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Unheated Cannabis sativa extracts and its major compounds THC-acid have potential anti-inflammatory properties not
Unheated Cannabis sativa extracts and its major compounds THC-acid
have potential anti-inflammatory properties not mediated by CB1 and CB2
receptor coupled pathways
Henrie Korthout 1 , Marcel de Wit 2 , Kitty Verhoeckx 3 , Mei Wang 4 and Renger Witkamp 3
1 Fytagoras B.V., Zernikedreef 9, 2333 CK Leiden, the Netherlands; 2 Maripharm B.V. Nieuw Mathenesserstraat 33, 3029 AV Rotterdam, the Netherlands; 3 TNO Pharma, Utrechtseweg 48, P.O.box 360,
3700 AJ Zeist, the Netherlands; 4 SU BioMedicine, Zernikedreef 9, 2333 CK, Leiden, the Netherlands
There is a great interest in the pharmacological properties of cannabinoid like compounds that are not linked to the adverse effects of ∆ 9 -tetrahydro-
cannabinol (THC), e.g. psychoactive properties. Here we present the anti-inflammatory properties of unheated Cannabis sativa extracts and its main
non-psychoactivie constituent ∆ 9 -tetrahydrocannabinoidic acid (THC-acid) in in vitro and in vivo studies
Receptor binding activity
PC-PLC activity
TNF-α release U937 macrophages
in vivo inflammatory response
18
160
CB1
CB2
1,0 0 E-
0
9
16
3
3 3 3
140
14
120
1,0 0 E-
2
2
2
2
0
8
12
100
10
80
1,0 0 E-
1
1 1 1
p=0.006
p=0.006
p=0.006
p=0.006
0
7
8
p=0.004
p=0.004
p=0.004
p=0.004
60
6
0
0 0 0
1,0 0 E-
40
4
0
6
placebo
placebo
placebo
placebo
THC -
THC -acid
THC -acid
THC -
cold extract
cold extract
20
2
Histological score of the effect of THC-acid and
1,0 0 E-
0
0
unheated cannabis extract on the inflammatory
0
5
+
-
controls
response in the brain stem in Experimental
Autoimmune Encephalomyelitis (EAE) induced
mice (female SJL). ♦: individual score;
score (n=9). The severity of the inflammatory
reaction was indicated using the following individual
score; 0: no infiltrates, 1: sporadic, mild perivascular
infiltration, 2: multifocal, mild perivascular
infiltration, 3: multifocal, severe perivascular
infiltration, 4: multifocal, severe perivascular
infiltration accompanied by spreading into
parachyme.
mean
Dissociation constants of pure THC, THC-acid and
cold and heated cannabis extracts (normalized for
the concentration of THC-acid and THC
respectively) for CB1 and CB2 receptors. The
“heated” extracts were heated at 200°C for 7
minutes.
Phosphatidylcholine specific phospholipase C
activity of U937 macrophages exposed to LPS
alone (negative control) or in combination with
THC, THC acid (both 30 µg/mL), unheated
cannabis extract (THC-acid = 30 µg/mL) or D609
(200 µM; positive control).
Release of TNF-alpha from U937 macrophages
incubated for 4 hours with LPS (black column) or
LPS in combination with THC, THC acid (both 30
µg/mL) or heated or unheated (cold) cannabis
extract (final THC or THC-acid concentrations 30
µg/mL)
These results suggest that THC-acid and unheated extracts have anti-inflammatory properties and are acting via different metabolic pathways than THC
and heated cannabis extracts. The anti inflammatory effect of THC-acid and unheated extracts was not only observed in vitro, but also in vivo. In a pilot
EAE animal study the effetcs of THC-acid and unheated cannabis extracts on the clinical and histological signs of EAE collectively suggest that these
may have therapeutic potential for Multiple Sclerosis, Arthritis etc.
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THC-acid
THC
extract cold
extract heated
THC-acid
THC
extract cold
extract heated
PLC activity in mU/mL
THC-acid
THC
Extract cold
TNF-alpha in ng/mg protein
THC-acid
THC
Extract cold
Extract heated
PMA
LPS
Histological score