
pophagic agents.”. Cell Metab. 3 (3): 167–175.
doi:10.1016/j.cmet.2006.02.004. PMID 16517404.

326
Chapter 250

PSN-632,408

PSN-632,408 is a selective ligand for the suggested novel

cannabinoid receptor GPR119.[1]

250.1 See also

• AR-231,453

• PSN-375,963

250.2 References
[1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner
LS, Griffin G, Jackson HC, Procter MJ, Rasamison
CM, Tang-Christensen M, Widdowson PS, Williams
GM, Reynet C. (2006). “Deorphanization of a G
protein-coupled receptor for oleoylethanolamide
and its use in the discovery of small-molecule hy-
pophagic agents.”. Cell Metab. 3 (3): 167–175.
doi:10.1016/j.cmet.2006.02.004. PMID 16517404.

327
Chapter 251

Soma Seeds

Soma Seeds (also known as Soma’s Sacred Seeds) is

an Amsterdam based medical cannabis seed company
owned by Soma. The company became internationally
famous after winning the 1999 High Times Cannabis
Cup with Soma’s 'Reclining Buddha' strain in the Indica
category;[1] in 2001, 2002, 2003 and 2004 with 'NYC
Diesel' strain in the Sativa category,[2] in 2002 with 'Bud-
dha’s Sister' strain in the Indica category [3] in 2004 with
'Amnesia Haze' in the best strain category [4] and in 2005
with 'Lavender' strain in the Indica category.[5]

251.1 References
[1] Cannabis Cup winners 1999.

[2] Cannabis Cup winners 2001.

[3] Cannabis Cup winners 2002.

[4] Cannabis Cup winners 2004.

[5] Cannabis Cup winners 2005.

251.2 External links

• http://www.somaseeds.nl/

328
Chapter 252

TM-38837

TM38837 is a new small molecule inverse ago-

nist/antagonist of the CB1 cannabinoid receptor. It is be-
ing developed for the treatment of obesity and metabolic
disorders by 7TM Pharma.[1] The company has an-
nounced phase I clinical trials.
TM38837 is among the first of a new generation of
cannabinoid receptor antagonist designed to avoid the
central nervous system liabilities of the first generation
CB1 receptor antagonists, for example rimonabant.[2]

252.1 See also

• AM-6545

252.2 References
[1] http://www.7tm.com

[2] Hung, M. S.; Chang, C. P.; Li, T. C.; Yeh, T. K.; Song,
J. S.; Lin, Y.; Wu, C. H.; Kuo, P. C.; Amancha, P. K.;
Wong, Y. C.; Hsiao, W. C.; Chao, Y. S.; Shia, K. S.
(2010). “Discovery of 1-(2,4-Dichlorophenyl)−4-ethyl-
5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-
2-yl)-N-(piperidin-1-yl)−1H-pyrazole-3-carboxamide
as a Potential Peripheral Cannabinoid-1 Receptor
Inverse Agonist”. ChemMedChem 5 (9): 1439–1443.
doi:10.1002/cmdc.201000246. PMID 20652930.

252.3 External links

• www.7tm.com

• Experimental obesity drug avoids brain effects that

troubled predecessors

329
330 CHAPTER 252. TM-38837

252.4 Text and image sources, contributors, and licenses

252.4.1 Text
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JWSchmidt, Nnh, AnthonyQBachler, Hadal, Fuelbottle, Centrx, Karn, Bensaccount, Jfdwolff, St3vo, Eequor, Christopherlin, OldakQuill,
Ferre, Mearlon, Lazypplunite, Freakofnurture, Rich Farmbrough, Cacycle, Kwamikagami, Tgeller, Renice, Arcadian, Kaf, Alansohn,
Eric Kvaalen, Howrealisreal, Axl, Mrholybrain, Ombudsman, Gene Nygaard, Natalya, Bobrayner, Qnonsense, Mpj17, WadeSimMiser,
Mandarax, SqueakBox, BD2412, Mendaliv, Zachjones4, Rjwilmsi, HappyCamper, Fred Bradstadt, X1987x, Avocado, FlaBot, Margos-
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Saric, Itub, SmackBot, Unyoyega, Jrockley, Antrophica, Timotheus Canens, Jpvinall, Edgar181, David.Throop, Chris the speller, Blue-
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ShelfSkewed, Meodipt, Kupirijo, Dougweller, Thijs!bot, Barticus88, RobArmstrong, Bendroz, Luke poa, Gharmon, Subvertc, Headbomb,
Java13690, E. Ripley, Big Bird, Smartse, Astavats, Dougher, Ph.eyes, MudPhud, Probios, PhilKnight, Iownutopia, Cannabis, Hiplibrari-
anship, CliffC, Leyo, Lumir, J.delanoy, Pharaoh of the Wizards, Extransit, Nonantum, Jeepday, Mikael Häggström, Tanevala, Enix150,
Funandtrvl, MenasimBot, Benrr101, LeaveSleaves, GeorgeLTirebiter, Glaman7, Carinabean1, Sapphic, Doc James, Ohiostandard, Non-
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BogBot, Trappist the monk, 564dude, Dcirovic, Cobaltcigs, DouglasMcHugh, The chemistds, Shisha-Tom, Metilisopropilisergamida and
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CheMoBot, Harbinary, BogBot, Jesse V., The chemistds and Skoot13
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Meodipt, Headbomb, Enix150, Addbot, C6541, CheMoBot, ‫حسن علي البط‬, Harbinary, Citation bot 1, Nirmos, BogBot, RjwilmsiBot,
Dcirovic, Skoot13, Purple Blanket, Destruktor5000, Shisha-Tom, BaeyerDrewson, Monkbot and Anonymous: 1
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Enix150, SamChem7, Addbot, C6541, CheMoBot, Lapuchca, BogBot, Yunshui, Dcirovic, Skoot13, Shisha-Tom, Monkbot and Anony-
mous: 1
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toast, Hazard-SJ, The chemistds and ChrisGualtieri
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harmonic, Meodipt, Enix150, C6541, CheMoBot, BogBot, The chemistds, Skoot13 and Monkbot
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harmonic, Beetstra, Meodipt, Enix150, Pdcook, ClueBot, C6541, Ettrig, CheMoBot, AnomieBOT, ‫حسن علي البط‬, Harbinary, Biker
Biker, BogBot, Jesse V., John of Reading, D42kn355, Verified72 and Anonymous: 7
332 CHAPTER 252. TM-38837

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CheMoBot, ‫حسن علي البط‬, BogBot and Addihockey10 (automated)
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Panoramix303, CheMoBot, ‫حسن علي البط‬, BogBot, Dcirovic and Skoot13
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Enix150, CheMoBot, ‫حسن علي البط‬, BogBot and Anonymous: 1
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CheMoBot, ‫حسن علي البط‬, BogBot and The chemistds
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Timberwolf, Rjwilmsi, Tavilis, Pegship, SmackBot, Edgar181, Deli nk, Beetstra, Ccroberts, Fvasconcellos, Cydebot, Probios, Magioladitis,
Cgingold, ChemNerd, Boghog, The Right Honourable, Enix150, Chemgirl131, Addbot, DOI bot, Yobot, CheMoBot, ‫حسن علي البط‬,
Xasodfuih, Custoo, Kpstewart, Citation bot 1, Tea with toast, BogBot, Trappist the monk, Bushwakko, EmausBot, BG19bot, Monkbot,
Medgirl131 and Anonymous: 12
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CheMoBot, ‫حسن علي البط‬, BogBot, Dcirovic, The chemistds, Lugia2453 and Anonymous: 1
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CheMoBot, ‫حسن علي البط‬, BogBot, Jesse V., The chemistds and Anonymous: 1
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CheMoBot, ‫حسن علي البط‬, BogBot and Skoot13
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Panoramix303, CheMoBot, ‫حسن علي البط‬, BogBot, Skoot13 and Anonymous: 1
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Ziggy Sawdust, Addbot, C6541, Yobot, AnomieBOT, Moscow Connection, EmausBot, ZéroBot, Soimort, Lionratz, The chemistds, An-
gusWOOF, Bcxfu75k, BaeyerDrewson, Yougotwarsh and Anonymous: 4
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tors: Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, 564dude and The chemistds
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Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, The chemistds and Skoot13
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bot, Trappist the monk, BG19bot, BattyBot, Kjkokesh, Anne Delong, Sanganik, HasteurBot, Monkbot, Medgirl131 and Anonymous: 2
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turegeek, Leodmacleod, Panoramix303, Chemgirl131, Dthomsen8, Addbot, C6541, DOI bot, Hermógenes Teixeira Pinto Filho, SamatBot,
Pigoutultra, Lightbot, Yobot, CheMoBot, Anypodetos, AnomieBOT, Götz, Royote, Jtmorgan, Citation bot, LilHelpa, Zad68, ‫حسن علي‬
‫البط‬, Harbinary, O0Alea0o, P-kun80, Custoo, Citation bot 1, Nirmos, DrM!KEY, A8UDI, Codwiki, Sucrase, Tea with toast, Oldmanein-
stein, BogBot, David Hedlund, Gtziavelis, Reach Out to the Truth, RjwilmsiBot, Dustin 3choes, Kefirmonger, Dcirovic, AManWithNoPlan,
Eagleye54321, Allethrin, Ehsan soltani, Bayhemp, Rachman321, Louisajb, ClueBot NG, Vjiced, BakuninGoldmanKropotkin, Osterluzei,
Soleil mouse, TeXnocrat, Redmitrow, Shabadahabada, Eeroth, Helpful Pixie Bot, Badmusician, BG19bot, Petrarchan47, Nikos 1993,
Exercisephys, MrBill3, NotWith, 123957a, Fuse809, BattyBot, TheBaur, ChrisGualtieri, Qxukhgiels, FoCuSandLeArN, Webclient101,
Will Sandberg, Steinsplitter, UseTheCommandLine, ComfyKem, ScoutKnot, Youtalkfunny, Tentinator, ArmbrustBot, Merff, Tired cana-
dian, Tankbank420, Dave Underbridge, HeyItsAedan, JaconaFrere, Zouloum, MissSpade602, Logan Lynn Roberts, C.o.young, Monkbot,
Mattdavid22, Silent Singularitarian, Wendywhatnot, Daveyboy9999, Jakens84, JackDemarco 420, Medgirl131, Tristonlarsen, Rowanbiggs,
Aethyta, Shirt0ripper0, DystoniaPatient and Anonymous: 156
• Cannabidivarin Source: http://en.wikipedia.org/wiki/Cannabidivarin?oldid=599332824 Contributors: RedWolf, Jorge Stolfi, Foo-
bar, Cacycle, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Frantik, Beetstra, Alaibot, Benrr101,
GeorgeLTirebiter, Panoramix303, DumZiBoT, Chemgirl131, Addbot, CheMoBot, Anypodetos, Casforty, ‫حسن علي البط‬, Nirmos,
MastiBot, BogBot, EmausBot, Davesynth, Nikos 1993, NotWith, BattyBot and Anonymous: 2
• Cannabigerol Source: http://en.wikipedia.org/wiki/Cannabigerol?oldid=618473245 Contributors: Renice, Cheyinka, Rjwilmsi, Pegship,
Edgar181, Beetstra, ChemNerd, Benrr101, Secretservgy, Chem-awb, Panoramix303, Chemgirl131, Addbot, Tide rolls, CheMoBot, Any-
podetos, Metalhead94, Citation bot, ‫حسن علي البط‬, Custoo, Nirmos, MastiBot, Tea with toast, BogBot, PotatoBot, Louisajb, MerlIwBot,
Nikos 1993, NotWith, Shisha-Tom, Sedind, Monkbot, Medgirl131 and Anonymous: 3
• Cannabinoidergic Source: http://en.wikipedia.org/wiki/Cannabinoidergic?oldid=630539739 Contributors: Rjwilmsi, Bhny, Fram, Wil-
helmina Will, Addbot, The Elves Of Dunsimore, Sunilaggarwal7, CitationCleanerBot, Monkbot and Medgirl131
• Cannabinol Source: http://en.wikipedia.org/wiki/Cannabinol?oldid=618473196 Contributors: Robbot, Cacycle, Pacula, Howrealisreal,
Ceyockey, Rjwilmsi, FlaBot, Physchim62, Pegship, SmackBot, Eskimbot, Frymaster, Edgar181, Lieutenant Colonel Frank Slade, Beetstra,
Saxbryn, Cydebot, Rifleman 82, Absentis, Alaibot, Subvertc, VolkovBot, MenasimBot, THC Loadee, Benrr101, Chem-awb, Anthonyvidal,
Eeekster, Panoramix303, Stevem848, Chemgirl131, Addbot, DOI bot, LaaknorBot, Wormantson, Luckas-bot, Ptbotgourou, Fraggle81,
CheMoBot, Anypodetos, Götz, ‫حسن علي البط‬, P-kun80, Custoo, Micasta, Citation bot 1, A8UDI, RedBot, MastiBot, BogBot, PotatoBot,
Peryeat, Osterluzei, Jonfarrimond, Bemopa, Nikos 1993, NotWith, ArmbrustBot, MissSpade602, Monkbot, Sentaloc, Medgirl131 and
Anonymous: 15
• Cannabivarin Source: http://en.wikipedia.org/wiki/Cannabivarin?oldid=599333620 Contributors: Jorge Stolfi, Cacycle, Aude, Ceyockey,
PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Beetstra, Saxbryn, Alaibot, Benrr101, Chem-awb, Panoramix303,
Addbot, CheMoBot, Casforty, ‫حسن علي البط‬, FrescoBot, EmausBot, Dcirovic, HiW-Bot, Nikos 1993 and Anonymous: 1
• Caryophyllene Source: http://en.wikipedia.org/wiki/Caryophyllene?oldid=622304553 Contributors: Mboverload, Rich Farmbrough,
Kwamikagami, Mendaliv, Rjwilmsi, WriterHound, Chris Capoccia, SmackBot, Edgar181, Sesquis, Mwtoews, DMacks, Beetstra, Tim-
othykinney, Meodipt, Cydebot, Calvero JP, Deflective, NEUROtiker, ChemNerd, Arsenal1508, TimofKingsland, Chem-awb, Sensonet,
Alexbot, Panoramix303, Addbot, DOI bot, Fothergill Volkensniff IV, LaaknorBot, Luckas-bot, Yobot, CheMoBot, Citation bot, Xqbot,
‫حسن علي البط‬, Itineranttrader, Andromeas, Custoo, FrescoBot, Citation bot 1, Sorneguer, EmausBot, Dcirovic, NotWith, Bcary, Daraf-
shBot, Mogism, ArmbrustBot, Monkbot, RohdeN and Anonymous: 14
• CB-13 Source: http://en.wikipedia.org/wiki/CB-13?oldid=590870232 Contributors: Meodipt, Enix150, Yobot, CheMoBot, ‫حسن علي‬
‫البط‬, BogBot, Hazard-SJ, BaeyerDrewson, Monkbot and Anonymous: 1
• CBS-0550 Source: http://en.wikipedia.org/wiki/CBS-0550?oldid=570619983 Contributors: Meodipt, The chemistds and Skoot13
• CP 47,497 Source: http://en.wikipedia.org/wiki/CP_47,497?oldid=610061328 Contributors: Cacycle, Alansohn, Poul818, Pegship, Cy-
bercobra, Valenciano, Beetstra, Meodipt, Cydebot, Thijs!bot, Smartse, Enix150, Funandtrvl, TXiKiBoT, ClueBot, Addbot, C6541, Mar-
tinezMD, Ryanjca, ‫حسن علي البط‬, Custoo, DrilBot, Biker Biker, BogBot, Akerans, LoverOfTheWord, Louisajb, ClueBot NG, Skoot13,
Nikos 1993, Verified72, Woo 24, Monkbot and Anonymous: 26
• CP 55,244 Source: http://en.wikipedia.org/wiki/CP_55,244?oldid=561022757 Contributors: Rjwilmsi, Pegship, Edgar181, Meodipt,
Rhadamante, Enix150, Funandtrvl, CheMoBot, ‫حسن علي البط‬, BogBot and Anonymous: 1
• CP 55,940 Source: http://en.wikipedia.org/wiki/CP_55,940?oldid=618472345 Contributors: DropDeadGorgias, Ktotam, St3vo, Sam Ho-
cevar, Cacycle, Flying Hamster, Ceyockey, Galaxiaad, Pol098, Rjwilmsi, Heah, Physchim62, Muijzo, Kajerm, SmackBot, GoldenXuniver-
sity, Hmains, Tsca.bot, Simonster, Rory096, Saxbryn, Ccroberts, Meodipt, Cydebot, CDrecche, Alaibot, MattTweedell, Astavats, Floater-
fluss, Tanevala, Enix150, Funandtrvl, Jonakimmen, Psych0-007, Wertyg, Modern Shaman, Addbot, C6541, Chempedia, AnomieBOT,
Citation bot, ‫حسن علي البط‬, Harbinary, Custoo, FrescoBot, BogBot, RjwilmsiBot, PotatoBot, Louisajb, Skoot13, Yukileoo, Delphine
Psychoyos, Medgirl131 and Anonymous: 27
• Dexanabinol Source: http://en.wikipedia.org/wiki/Dexanabinol?oldid=602665690 Contributors: Drphilharmonic, Beetstra, Meodipt,
Rod57, Enix150, Panoramix303, Addbot, CheMoBot, Anypodetos, ‫حسن علي البط‬, Citation bot 1, HRoestBot, Tea with toast, Bog-
Bot, The chemistds, ClueBot NG, Skoot13, Monkbot, Madtay and Anonymous: 3
• Dimethylheptylpyran Source: http://en.wikipedia.org/wiki/Dimethylheptylpyran?oldid=629287274 Contributors: Bkell, St3vo, GregorB,
Rjwilmsi, Pegship, Chris the speller, Beetstra, Meodipt, Astavats, Funandtrvl, Wikieditor12, Panoramix303, Chemgirl131, C6541,
CheMoBot, Anypodetos, Rifter0x0000, Metalhead94, Materialscientist, Citation bot, ‫حسن علي البط‬, Harbinary, BogBot, Lotje,
Dcirovic, K kisses, Daviesje, Nikos 1993, Testem, ChrisGualtieri, Medgirl131 and Anonymous: 7
334 CHAPTER 252. TM-38837

• Docosatetraenoylethanolamide Source: http://en.wikipedia.org/wiki/Docosatetraenoylethanolamide?oldid=479428373 Contributors:

Edgar181, Beetstra, Cydebot, CheMoBot, Citation bot, Erik9bot, Kpstewart, Citation bot 1, Tea with toast, The chemistds and Anonymous:
1
• Drinabant Source: http://en.wikipedia.org/wiki/Drinabant?oldid=608365837 Contributors: Woohookitty, Rjwilmsi, Edgar181, Meodipt,
Chemgirl131, Yobot, A412 and Anonymous: 1
• EAM-2201 Source: http://en.wikipedia.org/wiki/EAM-2201?oldid=602234811 Contributors: Dl2000, Meodipt, Magioladitis, Destruk-
tor5000, D42kn355 and Anonymous: 3
• Endocannabinoid reuptake inhibitor Source: http://en.wikipedia.org/wiki/Endocannabinoid_reuptake_inhibitor?oldid=630847750
Contributors: Firsfron, De728631, Mild Bill Hiccup, SchreiberBike, Custoo, Rideer13, AvicAWB, SaetaSolea, Beedublu, Jpgunner13,
Sbuinformation, Medgirl131 and Anonymous: 3
• Endocannabinoid system Source: http://en.wikipedia.org/wiki/Endocannabinoid_system?oldid=630033669 Contributors: Nagelfar, Rich
Farmbrough, Lycurgus, Jpgordon, C4 Diesel, Rjwilmsi, Chris Capoccia, Tavilis, Trovatore, Pb30, Winter Light, Banus, SmackBot, Road-
nottaken, Mini-Geek, Clicketyclack, Gobonobo, Kimdonndenman, Rhetth, Darthelmo, Inferiority, CopperKettle, Headbomb, Leon7, Nick
Number, MarshBot, Thibbs, Marcuj, Nono64, Boghog, Colincbn, Tanevala, Enix150, DragonBot, BDov777, ZuluPapa5, Wnt, DumZ-
iBoT, Chemgirl131, Mjpresson, Ost316, Vojtěch Dostál, Addbot, JayGSXR750, Yobot, Bunnyhop11, Jzlong, Wrightmj, AnomieBOT,
Materialscientist, Citation bot, Drilnoth, The myoclonic jerk, Lothar von Richthofen, Citation bot 1, I dream of horses, Tea with toast,
David Hedlund, Gtziavelis, Uploadvirus, Lucas Thoms, Jlb92, ClueBot NG, Vjiced, Osterluzei, SaetaSolea, Bibcode Bot, Snow Blizzard,
Glacialfox, Wyliea, BattyBot, Hoodjuice, Ramizein, Meteor sandwich yum, Monkbot, Medgirl131, Mrokiestar and Anonymous: 59
• Endocannabinoid transporters Source: http://en.wikipedia.org/wiki/Endocannabinoid_transporters?oldid=625857200 Contributors:
Rjwilmsi, Wavelength, Vigyani, Yobot, Citation bot, Alvin Seville, GoingBatty, Sbuinformation, Anaffen21, Medgirl131 and Anonymous:
1
• GW-405,833 Source: http://en.wikipedia.org/wiki/GW-405,833?oldid=610061444 Contributors: Rjwilmsi, Drphilharmonic, Meodipt,
Cydebot, Enix150, Addbot, CheMoBot, ‫حسن علي البط‬, Harbinary, Custoo, BogBot, Dcirovic and Louisajb
• GW-842,166X Source: http://en.wikipedia.org/wiki/GW-842,166X?oldid=591559628 Contributors: Meodipt, CheMoBot, BogBot, The
chemistds, Louisajb and Monkbot
• Hemopressin Source: http://en.wikipedia.org/wiki/Hemopressin?oldid=619651829 Contributors: Kielsky, Arcadian, Rjwilmsi, Meodipt,
Boghog, Enix150, Ronhjones, CheMoBot, ScottMHoward, Jesse V., RjwilmsiBot, The chemistds, Monkbot, Medgirl131 and Anonymous:
5
• HU-210 Source: http://en.wikipedia.org/wiki/HU-210?oldid=618472397 Contributors: Fnielsen, Rich Farmbrough, Cacycle, ZayZayEM,
SqueakBox, Heah, Margosbot, Physchim62, Fourdee, WriterHound, YurikBot, Gaius Cornelius, Daemon8666, Pegship, SmackBot,
C.Löser, GoldenXuniversity, Edgar181, Nuklear, Cybercobra, Drphilharmonic, Ourai, Beetstra, Ccroberts, CmdrObot, Meodipt, Alaibot,
Gharmon, Turkeyphant, Smartse, Hoffmeier, ThinkBlue, Enix150, Funandtrvl, VolkovBot, Fences and windows, Altzinn, SPECVLVM-
SINCERVS, Panoramix303, Addbot, DOI bot, Tide rolls, Alfie66, Luckas-bot, Yobot, CheMoBot, Metalhead94, Götz, Codc, ‫حسن علي‬
‫البط‬, Harbinary, FrescoBot, StrawberryCube, Biker Biker, Snazzra, Calmer Waters, JKChandler, BogBot, Gould363, SalviaFan, Nuujinn,
RenamedUser01302013, Daviesje, Phenomenologyx, Louisajb, Doctorarcane, RealMortimir, Skoot13, SubDural12, Verified72, Hmains-
bot1, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 51
• HU-243 Source: http://en.wikipedia.org/wiki/HU-243?oldid=536294331 Contributors: Meodipt
• HU-308 Source: http://en.wikipedia.org/wiki/HU-308?oldid=610213643 Contributors: St3vo, Wimvandorst, FlaBot, Pegship, Nuklear,
Drphilharmonic, Beetstra, Meodipt, Cydebot, Enix150, Panoramix303, Addbot, C6541, CheMoBot, ‫حسن علي البط‬, Custoo, BogBot,
Dcirovic, JimJoiner and Anonymous: 2
• HU-331 Source: http://en.wikipedia.org/wiki/HU-331?oldid=613064375 Contributors: BD2412, Drphilharmonic, Meodipt, R'n'B,
Enix150, SchreiberBike, Addbot, CheMoBot, Anypodetos, KamikazeBot, MALLUS, The chemistds, Skoot13, NotWith and ChrisGualtieri
• 11-Hydroxy-THC Source: http://en.wikipedia.org/wiki/11-Hydroxy-THC?oldid=620143359 Contributors: Yidele, Cacycle, Rjwilmsi,
Derek.cashman, Edgar181, Beetstra, Suboptimal Username, Meodipt, Isilanes, Equazcion, DorganBot, Danelo, Alexbot, Panoramix303,
MystBot, Addbot, Yobot, CheMoBot, KamikazeBot, Citation bot, ‫حسن علي البط‬, Harbinary, Citation bot 1, BogBot, Jynto, Medgirl131
and Anonymous: 3
• 9-nor-9β-Hydroxyhexahydrocannabinol Source: http://en.wikipedia.org/wiki/9-nor-9β-Hydroxyhexahydrocannabinol?oldid=
517509498 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, Yobot, Citation bot, ‫حسن علي البط‬, Skoot13 and Anonymous: 1
• Ibipinabant Source: http://en.wikipedia.org/wiki/Ibipinabant?oldid=618474939 Contributors: Rjwilmsi, Pegship, SmackBot, Meodipt,
Enix150, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Citation bot, ‫حسن علي البط‬, BogBot, Peryeat, The chemistds, Louisajb,
Pashihiko, Vaccinationist, Medgirl131 and Anonymous: 2
• IDFP Source: http://en.wikipedia.org/wiki/IDFP?oldid=576656123 Contributors: Meodipt
• 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene Source: http://en.wikipedia.org/wiki/
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene?oldid=545325142 Contributors: Cacycle, Deyyaz, Peg-
ship, Edgar181, Meodipt, Nono64, Enix150, Addbot, CheMoBot, Citation bot, ‫حسن علي البط‬, Citation bot 1, BogBot, EmausBot and
Anonymous: 1
• JTE 7-31 Source: http://en.wikipedia.org/wiki/JTE_7-31?oldid=546233677 Contributors: Meodipt, Enix150, Addbot, CheMoBot, Reve-
lationDirect, Skoot13 and AvocatoBot
• JTE-907 Source: http://en.wikipedia.org/wiki/JTE-907?oldid=606454861 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Smartse, Enix150, Addbot, CheMoBot, Citation bot, ‫حسن علي البط‬, Citation bot 1, BogBot, EmausBot, Skoot13, Stark1987, WildCation
and Anonymous: 1
• JWH-015 Source: http://en.wikipedia.org/wiki/JWH-015?oldid=616440152 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Cydebot, Headbomb, Boghog, Enix150, Addbot, C6541, Queenmomcat, CheMoBot, Citation bot, ‫حسن علي البط‬, Lapuchca, Custoo,
Jonesey95, BogBot, Tisane, Dcirovic, Skoot13, Monkbot, WildCation and Anonymous: 3
• JWH-051 Source: http://en.wikipedia.org/wiki/JWH-051?oldid=606457301 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150,
CheMoBot, Citation bot, ‫حسن علي البط‬, Citation bot 1, BogBot, Tisane, WildCation and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 335

• JWH-057 Source: http://en.wikipedia.org/wiki/JWH-057?oldid=606458240 Contributors: Bgwhite, Meodipt, Magioladitis, AnomieBOT,

BaeyerDrewson and WildCation
• JWH-120 Source: http://en.wikipedia.org/wiki/JWH-120?oldid=606478716 Contributors: Meodipt, BaeyerDrewson and WildCation
• JWH-122 Source: http://en.wikipedia.org/wiki/JWH-122?oldid=560783506 Contributors: Bearcat, Edgar181, Beetstra, Meodipt,
Katharineamy, Enix150, Cvf-ps, Addbot, C6541, Yobot, CheMoBot, A412, Diogenes2000, Skoot13, Snotbot, JamietwBot and Anony-
mous: 2
• JWH-133 Source: http://en.wikipedia.org/wiki/JWH-133?oldid=618472603 Contributors: St3vo, Arcadian, SmackBot, Zaphraud, Beet-
stra, Saxbryn, Ccroberts, CmdrObot, Meodipt, Cydebot, NewEnglandYankee, Tanevala, Enix150, Altzinn, Addbot, CheMoBot, ‫حسن‬
‫علي البط‬, Harbinary, Anonabyss, Custoo, BogBot, Tisane, Dcirovic, Frozen Wind, Rich Smith, Managermerrill, AwamerT, Drblizz,
Medgirl131 and Anonymous: 16
• JWH-148 Source: http://en.wikipedia.org/wiki/JWH-148?oldid=606481972 Contributors: Meodipt, BaeyerDrewson and WildCation
• JWH-149 Source: http://en.wikipedia.org/wiki/JWH-149?oldid=606483315 Contributors: Meodipt, C6541, BaeyerDrewson and Wild-
Cation
• JWH-161 Source: http://en.wikipedia.org/wiki/JWH-161?oldid=606483553 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150,
CheMoBot, ‫حسن علي البط‬, FrescoBot, BogBot and WildCation
• JWH-176 Source: http://en.wikipedia.org/wiki/JWH-176?oldid=606485810 Contributors: Pegship, Meodipt, Enix150, CheMoBot, ‫حسن‬
‫علي البط‬, BogBot, Tisane, Deathhell77 and WildCation
• JWH-359 Source: http://en.wikipedia.org/wiki/JWH-359?oldid=502194790 Contributors: Rjwilmsi, Nuklear, Meodipt, Headbomb,
Nono64, Enix150, CheMoBot, Grim23, ‫حسن علي البط‬, FrescoBot, BogBot, Tisane, Rich Smith, Managermerrill and Anonymous:
4
• JZL184 Source: http://en.wikipedia.org/wiki/JZL184?oldid=591975737 Contributors: Wimvandorst, Roadnottaken, Beetstra, Meodipt,
Enix150, Chem-awb, Addbot, CheMoBot, Anypodetos, Jzlong, ‫حسن علي البط‬, P-kun80, Citation bot 1, Nirmos, EmausBot, PotatoBot,
Monkbot and Anonymous: 3
• JZL195 Source: http://en.wikipedia.org/wiki/JZL195?oldid=546258079 Contributors: Enix150, Addbot, The Blade of the Northern Lights
and Rezabot
• KM-233 Source: http://en.wikipedia.org/wiki/KM-233?oldid=624180345 Contributors: BD2412, Meodipt, Dthomsen8, Yobot, Skoot13
and WildCation
• L-759,633 Source: http://en.wikipedia.org/wiki/L-759,633?oldid=610061479 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Cydebot, Enix150, Addbot, CheMoBot, Citation bot, ‫حسن علي البط‬, Custoo, Citation bot 1, BogBot, Dcirovic, Louisajb and Shisha-Tom
• L-759,656 Source: http://en.wikipedia.org/wiki/L-759,656?oldid=545322433 Contributors: Pegship, Nuklear, Drphilharmonic, Meodipt,
Enix150, ClueBot, Addbot, CheMoBot, ‫حسن علي البط‬, BogBot, Dcirovic, Louisajb and Anonymous: 1
• LASSBio-881 Source: http://en.wikipedia.org/wiki/LASSBio-881?oldid=489676335 Contributors: Meodipt
• LBP-1 (drug) Source: http://en.wikipedia.org/wiki/LBP-1_(drug)?oldid=587855670 Contributors: Meodipt, Hazard-SJ and Chris-
Gualtieri
• Leelamine Source: http://en.wikipedia.org/wiki/Leelamine?oldid=618475826 Contributors: Magioladitis, Eeekster, Sekio and Medgirl131
• Levonantradol Source: http://en.wikipedia.org/wiki/Levonantradol?oldid=618472637 Contributors: Howrealisreal, Wouterstomp,
Rjwilmsi, FlaBot, Pegship, Edgar181, Beetstra, Meodipt, Cydebot, Enix150, Funandtrvl, Sam Blacketer, Addbot, CheMoBot, Anypodetos,
‫حسن علي البط‬, Harbinary, Custoo, BogBot, ZéroBot, Peryeat, Skoot13, BattyBot, Najenager, Monkbot, Medgirl131 and Anonymous:
1
• List of AM cannabinoids Source: http://en.wikipedia.org/wiki/List_of_AM_cannabinoids?oldid=604703358 Contributors: Bearcat,
Chris the speller, Meodipt, Enix150, Citation bot, BattyBot, Monkbot and Anonymous: 5
• List of JWH cannabinoids Source: http://en.wikipedia.org/wiki/List_of_JWH_cannabinoids?oldid=607385076 Contributors: Rjwilmsi,
Meodipt, Uruiamme, Enix150, The Thing That Should Not Be, Ironholds, Quebec99, RjwilmsiBot, Tisane, 4321acb, BG19bot, Baeyer-
Drewson and Anonymous: 3
• LY-2183240 Source: http://en.wikipedia.org/wiki/LY-2183240?oldid=630847383 Contributors: Meodipt, Addbot, Rezabot, Fylbecatu-
lous, WildCation, Medgirl131 and Anonymous: 3
• LY-320,135 Source: http://en.wikipedia.org/wiki/LY-320,135?oldid=525861108 Contributors: Pegship, Meodipt, RXPhd, Yobot,
CheMoBot, ‫حسن علي البط‬, BogBot and Anonymous: 1
• MAM-2201 Source: http://en.wikipedia.org/wiki/MAM-2201?oldid=615014022 Contributors: Dl2000, Meodipt, C6541, AnomieBOT,
Harbinary and WildCation
• MDA-19 Source: http://en.wikipedia.org/wiki/MDA-19?oldid=517576564 Contributors: Drphilharmonic, Beetstra, Meodipt, CheMoBot
and Skoot13
• Menabitan Source: http://en.wikipedia.org/wiki/Menabitan?oldid=621328559 Contributors: Rjwilmsi, Edgar181, Meodipt, Chemgirl131,
Anypodetos, Braincricket, Monkbot and Medgirl131
• Methanandamide Source: http://en.wikipedia.org/wiki/Methanandamide?oldid=544106189 Contributors: Bearcat, St3vo, Wimvandorst,
Stemonitis, Rjwilmsi, SmackBot, Edgar181, Bluebot, Beetstra, Cytocon, Waacstats, STBot, Nono64, Enix150, Plasmic Physics, Addbot,
CheMoBot, Anypodetos, Citation bot, ‫حسن علي البط‬, Erik9bot, Tea with toast, Skoot13, Amolbot and Anonymous: 4
• MK-9470 Source: http://en.wikipedia.org/wiki/MK-9470?oldid=612370825 Contributors: Rjwilmsi, Pegship, Edgar181, DMacks, Cm-
drObot, Meodipt, MSBOT, Boghog, Chem-awb, Addbot, CheMoBot, Citation bot, ‫حسن علي البط‬, Citation bot 1, RedBot, Dcirovic and
WildCation
• N-(S)-Fenchyl-1-(2-morpholinoethyl)−7-methoxyindole-3-carboxamide Source: http://en.wikipedia.org/wiki/N-(S)
-Fenchyl-1-(2-morpholinoethyl)$-$7-methoxyindole-3-carboxamide?oldid=592608780 Contributors: Edgar181, A5b, Meodipt,
Smartse, Ben MacDui, Enix150, Denisarona, Addbot, CheMoBot, AnomieBOT, Citation bot, Xqbot, SDPatrolBot, Dcirovic, The
chemistds, Skoot13, ScottSteiner, Vasiliy 100, Vasiliy 101, ChrisGualtieri, Monkbot and Anonymous: 1
336 CHAPTER 252. TM-38837

• Nabazenil Source: http://en.wikipedia.org/wiki/Nabazenil?oldid=628470027 Contributors: Meodipt, ChemNerd, CheMoBot, ‫حسن علي‬

‫البط‬, BogBot, Peryeat, Helpful Pixie Bot, WildCation and Medgirl131
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Kjkolb, E=MC^2, Rad Racer, Rjwilmsi, Heah, FlaBot, Ground Zero, Kerowyn, Bgwhite, Asacarny, Pegship, JRey, Andrew73, SmackBot,
Edgar181, Zachorious, Cybercobra, Beetstra, CmdrObot, Meodipt, Guitarmankev1, Anthonyhcole, Alaibot, Tins128, Amontgomery, Gw-
ern, AliaGemma, ChemNerd, Gojo002, Floaterfluss, Enix150, Funandtrvl, McM.bot, Dr.michael.benjamin, Flyer22, Alexbrn, Atdavies,
Mlaffs, Zhile, Dr. Anymouse, Chemgirl131, Addbot, DOI bot, Earthguy69, Yobot, CheMoBot, Yngvadottir, AnomieBOT, Metalhead94,
Citation bot, Jü, ‫حسن علي البط‬, Harbinary, Apteekkarin poika, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot, ZéroBot, Peteb4,
Louisajb, ClueBot NG, Skoot13, Petrarchan47, PhnomPencil, Scopolaminemethylnitrate, Fuse809, Crocodile100100, Monkbot, Med-
girl131, SP1977 and Anonymous: 27
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foot69, Funandtrvl, Addbot, Yobot, CheMoBot, Anypodetos, ‫حسن علي البط‬, BogBot, Snubcube, NotWith and Medgirl131
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Tribble, Pacula, Eleland, Oasisbob, GJeffery, SidP, Galaxiaad, Urod, Tokek, SqueakBox, Vegaswikian, Aspro, WriterHound, YurikBot,
Shalmoo, Andrew73, Anarchist42, Poldavo, Uthbrian, Cybercobra, Beetstra, L'œuf, Yaris678, Anthonyhcole, Psilocin, Path2k6, DB1986,
Jamieliz, McM.bot, Martha p, VVVBot, Fibo1123581321, Toddst1, Dala11a, Denisarona, Morton12, Maxxx55, Mjpresson, Addbot,
C6541, DOI bot, Armyyo, Luckas-bot, Yobot, CheMoBot, Anypodetos, GrouchoBot, Fuz2y, Dpf90, The myoclonic jerk, RedBot, Tea
with toast, EmausBot, ZéroBot, Norsci, Satellizer, Vjiced, TheNoBrainer, Fuse809, Ellomo, Sedind, Medgirl131 and Anonymous: 49
• Naboctate Source: http://en.wikipedia.org/wiki/Naboctate?oldid=618475582 Contributors: Meodipt, Kupirijo, ChemNerd, CheMoBot,
‫حسن علي البط‬, BogBot, Peryeat, Helpful Pixie Bot and Medgirl131
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Tanevala, Enix150, Yobot, CheMoBot, Rjanag, ‫ حسن علي البط‬and BogBot
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• NMP-7 Source: http://en.wikipedia.org/wiki/NMP-7?oldid=574549912 Contributors: Meodipt and The chemistds
• Nonabine Source: http://en.wikipedia.org/wiki/Nonabine?oldid=618472034 Contributors: Wimvandorst, Pegship, Edgar181, Beetstra,
Meodipt, CheMoBot, Anypodetos, ‫حسن علي البط‬, BogBot, PotatoBot, Peryeat, NotWith, Medgirl131 and Anonymous: 1
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Rjwilmsi, Edgar181, Beetstra, Meodipt, ChemNerd, Bobber0001, Addbot, Luckas-bot, Legobot II, CheMoBot, Citation bot, ‫حسن علي‬
‫البط‬, Harbinary, Custoo, Citation bot 1, A8UDI, BogBot, 564dude, Jynto, EmausBot, Shisha-Tom, Igramudi, Medgirl131 and Anony-
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Panoramix303, CheMoBot, ‫حسن علي البط‬, BogBot, Gunnanmon, Skoot13 and WildCation
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‫حسن علي البط‬, BogBot and WildCation
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‫البط‬, BogBot, Gunnanmon, Skoot13 and Anonymous: 3
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Skoot13
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Dcirovic, The chemistds and Monkbot
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252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 337

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CheMoBot, Anypodetos, Rjanag, ‫حسن علي البط‬, Harbinary, Custoo, Citation bot 1, Jonesey95, BogBot, RjwilmsiBot, Peryeat, Louisajb,
Pashihiko, Skoot13, WildCation and Medgirl131
• Parahexyl Source: http://en.wikipedia.org/wiki/Parahexyl?oldid=618474777 Contributors: SqueakBox, Pegship, Beetstra, Meodipt, JaGa,
Funandtrvl, Panoramix303, DumZiBoT, Addbot, DOI bot, CheMoBot, Anypodetos, Citation bot, ‫حسن علي البط‬, BogBot, Nikos 1993,
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aswikian, Edgar181, Myxsoma, Beetstra, Meodipt, Smartse, JamesBWatson, ChemNerd, Boghog, Reedy Bot, Enix150, Yikrazuul, Car-
riearchdale, C6541, Download, CheMoBot, AnomieBOT, SDPatrolBot, AManWithNoPlan, ClueBot NG, Skoot13, Frietjes, O.Koslowski,
Ieponumos, Dipankan001, Vasiliy 100, Stark1987, ChrisGualtieri, BaeyerDrewson, Luxemoxie, Yougotwarsh, Rebrewind, Monkbot, Rusty
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Anypodetos, ‫حسن علي البط‬, BogBot and Anonymous: 2
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‫البط‬, BogBot, WildCation and Medgirl131
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BaeyerDrewson, Yougotwarsh and Anonymous: 7
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Yobot, AnomieBOT, SciRambar, AManWithNoPlan, The chemistds, BG19bot, BaeyerDrewson, Dr J.Rozen, Yougotwarsh and Anony-
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bradbury, Francs2000, Schutz, ZimZalaBim, Obli, Fjarlq, St3vo, Geni, BozMo, Beland, Nowster, M1ss1ontomars2k4, Monkeyman,
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SDC, Rjwilmsi, Darguz Parsilvan, Miserlou, Margosbot, Stevenfruitsmaak, Hydrargyrum, Janke, Semperf, Syldaril, Smaines, Yonidebest,
Bdell555, Zzuuzz, Closedmouth, Colin, Kajerm, Jeffreymcmanus, SmackBot, Edgar181, Gilliam, Amatulic, Deli nk, Cormagh, Janes-
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tast, Kkeane, Boghog, Mikael Häggström, Tanevala, Enix150, Danbearsea, TXiKiBoT, Celtus, Mikeaubert, GPryce, Nadsozinc, Eve
Teschlemacher, Poterala, Oreiser, Le feu, Vcare, Lightmouse, Phillymutt, Sabne, Rimonabant, Sisalgs, ClueBot, Schaea, Osm agha, Carlo
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R'n'B, Enix150, Carlo Banez, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Dagrun, ‫حسن علي البط‬, BogBot, PotatoBot, Peryeat,
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338 CHAPTER 252. TM-38837

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Kensington, Bayhemp, Tick avenger, DASHBotAV, Hetoi, Louisajb, ClueBot NG, Gaujo, Mini.knowledge.pea, Nielswillems26, FarmDee,
Billyrubin2008, Skoot13, Hempknight121, Cj005257, Avagad2, Mesoderm, O.Koslowski, Widr, Helpful Pixie Bot, Psychonaut25, Bib-
code Bot, Kenan133, DBigXray, BG19bot, Petrarchan47, Northamerica1000, Stuartteal, Spy12190, Nikos 1993, TheMan4000, Cbakker,
Snow Blizzard, NotWith, Zujua, Wyliea, Zmbonvallat, Fuse809, TheBaur, LegacyWeapon, Indirectantagonist, EuroCarGT, 14jay69,
Jeschjesch, Blazedbuddha, 00AgentBond93, Gareth CHEBI, Kilasic, Craigcrawford1988, CannaWikibiss, K-ronzagwarn, MidnightRe-
questLine, Babapcck, Rainyhemptree, JulianaPacheco, Camyoung54, ScoutKnot, Youtalkfunny, DavidLeighEllis, ArmbrustBot, PreCam-
brianBunny, Seppi333, Mjlphd, BOBBOBLEYBOBSON, Die Antwoorde, Korean181, Meteor sandwich yum, Lyschamb, Monkbot, 235N,
Formerly 98, A915, Joshuabumbarger, Santavy2014, JoPhoenix, Fuzznerdees, Medgirl131, Amc98, GP10698 and Anonymous: 949
• Tetrahydrocannabinol-C4 Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol-C4?oldid=618601612 Contributors: Cacycle, Na-
talya, BD2412, Pegship, Meodipt, Astavats, Benrr101, Mild Bill Hiccup, Phil Ian Manning, Chemgirl131, Yobot, CheMoBot, ‫حسن علي‬
‫البط‬, ZackRegit, BogBot, Nikos 1993, NotWith, Monkbot and Jakenowatzke
• Tetrahydrocannabinolic acid Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinolic_acid?oldid=614212282 Contributors:
Rjwilmsi, Meodipt, Wikieditor12, Benrr101, Götz, Jim1138, Monkbot and Anonymous: 4
• Tetrahydrocannabivarin Source: http://en.wikipedia.org/wiki/Tetrahydrocannabivarin?oldid=630568385 Contributors: William Avery,
St3vo, Rich Farmbrough, Cacycle, Ceyockey, Amire80, Fred Bradstadt, Physchim62, WriterHound, YurikBot, Gaius Cornelius, Pegship,
Edgar181, Naturalsol, Chris the speller, Fireemblem555, Smith609, Beetstra, Meodipt, Alaibot, Probios, VolkovBot, GeorgeLTirebiter,
Chem-awb, Panoramix303, Burner0718, Chemgirl131, MystBot, Addbot, DOI bot, Wormantson, CheMoBot, Casforty, Obersachsebot,
‫حسن علي البط‬, Custoo, Citation bot 1, UFO Reporter, MastiBot, BogBot, CrowzRSA, Jynto, ClueBot NG, Nikos 1993, NotWith,
Sfgiants1995, Jakenowatzke, Medgirl131, Mplanine and Anonymous: 20
• THC-O-acetate Source: http://en.wikipedia.org/wiki/THC-O-acetate?oldid=586788432 Contributors: Cacycle, Pegship, SmackBot,
Edgar181, Afasmit, Beetstra, Meodipt, JaGa, CheMoBot, ‫حسن علي البط‬, BogBot, Helpful Pixie Bot, ChrisGualtieri and Anonymous: 1
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 339

• THC-O-phosphate Source: http://en.wikipedia.org/wiki/THC-O-phosphate?oldid=447734263 Contributors: Koavf, Pegship, Edgar181,

Beetstra, Meodipt, Alaibot, Mojo Hand, Greatmajor55, CheMoBot, ‫ حسن علي البط‬and BogBot
• Tinabinol Source: http://en.wikipedia.org/wiki/Tinabinol?oldid=618475536 Contributors: Meodipt, OrenBochman, Chemgirl131, Any-
podetos, Braincricket, BG19bot and Medgirl131
• URB602 Source: http://en.wikipedia.org/wiki/URB602?oldid=600974517 Contributors: Rjwilmsi, Edgar181, Beetstra, Smartse, MSBOT,
Addbot, Yobot, CheMoBot, Citation bot, Tea with toast, The chemistds and Stark1987
• URB754 Source: http://en.wikipedia.org/wiki/URB754?oldid=618360159 Contributors: Arcadian, Fred Bradstadt, Itub, SmackBot, Blue-
bot, Roadnottaken, Bwduca, Beetstra, Smartse, Isilanes, Tanevala, Danelo, Chem-awb, Panoramix303, DOI bot, CheMoBot, ‫حسن علي‬
‫البط‬, P-kun80, RjwilmsiBot, GoingBatty, PotatoBot, Stark1987, Vaccinationist, Monkbot and Anonymous: 4
• VCHSR Source: http://en.wikipedia.org/wiki/VCHSR?oldid=600803681 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot,
Citation bot, ‫حسن علي البط‬, Citation bot 1, BogBot and Anonymous: 1
• VDM-11 Source: http://en.wikipedia.org/wiki/VDM-11?oldid=630848440 Contributors: RussBot, Edgar181, CommonsDelinker,
Enix150, Auntof6, Addbot, Yobot, CheMoBot, Rideer13, The chemistds, AvocatoBot, Medgirl131 and Anonymous: 2
• WIN 54,461 Source: http://en.wikipedia.org/wiki/WIN_54,461?oldid=593323168 Contributors: Drphilharmonic, Enix150, Anypodetos,
BogBot, Skoot13 and Monkbot
• WIN 55,212-2 Source: http://en.wikipedia.org/wiki/WIN_55,212-2?oldid=618472575 Contributors: GTBacchus, Howrealisreal, ^demon,
Mandarax, Zachjones4, Fred Bradstadt, WriterHound, Pegship, SmackBot, Edgar181, Bluebot, Mirshafie, Phaedriel, Nuklear, Drphilhar-
monic, Saxbryn, Iridescent, Ccroberts, Meodipt, Cydebot, RelentlessRecusant, D666D, CopperKettle, Sony 1, Tanevala, Enix150, Fu-
nandtrvl, Altzinn, Panoramix303, Yuhong wang, Addbot, Maclia, Yobot, CheMoBot, ‫حسن علي البط‬, Harbinary, Lapuchca, Custoo,
FrescoBot, BogBot, RjwilmsiBot, Gould363, DASHBot, ZéroBot, Louisajb, Skoot13, Jeff.keyser, Fuse809, Testem, Gareth CHEBI, Med-
girl131 and Anonymous: 12
• WIN 56,098 Source: http://en.wikipedia.org/wiki/WIN_56,098?oldid=605489228 Contributors: Enix150, Anypodetos, SwisterTwister,
BogBot, Snotbot, Crosstemplejay, BattyBot and Monkbot
• XLR-11 (drug) Source: http://en.wikipedia.org/wiki/XLR-11_(drug)?oldid=626107904 Contributors: Wainblatrobert, Dl2000, Meodipt,
Boghog, Enix150, Balst32, CMBJ, Yobot, AnomieBOT, SciRambar, The chemistds, Skoot13, BattyBot, Testem, ChrisGualtieri, Baeyer-
Drewson, Epicgenius, KMAnomalocaris, Rebrewind, Monkbot and Anonymous: 5
• AM251 Source: http://en.wikipedia.org/wiki/AM251?oldid=544204589 Contributors: Bearcat, Circeus, Vanky, BorisTM, Rjwilmsi, Lam-
inado, Beetstra, Ccroberts, Meodipt, Calvero JP, Astavats, Cgingold, Tanevala, Enix150, Panoramix303, Addbot, CheMoBot, Gongshow,
Rjanag, ‫حسن علي البط‬, BogBot, PotatoBot and Anonymous: 3
• Aminoalkylindole Source: http://en.wikipedia.org/wiki/Aminoalkylindole?oldid=582043905 Contributors: John Vandenberg, Smartse
and AnomieBOT
• Cannabipiperidiethanone Source: http://en.wikipedia.org/wiki/Cannabipiperidiethanone?oldid=618475932 Contributors: Rjwilmsi, Dr-
philharmonic, Meodipt, Addbot, Dcirovic, The chemistds, BaeyerDrewson, Medgirl131 and Anonymous: 1
• JWH-193 Source: http://en.wikipedia.org/wiki/JWH-193?oldid=606478297 Contributors: Rjwilmsi, Meodipt, Enix150, C6541,
CheMoBot, BogBot, Skoot13, Monkbot and WildCation
• JWH-198 Source: http://en.wikipedia.org/wiki/JWH-198?oldid=606597688 Contributors: Rjwilmsi, Meodipt, Enix150, C6541,
CheMoBot, BogBot, Skoot13, Monkbot and WildCation
• JWH-200 Source: http://en.wikipedia.org/wiki/JWH-200?oldid=606475531 Contributors: Rich Farmbrough, John Vandenberg, Velella,
Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, Smartse, Enix150, Funandtrvl, Addbot, C6541, Favonian, CheMoBot,
AnomieBOT, Citation bot, Grim23, ‫حسن علي البط‬, BogBot, Unceasing, Tisane, HarDNox, SmokingNewton, Frozen Wind, Caponex,
Silver Harshy, Managermerrill, Skoot13, Exercisephys, Fuse809, WildCation and Anonymous: 15
• Pravadoline Source: http://en.wikipedia.org/wiki/Pravadoline?oldid=607406644 Contributors: Rich Farmbrough, Wimvandorst, Natalya,
Pegship, Drphilharmonic, Beetstra, Hu12, Meodipt, Enix150, Lamro, Panoramix303, CheMoBot, Anypodetos, Citation bot, ‫حسن علي‬
‫البط‬, Citation bot 1, Jonesey95, BogBot, Peryeat, S1lv3rblad3, Skoot13, Snotbot, Yukileoo, ChrisGualtieri and Anonymous: 2
• RCS-4 Source: http://en.wikipedia.org/wiki/RCS-4?oldid=525171484 Contributors: Aardark, XLerate, SmackBot, Shoy, Beetstra,
Meodipt, Bobber0001, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, RenamedUser01302013, The chemistds, ClueBot NG,
Bped1985, VeiledReference, Pan Czy Pani and Anonymous: 2
• Anandamide Source: http://en.wikipedia.org/wiki/Anandamide?oldid=629335365 Contributors: MadSurgeon, Olivier, MartinHarper,
Sugarfish, Robbot, Sanders muc, Fuelbottle, Unfree, Giftlite, SoCal, Mearlon, Rich Farmbrough, Cacycle, Van Flamm, Mjpieters, Bit-
plane, Mykhal, El C, Arcadian, Eritain, M7, Max rspct, Reaverdrop, Mahanga, Josh Parris, Rjwilmsi, Fred Bradstadt, FlaBot, Doc glas-
gow, RexNL, WriterHound, YurikBot, RobotE, Tavilis, El Cazangero, A314268, Joncolvin, Gamerider, Laminado, SmackBot, Saravask,
AlexNordeen, Edgar181, Lennert B, Colonies Chris, Oatmeal batman, Roadnottaken, Drphilharmonic, Beetstra, Saxbryn, Chirality, Fvas-
concellos, Mellery, Icek, Cydebot, Bendroz, Dream Focus, Trapezoidal, Belizefan3000, Lumir, .José, Boghog, Mikael Häggström, Pmal-
let, Tanevala, Enix150, DorganBot, VolkovBot, Chango369w, Cotard, Hertz1888, Djadvance, Chem-awb, Orbitalcombustion, ClueBot,
Plastikspork, Redspades, Ltnemo2000, Nettacog, Yonskii, Chemgirl131, Dthomsen8, Addbot, DOI bot, Chempedia, Lightbot, Jarble,
Gaberdine2, Yobot, Legobot II, CheMoBot, Götz, Citation bot, ‫حسن علي البط‬, Jyffeh, GrouchoBot, Xasodfuih, Custoo, FrescoBot,
Akshatrathi294, Tea with toast, BogBot, 564dude, RjwilmsiBot, Dcirovic, Tomásdearg92, Ronhirzmd, ClueBot NG, Gilderien, Vjiced,
Skoot13, BG19bot, Lifeformnoho, Enomai, Valera123, Vjiced1, Anaffen21, JaconaFrere, Monkbot, Medgirl131 and Anonymous: 76
• N-Arachidonoyl dopamine Source: http://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine?oldid=618471241 Contributors: St3vo,
Rich Farmbrough, Rjwilmsi, Edgar181, Beetstra, Rhetth, Cydebot, ChemNerd, Enix150, Benrr101, Accounting4Taste, PookeyMaster,
Chem-awb, Panoramix303, Chemgirl131, Addbot, DOI bot, CheMoBot, ‫حسن علي البط‬, Custoo, Nirmos, Tea with toast, ZéroBot, The
chemistds, Brainiacal, Monkbot, Medgirl131 and Anonymous: 3
• 2-Arachidonoylglycerol Source: http://en.wikipedia.org/wiki/2-Arachidonoylglycerol?oldid=618471104 Contributors: Rich Farmbrough,
Rjwilmsi, WriterHound, Shaddack, El Cazangero, SmackBot, Edgar181, Roadnottaken, Beetstra, Rhetth, Cydebot, Astavats, Kilrothi,
ChemNerd, Tanevala, Enix150, Michaël George, SieBot, Chem-awb, Drmies, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot,
K-MUS, DOI bot, Ginosbot, Yobot, CheMoBot, Jzlong, Citation bot, Xasodfuih, Custoo, Citation bot 1, RedBot, BogBot, CrowzRSA,
564dude, Dcirovic, ZéroBot, Helpful Pixie Bot, Shisha-Tom, Cotedesneiges, Austinpk, Jianhui67, Anaffen21, Monkbot, Medgirl131 and
Anonymous: 15
340 CHAPTER 252. TM-38837

• 2-Arachidonyl glyceryl ether Source: http://en.wikipedia.org/wiki/2-Arachidonyl_glyceryl_ether?oldid=618471126 Contributors: St3vo,

Rich Farmbrough, Physchim62, WriterHound, Slashme, Edgar181, Beetstra, Cydebot, Benrr101, Chem-awb, Panoramix303, ChemSpi-
derMan, Chemgirl131, Addbot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, CrowzRSA, Dcirovic, Cimmerian praetor,
ChrisGualtieri, Gareth CHEBI, Medgirl131 and Anonymous: 5
• Oleamide Source: http://en.wikipedia.org/wiki/Oleamide?oldid=618471264 Contributors: AxelBoldt, Richard Taytor, Henrik, Rjwilmsi,
WriterHound, SmackBot, Edgar181, Roadnottaken, Beetstra, Meodipt, Scouse123, ChemNerd, Ejhoekstra, TXiKiBoT, Benrr101, Living
under a rock, Chem-awb, Yikrazuul, DumZiBoT, Chemgirl131, Addbot, DOI bot, CheMoBot, Neoligand, Citation bot, Custoo, Citation
bot 1, Abductive, Tea with toast, BogBot, ZéroBot, Cimmerian praetor, Skoot13, Rezabot, Drpainless, Makecat-bot, Monkbot, Medgirl131
and Anonymous: 15
• RVD-Hpα Source: http://en.wikipedia.org/wiki/RVD-Hpα?oldid=618471413 Contributors: Meodipt, Magioladitis, Boghog, Yobot, Cus-
too, BG19bot, Medgirl131 and Anonymous: 1
• Virodhamine Source: http://en.wikipedia.org/wiki/Virodhamine?oldid=618471494 Contributors: Rich Farmbrough, Arcadian, Natalya,
WriterHound, BlueZenith, Edgar181, David.Throop, Drphilharmonic, Beetstra, Rhetth, Cydebot, Enix150, Benrr101, Chem-awb, Plasmic
Physics, Chemgirl131, Addbot, Luckas-bot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, ZéroBot, Medgirl131 and
Anonymous: 1
• HU-320 Source: http://en.wikipedia.org/wiki/HU-320?oldid=517594060 Contributors: Rjwilmsi, Meodipt, Enix150, CheMoBot, Any-
podetos, RjwilmsiBot and Skoot13
• HU-336 Source: http://en.wikipedia.org/wiki/HU-336?oldid=580010784 Contributors: Rjwilmsi, Enix150, CheMoBot, Anypodetos,
RjwilmsiBot and Skoot13
• HU-345 Source: http://en.wikipedia.org/wiki/HU-345?oldid=580010824 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt,
Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13
• Raphael Mechoulam Source: http://en.wikipedia.org/wiki/Raphael_Mechoulam?oldid=621871273 Contributors: GreatWhiteNortherner,
Andycjp, WadeSimMiser, SqueakBox, Rjwilmsi, Bgwhite, RussBot, El Cazangero, Shuki, Mqzspa, Meodipt, Cydebot, Dougweller,
J.delanoy, Enix150, Juliancolton, Tzahy, Panoramix303, Qwfp, Addbot, Lightbot, ‫דוד‬55, Luckas-bot, Yobot, Amirobot, Davshul, Almabot,
FrescoBot, Anti-Nationalist, ZéroBot, Cimmerian praetor, Vjiced, Drkup(IMJ), Cyberbot II, Jethro B, Reverend Mick man34, VIAFbot,
Looppushh, Monkbot, Jonarnold1985 and Anonymous: 15
• John W. Huffman Source: http://en.wikipedia.org/wiki/John_W._Huffman?oldid=604651417 Contributors: Delirium, Wdfarmer, Dis-
mas, Patken4, Stormbay, KGasso, SmackBot, Meodipt, Lugnuts, Spyder Monkey, Smartse, Trusilver, NewEnglandYankee, KudzuVine,
Jackfork, Panoramix303, Addbot, Yobot, AVB, AnomieBOT, OlYeller21, Grim23, Sgravn, Gunnanmon, Tisane, ZéroBot, Andyman1125,
Dagko, Allethrin, Frozen Wind, ClueBot NG, Skoot13, 4321acb, Nickt0963, Wiki magnet, Touchhole97 and Anonymous: 19
• JWH-007 Source: http://en.wikipedia.org/wiki/JWH-007?oldid=606455199 Contributors: Meodipt, Enix150, Ziggy Sawdust, C6541,
CheMoBot, ‫حسن علي البط‬, FrescoBot, BogBot, John of Reading, Tisane, Kabutop, Pan Czy Pani, D42kn355, NotWith and WildCation
• JWH-018 Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch,
Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser,
Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilhar-
monic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT,
Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemN-
erd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21,
Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dhusereau, Hobartimus, ClueBot, Go-
rillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot,
Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favo-
nian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal,
Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, ‫حسن علي البط‬,
Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid,
Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund,
Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesul-
fate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort,
ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123,
Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot
NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Ex-
ley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot,
BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417
• JWH-019 Source: http://en.wikipedia.org/wiki/JWH-019?oldid=606455993 Contributors: Drphilharmonic, Meodipt, Leyo, Enix150,
Alexbot, Addbot, C6541, CheMoBot, Citation bot, ‫حسن علي البط‬, Citation bot 1, Biker Biker, BogBot, Skoot13, Pan Czy Pani, Veri-
fied72, Shisha-Tom, Monkbot, WildCation and Anonymous: 2
• JWH-030 Source: http://en.wikipedia.org/wiki/JWH-030?oldid=628060353 Contributors: Wimvandorst, Pegship, Nuklear, Beetstra,
Meodipt, Enix150, Funandtrvl, CheMoBot, ‫حسن علي البط‬, BogBot, Tisane, Louisajb, WildCation and Anonymous: 4
• JWH-047 Source: http://en.wikipedia.org/wiki/JWH-047?oldid=540030725 Contributors: Rjwilmsi, RjwilmsiBot and BaeyerDrewson
• JWH-048 Source: http://en.wikipedia.org/wiki/JWH-048?oldid=606457011 Contributors: Rjwilmsi, Wikieditor12, C6541, RjwilmsiBot,
BaeyerDrewson and WildCation
• JWH-073 Source: http://en.wikipedia.org/wiki/JWH-073?oldid=618472305 Contributors: Rich Farmbrough, Cacycle, LindsayH, Blax-
thos, Grafen, Pegship, SmackBot, Cybercobra, Drphilharmonic, Meodipt, Cydebot, Marek69, Turkeyphant, Theguy0000, Iownutopia,
Leyo, Enix150, Funandtrvl, X!, Krakaet, ClueBot, Panoramix303, Alibobar, Yoman82, ErgoSum88, Addbot, C6541, MartinezMD,
Luckas-bot, Yobot, CheMoBot, XLocal, Piano non troppo, Addihockey10, OlYeller21, Grim23, ‫حسن علي البط‬, Custoo, Weetoddid,
Citation bot 1, Biker Biker, BogBot, Noraft, Tisane, Ocaasi, PeterGriffinJK, Darksp000n, Caponex, ClueBot NG, Dvsbmx, Skoot13,
Exercisephys, Verified72, Cerabot, Woo 24, Monkbot, WildCation, Cbmacewan, Medgirl131 and Anonymous: 36
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 341

• JWH-081 Source: http://en.wikipedia.org/wiki/JWH-081?oldid=627566683 Contributors: Pegship, Beetstra, Meodipt, Turkeyphant, Ter-

rek, Enix150, TopGun, Funandtrvl, Svick, Michał Sobkowski, Addbot, C6541, CheMoBot, Grim23, ‫حسن علي البط‬, Biker Biker, Bog-
Bot, Tisane, ZéroBot, Frozen Wind, Caponex, ClueBot NG, Skoot13, Pan Czy Pani, Verified72, WildCation and Anonymous: 10
• JWH-098 Source: http://en.wikipedia.org/wiki/JWH-098?oldid=606459363 Contributors: Meodipt, Enix150, C6541, CheMoBot, ‫حسن‬
‫علي البط‬, BogBot, Skoot13 and WildCation
• JWH-116 Source: http://en.wikipedia.org/wiki/JWH-116?oldid=608540716 Contributors: Rjwilmsi, C6541, BaeyerDrewson and Wild-
Cation
• JWH-147 Source: http://en.wikipedia.org/wiki/JWH-147?oldid=606479371 Contributors: Pegship, Meodipt, Enix150, Yobot,
CheMoBot, ‫حسن علي البط‬, BogBot, Tisane, Destruktor5000, WildCation and Anonymous: 1
• JWH-164 Source: http://en.wikipedia.org/wiki/JWH-164?oldid=606483862 Contributors: Meodipt, Enix150, CheMoBot, ‫حسن علي‬
‫البط‬, FrescoBot, BogBot, Skoot13 and WildCation
• JWH-167 Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog,
Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1
• JWH-175 Source: http://en.wikipedia.org/wiki/JWH-175?oldid=607110954 Contributors: Jorge Stolfi, Meodipt, Enix150, CheMoBot and
WildCation
• JWH-184 Source: http://en.wikipedia.org/wiki/JWH-184?oldid=608540728 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson
• JWH-185 Source: http://en.wikipedia.org/wiki/JWH-185?oldid=608540720 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson
• JWH-196 Source: http://en.wikipedia.org/wiki/JWH-196?oldid=608540711 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson
• JWH-203 Source: http://en.wikipedia.org/wiki/JWH-203?oldid=607451648 Contributors: Rich Farmbrough, Rjwilmsi, Bazonka, Dr-
philharmonic, Meodipt, Enix150, C6541, CheMoBot, Citation bot, Grim23, ‫حسن علي البط‬, BogBot, Gunnanmon, Tisane, Caponex,
Skoot13, Pan Czy Pani, Monkbot, WildCation and Anonymous: 3
• JWH-210 Source: http://en.wikipedia.org/wiki/JWH-210?oldid=625525612 Contributors: Mike Rosoft, KGasso, Edgar181, Meodipt,
Christian75, DumbBOT, MER-C, Enix150, Addbot, C6541, Luckas-bot, CheMoBot, Anypodetos, Mdog228, Grim23, ‫حسن علي البط‬,
FrescoBot, BogBot, NotAnonymous0, Tisane, ZéroBot, DASHBotAV, Caponex, Tryptamines, Pan Czy Pani, WildCation and Anonymous:
16
• JWH-249 Source: http://en.wikipedia.org/wiki/JWH-249?oldid=600743349 Contributors: Rjwilmsi, Shoy, Beetstra, Meodipt, Enix150,
Squids and Chips, Ben Ben, CheMoBot, Citation bot, BogBot and The chemistds
• JWH-250 Source: http://en.wikipedia.org/wiki/JWH-250?oldid=606791115 Contributors: Mike Rosoft, Blaxthos, Rjwilmsi, Writer-
Hound, KGasso, Edgar181, Drphilharmonic, Meodipt, Smartse, Salih, Enix150, Panoramix303, Chemgirl131, Addbot, C6541, Yobot,
CheMoBot, Sarrus, XLocal, Citation bot, ArthurBot, OlYeller21, Grim23, ‫حسن علي البط‬, Harbinary, Citation bot 1, BogBot, Tbhotch,
EmausBot, Tisane, PotatoBot, Joseph3311, IGeMiNix, ChuispastonBot, DASHBotAV, Caponex, Louisajb, MelbourneStar, Skoot13,
Names are hard to think of, Purple Blanket, Rebrewind, WildCation and Anonymous: 17
• JWH-251 Source: http://en.wikipedia.org/wiki/JWH-251?oldid=600909501 Contributors: Rjwilmsi, Bazonka, Beetstra, Meodipt,
Enix150, Addbot, C6541, CheMoBot, Citation bot, The chemistds and AvocatoBot
• JWH-302 Source: http://en.wikipedia.org/wiki/JWH-302?oldid=517587317 Contributors: Rjwilmsi, Beetstra, Meodipt, CheMoBot, Bog-
Bot, The chemistds and Skoot13
• JWH-307 Source: http://en.wikipedia.org/wiki/JWH-307?oldid=606472694 Contributors: Cacycle, NawlinWiki, Pegship, KGasso,
Edgar181, Meodipt, Smartse, MER-C, Enix150, Addbot, CheMoBot, Sarrus, Grim23, ‫حسن علي البط‬, Biker Biker, BogBot, Dinamik-
bot, Tbhotch, Tisane, Somerwind, Caponex, ClueBot NG, Verified72, WildCation and Anonymous: 14
• JWH-398 Source: http://en.wikipedia.org/wiki/JWH-398?oldid=622353964 Contributors: Rjwilmsi, Meodipt, Enix150, C6541,
CheMoBot, Grim23, ‫حسن علي البط‬, Harbinary, BogBot, Tisane, Skoot13, WildCation and Anonymous: 1
• JWH-424 Source: http://en.wikipedia.org/wiki/JWH-424?oldid=606469047 Contributors: Meodipt, Enix150, C6541, CheMoBot, Gong-
show, FrescoBot, BogBot, Skoot13, BaeyerDrewson and WildCation
• Naphthoylindole Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch,
Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser,
Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilhar-
monic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT,
Nirigihimu, Turkeyphant, Zefiel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemN-
erd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21,
Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dhusereau, Hobartimus, ClueBot, Go-
rillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot,
Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluffernutter, LaaknorBot, DFS454, Favo-
nian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal,
Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, Δζ, Pontificalibus, Nasnema, Rhoodey, ‫حسن علي البط‬,
Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid,
Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund,
Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesul-
fate, Tommy2010, Sraab2, Wikipelli, White Trillium, Fæ, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort,
ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGriffinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123,
Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot
NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Ex-
ley1989, Exercisephys, Verified72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot,
BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417
• Phenylacetylindole Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra,
Boghog, Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1
342 CHAPTER 252. TM-38837

• RCS-8 Source: http://en.wikipedia.org/wiki/RCS-8?oldid=568307281 Contributors: Shoy, Drphilharmonic, Meodipt, Enix150, C6541,

CheMoBot, AnomieBOT, BogBot, The chemistds, Bped1985 and BaeyerDrewson
• Intravenous Marijuana Syndrome Source: http://en.wikipedia.org/wiki/Intravenous_Marijuana_Syndrome?oldid=619005877 Contrib-
utors: Nagelfar, ESkog, TheoClarke, GregorB, SqueakBox, Rjwilmsi, Wavelength, Kirix, Sadads, Slakr, Fences and windows, Another
Believer, NJGW, Mjpresson, C6541, Anypodetos, ThaddeusB, Blueharvest26, Citation bot, Haeinous, Donner60, BG19bot, Darthgreg
and Anonymous: 9
• Mellow Yellow coffeeshop Source: http://en.wikipedia.org/wiki/Mellow_Yellow_coffeeshop?oldid=606996853 Contributors: Rpyle731,
SqueakBox, MrSativa, Katharineamy, Addbot, Diannaa, Ihakeycakeyabreak, Emayv, BattyBot, Mrt3366, Comatmebro, Mogism, Smokey
McSmokealot, Tough brown zealot and Anonymous: 1
• The Night Train Seizure Source: http://en.wikipedia.org/wiki/The_Night_Train_Seizure?oldid=627809729 Contributors: Bearcat,
ChrisCork, Slazenger, Katharineamy, Themoodyblue, Pjoef, Mcrabb23 and Ca2flbroker
• PSN-375,963 Source: http://en.wikipedia.org/wiki/PSN-375,963?oldid=450845362 Contributors: Meodipt, Chemgirl131, CheMoBot,
‫حسن علي البط‬, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot
• PSN-632,408 Source: http://en.wikipedia.org/wiki/PSN-632,408?oldid=450845292 Contributors: Meodipt, Chemgirl131, CheMoBot,
‫حسن علي البط‬, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot and PotatoBot
• Soma Seeds Source: http://en.wikipedia.org/wiki/Soma_Seeds?oldid=608038890 Contributors: Bearcat, Rpyle731, Alexf, Grafen,
SmackBot, Berean Hunter, Guygoldman, Yobot, Hahamgaon, Soma Seeds, WeedFreak, Bakuto459, BitcoinSeeds and Anonymous: 1
• TM-38837 Source: http://en.wikipedia.org/wiki/TM-38837?oldid=608356887 Contributors: BD2412, Racklever, Meodipt, Enix150,
Yobot, Custoo, The chemistds, Paul269, BG19bot, Vaccinationist and Anonymous: 1

252.4.2 Images
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252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 343

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344 CHAPTER 252. TM-38837

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• File:Tedalinab_structure.png Source: http://upload.wikimedia.org/wikipedia/commons/6/6d/Tedalinab_structure.png License: Public
domain Contributors: Own work Original artist: Meodipt
252.4. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 353

• File:Tetrahydrocannabinol.svg Source: http://upload.wikimedia.org/wikipedia/commons/4/4c/Tetrahydrocannabinol.svg License: Pub-

lic domain Contributors: Own work Original artist: Yikrazuul
• File:Tetrahydrocannabiorcol.png Source: http://upload.wikimedia.org/wikipedia/commons/8/85/Tetrahydrocannabiorcol.png License:
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with_red_question_mark.svg License: Public domain Contributors: Created by bdesham with Inkscape; based upon Text-x-generic.svg
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• File:Thc.pdb.gif Source: http://upload.wikimedia.org/wikipedia/commons/7/77/Thc.pdb.gif License: Public domain Contributors: ?
Original artist: ?
• File:Trans-cannabitriol-C3.png Source: http://upload.wikimedia.org/wikipedia/commons/b/ba/Trans-cannabitriol-C3.png License:
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• File:Trans-cannabitriol_ethyl_ether.png Source: http://upload.wikimedia.org/wikipedia/commons/f/f1/Trans-cannabitriol_ethyl_
ether.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ?
• File:Trichomes_on_a_Cannabis_Sativa_Flower.jpg Source: http://upload.wikimedia.org/wikipedia/commons/4/46/Trichomes_on_
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• File:UR-12_structure.png Source: http://upload.wikimedia.org/wikipedia/commons/e/e2/UR-12_structure.png License: Public domain
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work Original artist: Isilanes
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• File:US-CoastGuard-Seal.svg Source: http://upload.wikimedia.org/wikipedia/commons/8/8d/US-CoastGuard-Seal.svg License: Public
domain Contributors: Extracted from the cover of the PDF version of the March 2008 The Navy Reservist (direct PDF URL [1]). Original
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work Original artist: User:Gmaxwell
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252.4.3 Content license

• Creative Commons Attribution-Share Alike 3.0