Schizophrenia Research 121 (2010) 107117

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Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Review

Does dopamine mediate the psychosis-inducing effects of cannabis?

A review and integration of ndings across disciplines
Rebecca Kuepper a, Paul D. Morrison c, Jim van Os a,c, Robin M. Murray c,d,
Gunter Kenis a, Ccile Henquet a,b,
a
Department of Psychiatry and Psychology, EURON, Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network,
Maastricht, The Netherlands
b
Mondriaan Zorggroep, Division Addiction Care, South Limburg, The Netherlands
c
Kings College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, UK
d
NIHR Biomedical Research Centre, Institute of Psychiatry, Kings College, London, United Kingdom

a r t i c l e

i n f o

Article history:
Received 14 January 2010
Received in revised form 22 March 2010
Accepted 16 May 2010
Available online 26 June 2010
Keywords:
Cannabis
Psychosis
THC
Dopamine
Endocannabinoid system

a b s t r a c t
General population epidemiological studies have consistently found that cannabis use increases
the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological
signal between cannabis and psychosis has gained considerable attention, the biological
mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal
research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of
cannabis) increases dopamine levels in several regions of the brain, including striatal and
prefrontal areas. Since dopamine is hypothesized to represent a crucial common nal pathway
between brain biology and actual experience of psychosis, a focus on dopamine may initially be
productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review
examines the evidence concerning the interactions between THC, endocannabinoids and
dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers
possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to
delusions and hallucinations. It is concluded that further study of the mechanisms underlying the
link between cannabis and psychosis may be conducted productively from the perspective of
progressive developmental sensitization, resulting from geneenvironment interactions.
2010 Elsevier B.V. All rights reserved.

1. Introduction
Stimulant drugs such as amphetamine have long been
associated with psychotic symptoms. High doses can induce
positive symptoms in people with no previous psychiatric
history while even low doses can exacerbate positive symptoms in patients with a psychotic disorder (Abi-Dargham,
2004; Curran et al., 2004). By the mid 1970s, experimental
replications of the psychotomimetic effects of stimulant drugs,
in combination with the observed anti-psychotic effects of
D2-blocking drugs, had given rise to the initial dopamine

Corresponding author. Department of Psychiatry and Psychology,

EURON, Maastricht University Medical Centre, South Limburg Mental Health
Research and Teaching Network, Maastricht, The Netherlands.
E-mail address: cecile.henquet@sp.unimaas.nl (C. Henquet).
0920-9964/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2010.05.031

hypothesis of schizophrenia. Rened and modied in subsequent years, this theory remains central to theories about
psychosis (Carlsson and Carlsson, 2006; Laruelle et al., 2003;
Lieberman et al., 1997; Murray et al., 2008b).
Recent developments suggest that the dopamine hypothesis may need to be re-examined in order to incorporate recent,
seemingly unrelated research ndings concerning risk factors
for the development of psychosis (Di Forti et al., 2007). One
example concerns the insight that use of cannabis may impact
negatively on mental health (Murray et al., 2007). Cannabis use
is associated with poor outcome in existing psychotic illness
(Zammit et al., 2008) and has consistently been shown to
increase the risk to develop psychotic symptoms or disorder in
healthy individuals (Henquet et al., 2005b; Moore et al., 2007;
Semple et al., 2005). However, the vast majority of cannabis
users never develop any psychotic symptoms or mental health

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problems. Thus, cannabis is not a sufcient cause for psychotic

illness but rather may constitute a component cause, interacting with other environmental and genetic factors (Henquet
et al., 2008).
Although the epidemiological link between cannabis and
psychosis has been investigated extensively, the biological basis
of this association remains poorly understood (see Box 1 for a
summary of main ndings). Recent research suggests that
heavy long-term cannabis use, particularly when started during
adolescence, may lead to abnormalities in brain structure
(Arnone et al., 2008; Matochik et al., 2005; Welch et al., 2010;
Wilson et al., 2000; Yucel et al., 2008), but it seems unlikely that
the use of cannabis increases the risk of psychosis by inducing
major structural brain changes (DeLisi, 2008; Linszen and van
Amelsvoort, 2007). Its neurochemical interactions with neurotransmitters such as dopamine, however, are in urgent need of
further investigation (DeLisi, 2008). Pharmacological and geneknock-out studies have demonstrated that the central effects of
THC are mediated via partial agonism at cannabinoid 1
receptors (CB1 receptors), the primary binding site of endogenous cannabinoids (eCBs) (Pertwee, 2006). Expression of CB1
receptors is high in the hippocampus, cerebellum, basal ganglia,
prefrontal cortex (PFC), amygdala and substantia nigra pars
reticulata (Freund et al., 2003). Endocannabinoids, of which the
best characterized are anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG), are synthesized in and released from postsynaptic neurons but act
predominantly at CB1 receptors located on neighboring presynaptic terminals, that is, they act in a retrograde fashion
(Devane et al., 1992; Mechoulam et al., 1995; Wilson and Nicoll,
2001). Activation of CB1 receptors inhibits pre-synaptic
neurotransmitter release (direct targets are GABA and gluta-

mate terminals) and consequently modulates several neurotransmitter systems, including the dopamine system
(Chevaleyre et al., 2006). Furthermore, it is thought that
principal output neurons, such as mesencephalic dopamine
neurons, regulate their excitatory and inhibitory inputs via
retrograde eCB signaling (Chevaleyre et al., 2006).
In order to discuss how modulation of dopaminergic
neurotransmission by cannabinoids, including THC, may
contribute to the development of psychotic symptoms and
ultimately schizophrenia following persistent cannabis use,
the literature (using the databases Pubmed and Psychinfo) was
searched systematically for relevant experimental, clinical and
epidemiological ndings across different disciplines, including
molecular, neurobiological and behavioral ndings. This review
will therefore rst outline the involvement of dopamine in the
pathophysiology of schizophrenia, with an emphasis on
mechanisms of how dopaminergic dysregulations may translate into delusions and hallucinations. Subsequently, the
question of how cannabinoids, such as THC, may impact on
dopaminergic pathways to provoke psychosis will be examined. We also address the potential role of cannabinoids in
sensitization (Collip et al., 2008) processes in psychosis.
2. What are the dopaminergic pathways to psychosis?
The involvement of dopamine in the pathophysiology of
schizophrenia is still central to the understanding of psychosis
(Carlsson, 1977, 2006; Guillin et al., 2007). The classic
dopamine hypothesis of schizophrenia assumed a hyperfunctioning dopamine system to be the central feature of schizophrenia symptomatology, primarily in terms of the positive
symptom cluster (Carlsson, 1978; Kapur and Mamo, 2003).

Box 1
What do we know about the association between cannabis and psychosis?
1. Epidemiological studies have shown that cannabis use increases the risk of developing psychotic symptoms in a
doseresponse fashion, independent of possible confounding factors and self-medication effects. Effects may be
more prominent during early adolescence (Arseneault et al., 2002; Konings et al., 2008; McGrath et al., 2010;
Moore et al., 2007).
2. Cannabis use is neither a necessary nor a sufficient cause of psychotic illness. Therefore, the link between
cannabis use and psychosis may best be understood in terms of geneenvironment interactions (Henquet et al.,
2008):
a. Patients with a diagnosis of schizophrenia are more sensitive to the cognitive and behavioral effects of
cannabis than controls (D'Souza et al., 2005).
b. High schizotypy, psychotic disorder and COMT val158met genotype have been found to moderate
sensitivity to the psychosis-inducing effects of cannabis (Caspi et al., 2005; D'Souza et al., 2005; Henquet
et al., 2005a, 2006; van Os et al., 2002).
c. Environmental risk factors may induce differential sensitivity to cannabis in terms of psychosis risk, e.g.
childhood trauma (Harley et al., 2009; Houston et al., 2008) and urban rearing environment (Henquet et al.,
2009).
3. Cumulative exposure to environmental risks may increase the risk for psychosis in an additive fashion. The
concept of behavioral sensitization may therefore provide a plausible mechanism for the link between cannabis
and psychosis (Collip et al., 2008; Cougnard et al., 2007; Dominguez et al., 2009).
4. Although some studies did not find cannabis-use related changes in brain morphology (Delisi et al., 2006), others
do suggest that long-term heavy cannabis use may lead to structural brain changes (Matochik et al., 2005; Welch
et al., 2010; Yucel et al., 2008), possibly related to early onset of use (Arnone et al., 2008; Wilson et al., 2000).
5. Alterations in the endocannabinoid system have been revealed in schizophrenia, in particular increased levels of
anandamide and increased CB1 receptor availability, independent of cannabis use (Dean et al., 2001; Koethe et
al., 2007; Leweke et al., 1999).

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Additional formulations later proposed that reduced dopaminergic activity in prefrontal cortical brain regions might be
linked to negative and cognitive symptoms (Lynch, 1992;
Murray and Lewis, 1987; Weinberger, 1987). Although current
models of schizophrenia pathophysiology also consider other
neurotransmitters such as glutamate and GABA (Carlsson,
2006; Laruelle, et al., 2003), dopamine is still assumed to play a
key role in the emergence and experience of positive as well as
negative and cognitive symptoms in schizophrenia (Howes and
Kapur, 2009; Murray et al., 2008b).
2.1. The subcortical pathway
Indirect evidence supporting the notion of a hyperfunction
in the mesolimbic dopamine system comes from observations
that amphetamine, through a mechanism of hyperdopaminergia, induces positive psychotic symptoms whereas antipsychotic medications, blocking dopamine D2 receptors,
dampen symptoms (Carlsson, 1978; Kapur et al., 2003; Laruelle
and Abi-Dargham, 1999; Seeman, 1987). Direct empirical
support for hyperdopaminergia, showing alterations in the
mesolimbic dopamine system of schizophrenia patients, was
initially elusive. While some studies found increased striatal D2
receptor availability in schizophrenia patients compared to
healthy controls (Abi-Dargham et al., 2000; Hietala et al., 1994;
Seeman, 1987), others failed to reveal such a difference
(Martinot et al., 1990; Nordstrom et al., 1995; Pilowsky et al.,
1994). However, more recent evidence suggests that it is
elevated pre-synaptic dopamine function that is associated
with schizophrenia (reviewed in Howes and Kapur, 2009).
Furthermore, elevated pre-synaptic dopamine function was
also reported in individuals with prodromal signs of schizophrenia (Howes et al., 2009) and in rst-degree relatives of
patients with schizophrenia (Huttunen et al., 2008).
Assuming that mesolimbic hyperdopaminergia plays an
important role in the emergence and experience of psychotic
symptoms, the question arises how dopaminergic alterations in
mesolimbic brain regions actually give rise to the experience of
hallucinations and delusions. Altered salience attribution has
been suggested as a possible mechanism (Kapur et al., 2005).
The mesolimbic dopamine system projects from the ventral
tegmental area (VTA) to, among other areas, the ventral
striatum. Burst ring of dopamine neurons in the VTA markedly
increases dopamine release in the striatum (Floresco et al.,
2003) and is believed to mediate the perception of salience or
reward associated with stimuli (Berridge and Robinson, 1998;
Schultz, 1998; Stuber et al., 2008). The phasic bursts of
dopamine release, which are highly dependent on glutamatergic excitatory afferents, have been shown to be regulated by
constant low-frequency tonic ring of dopamine neurons (Goto
et al., 2007). Tonic dopamine tone in turn is under control of
GABAergic inhibition. Increased levels of tonic dopamine ring
may result in decreased amplitude of phasic dopamine burst
ring, thus dampening responsivity of this system. Decreased
tonic dopamine levels, on the other hand, may result in a
heightened responsivity of the phasic dopamine component
(Bilder et al., 2004; Goto et al., 2007).
Kapur has suggested that, in schizophrenia, dopamine
dysregulation results in a psychological state of aberrant
salience, in which mundane events and ideas may be attributed
with undue signicance (Kapur et al., 2005). Thus, a hyperdo-

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paminergic state in striatal brain regions is believed to create a

condition in which logically unconnected ideas and associations are weaved together and elaborated upon, eventually
leading to the emergence of a delusional system.
Only a few experimental studies have actually studied the
process of salience attribution in schizophrenia. This process
has been related to associative and reinforcement learning, in
which what is called reward prediction error plays a key role
(Smith et al., 2006). It is hypothesized that previous reward
outcomes are used to form a reward prediction, which is then
compared to the actual current reward. The difference between
reward prediction and actual outcome is referred to as the
reward prediction error (Smith et al., 2006). Reward prediction
error signaling is mediated, in animals as well as in humans, by
dopamine activity in ventral midbrain and striatum (Abler
et al., 2006; Bayer and Glimcher, 2005; D'Ardenne et al., 2008;
Pessiglione et al., 2006). Compared to healthy controls, patients
with psychosis seem to exhibit aberrant reward prediction and
reward-related learning, both at the behavioral and the neural
level (Jensen et al., 2008; Juckel et al., 2006). G. K. Murray et al.
(2008a) employed a functional magnetic resonance imaging
(fMRI) paradigm using a monetary reward task, and found that
patients were less able to distinguish between neutral and
rewarding stimuli. This was also evident at the brain activation
level as patients with schizophrenia showed an increased
midbrain response to neutral prediction, but attenuated activity
in response to reward prediction (Murray et al., 2008a). Taken
together, these results support the notion that hyperactivity in
the mesolimbic dopamine system promotes psychotic symptoms by disrupting the process of salience attribution.
2.2. The cortical pathway
In addition to mesolimbic dopamine hyperfunction, schizophrenia has been associated with decreased activity in the
mesocortical dopamine pathway, which projects from the VTA
to, among other areas, the PFC (Abi-Dargham, 2004). As
dopaminergic neurotransmission at prefrontal dopamine D1
receptors is critical for PFC functioning and cognition (Arnsten,
2007; Goldman-Rakic, 1999), cortical hypodopaminergia has
been associated with the cognitive and negative symptoms of
schizophrenia, such as impairments in working memory and
executive functioning as well as anhedonia and attened affect
(Abi-Dargham et al., 2002; Goldman-Rakic et al., 2004; Lynch,
1992). Evidence for this, however, has been mainly indirect and
primarily stems from neuroimaging studies investigating
prefrontal D1 receptor availability (Abi-Dargham and Moore,
2003; Erritzoe et al., 2003).
2.3. Subcortical and cortical dopamine: two distinct pathways?
As outlined above, schizophrenia may be associated with
dopamine imbalances in both cortical and subcortical brain
regions. Furthermore, the mesocortical dopamine pathway,
projecting from VTA to PFC, has been shown to exert inhibitory inuences on mesolimbic dopamine activity (Deutch,
1992; Deutch et al., 1990). It has thus been proposed that
mesolimbic hyperdopaminergia in schizophrenia may result
from failed inhibition by cortical dopamine (Deutch, 1992;
Deutch, et al., 1990). Meyer-Lindenberg et al. (2002) used
Positron Emission Tomography to study regional cerebral

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blood ow (with [15O]H2O as radiotracer) and pre-synaptic

dopaminergic function (with 6-[18F]DOPA as radiotracer) in
the same session. Patients with a diagnosis of schizophrenia
exhibited signicantly lower levels of prefrontal cortical
activity during an executive functioning task, compared to
controls. Furthermore, the decrease in PFC activity in the patient
group was predictive of a relative increase in striatal dopaminergic function, indicating that frontal hypodopaminergia leads
to mesolimbic hyperdopaminergia.
While the above suggests that striatal dopamine transmission is under the inuence of PFC dopamine, Kellendonk and
colleagues have demonstrated the opposite as well: mesolimbic dopamine activity may exert inuences on prefrontal
dopamine function (Bach et al., 2008; Drew et al., 2007;
Kellendonk et al., 2006). Transgenic mice over-expressing
striatal D2 receptors were found to be characterized by
impairments in working memory and executive functioning,
both of which are functions that critically require prefrontal
dopamine activity. At the molecular level, over-expression of
striatal D2 receptors was associated with increased dopamine
turnover in the PFC and increased activation of prefrontal D1
receptors (Kellendonk et al., 2006). It was further demonstrated that over-expression of striatal D2 receptors resulted in
disturbed motivational and associative learning (Bach et al.,
2008; Drew et al., 2007), core features of schizophrenia. There is
thus some evidence that the cortical and subcortical dopamine
pathways are subject to bi-directional inuences.
3. Does THC inuence dopaminergic pathways to psychosis?
Is it possible that some of the psychosis-inducing effects of
exogenous cannabinoids such as THC may be mediated by
dopamine? THC has been shown to affect endocannabinoid
neurotransmission and much evidence indicates that eCBs are
key components in the regulation of dopamine neurotransmission (Cheer et al., 2007; Lupica and Riegel, 2005; Maldonado
et al., 2006). Animal research furthermore suggests that
exogenous cannabinoids like THC facilitate dopaminergic neurotransmission in several regions of the brain, including striatum
and PFC (Cheer et al., 2004; Chen et al., 1990; Tanda et al., 1997).

3.1. Do cannabinoids inuence subcortical dopamine?

Dopamine neuronal ring in the VTA is controlled by excitatory glutamatergic and inhibitory GABAergic inputs, which in
turn are reciprocally modulated by eCBs released from dopaminergic dendrites (Fig. 1) (Lupica and Riegel, 2005; Matyas et al.,
2008; Melis et al., 2004). Findings from numerous animal studies
have shown that the overall result of exogenous CB1 receptor
agonists, such as THC, is to evoke burst ring in the VTA and
thereby increase extracellular dopamine concentrations in
striatal brain regions (Fig. 1) (Cheer et al., 2004; French et al.,
1997; Riegel and Lupica, 2004; Tanda et al., 1997). Recently, the
acute effects of THC on striatal dopamine transmission have been
investigated in human volunteers, using experimental Positron
Emission Tomography (PET) paradigms. However, ndings were
inconsistent. While one study reported a THC-induced increase in
striatal dopamine release (Bossong et al., 2009), another study
failed to detect such an effect (Stokes et al., 2009). An earlier
Single Photon Emission Computed Tomography (SPECT)
study, however, did nd increased dopamine release in the
striatum of a single patient with schizophrenia following
cannabis exposure; in addition, the dopamine response in the
patient was followed by an acute worsening of positive psychotic
symptoms (Voruganti et al., 2001). Researchers have therefore
asked whether D2 blockade might prevent such an effect.
D'Souza and colleagues showed that haloperidol (a D2 antagonist) did not signicantly inhibit acute THC-induced psychopathology in healthy subjects, which was in agreement with their
earlier nding that ongoing D2 blockade in schizophrenia
patients (i.e. anti-psychotic treatment) offered no protection
against THC-elicited acute positive psychotic symptoms (D'Souza
et al., 2005, 2008). Liem-Moolenaar et al. (2010) on the other
hand demonstrated that pre-treatment with haloperidol did
reverse THC-induced increases in Positive and Negative Syndrome Scale scores in healthy volunteers (Liem-Moolenaar et al.,
2010).
At the molecular level, both dopamine and eCBs are
fundamental for the synaptic re-organisation which underpins
new striatal learning (Calabresi et al., 2007; Hilario et al., 2007;
Kreitzer and Malenka, 2005a; Yin et al., 2009). So called spike-

Fig. 1. The convergence of dopamine and the endocannabinoids in the VTA. A. Firing patterns in midbrain dopaminergic (DA) neurons are inuenced by a host of
excitatory (glutamatergic, GLU, as indicated in grey) and inhibitory (GABAergic, GABA, as indicated in grey) inputs. DA neurons regulate neighboring pre-synaptic
terminals via retrograde endocannabinoid (2-AG, as indicated in blue) signaling. B. When exogenous cannabinoids (THC, as indicated by cannabis leaves) bind to
CB1 receptors located on glutamatergic (GLU) and GABAergic (GABA) terminals, retrograde endocannabinoid signaling (2-AG, as indicated in blue) is disrupted
and stimulation of CB1 receptors by THC inhibits glutamate and GABA release.

R. Kuepper et al. / Schizophrenia Research 121 (2010) 107117

timing dependent plasticity (STDP) has an absolute requirement

for near-simultaneous electrical activity in pre-synaptic terminals (cortical inputs) and the dendritic spines of medium spiny
neurons (MSNs), the major striatal neuron. Crucially, change
occurs rapidly, after only one or two spike pairings, conditions
which are feasible under normal physiological conditions
(Pawlak and Kerr, 2008; Shen et al., 2008). In the striatum,
long-term depression (LTD) of cortical inputs onto MSNs has
repeatedly been shown to be mediated by retrograde endocannabinoid signaling (Gerdeman et al., 2002; Robbe et al., 2002;
Ronesi et al., 2004). In addition corticostriatal LTD often requires
the activation of D2 receptors by dopamine (Fig. 2) (Kreitzer and
Malenka, 2005b; Pawlak and Kerr, 2008; Yin and Lovinger, 2006).
For instance, in mice in which dopamine was depleted by
reserpine or 6-hydroxy-dopamine, LTD of corticostriatal synapses was absent but could be restored by administration of the D2
receptor agonist quinpirole; and quinpirole combined with an
inhibitor of eCB clearance showed synergistic effects in improving the severe psychomotor impairments associated with
dopamine depletion (Kreitzer and Malenka, 2007).
New insights into the roles of dopamine and eCBs in striatal
learning and plasticity have been provided by Shen et al. (2008).
They investigated plasticity at identied populations of striatal
MSNs. MSNs can be divided into two roughly equally sized
groups. MSNs belonging to the direct pathway express D1
receptors while MSNs of the indirect pathway express D2
receptors. Shen et al. (2008) showed that cortical inputs onto
both MSN sub-types exhibit bi-directional plasticity (strengthening or weakening), dependent on the pattern of ongoing
neuromodulation: At D2 MSNs, LTD was expressed presynaptically via retrograde endocannabinoid signaling, but

111

only as long as dopamine was present at D2 receptors. Cojoint adenosine A2a receptor and glutamate NMDA receptor
stimulation could overpower LTD and trigger LTP instead
(Fig. 2). For completeness, the opposite was observed at D1
expressing MSNs. Here, endocannabinoid-mediated LTD was
induced in the absence of dopamine from D1 receptors, whereas
D1 agonists led to the induction of LTP (Shen et al., 2008). These
ndings indicate that eCBs, glutamate, adenosine and dopamine
act in concert to promote plasticity at simultaneously active
corticostriatal synapses. One could speculate that under tonic
D2 receptor stimulation, active MSN's belonging to the indirect
pathway weaken their cortical inputs via endocannabinoidmediated LTD (Fig. 2) and a net positive signal would be
returned to the cortex, facilitating an emerging psychomotor
program. In contrast, if extracellular dopamine levels fall, albeit
transiently following the non-arrival of a predicted reward
(Schultz, 2002), the indirect pathway would tend towards LTP
(strengthening), and an overall negative signal would be
returned to the cortex. Failure to signal the non-arrival of
reward, that is, failure to inhibit tonic D2 signaling would be
predicted to have major effects on corticostriatal loops and
psychomotor health.
Returning to the pharmacology, caffeine, an antagonist at A2A
receptors (LTP blockade), has been shown to exacerbate positive
psychotic symptoms as well (Broderick and Benjamin, 2004;
Hedges et al., 2009), while A2A receptor agonists (LTP promotion)
such as CGS 21680 appear to have anti-psychotic properties
(Andersen et al., 2002; Weiss et al., 2003). Further, inhibitors of
adenosine re-uptake or metabolic degradation have antipsychotic properties in schizophrenia patients (Akhondzadeh
et al., 2005, 2000; Brunstein et al., 2005; Dickerson et al., 2009). In
addition, it is widely acknowledged that CB1 receptor agonists,
such as THC (LTD promotion), are psychotomimetic and
constitute a component risk factor for the development of
schizophrenia, whereas cannabidiol (CBD) an allosteric inverse
agonist at CB1 receptors (and inhibitor of adenosine re-uptake)
has shown promise as an anti-psychotic (Bhattacharyya et al.,
2010; Leweke et al., 2000; Pertwee, 2007; Zuardi et al., 2008).
Overall, pharmaceutical manipulations which alter the
balance of corticostriatal synapses of the indirect pathway
display consistent pro- or anti-psychotic properties. Drugs
which weaken cortical inputs onto MSNs of the indirect pathway
(LTD) appear to be pro-psychotic. In contrast, drugs which favor
a shift towards strengthening (LTP) of the same synapses appear
to be anti-psychotic (Morrison and Murray, 2009).
3.2. Do cannabinoids interact with the cortical dopamine pathway?

Fig. 2. Striatal plasticity at medium spiny neurons belonging to the indirect

pathway. Cortical bers form glutamatergic synapses (GLU) at the medium spiny
neuron (MSN). At these synapses, endocannabinoid-mediated (as indicated in
blue) long-term depression (LTD) is induced as long as dopamine (as indicated in
orange) is present at D2 receptors. In the absence of dopamine or in the presence
of A2A receptor agonists (as indicated in grey) long-term potentiation (LTP) is
induced.

In addition to inuencing dopaminergic neurotransmission in the mesolimbic pathway, THC also seems to affect
dopaminergic neurotransmission in the PFC, at least as far as
evidence from animal studies is concerned (Chen et al., 1990;
Verrico et al., 2003). At the human behavioral level, the acute
effects of THC include cognitive impairment in domains such
as memory and attention (Lundqvist, 2005; Ranganathan and
D'Souza, 2006). Furthermore, short term cognitive impairment following cannabis use has been suggested to overlap
largely with cognitive dysfunctions as observed in schizophrenia (Solowij and Michie, 2007). It is well established that
cognitive performance strongly depends on optimal prefrontal dopamine levels, with too low as well as too high levels of

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dopamine being equally detrimental to cognition (Arnsten,

2007). In rats, acute administration of THC has been shown to
increase prefrontal dopamine levels (Pistis et al., 2002, 2001),
and to impair spatial working memory (Jentsch et al., 1997).
Furthermore, Pistis et al. (2002) found that THC-induced
increases in prefrontal dopamine could be prevented by
administration of rimonabant, a CB1 receptor antagonist. This
suggests that the effects of THC on dopamine transmission are
mediated by the activation of CB1 receptors (Pistis et al.,
2002). In contrast to these acute effects, repeated exposure to
THC has been found to result in a reduction of dopamine
metabolism in the rat PFC (Jentsch et al., 1998; Verrico et al.,
2003). The mechanism underlying the differences associated
with acute and repeated exposure needs to be investigated
further sensitization, as discussed below, may provide a
concept to advance this eld. The effects of repeated exposure
again were accompanied by cognitive impairment, which
follows the inverted U-curve association between dopamine
levels and cognitive performance (Verrico et al., 2004). In an
experimental study in human volunteers, carriers of the Val
allele of the COMT (catechol-o-methyltransferase) val158met
polymorphism who had repeatedly used cannabis were more
sensitive to both the psychosis-inducing and the cognitive
effects of THC than Met allele carriers (Henquet et al., 2006).
The Val allele of this common polymorphism is associated
with higher enzymatic activity of COMT and accordingly
lower levels of prefrontal dopamine (Akil et al., 2003).
Although THC has been found to affect dopaminergic
processes in PFC, the nature of endocannabinoid function in
the human PFC remains largely unknown (Egerton et al., 2006).
CB1 receptors are densely expressed in the PFC (Herkenham
et al., 1990) and studies on CB1 receptor knock-out mice have
provided insights in prefrontal endocannabinoid function. By
using the Morris water maze paradigm, Varvel and Lichtman
(2002) showed that CB1 receptor knock-out mice did not differ
from wild type control mice with regard to recognition
memory. However, CB1 receptor knock-out mice made
signicantly more perseveration errors after the location of
the platform had been changed. In addition, administration of
THC was found to signicantly worsen mnemonic performance
in the wild type control mice, while task performance of the CB1

receptor knock-out was unaffected (Varvel and Lichtman,

2002). Since memory function partly relies on prefrontal
brain functioning, it may be hypothesized that the observed
performance impairments are attributable to THC effects in
prefrontal brain regions.
Taken together, it seems that the repeated administration
of THC alters PFC function and impairs cognition by acting on
dopamine signaling via activation of CB1 receptors. In particular, repeated exposure to THC has been found to decrease
dopamine levels in the PFC. As decreased prefrontal dopaminergic function is postulated to constitute a core feature of
schizophrenia pathophysiology (Abi-Dargham and Moore,
2003), cannabis use may increase the risk for psychosis partly
by contributing to a hypodopaminergic state in the PFC.
Taking into account THC effects in striatal regions, it thus
appears that THC aggravates dopaminergic imbalances by
increasing the dopaminergic tone in striatal regions of the
brain, while, when administered repeatedly, decreasing dopamine levels in prefrontal regions of the brain. Evidence to
support this idea predominantly stems from animal research
and it remains speculative whether this applies to humans as
well.
3.3. Does dopamine-mediated behavioral sensitization constitute
a potential mechanism behind the cannabispsychosis
relationship?
The above suggests that repeated exposure to THC may
cause changes in the dopamine system and subsequently
progressively greater behavioral responses over time (Cadoni
et al., 2001, 2008). A process of dopamine sensitization thus
may constitute a possible mechanism by which environmental
factors such as stress or stimulant drugs contribute to psychosis
risk (Fig. 3) (Collip et al., 2008; Myin-Germeys et al., 2005;
O'Daly et al., 2005). Rats pretreated with THC twice a day over a
period of three days, were found to be more sensitive to the
locomotor effects of a THC challenge, after a 14-day washout
period, compared to rats that had not been pretreated (Cadoni
et al., 2001). Neurobiologically, the process of sensitization is
thought to involve dopaminergic signaling in the mesolimbic
pathway, as sensitization to stimulants, such as amphetamine,

Fig. 3. Sensitization Behavioral Phenotype. Person A has normal developmental expression of subclinical psychotic experiences that are mild and transient.
Person B has similar expression but longer persistence due to additional environmental exposure such as stress (as indicated by zigzag arrows). Person C has
prolonged persistence and subsequent transition to clinical psychotic disorder possibly due to severe repeated environmental exposure such as repeated cannabis
use (as indicated by cannabis leaves) in addition to prior stress. Adapted with permission from Collip et al., 2008.

R. Kuepper et al. / Schizophrenia Research 121 (2010) 107117

has frequently been shown to lead to increased activity of

dopamine neurons in the VTA (Lodge and Grace, 2008) and
increased dopamine release in the striatum (Boileau et al.,
2006; Chen et al., 2001; Patrick et al., 1991; Robinson and
Becker, 1982) (Cadoni et al., 2008).
Cross-sensitization between stimulant drugs and stress
has been shown as well. de Jong et al. (2005) demonstrated
that mice, after being exposed to psychosocial stress using a
social defeat paradigm, exhibited an enhanced locomotor
response to an amphetamine challenge compared to mice
that had not been stressed previously. Using repeated
maternal separation as a psychosocial stress paradigm,
Kikusui et al. (2005) found that mice which were kept
separated from their mothers from day 1 to day 13 in the
post-natal period, were more sensitive to the locomotor
effects of a cocaine challenge at day 50, than mice which had
not been stressed (Kikusui et al., 2005). Most likely, crosssensitization between stress and stimulants is mediated by
striatal dopamine, as cocaine-induced striatal dopamine
increase was higher in rats which had been repeatedly preexposed to a stressor in form of foot shocks (Prasad et al.,
1995; Sorg and Kalivas, 1991).
Although THC shows cross-sensitization with other drugs
such as amphetamine, heroin and morphine (Cadoni et al.,
2001; Lamarque et al., 2001), only a few studies have
investigated cross-sensitization between THC and stress.
Findings from animal studies have shown that the effects of
THC seem to be contingent on the environmental conditions
under which THC is administered (MacLean and Littleton,
1977). In rats housed under normal conditions (housed in
groups with water and food freely available) the exposure to
THC only caused slight behavioral changes in form of mild
sedation and hypothermia and did not alter dopaminergic
neurotransmission. In contrast, under stressful housing
conditions (isolation and food deprivation), THC administration had marked behavioral consequences, including immobility and hyperactivity. Furthermore, exposure to THC in the
stressful environment resulted in signicantly increased
striatal dopamine uptake (MacLean and Littleton, 1977).
Mokler et al. (1987) showed that in rats, pre-treatment with
THC on days 4, 6 and 8 postnatally changed the behavioral
response to electric foot shocks in the adult period. THC pretreatment furthermore altered the stress-induced dopamine
response in the hypothalamus and frontal cortex (Mokler
et al., 1987). Houston et al. (2008) investigated interaction
between early cannabis use and childhood sexual trauma on
the development of psychotic disorder in a large populationbased sample (N = 5877). The data were suggestive of crosssensitization between stress and early cannabis exposure, as
the effect of cannabis on psychosis outcome was signicant
only in the individuals who had been exposed to trauma
during early childhood. The interactive effective of cannabis
use and childhood trauma on psychosis risk was replicated by
Harley et al. (2009).
At the molecular level, sensitization processes seem to
involve endocannabinoid signaling. Filip et al. (2006) demonstrated that administration of rimonabant, a CB1 receptor
antagonist potently blocked the expression of hypersensitivity to cocaine (Filip et al., 2006). Further, Corbille and
colleagues showed that sensitization following a single dose
of cocaine or amphetamine was reduced in CB1 receptor

113

knock-out mice (Corbille et al., 2007) and CB1 receptor

knockouts failed to sensitize to amphetamine administered
daily for 7 days (Thiemann et al., 2008b). In addition, it was
shown that mice treated with the CB1 receptor antagonist
AM251 in both a single and 7 day dosing paradigm showed a
reduction in the development of sensitization to stimulants
(Thiemann et al., 2008a). Finally, Chiang and Chen showed
that microinjection of the CB1-R inverse agonist/antagonist
SR147778 directly into the ventral striatum potently blocked
the expression of hypersensitivity to methamphetamine
(Chiang and Chen, 2007).
Thus, despite some contradictory ndings, research
suggests an important role for the endocannabinoid system
in the neurochemical processes underlying sensitization.
Repeated exposure to THC may sensitize an individual to
the psychotic effects of THC, in interaction with other
environmental risk factors such as stress, and this may be
particularly relevant for individuals genetically at risk of
dopamine dysregulation (Henquet et al., 2008).
4. Conclusion
Although advances in the understanding of endocannabinoid function have been made, the endocannabinoid system
is still far from being understood and its interactions with
other neurotransmitter systems including the dopamine
system are complex. While in the VTA, dopamine seems to
be downstream of endocannabinoid function, it appears that,
in the ventral striatum, part of dopaminergic neurotransmission is actually upstream of endocannabinoid function, at
least concerning its involvement in plasticity at striatal
MSN's. Accordingly, although THC might stimulate burst
ring of DA neurons in the VTA and as a consequence increase
DA levels in the striatum, here THC might additionally exert
its effects by directly inuencing synaptic plasticity (Morrison
and Murray, 2009).
Most evidence to date, however, stems from animal research
and to date, a clear answer to the question of whether there is a
case for dopamine mediating the psychosis-inducing effects of
cannabis cannot be given. There is a lack of studies investigating
the acute and long-term effects of THC on dopaminergic
neurotransmission, learning and reward experience in humans.
Advances in imaging techniques, such as the development of
novel radiotracers, as well as a growing understanding of the
biology and psychology of positive psychotic symptoms, hold
promise for the future study of how the biological underpinnings of the cannabispsychosis relationship may alter
experience in such a way that psychotic symptoms ensue.
Role of the funding source
None.
Contributors
All authors contributed to and approved the nal manuscript.

Conicts of interest
J. van Os is/has been an unrestricted research grant holder with, or has
received nancial compensation as an independent symposium speaker
from Eli Lilly, BMS, Lundbeck, Organon, Janssen-Cilag, GSK, AstraZeneca,
Pzer and Servier, companies that have an interest in the treatment of
psychosis. Robin Murray has received honoraria as an independent
symposium speaker from Eli Lilly, BMS, Lundbeck, Organon, Janssen-Cilag,

114

R. Kuepper et al. / Schizophrenia Research 121 (2010) 107117

GSK, AstraZeneca, Pzer and Servier, companies that have an interest in the
treatment of psychosis.
Acknowledgments
C. Henquet was supported by the Dutch Medical Research Council (VENI
grant). P. Morrison was funded by the MRC.

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