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European Neuropsychopharmacology (2015) 25, 12011224

www.elsevier.com/locate/euroneuro

Does cannabis affect dopaminergic signaling


in the human brain? A systematic review
of evidence to date
Musa Basser Samia,b, Eugenii A. Rabinerc,d,
Sagnik Bhattacharyyab,n

a
Kent and Medway Partnership, NHS Trust, UK
b
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience,
King's College London, De Crespigny Park, London SE5 8AF, UK
c
Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience,
King's College London, UK
d
Imanova, Centre for Imaging Sciences, London, UK

Received 20 October 2014; received in revised form 23 February 2015; accepted 22 March 2015

KEYWORDS Abstract
Cannabis; A signicant body of epidemiological evidence has linked psychotic symptoms with both acute and
Dopamine; chronic use of cannabis. Precisely how these effects of THC are mediated at the neurochemical level
Dopamine receptor; is unclear. While abnormalities in multiple pathways may lead to schizophrenia, an abnormality in
Neurotransmitter; dopamine neurotransmission is considered to be the nal common abnormality. One would thus
Human;
expect cannabis use to be associated with dopamine signaling alterations. This is the rst systematic
Review
review of all studies, both observational as well as experimental, examining the acute as well as
chronic effect of cannabis or its main psychoactive ingredient, THC, on the dopamine system in man.
We aimed to review all studies conducted in man, with any reported neurochemical outcomes related
to the dopamine system after cannabis, cannabinoid or endocannabinoid administration or use. We
identied 25 studies reporting outcomes on over 568 participants, of which 244 participants belonged
to the cannabis/cannabinoid exposure group. In man, there is as yet little direct evidence to suggest
that cannabis use affects acute striatal dopamine release or affects chronic dopamine receptor status
in healthy human volunteers. However some work has suggested that acute cannabis exposure
increases dopamine release in striatal and pre-frontal areas in those genetically predisposed for, or at
clinical high risk of psychosis. Furthermore, recent studies are suggesting that chronic cannabis use
blunts dopamine synthesis and dopamine release capacity. Further well-designed studies are required
to denitively delineate the effects of cannabis use on the dopaminergic system in man.
& 2015 Elsevier B.V. and ECNP. All rights reserved.

n
Corresponding author. Tel.: +44 207 848 0955.
E-mail address: sagnik.2.bhattacharyya@kcl.ac.uk (S. Bhattacharyya).

http://dx.doi.org/10.1016/j.euroneuro.2015.03.011
0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.
1202 M.B. Sami et al.

1. Introduction that have been used. The purpose of this review is to synthesize
following a systematic literature search all available evidence
Cannabis is the most prevalent illicit drug of use worldwide, from human studies that have investigated the acute and
with use rates of 3.9% across cultures, accounting for 180.6 chronic effects of cannabis and THC on the dopaminergic
million users, 13.1 million of whom are dependent on the drug system.
(Degenhardt et al., 2013; United Nations Ofce on Drugs and
Crime, 2013). A signicant body of epidemiological evidence 1.1. Objectives
has consistently linked psychotic symptoms with both acute and
This review was conducted in order to review systematically
chronic use of cannabis (Andrasson et al., 1987; Moore et al.,
the literature for the effect of cannabis and cannabinoids on
2007; Schimmelmann et al., 2011). Cannabis use has also been
the dopaminergic system in humans. We aimed to review all
implicated in the approximate doubling of the risk of develop-
studies conducted in man, both interventional and observa-
ment of psychotic disorders such as schizophrenia in regular
tional, employing both retrospective and prospective meth-
cannabis users (Arseneault et al., 2004; Davis et al., 2013;
odologies with any reported neurochemical outcomes rela-
Moore et al., 2007) and an increase in rates of relapse of
ted to the dopamine system after cannabis, cannabinoid or
schizophrenia in those patients with comorbid cannabis use,
endocannabinoid administration or use.
up to three-quarters of whom may be using the drug
(Schimmelmann et al., 2011; Zammit et al., 2008). Under
experimental conditions, a single dose of its main psychoactive 2. Experimental procedures
ingredient, delta-9-tetrahydrocannabinol (THC), can result in 2.1. Inclusion/exclusion criteria
the acute induction of transient psychotic symptoms in man
similar to that seen under the inuence of cannabis, and these Inclusion criteria for studies were: (1) human studies, (2) investigat-
acute effects have been linked to its effects on prefrontal, ing the acute and long-term effects of cannabinoid administration,
medial temporal and striatal function (Bhattacharyya et al., (3) measuring molecular markers related to dopaminergic neuro-
2009, 2012a, 2012b; DSouza et al., 2008, 2004). transmission including (a) biomarkers in peripheral blood,
Precisely how these effects of THC are mediated at the (b) in vivo (imaging) or (c) post mortem brain tissue.
neurochemical level is unclear. While abnormalities in multiple Exclusion criteria were (1) studies where cannabinoid administra-
pathways may lead to schizophrenia, an abnormality in dopa- tion was not the intervention or exposure of interest and (2) studies
mine neurotransmission, particularly in striatal regions, is where neurochemical outcomes were not directly reported upon.
considered to be the nal common abnormality that may
explain some of the prominent symptoms of the disorder, 2.2. Search strategy
especially psychotic symptoms (Davis et al., 1991; Howes and
Kapur, 2009; Snyder, 1976). Consequently one would expect A nal search was undertaken on the 18 July 2014. The search terms
cannabis use, an environmental risk factor with strong links to used were: (Cannabidiol or cannabinoid or cannabis or CBD or THC
or hashish or marijuana or tetrahydrocannabinol or endocannabi-
psychosis, to be associated with dopamine signaling alterations.
noid) and (dopan or dopamine or PHNO or raclopride or fallypride or
In animal models, THC has been shown to increase dopamine
iodobenzamide or IBZM or FMT or PE21 or CIT or NNC112 or
neuron ring rates in the ventral tegmental area in a cannabi- SCH23390 or D1 or D2 or D3 or DAT or AADC or MAO) Search was
noid 1 (CB1) receptor mediated mechanism (Cheer et al., 2000; undertaken in Medline, EMBASE, and PsychInfo using OvidSP plat-
French et al., 1997). Administration of THC also leads to an form ltering for human studies. All studies published in any
accumulation of dopamine in the nucleus accumbens which can language up to July 2014 and indexed in the above databases were
be inhibited by CB1 and opioid receptor antagonists as well as included. Further searches, using the same search terms were
the axonal blocking agent Tetrodotoxin (TTX) (Cheer et al., undertaken on the Cochrane Clinical Trials Database and the TRIP
2004; Chen et al., 1990; Tanda et al., 1997). THC administration Medical database (www.tripdatabase.com/). All identied relevant
has also been associated with increase in striatal dopamine studies, reviews and conference abstracts were hand-searched for
any additional relevant references.
levels with microdialysis, estimated as being of the order of 25
100% increase (Chen et al., 1990; Gardner, 2005; Ginovart
et al., 2012; Tanda and Goldberg, 2003; Tanda et al., 1997). 2.3. Data extraction
Taken together, it appears that THC acts upon CB1 receptor in
the ventral tegmental area to evoke burst ring leading to Demographic and methodological variables and outcome data for
studies identied were extracted into a spreadsheet. Primary outcomes
dopamine increases in striatal areas and the nucleus accumbens
of interest were central or peripheral neurochemical markers pertaining
(Kuepper et al., 2010; Lupica et al., 2004). CB1 receptor
to the dopaminergic system. These were compared between interven-
mediated modulation of dopamine levels in the pre-frontal tional/exposed cohorts and non-exposed control groups. Studies were
cortex has also been demonstrated (Pistis et al., 2001). grouped based on study design (acute vs. chronic effect) and type of
However, since schizophrenia is a uniquely human disease, dopamine measure investigated into (a) peripheral markers of dopa-
delineation in man of the neurochemical mechanisms that may mine release, (b) post-mortem and in-vitro studies, (c) case reports,
underlie the increase in risk of developing schizophrenia (d) in vivo acute imaging studies and (e) in vivo imaging studies in
associated with cannabis use is imperative to precisely under- chronic users.
stand and accurately model disease pathogenesis. Although,
there have now been a number of studies investigating the 2.4. Risk of bias
effect of exogenous cannabinoids on dopamine signaling in
man, the results of these studies are as varied as the different Risk of bias and quality assessment of the methodologically
outcome measures, including central and peripheral markers, heterogeneous group of individual studies (Table 1) reviewed here
Does cannabis affect dopaminergic signaling in the human brain 1203

Table 1 Identied papers.

Study Type of study Region of interest Site of dopamine pathway

Messiha and Soskin (1973) Peripheral markers Peripheral Peripheral measures


Markianos and Stefanis Peripheral markers Peripheral Peripheral measures
(1982)
Markianos and Vakis, Peripheral markers Peripheral Peripheral measures
(1984)
Musselmann et al. (1994) Peripheral markers Peripheral Peripheral measures
Bowers and Kantrowitz Peripheral markers Peripheral Peripheral measures
(2007)
Dean et al. (2003) Post-mortem and in-vitro Striatum (caudate) (1) Dopamine synthesis capacity; (2) Synaptic
studies Clearance
Steffens et al. (2004) Post-mortem and in-vitro Neocortex Dopamine Release
studies
Voruganti et al. (2001) Case report Striatum D2/3 Receptor -intrasynaptic dopamine
release acutely
Rominger et al. (2013) Case report Whole brain D2/3 Receptor
Bossong et al. (2009) Acute imaging studies Striatum D2/3 Receptor -intrasynaptic dopamine
release acutely
Stokes et al. (2009) Acute imaging studies Frontal cortex D2/3 Receptor -intrasynaptic dopamine
release acutely
Stokes et al. (2010) Acute imaging studies Striatum D2/3 Receptor -intrasynaptic dopamine
release acutely
Barkus et al. (2011) Acute imaging studies Striatum D2/3 Receptor -intrasynaptic dopamine
release acutely
Kuepper et al. (2013) Acute imaging studies Striatum D2/3 Receptor -intrasynaptic dopamine
release acutely
Sevy et al. (2008) Imaging studies in chronic Striatum D2/3 Receptor
users
Safont et al. (2011) Imaging studies in chronic Striatum D2/3 Receptor
users
Stokes et al. (2012) Imaging studies in chronic Striatum D2/3 Receptor
users
Albrecht et al. (2013) Imaging studies in chronic Striatum D2/3 Receptor
users
Urban et al. (2012) Imaging studies in chronic Striatum D2/3 Receptor +Dopamine Release
users intrasynaptically
Mizrahi et al. (2013) Imaging studies in chronic Striatum Dopamine release intrasynaptically
users
Mizrahi et al. (2014) Imaging studies in chronic Striatum Dopamine release intrasynaptically
users
Leroy et al. (2012) Imaging studies in chronic Striatum, midbrain, Synaptic clearance
users thalamus
Bloomeld et al. (2014a, Imaging studies in chronic Striatum Dopamine synthesis capacity
2014b) users
Volkow et al. (2014) Imaging studies in chronic Striatum D2/3 Receptor +Dopamine Release
users intrasynaptically

required a suitably inclusive and exible approach. For this 3. Results


purpose, an adapted set of criteria by Agency for Healthcare
Research and Quality (AHRQ) guidance (West et al., 2002) amended 3.1. Study selection
as appropriate for interventional and observational trials were used
(see Tables 2B7B).
Risk of systematic bias across studies was further identied by In total 2796 records were identied, of which 2044
assessing all papers for possible confounding with tobacco and other remained when duplicates were removed. All abstracts of
substance misuse in cannabis users. the records were screened against the inclusion and
1204 M.B. Sami et al.

exclusion criteria. A nal list of 25 studies was identied for Stefanis, 1982), while another investigated this in cere-
systematic analysis in this review (see Figure 1). Cumula- brospinal uid (CSF) (Musselmann et al., 1994).
tively, these studies reported outcomes on over 568 parti- Messiha and Soskin (1973) conducted the rst study in
cipants (sample size was not available for one paper humans investigating the urinary excretion of biogenic
(Steffens et al., 2004)) of which 244 participants belonged amines in 6 healthy individuals who smoked cannabis at
to the cannabis/cannabinoid exposure group. both higher and lower concentrations (2.24 mg THC vs.
Characteristics of included studies is reported in 0.8 mg THC). Urinary excretion of dopamine and its meta-
Tables 2A7A. Methodological quality of studies included bolites (3MT, HVA, DOPAC) were non-signicantly decreased
is reported in Tables 2B7B. Studies included investiga- at the higher dose at 2 h by 3354% and by 5 h by 1536%.
ted different aspects of the dopamine signaling pathway Markianos and Stefanis, (1982) in a similarly sized study
(Figure 2) in response to cannabis or THC exposure. These (n =6) undertook a use-deprivation-use trial of 6 long-term
include (1) peripheral blood biomarkers; (2) effect of cannabis users over 4 days. They showed sustained increas-
cannabinoids on dopamine release striatal and cortical; ing prolactin over the 3-day withdrawal period (30%), which
(3) effect of cannabinoids on dopamine synthesis; and reverted to baseline after smoking cannabis, suggesting
(4) effect of cannabinoids on dopamine receptor and sustained dopaminergic changes in the withdrawal state
transporter density. A brief synopsis of the key ndings is that returned to baseline with re-use. Markianos and Vakis,
reported below. (1984) further studied 5 healthy volunteers who smoked
cannabis on 2 occasions 3 weeks apart. Comparison of
overnight urinary excretion of dopamine metabolites
3.2. Peripheral dopamine markers in response to revealed a 49% increase in HVA urinary concentration after
cannabis use: smoking cannabis as compared to not smoking cannabis
indicating a signicant dopamine release following expo-
Five studies have addressed this area (see Tables 2A and 2B) sure. Taken together, these studies provided some early
2 studies each investigated metabolites of dopamine in evidence for alteration in dopamine measures after canna-
urine (Markianos and Vakis, 1984; Messiha and Soskin, 1973) bis exposure in man although the direction of association
and plasma (Bowers and Kantrowitz, 2007; Markianos and was not clear. However these studies were considerably

Figure 1 Systematic review ow diagram.


Does cannabis affect dopaminergic signaling in the human brain
Table 2A Characteristics of studies of peripheral dopamine markers in cannabis use.

Study Duration n Sample Dopamine Methodology Intervention/ Control Cannabis Healthy Other group Results
chemical Exposure group controls
measures

Messiha and 5 hours 6 Urine Dopamine, Cross-over. 2.24 mg THC 0.8 mg THC 6 6 N/A Decrease dopamine
Soskin participants DOPAC, Levels taken and 0.3 mg and markers 15-54%. No
(1974) HVA, 3-MT baseline, Cannabidiol 0.016 mg signicant difference
2 and 5 h Cannabidiol
and
0.016 mg
Cannabinal
Markianos 4 days 6 Plasma Prolactin Use- D1: CBS use, No control 6 0 N/A Increasing prolactin over
and participants withdrawal- D2-4 the 3 day withdrawal
Stefanis use trial abstinence, period (30%) reverted to
(1982) D4 CBSre- use baseline after re-use
(p = 0.01)
Markianos Overnight 5 Urine HVA Crossover, Cannabis oil No control 5 5 N/A 49% increase HVA
and Vakis urine participants urine smoked with concentration in CBS
(1984) collection collection tobacco group (p = 0.001)
11PM-8AM single use
Musselmann N/A 116 total, CSF HVA post-hoc CBS test +ve CBS test -ve 19 97 N/A Increase of 3.7% HVA levels
et al. 19 CBS analysis of in CBS group. Not
(1994) screen CSF levels signicant (p=0.15).
positive
Bowers and First 37 Plasma HVA Comparison CBS test +ve CBS test -ve Cannabis N/A First Episode FEP + Cannabis group
Kantro- morning participants of Plasma group: First Psychosis elevated HVA levels than
witz after levels taken Episode without FEPnoCannabis group
(2007) admission morning Psychosis Cannabis use (64%,p = 0.001) and non-
after with (n= 15), non- psychotic admissions
inpatient Cannabis psychotic (159%, p = 0.001).
admission use (n =5) admissions
(n= 17)

1205
1206
Table 2B Methodological quality of studies of peripheral dopamine markers in cannabis use. (Source: adapted from West et al., 2002.)

Study Comparability of Subjects Randomization Blinding (for Exposure or Adequate control Outcome Statistical Excluded/ Funding or
(for interventional intervention state measurement analyisis adjustment sponsorship
interventional trials only) for tobacco
trials only) confounding?

Messiha and Yes. Crossover subject effects No No Cannabis / Use of Dopamine, t-test, Not Not
Soskin minimized smoked. controls. Not true DOPAC, HVA correlated discussed discussed
(1973) placebo means
Markianos No control group No No Cannabis No control group Prolactin Paired t- No Not
and smoked test, discussed
Stefanis use- means
(1982) withdrawal-
use
Markianos Crossover subject effects No No Cannabis / Use of Urine HVA Paired No Not
and Vakis minimized smoked with controls. Not true t-test, discussed
(1984) tobacco placebo means
Musselmann Demonstrated in baseline N/A N/A / Test CSF HVA Matched Not Not
et al. analysis (observational) (observational) positive. paried t- discussed discussed
(1994) Frequency/ tests
quantity of
CBS use
unclear
Bowers and / Demonstrated in baseline N/A N/A / / Adequate Plasma HVA Not Not
Kantro- analysis.No difference between (observational) (observational) Documented psychotic controls. Student's t discussed discussed
witz psychotic and non-psychotic CBS use. Not clear if non- tests
(2007) groups. Age difference between Frequency/ psychotic
non-psychotic controls and quantity of admissions were
exposure group. CBS use not using cannabis.
unclear

THC tetrahydrocannabinol; CBS cannabis; FEP rst episode psychosis; DOPAC 3,4-dihydroxyphenylacetic acid (dopamine metabolite); HVA homovanillic acid (dopamine metabolite);
CSF cerebrospinal uid.

M.B. Sami et al.


Does cannabis affect dopaminergic signaling in the human brain
Table 3A Characteristics of studies of post-mortem and in-vitro studies of dopamine markers in cannabis use.

Study Duration n Sample Dopamine Methodology Intervention/ Control Cannabis Healthy Other group Results
chemical Exposure group controls
measures

Dean N/A 28 post- Caudate [3H]Mazidol Case control: Postmortem Postmortem 9 Cannabis test N/A 19 cannabis No signicant
et al. mortems 14 for DAT; Comparison CBS levels +ve CBS levels positive (5 test negative difference between
(2003) schizophrenics, Tyrosine of DAT and TH ve schizophrenia, (9 CBS users and non-
14 controls Hydroxylase levels 4 non schizophrenia, users
schizophrenia) 10 non
schizophrenia)
Steffens N/A Unknown Neocortex [3H] Preclinical Administration Rat N/A N/A N/A CB1 Agonist/
et al. and Dopamine experimental of CB1 agonist/ neocortex Antagonist
(2004) amygdyla release trial antagonist and depressed/
amygdyla enhanced [3H]-
Dopamine release
in human tisue but
not in rat

Table 3B Methodological quality of studies of peripheral dopamine markers in cannabis use. (Source: adapted from West et al., 2002.)

Study Comparability of subjects Randomisation Blinding (for Exposure or Adequate Outcome Statistical Excluded/adjustment for Funding or
(for interventional intervention control measurement analyisis tobacco confounding? sponsorship
interventional trials only)
trials only)

Dean Age and Sex matched. N/A N/A / Test ANOVA, No Declared
et al. No signicant differences (observational) (observational) positive. post-hoc
(2003) in age, post mortem Frequency/ Bonfoeronni
interval, brain pH. quantity of CBS correction
use unclear
Steffens N/A N/A preclinical N/A preclinical Rat [3H] Students Preclinical experimental Not
et al. experimental experimental tissue Dopamine t-test of with CB1 agonist/ discussed
(2004) release mean antagonist. No tobacco
confounding possible

CBS cannabis; TH tyrosine hydroxylase; DAT dopamine active transporter; CB1 cannabinoid receptor Type 1; ANOVA analysis of varience; N/A not applicable.

1207
1208 M.B. Sami et al.

Figure 2 Neuro-chemical outcomes measured in human studies of cannabinoid effects on the dopamine system. HVA: homovanillic
acid; DOPAC: 3,4-dihydoxyphenylactetic acid; 3-MT: 3-methoxytyramine; D2/3R: dopamine 2/3 receptor; BBB: bloodBrain Barrier
(number of trials, n = number of participants).

limited by very small sample sizes, lack of appropriate These results, which replicate those of Markianos and
strategies with regard to blinding and control conditions. Vakis (1984), suggest a state of hyperdopaminergia asso-
Furthermore, studies did not control for concomitant ciated with cannabis exposure even relative to non-cannabis
tobacco use, which has been linked to dopamine release using psychotic controls. However, the major limitations are
(Faure et al., 2014). the modest sample size and characterization of cannabis
Musselmann et al. (1994) undertook a post-hoc analysis exposure only on the basis of urine screening. While, urine
examining the CSF of healthy controls (n = 116), a subset of drug screen validates recent exposure, it does not inform
whom (n= 19) tested positive for cannabinoid use on urine about the amount and frequency of use.
toxicology screen. A marginal and non-signicant increase
of 3.7% in the level of dopamine metabolite HVA in those
healthy individuals who tested positive for cannabis on urine 3.3. Effect of cannabinoids on dopamine release
testing relative to those that did not was reported. How-
ever, it is difcult to draw rm conclusions from this as the 3.3.1. Striatal dopamine release
precise temporal relationship of cannabis exposure in rela- Acute dopamine release may be assayed by measuring
tion to the sampling of CSF in those that tested positive was change in D2/3 binding of specic radioligands following
not available. This is especially important as the change in cannabinoid challenge; with the change in specic binding
dopamine may be an acute effect and hence change in being an index of changes in extracellular dopamine. After
dopamine metabolites may not be detectable in CSF beyond an initial case report suggested 20% reduction of striatal
the acute period, while urine may still continue to test dopamine D2/3 receptor following cannabis exposure in a
positive for cannabis exposure for over 2 months (Huestis, single subject (Voruganti et al., 2001), three studies have
2007). investigated the effect of THC challenge on striatal release
Bowers and Kantrowitz (2007) investigated plasma HVA using a randomized, double-blind, placebo-controlled,
levels in 3 groups of hospital admissions: 5 patients with cross-over design in healthy controls (n = 31) (Barkus
First Episode Psychosis (FEP) with a positive urine drugs et al., 2011; Bossong et al., 2009; Stokes et al., 2009)
screen for cannabis at inpatient admission, 15 FEP patients (see Tables 4A and 4B). At the level of the whole striatum all
with a negative urinary drug screen and 17 patients without three studies showed no signicant differences in total D2/3
a psychotic disorder diagnosis with a negative urinary drug receptor uptake following THC challenge in the striatum.
screen. The cannabis-positive FEP patient group had sig- However, when looking at striatal subdivisions, Bossong
nicantly elevated HVA levels compared to the FEP patients et al. (2009) reported a modest (3.43.9%) but signicant
who did not test positive for cannabis (64%, po0.001) as reduction in binding in the ventral striatum and preco-
well as the non-psychotic admissions (159%, po0.001). missural dorsal putamen. However, this nding was not
Does cannabis affect dopaminergic signaling in the human brain 1209

Table 4A Characteristics of imaging studies of acute thc challenge on dopaminergic function.

Study Tracer Population n Methodology THC Results


challenge

Bossong [11C] Healthy Volunteers. Mild CBS 7 Randomized, 8 mg Whole Striatum no signicant
et al. Raclopride use at least 1 year. Urine test double blinded, Inhaled difference.
(2009) ve study day cross over Ventral Striatum -3.5% BPND
p = 0.029 Precommisural Dorsal
Putamen 4% p = 0.042
Stokes [11C] Healthy Volunteers 13 Randomized, 10 mg Whole Striatum and striatal
et al., Raclopride double blinded, oral subdivisions no signicant
(2009, cross over difference between groups
2010) Use 420 CBS (mean =8127671) No striatal correlations between
COMT Val/Met status and D2R
binding.
No Mental Illness No substance Decreased BPND in frontal
dependence regions of 30.650.1% of THC
group vs. placebo
COMT Val/Met signicant
correlation with genotype and
Raclopride uptake in the left
superior frontal gyrus
Barkus [123]IBZM Healthy Male volunteers 11 Randomized, 2.5 mg IV No signicant difference from
et al. Age 26.374.2 double blinded, placebo in stimulating dopamine
(2011) No drug (except nicotine) cross over release from striatum
dependence
Urine free sample study day
Previous use of CBS
Kuepper [18F] 9 healthy cannabis users; 24 Single blinded to 8 mg THC induced signicant striatal
et al. Fallypride 8 patients with psychotic placebo and Inhaled displacement of Fallypride in
(2013) disorder; 7 unrelated rst conducted in a both patients (13.2) and
degree relatives of persons with sham randomized relatives (12.6) but not in
psychosis design controls (2.3)

replicated by Stokes et al. (2009) using a similar region of (n = 7). THC induced signicant striatal displacement of the
interest (ROI) approach. Consequently, the results of these high afnity D2/3receptor radioligand [18F]fallypride indicat-
human studies are in contrast to the fairly robust evidence ing dopamine release in both patients and relatives but not
from animal studies that suggest striatal dopaminergic in controls. These results indicate that THC may have
modulation by THC (Chen et al., 1990; Gardner, 2005; different effects on striatal dopamine release that may be
Ginovart et al., 2012; Tanda and Goldberg, 2003; Tanda contingent upon genetic pre-disposition to psychotic dis-
et al., 1997). orders. Use of a single-blinded and sham-randomized design
While generally well-designed, these results need to be limits the conclusions that one may draw from this study.
considered in light of certain limitations: all of these studies Four studies investigated the capacity for striatal dopa-
investigated modest-sized samples and differing methods of mine release in cannabis users versus healthy controls
administration (Stokes et al.: oral; Bossong et al.: inhala- (Mizrahi et al., 2014, 2013; Urban et al., 2012; Volkow
tion) associated with considerable inter-individual variation et al., 2014) using an approach that did not involve THC
in bio-availability in the brain. Oral THC bioavailability may administration (see Tables 5A and 5B). Urban et al. (2012)
be as little as 1020%, whereas bioavailability of inhaled (n = 32) used amphetamine challenge to determine this in 16
THC varies between 2% and 56% (Huestis, 2007). Further- cannabis users and 16 healthy controls, to nd no signicant
more, both the studies that reported negative results difference in [11C]raclopride binding between the groups.
(Barkus et al., 2011; Stokes et al., 2009) studied chronic However, they found a signicant correlation between
cannabis users who were more likely to have a blunted younger age of onset of cannabis use associated with
response to the effects of THC as well as lower baseline smaller dopamine release in the associative striatum. This
dopamine levels (DSouza et al., 2008). may suggest a possible blunting of the responsiveness of the
Kuepper et al. (2013) examined striatal dopamine release dopaminergic system related to previous exposure. This
in response to THC in 3 groups of individuals with varying study suffered from a high dropout rate, with 32 cannabis
genetic predisposition to psychosis: healthy controls (n= 9), users initially recruited, as more severe users could not
untreated patients with psychosis (n= 8) and unrelated rst- tolerate the abstinence required of study conditions. This
degree relatives of individuals with a psychotic disorder may have thus excluded those with more signicant blunting
1210 M.B. Sami et al.

Table 4B Methodological quality of studies of imaging studies of acute thc challenge on dopaminergic function.

Study Dened Rando- Blinding Inter- Ade- Out- Statisti- Drop- Exclu- Funding
Study misa- vention quate come cal out rate ded/ or
popula- tion control mea- analyi- speci- adjust- spon-
tion sure- sis ed? ment sorship
ment for
tobacco
con-
found-
ing?

Bossong THC BPND 2/9 No


et al., Healthy Double chal- Placebo striatal ANOVA, (22%) tobacco Declared
2009 Volun- lenge post-hoc con-
teers Paired t founding
test with
THC
Stokes THC BPND Paired Not No
et al., Healthy Double chal- Placebo striatal t test speci- tobacco Declared
2009 Volun- lenge ed con-
teers founding
with
THC
Stokes THC BPND Not No
et al. Healthy Double chal- Placebo frontal Repe- speci- tobacco Declared
(2010) Volun- lenge ated ed con-
teers mea- founding
sures with
ANOVA THC
Barkus THC Paired 2/11 No
et al., Healthy Double chal- Placebo [123I]- t test (18%) tobacco Declared
2011 Volun- lenge IBZM con-
teers Subtrac- founding
tion with
Index THC
Kuepper / THC BPND Linear 6/30 No
et al. Psycho- Pseudo- Single chal- Placebo striatal regres- (20%) tobacco Declared
(2013) tic rando- lenge sion con-
patients misation model founding
vs. rst with
degree THC
relatives
vs.
healthy
cannabis
users

THC tetrahydrocannabinol; CBS cannabis; PET positron Emission Tomography; BPND binding potential non-displaceable; COMT
catechol-O-methyltransferase; Val/Met valine/methionine; [123I]-IBZM iodobenzamide; 18F-fallypride 18-uoro-fallypride;
ANOVA analysis of variance

of dopamine release capacity. Volkow et al. (2014) investi- signicant care should be taken in the interpretation of PET
gated 24 cannabis-users and 24 healthy controls using [11C] data as indicating changes in dopamine release, due to
raclopride with a methylphenidate challenge. They similarly changes in vascular resistance, and hence potential changes
found no signicant group difference in baseline D2/3 levels in regional blood ow in cannabis users (Herning et al.,
or BPND after administration of methylphenidate. However 2005).
they found methylphenidate challenge resulted in signi- Mizrahi et al. (2013) examined dopamine release in
cantly larger decrease in the distribution volume of [11C] chronic cannabis users, using the [11C]PHNO D2/3 receptor
raclopride in controls than cannabis users across the whole radiotracer and studied them in a control state using a
brain, which held on region of interest (ROI) analysis for sensorimotor control task and in a stress state using the
the striatum and cerebellum. These ndings indicate that Montreal Imaging Stress Task. There was no signicant
Does cannabis affect dopaminergic signaling in the human brain
Table 5A Characteristics of imaging studies of effect of chronic cannabis use on dopaminergic release.

Study Tracer Study aim Population n Cannabis use Controls Results

Urban et al. [11C]Raclopride 1. D2/3 Receptor 16 cannabis 32 Use at least 16 Healthy 1. D2/3R
(2012) Availability in users. 5 times/week. Controls displacement
chronic CBS use Need to abstain after
2. Dopamine for CBS to Amphetamine
release in become negative Challenge (DA
chronic CBS users in urine release): no
in response to signicant
amphetamine difference. 2.
challenge Signicant + ve
association
between DA
release and
earlier age of
cannabis use
onset R= 0.567,
p= 0.03.
Mizrahi et al. [11C]PHNO Dopamine 13 cannabis 25 Use at least 12 Healthy 1. In both tasks
(2013) release in users. 3 times/week Controls D2/3R binding
chronic CBS users was increased in
in response to CBS group (12-
stress task 14%). 2. No
signicant
change in
displacement of
radioligand by
Stress Task 3.
Duration of CBS
use associated
with stress
induced
displacement in
Limbic striatum.
4. No correlation
between age of
onset and DA
release.
Mizrahi et al. [11C]PHNO Dopamine 12 cannabis users 24 Use at least 12 non-CBS users 1. No signicant
(2014) release in with CHR 3 times/week with CHR difference
patients with between tasks in
clinical high risk control task. 2.

1211
(CHR) with and Stress task
1212
Table 5A (continued )

Study Tracer Study aim Population n Cannabis use Controls Results

without chronic elicited increase


CBS use in in BPND
response to CHRnoCBS group
stress task and decrease in
BPND CHR-CBS
group 3.
Signicant
differences in all
regions of
striatum and
whole striatum
(p = 0.001)
Volkow et al. [11C]Raclopride 1. D2/3 Receptor 24 cannabis 48 DSM IV Cannabis 24 Healthy 1. D2/3R
(2014) Availability in users. use/dependence. Controls displacement
chronic CBS use Mean use measured via
2. Dopamine 4.8 joints/day BPND after
release in (73), mean methylphenidate
chronic CBS users years of use 10.5 Challenge (DA
in response to (72). Last use 1 release): No
methylphenidate 7 d prior to scan Signicant
challenge Difference across
whole striatum.
2.
Methylphenidate
has signicantly
larger decrease
of distribution
volume of
Raclopride in
controls than
cannabis users
across brain,
striatum and
cerebellum

M.B. Sami et al.


Does cannabis affect dopaminergic signaling in the human brain
Table 5B Methodological quality of imaging studies of effect of chronic cannabis use on dopamine release.

Study Dened study Comparability of subjects Adequate exposure Control Outcome Statistical Excluded/ Funding or
population measurement analyisis adjustment sponsorship
for tobacco
confounding?

Urban et al. Current / Demographic characteristics matched. DSM IV criteria BPND Two- No Declared
(2012) chronic Information not available on other conrmed by PRISM IV Striatum and group t
cannabis users recreational drug use in cannabis group and interview. Bi-weekly BPND test
briey healthy controls cannabis testing to Striatum
abstinant conrm brief abstinance
Mizrahi et al. Current / Demographic characteristics matched. Use of SCID BPND Paired No Declared
(2013) chronic Other recreational drug use in cannabis questionnaire and Striatum t-test
cannabis users group information not availiable in healthy Marijuana Craving
controls Questionnaire
Mizrahi et al. Patients / Demographic characteristics matched. Use of SCID BPND Paired t- Undertook Declared
(2014) with clinical More tobacco smokers in CBS group. Other questionnaire and Striatum test analysis with
high risk, with recreational drug use in cannabis group Marijuana Craving and without
and without information not availiable in healthy Questionnaire. Use of SIPS tobacco
CBS use controls to establish CHR status smokers
Volkow et al. Current / Demographic characteristics matched. DSM IV criteria BPND Yes CO used Declared
(2014) chronic Signicant difference in tobacco usage, but conrmed by 2 clinician Striatum, Factorial as covariate
cannabis users this was corrected. Other active ussage of interview using semi- BPND striatum repeated
drugs excluded via urine sampling structred instrument and distribution ANOVA
volume (DV)

D2/3R dopamine 2/3 receptor; CBS cannabis; PET positron emission tomography; PHNO (+)-4-propyl-9-hydroxynaphthoxazine; 18F-DOPA L-6-uoro 3,4-dihyroxyphenylalanine; DSM
IV Diagnostic and Statistical Manual of Mental Disorders IV; PRISM IV Psychiatric Research Interview for Substance and Mental Disorders IV; SCID Structured Clinical Interview for DSM IV;
BPND binding potential non-displaceable; BPND change in binding potential non-displaceable; ANCOVA- Analysis of covarience; CHR: clinical high risk; COPS criteria of prodromal
syndromes.

1213
1214 M.B. Sami et al.

difference between the chronic cannabis users and healthy (COMT) Val108/158Met status. COMT acts primarily in the
controls in terms of percentage of displacement of the synaptic cleft in cortical regions to degrade dopamine to its
radiotracer bound to D2/3 receptors (which indicates dopa- metabolites and has been proposed as a candidate gene for
mine release). However, as a result of exposure to stress, schizophrenia (Williams et al., 2007). In the study homo-
the authors found that D2/3receptor binding measured zygotes for the COMT val allele at this locus (n =6) had the
during the control sensorimotor task condition was 12 largest decreases in D2/3 receptor binding (7087%), fol-
14% higher in the cannabis user group compared to the lowed by heterozygotes (2756%) with the lowest decreases
healthy volunteers. Mizrahi et al. (2014) further investi- being observed in the met homozygotes ( 10% to 36%).
gated stress-induced dopamine release using identical para- These reached signicance in the left superior frontal gyrus
digms and radioligand in patients with clinical high-risk of (p= 0.02) (Stokes et al., 2010). This contrasts with the
psychosis with and without cannabis use. Of the 12 cannabis ndings in the striatum (Stokes et al., 2009) where no
users 11 were dependent on cannabis and all smoked signicant correlation was found. Overall, caution should be
cannabis at least 3 times a week. They found that the applied when interpreting the changes in [11C]raclopride
stress task resulted in a decrease in BPND in cannabis non- binding in the frontal cortex as the effects of change in
users, while in the cannabis users BPND increased during the dopamine release. The baseline BPND of [11C]raclopride in
stress task. Signicant differences between cannabis and the cortex is low ( 0.3), making measurements in this
non-users were found for the whole striatum as well as the area vulnerable to confounding methodological effects (e.g.
associative, limbic and sensorimotor subregions. The same changes in blood ow, minor differences in non-displaceable
pattern of results remained on excluding tobacco smokers binding between cortex and cerebellum, etc).
from analysis. These results are difcult to interpret in the
context of changes in dopamine release, as they would
imply a reduction in dopamine release in cannabis using 3.4. Effect of cannabinoids on dopamine synthesis
patients, rather than just blunting of the response. Changes capacity
in regional blood ow in cannabis users may go some way to
inform on the results in cannabis users, but overall the most One study investigated 28 post-mortem brain specimens, 14
consistent interpretation of these results is that cannabis with diagnosed and treated schizophrenia and 14 without
use does not increase the sensitivity of the dopamine system schizophrenia (Dean et al., 2003). Nine participants across
response to stressful stimuli. both groups had THC present in blood sampled at autopsy.
There was no signicant difference in tyrosine hyroxylase
levels in the caudate nucleus between cannabis users and
3.3.2. Cortical dopamine release non-users. A major limitation in addition to the modest
In comparison to the studies on striatal dopamine release, sample size in this study was lack of information about the
comparatively fewer have investigated dopamine release in quantity or frequency of cannabis use in the cannabis-
cortical areas (particularly the pre-frontal cortex). Steffens positive subjects tested at autopsy. All that could be
et al. (2004) investigated neocortex and amygdala in vitro, assumed was use within 2 weeks of death.
comparing human and rat neuronal tissue for the effects of Bloomeld et al. (2014a) used [18F]DOPA scans to study
CB1 stimulation on dopamine release. In human neocortex, 19 regular cannabis users (10 dependent, 9 abusers) who
direct agonism of CB1 by administration of CP55,940 experienced psychotic symptoms when they consumed
depressed [3H]-dopamine release in a concentration- cannabis versus 19 age and sex-matched controls. They
dependent fashion. Similarly AM251 (CB1receptor inhibitor) found dopamine synthesis capacity to be signicantly
enhanced [3H]-dopamine release. Notably, in the rat neo- reduced in the whole striatum in response to chronic
cortex administration of CP55,940 and AM251 did not cannabis use. This reduction reached signicance in the
inuence [3H]-dopamine release. Furthermore, in the pre- associative and limbic striatum that remained when adjust-
sence of the axonal blocker tetrodotoxin (TTX): K + evoked ing for other drugs of use including nicotine. A greater level
[3H]-dopamine release was inhibited in human tissue but not of use was also signicantly associated with reduction in
in rat tissue. These results suggest that presence of CB1 dopamine synthesis capacity (shorter time to smoke an
receptors in human neocortical dopaminergic nerve term- eighth (standard measure of cannabis) r = 0.77,
inals inuences dopamine release. The authors inferred a po0.01). These ndings may suggest that cannabis use is
tonic effect of endocannabinoids on CB1 receptors in human associated with blunted dopamine synthesis capacity in
neocortex resulting in the inhibition of dopamine release. those users sensitive to the psychotomimetic effects of
In a post-hoc analysis of the imaging data obtained in cannabis (Bloomeld et al., 2014a).
their earlier study, Stokes et al. (2010) examined changes in The same group further examined the association of
frontal and temporal [11C]raclopride binding following THC dopamine synthesis capacity with the Apathy Evaluation
challenge. They demonstrated decreased [11C]raclopride Scale (AES) in 14 of the above participants who engaged in
binding in the right middle frontal gyrus, left superior heavy cannabis users (Bloomeld et al., 2014b). In this
frontal gyrus and left superior temporal gyrus with group of young (average age 20.4) mostly male (13 out of
decreased BPND of 30.650.1% following THC administration 14) regular cannabis users smoking on at least a weekly basis
relative to the placebo condition, which were maintained for 4.9 years, there was signicant inverse correlation
when adjusted for blood ow measures and were greater between dopamine synthesis capacity as measured using
than the testretest variability (18.323.7%) for this mea- [18F]DOPA PET scan and apathy. Although this cross-
sure. Stokes et al. also demonstrated variation in corti- sectional study does not itself establish a causal relation-
cal dopamine binding with Catechol-O-methyltransferase ship, taken together these two studies from Bloomeld and
Does cannabis affect dopaminergic signaling in the human brain 1215

colleagues suggest that a blunting of striatal dopamine receptor availability using [18F]fallypride indicated dysre-
synthesis capacity from chronic cannabis use may result in gulation in the early, symptomatic withdrawal state; with
apathy, a key feature of the amotivational syndrome that normalization of dopaminergic state after symptoms have
has long been associated with cannabis use (Musty and abated as against three normal controls. This is in accor-
Kaback, 1995; Paule, 2005). dance with the results of Markianos and Stefanis (1982),
which additionally suggest normalization of peripheral
3.5. Effect of cannabinoids on dopamine receptor levels with reinstatement. However, there is no evidence
density: of continued D2/3 receptor alterations in those who remain
abstinent beyond the rst week as demonstrated in
repeated studies discussed above (Sevy et al., 2008;
3.5.1. D2/3 receptor availability
Stokes et al., 2012; Urban et al., 2012).
All 6 studies investigating striatal D2/3receptor density
reported no difference between cannabis users and
matched controls (Albrecht et al., 2013; Safont et al., 3.7. Risk of systematic bias across all studies
2011; Sevy et al., 2008; Stokes et al., 2012; Urban et al.,
2012; Volkow et al., 2014) (see Tables 7A and 7B). Two of Of the 23 studies which were evaluated for methodological
these studies (Albrecht et al., 2013; Safont et al., 2011) quality, 12/23 (52%) did not attempt to adjust or exclude
included cannabis users who were still using at the time of tobacco or other substance use when evaluating cannabi-
taking part in the studies. In three other studies, cannabis noid exposed groups versus control. In a further study, Leroy
users had remained abstinent from cannabis for varying and colleagues (Leroy et al., 2012) studied three groups,
duration ranging from about 2 to 4 weeks (as estimated cannabis and tobacco smokers, tobacco smokers alone and
based on rst negative urine sample) (Urban et al., 2012) non-smokers, but this did not allow for identication of the
through to 3 (Sevy et al., 2008) and 18 months (Stokes effects of cannabis alone but this did not allow for
et al., 2012). Although one study reported a signicant identication of effects of cannabis alone. Consequently
difference between cannabis-using patients with rst epi- the majority of studies did not control for tobacco or other
sode psychosis and non-psychotic healthy controls, there substance misuse as a confounding variable.
was no difference between rst episode psychosis patients Studies of peripheral markers were overall noted to be
who used cannabis and those who did not (Safont et al., weaker in methodological quality than acute imaging and
2011). Another study reported a signicant negative corre- chronic imaging studies. This is likely because imaging
lation with use of cannabis as measured by self-report and studies are of a later period where more robust metho-
urine cannabis levels and striatal [11C]raclopride BPND, but dological criteria and design have been employed, with
no group difference between cannabis and non-cannabis the use of adequate controls, ensuring adequate exposure
users overall (Albrecht et al., 2013). and using randomization and blinding techniques more
prevalent.
3.5.2. DAT receptor availability
The post-mortem study by Dean et al. (2003), discussed 4. Discussion
above, found no difference between cannabis users and
non-users for dopamine active transporter (DAT) levels as
This is the rst systematic review of all studies, both
measured by [3H]mazindol binding at the caudate. This
observational as well as experimental, examining the acute
outcome suffers from the same limitations of possible Type
as well as chronic effect of cannabis or its main psychoac-
II error and lack of information on frequency and quantity of
tive ingredient, THC, on the dopamine system in man. One
cannabis use. A further study investigated 38 participants
previous review suggested dopamine transmission altera-
including 11 non-smokers, 14 tobacco smokers, and 13
tions in cannabis use relying on largely animal models
mixed cannabis-dependent and tobacco smokers using
(Kuepper et al., 2010). A further previous selective review
[11C]PE21 PET scans to determine DAT availability as a
critically examined the imaging ndings in humans
measure of dopamine synaptic clearance capacity (Leroy
(Ghazzaoui and Abi-Dargham, 2014) and was more sceptical
et al., 2012). They reported decreased DAT density in
of associations but did not draw on alternate lines of
tobacco smokers and cannabis and tobacco smokers in
evidence and did not include more recent work
ventral, dorsal striatum, midbrain, middle cingulate and
(Bloomeld et al., 2014a, 2014b; Mizrahi et al., 2014;
thalamus (1530%) versus healthy controls. There was
Volkow et al., 2014). Another recent review has critically
slightly decreased striatal DAT density in mixed cannabis
examined epidemiological, genetic and neurobiological
and tobacco users relative to tobacco users only, but this did
approaches, concluding that there is a probable causal
not reach statistical signicance. Lack of a group of pure
association between cannabis use and psychosis, but the
cannabis smokers makes it unclear to what extent the
evidence for dopaminergic involvement is less consistent
reported dopaminergic changes are related to cannabis
(Van Winkel and Kuepper, 2014).
use, as opposed to being an effect of tobacco use alone.
Cannabis use has now been established as increasing the
risk of onset and relapse of psychotic disorders such as
3.6. Dopaminergic changes in the cannabis schizophrenia as well as bringing forward the age of onset in
withdrawal state vulnerable individuals (Gonzlez-Pinto et al., 2008; Moore
et al., 2007; Zammit et al., 2008). Dopaminergic changes
A single case study involving a high potency synthetic are by now well established in schizophrenia (Howes and
cannabinoid (Rominger et al., 2013), measuring D2/3 Kapur, 2009; Howes et al., 2012), however dopaminergic
1216 M.B. Sami et al.

Table 6A Characteristics of imaging studies of effect of chronic cannabis use on dopamine synthesis capacity.

Study Tracer study aim Population n Cannabis use Controls Results

Bloomeld [18F]- Dopamine 19 regular 38 Current at least weekly 19 1. Uptake signicantly


et al. DOPA synthesis cannabis users users: 10 dependent, healthy reduced in cannabis users
(2014a) capacity in who experience 9 abusers controls relative to whole
chronic CBS psychotic striatum. This reduction
users symptoms when reached signicance in
consume cannabis associative and limbic
striatum. 2 Greater level
of use also signicantly
associated with lower
uptake 3 Dependent users
are signicantly more
likely than nondependent
abusers of CBS to have
lower uptake
Bloomeld [18F]- Dopamine 14 regular 14 Current at least weekly Own 1. Signicant inverse
et al. DOPA synthesis cannabis users users for 41 year. controls relationship between
(2014b) capacity in who experience Average use of cannabis striatal dopamine
chronic CBS psychotic 28.1 g/month, average at synthesis and apathy
users symptoms when least weekly use for score. 2. This holds true
correlation consume cannabis 4.9 years for whole striatum
with AES (p= 0.015) and associative
striatum (p= 0.006)

Table 6B Methodological quality of imaging studies of effect of chronic cannabis use on dopamine synthesis capacity.

Study Dened Comparability of Adequate Control Outcome Statistical Excluded/ Funding or


study subjects exposure measurement analyisis adjustment sponsorship
population for tobacco
confounding?

Bloomeld Current / Met DSM Kicer Adjusted Declared


et al. chronic Demographic IV criteria. Striatum Independent for nicotine
(2014a) cannabis characteristics Positive samples t and
users who matched. change of test substance
experience Signicant Psychotic misuse. No
psychotic increased States effect on
symptoms tobacco use in Inventory results
on use cannabis group score after
compared to smoking CBS
healthy controls
Bloomeld Current / 19 regular No Kicer Spearman's Not stated Declared
et al. chronic Demographic cannabis Striatum rho
(2014b) cannabis characteristics users who
users who matched. experience
experience Signicant psychotic
psychotic increased symptoms
symptoms tobacco use in when
on use cannabis group consume
compared to cannabis
healthy controls

D2/3R dopamine 2/3 Receptor; CBS cannabis; PET positron emission tomography; PHNO (+)-4-propyl-9-hydroxynaphthoxazine;
18F-DOPA L-6-uoro 3,4-dihyroxyphenylalanine; DSM IV Diagnostic and Statistical Manual of Mental Disorders IV; PRISM IV
Psychiatric Research Interview for Substance and Mental Disorders IV; SCID Structured Clinical Interview for DSM IV; AES Apathy
Evaluation Scale.
Does cannabis affect dopaminergic signaling in the human brain 1217

Table 7A Characteristics of imaging studies of effect of chronic cannabis use on receptor density.

Study Tracer Study aim Population n Cannabis use Controls Results

Sevy [11C] D2/3 Receptor Previously 12 3 months since last use 6 healthy No signicant difference
et al. Raclopride Availability in chronic Cannabis (n =6) controls between groups for D2/
(2008) CBS use dependent 3R binding
Safont [123I]IBZM D2/3 Receptor 14 First 55 Use 3 units/day for last 23 FEP no 1. No Signicant
et al. SPECT Availability in chronic Episode 3 months (n =14) CBS; 18 Difference between FEP
(2011) CBS use Psychosis healthy +CBS and FEPnoCBS. 2.
(FEP) controls Signicant Difference
+Cannabis between FEP+ CBS and
users HC (no FEP no CBS)
(untreated)
Stokes [11C] D2/3 Receptor 10 ex- 20 450 times in lifetime. 10 No signicant difference
et al. Raclopride Availability in chronic cannabis Average 18 months Healthy in striatal uptake
(2012) CBS use smokers since abstinence Controls between CBS and HC.
(n=10)
Albrecht [11C] D2/3 Receptor 10 male 18 At least 1 joint/week 8 male 1. No signicant group
et al. Raclopride Availability in chronic cannabis over last 1/12 and +ve healthy difference between any
(2013) CBS use users. urine toxicology. controls striatal region between
Average last use 20.6 CBS users vs HC. 2. In
hours prior to scan CBS group: BPND has
negative signicant
correlation with use of
CBS (po0.01).
Urban [11C] 1. D2/3 Receptor 16 cannabis 32 Use at least 5 times/ 16 1. Baseline D2/3R
et al. Raclopride Availability in chronic users. week. Need to abstain Healthy availability: No
(2012) CBS use 2. Dopamine for CBS to become Controls signicant difference.
release in chronic CBS negative in urine
users in response to
amphetamine challenge
Volkow [11C] 1. D2/3 Receptor 24 cannabis 48 DSM IV Cannabis use/ 24 1. Baseline D2/3R
et al. Raclopride Availability in chronic users. dependence. Mean use Healthy availability: No
(2014) CBS use 2. Dopamine 4.8 joints/day (73), Controls signicant difference
release in chronic CBS mean years of use 10.5 across whole striatum 2.
users in response to (72). Last use 1-7 d Lower D2/3R
methylphenidate prior to scan availability in
challenge marijuana users in
ventral striatum
(uncorrected), not
signicant when
corrected
Leroy [11C]PE21 DAT Availability in 13 mixed 38 Cannabis dependent 14 1. Decreased DAT
et al. chronic CBS users cannabis mean 4.8 joints/day tobacco density in tobacco
(2012) and smokers, smokers and cannabis
tobacco 11 non- and tobacco smokers in
smokers smokers ventral, dorsal
striatum, midbrain,
middle cingulate and
thalamus (15-30%)
versus healthy controls
2. No signicant
difference between
tobacco and cannabis
smokers

changes have been less well documented in response to inhibits dopamine uptake (Banerjee et al., 1975; Poddar and
acute as well as longer term cannabinoid use in man. Dewey, 1980) and increases mesolimbic dopamine activity
Preclinical research suggests that acute THC administration (Chen et al., 1990; French et al., 1997) in animals. Chronic
increases central dopamine synthesis (Bloom et al., 1978), THC use has been demonstrated to increase D2/3 receptor
1218
Table 7B Methodological quality of imaging studies of effect of chronic cannabis use on receptor density.

Study Dened Comparability of subjects Adequate exposure Control Outcome Statistical Excluded/adjustment for Funding or
study measurement analyisis tobacco confounding? sponsorship
population

Sevy Chronic / Demographic characteristics DSM IV cannabis BPND Two- No Declared


et al. cannabis matched. Signicant increased tobacco dependence, use of SCID Striatum sample t-test
(2008) users now use in cannabis group compared to and CASI-A. Random
abstinant healthy controls urine toxicology to
conrm abstinance
Safont Current / CBS groups similar in gender and Use of self-report and / S/F Ratio One way No Declared
et al. chronic in psychotic syx to non CBS users urinary screening test frontal ANCOVA
(2011) cannabis demonstrated in baseline analysis, binding may
users groups differed in age also be altered
in CBS use
Stokes Chronic / Demographic characteristics Based on CEQ3 or self- BPND MANOVA Adjusted for nicotine, Declared
et al. cannabis matched. Signicant increased report of frequency of Striatum alcohol and substance
(2012) users now recreational drug use in cannabis group use misuse. No effect on results
abstinant compared to healthy controls
Albrecht Current Demonstrated in baseline analysis Met DSM IV criteria. BPND No Declared
et al. chronic Screened using SCID and Striatum Independent
(2013) cannabis urine testing t-test
users
Urban Current / Demographic characteristics DSM IV criteria BPND Two-group No Declared
et al. chronic matched. Information not available on conrmed by PRISM IV Striatum and t test
(2012) cannabis other recreational drug use in cannabis interview. Bi-weekly BPND
users group and healthy controls cannabis testing to Striatum
briey conrm brief abstinance
abstinant
Volkow Current / Demographic characteristics DSM IV criteria BPND Factorial Yes CO used as covariate Declared
et al. chronic matched. Signicant difference in conrmed by 2 clinician Striatum, repeated
(2014) cannabis tobacco usage, but this was corrected. interview using semi- BPND ANOVA
users Other active ussage of drugs excluded structred instrument Striatum and
via urine sampling Distribution
Volume (DV)
Leroy Mixed Not enough detail given to determine Use of DSM IV nicotene BPND ANCOVA / Compared mixed Declared
et al. tobacco and and cannabis Striatum tobacco and cannabis users
(2012) cannabis dependence criteria to tobacco users. Unable to
users determine changes due to

M.B. Sami et al.


cannabis only

D2/3R dopamine 2/3 receptor; FDG-PET uorodeoxyglucose positron emission tomography; [123I]IBZM SPECT iodobenzamide single photon emission; CBS cannabis computed
tomography; HC healthy controls; DSM IV Diagnostic and Statistical Manual of Mental Disorders IV; SCID Structured Clinical Interview for DSM IV; CASI-I Comprehensive Addiction
Severity Index; CEQ3 Cannabis Experiences Questionnaire. ANCOVA Analysis of covarience; MANOVA Multivariate anlysis of varience; PRISM IV Psychiatric Research Interview for
Substance and Mental Disorders IV; BPND Binding potential non-displaceable; BPND change in binding potential non-displaceable
Does cannabis affect dopaminergic signaling in the human brain 1219

availability in the nucleus accumbens and striatal areas with possible that this may be accounted for by inter-species
reduction in dopamine synthesis in the midbrain in rodents variation, which has confounded our understanding of the
(Ginovart et al., 2012). Although these studies have been effect of cannabis use on dopaminergic signaling (Pertwee
illustrative, this review demonstrates important differences and Ross, 2002). Further human studies are required to
in the effects of cannabis and THC on central dopaminergic replicate the results of Steffens et al. (2004) and to also
neurotransmission in humans, highlighting perhaps not just investigate effects in subcortical areas such as striatum and
the complexities in replicating the pharmacological effects other relevant sites of interest to generate a working model
of a drug in a different species with a different distribution in man.
of the target CB1 receptor and efcacy of the drug at this
target (Gifford et al., 1997; Kathmann et al., 1999; Pertwee
and Ross, 2002; Schlicker et al., 1997) but also the lesser 4.3. Acute neuroimaging studies
degree of experimental control in human studies and hence
greater amount of noise in the data compared to those Evidence from animal studies has previously suggested that
carried out in animals. Overall, this may suggest that while THC administration is associated with increase in striatal
cannabis administration has denite effects on dopamine in dopamine levels (Chen et al., 1990; Gardner, 2005; Ginovart
preclinical models, the effects in human are less clear-cut. et al., 2012; Tanda and Goldberg, 2003; Tanda et al., 1997).
While some limited clinical evidence indicates possible One would expect THC to behave like amphetamine,
interactions between the cannabinoid and dopaminergic another psychotomimetic substance, which demonstrates
systems, this effect is very likely to be modest and hence between 5% and 25% decreased striatal D2/3receptor binding
perhaps at the margins of detection sensitivity of current depending on tracer used (Drevets et al., 2001; Ginovart
measurement techniques in man. These are discussed in et al., 2006; Leyton et al., 2002; Munro et al., 2006;
more detail below. Narendran et al., 2010; Oswald et al., 2005; Shotbolt
et al., 2012). However the pre-clinical results have failed
4.1. Peripheral markers to nd replication in robust human studies of THC challenge
in healthy volunteers (Barkus et al., 2011; Bossong et al.,
2009; Stokes et al., 2010). However, this does not necessa-
Taken together, the 5 studies identied in this area show
rily exclude dopaminergic signal alterations by THC. It has
conicting results, which tend towards showing weak evi-
been argued that the effect-size is modest and less detect-
dence that cannabis use affects peripheral dopamine mea-
able in humans, with a demonstrated ratio of 40:1 between
sures. While the largest study (Musselmann et al., 1994) is
increase in dopamine and reductions in raclopride (Breier
not supportive, it was not specically designed for this
et al., 1997; Laruelle et al., 1997). Consequently, increases
purpose with resulting methodological limitations. The
in dopamine level following THC challenge of the order of
direction of association is not clear although two studies
25100% as determined by animal studies cited above would
(Bowers and Kantrowitz, 2007; Markianos and Vakis, 1984)
correspond to a reduction in raclopride binding of 0.62.5%
report signicant increase in peripheral dopamine levels in
in human studies, which falls below the lower threshold for
response to cannabis. A further study suggests alterations in
detection at the sample sizes employed in the human
the withdrawal state, which is relieved by re-use (Markianos
studies to date.
and Stefanis, 1982). However work in this area is by limited
The work of Kuepper et al. (2013) and Stokes et al. (2010)
by small sample sizes, inadequate controls, heterogeneity
does however suggest that genetic variability in dopaminer-
of methods and failure to adjust for tobacco use as a
gic response to THC may also partly explain the inconsis-
confounding factor. Consequently larger trials of peripheral
tency in results between preclinical research and human
dopamine markers, designed for purpose, of THC or canna-
studies. Importance of genetic differences in mediating
binoid challenge without concurrent tobacco administra-
variable response to THC is also consistent with evidence
tion, are required in order to further our understanding in
suggesting the role of genes regulating central dopaminergic
this area.
neurotransmission in mediating variability in the acute
(Bhattacharyya et al., 2014, 2012a, 2012b) and longer-
4.2. Post mortem/in-vitro studies term effects (Di Forti et al., 2012; Van Winkel, 2011) of
cannabis on behavior and some of its neural underpinnings
There is a paucity of work in this area with only 2 studies (Bhattacharyya et al., 2014, 2012a, 2012b). In particular,
identied. The work of Steffens et al. (2004) suggests a Bhattacharyya et al. (2012a, 2012b) demonstrated that
hypo-dopaminergic state in the neocortex in important sites individuals with a risk variant linked to higher synaptic
such as the pre-frontal cortex from cannabis use. Further- dopamine levels (Heinz et al., 2000) of the gene coding for
more, this work demonstrates an important difference the dopamine transporter (DAT1), involved in clearing
between human and rat neocortex, with human dopaminer- dopamine from subcortical synapses (Bannon et al., 2001)
gic response inhibited by cannabinoid stimulation but no experienced a stronger effect of THC on neural activation in
similar inhibition seen in the rat tissue. Previous studies the striatum (Bhattacharyya et al., 2012a, 2012b), a proxy
have demonstrated contrasting results with different animal measure that may be linked to local dopamine change in a
species. One study found no co-localization of CB1 and D1/2 key dopaminergic area of the brain. Similarly the study by
receptors in the neocortex in C57BL/6 laboratory mice, Stokes et al. (2010) showing variation in dopamine release
whereas other studies (Pistis et al., 2002, 2001) found THC in frontal cortex based on COMT Val108/158Met status is
and the synthetic cannabinoid WIN55,212-2 modulate pre- signicant as in the striatum extracellular dopamine is
frontal dopamine release in SpragueDawley rats. It is primarily under the control of the DAT, while in the
1220 M.B. Sami et al.

prefrontal cortex COMT may have a much more important Leroy et al. (2012) found decreased DAT density in
role. This suggests that genetic predisposition may play a cannabis and tobacco users as opposed to non-users.
role in identifying individuals who have increased dopami- Although DAT clears dopamine intrasynaptically and we
nergic release in the prefrontal cortex in response to may expect decreased DAT to suggest increased dopamine
cannabinoids. There is a thus a need for further studies intrasynaptically, DAT density maybe a marker for dopami-
that takes into account genotype status and dopaminergic nergic neurons. The authors suggest that since DAT is
acute release to further understand these mechanisms. regulated according to dopamine homeostasis these results
are more consistent with decreased basal dopamine levels
in response to chronic consumption. This would be consis-
tent with the results of Bloomeld et al. (2014a). However
4.4. Dopaminergic changes in chronic cannabis this may be explained by tobacco use, rather than cannabis
users use, as tobacco intake was not adjusted for. Furthermore if
nicotine/tobacco dependence affects dopaminergic path-
Similar to the results of acute challenge studies, discussed ways in the striatum, as has also been suggested in the post-
above, 6 studies show no difference in D2/3 receptor hoc analysis of nicotine users by Stokes et al. (2012), this
availability to PET ligands between cannabis and non- may suggest that such changes are markers of drug depen-
cannabis users in striatal dopamine uptake. dency rather than an adaptive response of the dopaminergic
Dopamine release in chronic cannabis users has also been system to chronically raised dopamine levels as a result of
an area of considerable interest. Three studies have demon- regular cannabis use. Hence, further studies of both dopa-
strated no difference between cannabis users and healthy mine synthesis and clearance capacity are required, adjust-
controls using conventional measures (striatal BPND) ing for tobacco and nicotine use.
(Mizrahi et al., 2013; Urban et al., 2012; Volkow et al.,
2014). Volkow et al. (2014), measured distribution volume
of raclopride, and noted signicant differences between 4.5. Limitations
groups following methylphenidate induced dopamine
release throughout the brain, even in areas where dopamine We have attempted a comprehensive review of the human
release cannot affect the binding of D2/3 PET ligands. Thus literature on the direct effect of cannabinoids on the
interpretation of these studies in chronic cannabis abusers dopaminergic system. Nonetheless we do judge this work
should be done with caution, considering the possible to have some limitations. Firstly, there is the risk of
inuence of methodological confounders such as alterations publication bias. We have attempted to minimize this by
in regional cerebral blood ow, or changes in the brain and using an extensive search strategy, including conference
plasma free fractions of the radioligand. This conclusion is abstracts, using multiple databases, and avoiding date and
supported by the results of a further study which suggests language restrictions.
signicant differences to a challenge eliciting dopamine Secondly, there is a relative paucity of human studies in
release between cannabis users with clinical high risk of this eld. This has also meant that there is a variable
psychosis and to non-cannabis users with clinical high risk methodological quality of the data, particularly with earlier
(Mizrahi et al., 2014). In this study we again see changes in studies of peripheral markers being less robust, while PET
PET ligand binding ([11C]PHNO in this case) in cannabis data is sensitive to various methodological caveats which
users, that are difcult to reconcile with the direct effects should be considered carefully in the biological interpreta-
of dopamine release. Further studies are required to tion of the data. Further, suitably designed studies in this
investigate these issues. area are required to be able to more denitively ascertain
Very little work has been done on (1) dopamine synaptic ndings.
clearance capacity measured via DAT and (2) pre-synaptic Thirdly, as has been identied above, there is a risk of
dopamine synthesis in cannabis users. Dean et al. (2003) systematic bias with 12/23 studies failing to adjust for
showed no changes in DAT levels between cannabis users tobacco or other substance misuse. Although we have
and non-users in their modestly sized post mortem study of focused more specically on tobacco misuse as a marker
schizophrenics and age and sex matched controls. However for methodological rigor, our ndings equally apply to other
no denite conclusions can be drawn from this study, as substances of abuse. Tobacco, alcohol, opiates and amphe-
there is a marked paucity of information regarding fre- tamines are known to increase dopamine levels in areas of
quency, use and adjustment for confounders such as alter- the mesolimbic system, particularly the ventral striatum
nate substance misuse, from a single plasma test at autopsy. and nucleus accumbens which may confound results of
The work of Bloomeld et al. (2014a) show dopamine cannabis studies (Pierce and Kumaresan, 2006). Tobacco
synthesis capacity, measured via [18F]-DOPA, is reduced in use specically is highly co-prevalent with cannabis and may
response to chronic cannabis use, in a group where other confound results. In addition to co-morbid tobacco and
substance dependence other than cannabis and tobacco has cannabis misuse, combined use in practices such as mul-
been excluded, and this may thus represent an adaptive ling are particularly prevalent in Europe and need to be
change. This may add to suggestions of a blunting of accounted for carefully in future studies (Blanger et al.,
dopaminergic system in response to drug use (DSouza 2011). Consequently, future studies should acknowledge and
et al., 2008). Suggestions of clinical sequalae are supported seek to minimize this effect.
by cross-sectional analysis which shows decreased dopamine Fourthly, our paper only examined direct neurochemical
synthesis capacity in cannabis users to be correlated with outcomes of dopamine markers in response to cannabinoid
apathy (Bloomeld et al., 2014b). use. Indirect evidence, of studies where proxy measures
Does cannabis affect dopaminergic signaling in the human brain 1221

linked to dopamine were reported, such as (1) effect of Acknowledgments


dopaminergic genotypes on cannabis consumption or depen-
dence (Baransel Isir et al., 2008; Vaske et al., 2013) or We acknowledge the help of Adam Blackwell, Emma Ramstead and
psychotic response to cannabis (Bhattacharyya et al., 2009, Karen Stringer, librarians at East Surrey Hospital.
2012a, 2012b; DSouza et al., 2005, 2004; Henquet et al.,
2006); (2) the effect of the antipsychotic D2 recep- Appendix A. Supporting information
tor antagonists on cannabis consumption or craving
(Machielsen et al., 2012; Van Nimwegen et al., 2008) or Supplementary data associated with this article can be
psychotic features (DSouza et al., 2005; Kleinloog et al., found in the online version at http://dx.doi.org/10.1016/
2012; Liem-Moolenaar et al., 2010); and (3) effect of j.euroneuro.2015.03.011.
cannabis on neural activation in dopamine-rich areas such
as striatum and midbrain (Bhattacharyya et al., 2009,
2012a, 2012b) were not considered for the purposes of this
review. A review of such studies would not provide direct References
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