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ANNUAL
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Epidemiological,
Neurobiological, and Genetic
Clues to the Mechanisms
Linking Cannabis Use to Risk
for Nonaffective Psychosis
Ruud van Winkel1,2 and Rebecca Kuepper1
1
Department of Psychiatry and Psychology, School of Mental Health and Neuroscience,
European Graduate School of Neuroscience (EURON), South Limburg Mental Health
Research and Teaching Network (SEARCH), Maastricht University Medical Center,
Maastricht, The Netherlands; email: ruud.vanwinkel@maastrichtuniversity.nl
2
University Psychiatric Center, Catholic University Leuven, 3070 Kortenberg, Belgium
Annu. Rev. Clin. Psychol. 2014. 10:767–91
Keywords
First published online as a Review in Advance on
January 20, 2014
THC, cannabidiol, psychosis, schizophrenia, gene-environment interaction
The Annual Review of Clinical Psychology is online at
clinpsy.annualreviews.org
Abstract
This article’s doi:
10.1146/annurev-clinpsy-032813-153631
c 2014 by Annual Reviews.
Copyright All rights reserved
Epidemiological studies have shown that the association between cannabis
and psychosis is robust and consistent across different samples, with compelling evidence for a dose-response relationship. Because longitudinal work
indicates that cannabis use precedes psychotic symptoms, it seems reasonable
to assume a causal relationship. However, more work is needed to address
the possibility of gene-environment correlation (for example, genetic risk
for psychosis causing onset of cannabis use). Moreover, knowledge about
underlying biological mechanisms linking cannabis use and psychosis is still
relatively limited. In order to understand how cannabis use may lead to an
increased risk for psychosis, in the present article we (a) review the epidemiological, neurobiological, and genetic evidence linking cannabinoids and psychosis, (b) assess the quality of the evidence, and finally (c) try to integrate the
most robust findings into a neurodevelopmental model of cannabis-induced
psychosis and identify the gaps in knowledge that are in need of further
investigation.
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Contents
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THE ASSOCIATION BETWEEN CANNABIS AND PSYCHOSIS . . . . . . . . . . . . . . .
Self-Medication or Reverse Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gene-Environment Correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INSIGHTS FROM EPIDEMIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Age of Onset of Cannabis Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Amount of THC and CBD in the Cannabis Consumed . . . . . . . . . . . . . . . . . . . . . .
Interaction with Other Environmental Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INSIGHTS FROM NEUROBIOLOGICAL STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neurobiology of the Endocannabinoid System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of THC on the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of CBD on the Human Brain in Interaction with THC . . . . . . . . . . . . . . . . . . . .
Cannabis Use and the Dopamine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INSIGHTS FROM GENETIC STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evidence for G×E: Omnibus Approach Using Familial Risk . . . . . . . . . . . . . . . . . . . . . .
Candidate Gene Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FACTS, CONTROVERSIES, AND MYTHS IN THE
CANNABIS-PSYCHOSIS RELATIONSHIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Compiling the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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THE ASSOCIATION BETWEEN CANNABIS AND PSYCHOSIS
Since the initial reports linking cannabis use to risk of schizophrenia were published in the late
1960s, a large body of epidemiological studies and meta-analytic work has demonstrated an association between psychotic disorder and cannabis use, with a twofold increased risk for psychotic
disorder associated with the use of relevant amounts of cannabis (Henquet et al. 2005b, Moore
et al. 2007). The association has now been clearly established and quantified, and the issue that
deserves further scrutiny is the nature of this association. Most investigators assume that cannabis
is a “component cause” of schizophrenia, that is, its influence on the risk of schizophrenia is
causal, but cannabis in itself is neither necessary nor sufficient to induce the illness (Murray et al.
2007). However, alternative explanations need to be considered before claims of causality can be
substantiated and possible underlying causal mechanisms can be discussed.
Self-Medication or Reverse Causality
A first alternative explanation for the association between cannabis and psychosis is that emerging
psychotic symptoms may lead to cannabis use as a way of dealing with these symptoms; this
explanation is also referred to as the “self-medication hypothesis.” A number of studies have
addressed this hypothesis using longitudinal designs. Henquet and colleagues (2005a) found no
evidence for self-medication but did find a significant association between cannabis use at baseline
and psychotic symptoms at four-year follow-up in 2,437 individuals from the general population
between ages 14 and 24 years, and similar findings were reported by Fergusson and coworkers from
a seven-year follow-up (from ages 18 to 25) of a New Zealand birth cohort (N = 1,055) (Fergusson
et al. 2003). Ferdinand and coworkers (2005), however, found a bidirectional association between
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cannabis use and psychotic symptoms in a 14-year follow-up of a general population sample of
1,580 individuals (ages 4 to 16 at baseline), as did McGrath and colleagues (2010) in a birth
cohort study of 3,801 individuals assessed at ages 14 and 21 years. Importantly, the latter study
also included a sibling-pair analysis (228 pairs), confirming the association between duration
since first cannabis use (as proxy for age at first cannabis exposure) and incident delusionallike experiences in nonaffected sibling pairs. The inclusion of a sibling-pair analysis reduces the
likelihood that the reported association could be explained by unmeasured residual confounding
because many of the unmeasured potential confounders can be assumed to be similar for both
siblings.
The most methodologically rigorous study so far reported that over a ten-year follow-up
period, in individuals without psychotic symptoms and without cannabis use at baseline, the onset
of cannabis use at the four-year follow-up measurement increased the risk of incident psychotic
symptoms at the nine-year follow-up assessment, and there was no evidence for self-medication
(Kuepper et al. 2011c). Thus, although some studies found evidence for self-medication with
cannabis, this finding was inconsistent across different studies; in contrast, evidence for a temporal
relationship between onset of cannabis use and later psychotic symptoms was strong, significant,
and consistent across different studies (Decoster et al. 2012).
Gene-Environment Correlation
An alternative explanation for the association between cannabis and psychosis is genetic confounding, or gene-environment correlation (for schematic overview, see Figure 1), which would
indicate that genetic risk for schizophrenia also results in higher risk of cannabis use. This could
take the form of genetic confounding (cannabis use does not cause psychosis but is merely an
epiphenomenon of genetic risk for schizophrenia) or environmental mediation of genetic risk
(genetic risk leads to cannabis use, which subsequently leads to even higher risk for psychosis
compared to genetic risk alone). Unfortunately, very few studies have examined the possibility of
gene-environment correlation. Veling and colleagues (2008) studied patterns of cannabis use in
100 patients with psychotic disorder, their unaffected siblings (N = 63), and 100 healthy controls
(matched for age, gender, and ethnicity). In this sample, the healthy siblings displayed rates of
cannabis use similar to those of the healthy controls, a finding that argues against the possibility
that a genetic predisposition for schizophrenia also leads to a genetic predisposition for cannabis
use. Similarly, the Genetic Risk and Outcome in Psychosis (GROUP) investigators did not find
evidence for genetic confounding in a study using a cross-sibling, cross-trait design to investigate
sensitivity to the psychotomimetic effect of cannabis in a sample of 1,120 patients with psychotic
disorder, 1,057 unaffected siblings, and 590 controls [Genetic Risk Outcome Psychos. (GROUP)
Investig. 2011]. By contrast, Smith and colleagues did report that rates of cannabis use were higher
in 53 nonpsychotic siblings of patients with psychotic disorder than in 75 siblings of community
controls (Smith et al. 2008).
These reports have all used family membership as a proxy of genetic risk, which has both
advantages and disadvantages. The largest advantage of such an approach is that it takes into
account the net genetic risk, including the risk brought about by epistatic interactions between
genes (van Os et al. 2008). The major disadvantage is that it is unable to take into account underlying genetic heterogeneity and assumes genetic risk to be equal across different families (which
is unlikely to be the case). Moreover, familial clustering of cannabis use in families with psychosis
does not necessarily indicate a relationship to genetic risk for psychosis, as this may also merely
indicate that cannabis use per se tends to cluster in families. Recent advances in molecular genetics
have resulted in the possibility to quantify genetic risk using polygenic risk scores derived from
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Causal association
Psychosis
Reverse causality
Psychosis
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Genetic confounding
Genetic risk
Psychosis
Genetic risk
Psychosis
Gene-environment interaction
Genetic risk
Psychosis
Figure 1
Representation of the different possible relationships among cannabis use, genetic risk, and expression of
psychosis.
genome-wide association studies (Purcell et al. 2009). Studies using these polygenic risk scores
may therefore provide a novel means to examine the possibility of gene-environment correlation
in a more methodologically rigorous way. At present, given the relative scarcity of data on the
relationship between genetic risk for psychosis and onset of cannabis use, gene-environment correlation cannot be ruled out as (at least a partial) explanation of the association between cannabis
and psychosis.
Interestingly, studies using polygenic risk scores have convincingly shown that polygenic risk
for schizophrenia is not only associated with risk for schizophrenia in independent samples, but also
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for depression and bipolar disorder and, to a lesser extent, autism and attention-deficit hyperactivity
disorder (ADHD) (Cross-Disord. Group Psychiatr. Genomics Consort. et al. 2013). This raises
the question of whether the association between cannabis use and mental disorders is specific to
psychosis. This question was addressed in a meta-analysis conducted by Moore and colleagues,
who reported that, although several studies found an association with affective outcomes, effect
sizes were much smaller than for psychotic outcomes, and fewer attempts were made to address
noncausal explanations such as confounding or reverse causality (Moore et al. 2007).
Given that (a) the association between cannabis and psychosis is robust, (b) the association is
consistent across different samples, (c) compelling evidence exists for a dose-response relationship
(Moore et al. 2007), (d ) the temporal relationship indicates that cannabis use precedes psychotic
symptoms (Kuepper et al. 2011c), and (e) alternative explanations are unlikely to explain the
link between cannabis and psychosis, it seems reasonable to assume a causal relationship. In
order to understand how cannabis use may lead to an increased risk for psychosis, we (a) review
the epidemiological, neurobiological, and genetic evidence linking cannabinoids and psychosis,
(b) assess the quality of the evidence, and (c) integrate the most robust findings and identify the
gaps in knowledge that are in need of further investigation.
INSIGHTS FROM EPIDEMIOLOGY
A number of findings from epidemiological studies may help to elucidate the underlying mechanisms linking cannabis use to risk for psychosis. These include (a) the influence of age of onset of
first use, (b) the importance of the ratio of tetrahydrocannabinol (THC) to CBD (cannabidiol, a
further cannabis constituent) in the type of cannabis consumed, and (c) evidence for interaction
with other epidemiological risk factors for psychosis.
Age of Onset of Cannabis Use
There is good epidemiological evidence that the link between cannabis use and later psychotic
illness may be modulated by age of first exposure. In the prospective Dunedin Multidisciplinary
Health and Development Study, a general population birth cohort study, 1,037 individuals were
assessed and follow-ups were conducted with regard to substance use and psychiatric outcomes,
including psychotic and depressive symptoms as well as disorders, at ages 11, 15, 18, and 26
(Arseneault et al. 2002). When self-reported psychotic symptoms at age 11 were accounted for,
cannabis use at age 15 and 18 was associated with a higher risk of psychotic symptoms at age 26,
and this effect was stronger for earlier cannabis use. Similarly, the association between cannabis
use and a later diagnosis of psychotic disorder was stronger, yet no longer significant, for early
cannabis use (Arseneault et al. 2002). Stefanis and colleagues (2004) investigated the association
between adolescent cannabis use and subclinical positive and negative psychotic symptoms using
cross-sectional data for 3,500 individuals from a Greek birth cohort. Information on psychotic
symptoms was gathered using the Community Assessment of Psychic Experiences questionnaire
(Konings et al. 2006), and cannabis use was assessed by means of self-report. Results showed that
age of onset of use moderated the association between cannabis use and subclinical psychotic
symptoms: Independent of lifetime frequency of use, the association between cannabis use and
psychotic experiences in both the positive and the negative symptom dimension was much stronger
for individuals who had started to use cannabis before the age of 16 compared to those who started
to use cannabis thereafter (Stefanis et al. 2004). A similar interaction between cannabis use and
age of onset of use was revealed in a non-Western sample of 472 individuals randomly drawn from
the general population in Trinidad (Konings et al. 2008). Participants provided information on
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past and current cannabis use and completed the Community Assessment of Psychic Experiences.
After adjustment for age, gender, school type, current use of cannabis, and use of other drugs,
lifetime use of cannabis was associated with psychotic experiences only in individuals who started
using cannabis before the age of 14; no such association was revealed for individuals with later
onset of cannabis use (Konings et al. 2008). More recently, Schubart and colleagues (2011a)
reported that cannabis use before the age of 12 was associated with a fourfold risk for psychiatric
hospitalizations compared to individuals with later initial use in a sample of about 17,000
individuals from the general population. Similarly, Stowkowy and colleagues (2013) reported on
predictors of clinical high-risk symptoms for psychotic disorder and revealed that lower age of
onset of cannabis use was significantly associated with clinical high-risk status. Average age of
onset of use was 15.56 ( ±2.19) and 15.67 ( ±1.67) for healthy controls and individuals with a
family history of psychosis who did not present clinical high-risk symptoms, respectively, whereas
the average age of onset of cannabis use was 13.94 ( ±1.83) in individuals who presented with both
a familial liability and clinical high-risk symptoms of psychosis (Stowkowy & Addington 2013).
In addition, several studies demonstrate worse cognitive performance as well as morphological
brain changes in adults who started to use cannabis before the age of 17 compared to individuals
who started at a later age (Ehrenreich et al. 1999, Pope et al. 2003, Wilson et al. 2000). This
is supported by animal studies demonstrating that exposure to THC during puberty but not
adulthood may lead to long-lasting changes in adult brain function and morphology that are
associated with deficits in cognitive functioning as well as neurobehavioral alterations implicated
in addictive behavior such as increased sensitivity to other drugs of abuse (Klugmann et al. 2011,
Pistis et al. 2004, Realini et al. 2009, Rubino et al. 2009, Schneider et al. 2005, 2008; Schneider &
Koch 2003, 2007; Wegener & Koch 2009). Thus, evidence from both animal and human studies
suggests that puberty represents a period of particular vulnerability for cannabis exposure, which
is not surprising given the neurodevelopmental changes and maturational processes that happen
in the pubertal brain (Bossong & Niesink 2010).
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The Amount of THC and CBD in the Cannabis Consumed
Another important aspect may be the ratio between THC and CBD, which differs considerably
between the various cannabis preparations. In contrast to THC, which has been shown to induce
psychotomimetic effects and anxiety, to worsen cognitive performance, and to have a neurotoxic
effect, CBD has been shown to have neuroprotective, antioxidative, and anti-inflammatory properties and may antagonize the negative effects of THC (Arnold et al. 2012, Zuardi et al. 2012).
In a series of naturalistic studies, Morgan and colleagues analyzed hair samples from regular and
recreational cannabis users and measured the amount of THC and CBD. Cannabis users with
only traces of THC in hair had significantly higher levels of schizophrenia-like symptoms compared to cannabis users with THC + CBD or no cannabinoid in hair (Morgan & Curran 2008).
Individuals who smoked cannabis low in CBD further showed impaired recall on a verbal learning
task while intoxicated with their own cannabis, whereas no such memory impairment was detected
in individuals smoking cannabis high in CBD (Morgan et al. 2010). Notably, the amount of CBD
had no effect on acute psychotomimetic effects, which were elevated in all individuals during intoxication. Finally, it was demonstrated that the memory-impairing effects of cannabis containing
high levels of THC persisted beyond the period of intoxication and that higher THC levels in hair
were associated with greater depression and anxiety, yet irrespective of CBD levels (Morgan et al.
2012). In line with the above, Schubart and colleagues (2011b) found lower levels of self-reported
subclinical positive psychotic but not negative or depressive symptoms in individuals from the
general population (N = 1,877) who smoked cannabis containing high levels of CBD.
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Interaction with Other Environmental Risk Factors
Finally, evidence has emerged recently that environmental risk factors such as early trauma, urbanicity, and cannabis use might interact with each other in increasing psychosis risk (Cougnard
et al. 2007). Subclinical psychotic symptoms constitute a common but transitory developmental
phenomenon in the general population (van Os et al. 2009). However, common, nonclinical developmental expression of psychosis may become abnormally persistent and eventually translate
into psychotic illness when synergistically combined with environmental exposures such as early
trauma, growing up in an urban environment, and cannabis use (Cougnard et al. 2007, Dominguez
et al. 2011, van Os et al. 2009). In line with this, two cross-sectional studies reported that individuals who were exposed to trauma early in life had a much higher risk to develop psychotic outcomes
following adolescent cannabis use compared to those without trauma (Harley et al. 2010, Houston
et al. 2008). The interaction between cannabis use and childhood trauma has since been replicated
in two independent population-based cohorts making use of longitudinal data (Konings et al.
2012) as well as in two further cross-sectional data sets including 7,403 and 2,355 individuals from
the general population, respectively (Houston et al. 2011, Murphy et al. 2013). In contrast, the
prospective German Early Developmental Stages of Psychopathology study did not find evidence
for an interaction between cannabis use and childhood trauma (Kuepper et al. 2011a).
One longitudinal cohort study provided evidence that cannabis use also interacts with urbanicity
in increasing psychosis risk by showing that the association between baseline cannabis use and
psychotic symptoms at follow-up was much stronger in individuals who grew up in an urban
environment than in individuals from rural areas. This effect was independent of baseline cannabis
use, age, gender, socioeconomic status, use of other drugs, and childhood trauma (Kuepper et al.
2011b).
INSIGHTS FROM NEUROBIOLOGICAL STUDIES
In addition to epidemiological studies examining the link between cannabis use and psychosis and
the biology of the endocannabinoid system, additional studies examining the effects of cannabinoids on brain development and function may be helpful to explicate why cannabis use would lead
to acute psychotic symptoms and even nonaffective psychotic disorders such as schizophrenia.
Neurobiology of the Endocannabinoid System
Extensive research throughout the past decade has contributed greatly to the understanding of
the complex molecular basis and function of the endocannabinoid system (Castillo et al. 2012,
Ohno-Shosaku et al. 2012). Two main types of cannabinoid receptors have been identified so
far: CB1 receptors, which are predominantly distributed in the brain, and CB2 receptors, which
are mainly expressed in peripheral tissues, particularly in the immune system (Pertwee 1997,
2008). Recently, the existence of additional cannabinoid receptors has been suggested (Pertwee
2010); the most thoroughly characterized so far is the GPR55, a G-protein coupled receptor
with 13–14% homology with the CB1 receptor and a similar brain distribution (Anavi-Goffer
et al. 2012, Ryberg et al. 2007). Expression of CB1 receptors is high in cortical regions, particularly the frontal regions, basal ganglia, cerebellum, hippocampus, amygdala, and substantia nigra
pars reticulata (Mackie 2005). CB1 receptors are activated by their endogenous ligands, the endocannabinoids, of which the best characterized are anandamide (N-arachidonoylethanolamine) and
2-arachidonoylglycerol (Devane et al. 1992, Mechoulam et al. 1995). Endocannabinoid signaling
has been found to primarily occur in a retrograde fashion, i.e., endocannabinoids are stored and
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released on demand by postsynaptic neurons to activate presynaptic CB1 receptors. Activation
of CB1 receptors leads to the presynaptic inhibition of both inhibitory [gamma-aminobutyric
acid (GABA)] and excitatory (glutamate) neurotransmitter release (Chevaleyre et al. 2006) as
well as manipulation of neuromodulators such as dopamine, noradrenalin, serotonin, and acetylcholine (Lopez-Moreno et al. 2008). It is thought that principal output neurons such as cerebellar
Purkinje cells, cortical pyramidal cells, striatal medium spiny neurons, and mesencephalic
dopamine neurons fine-tune their excitatory and inhibitory inputs via retrograde endocannabinoid signaling (Chevaleyre et al. 2006). Moreover, by controlling both inhibitory and excitatory
neurotransmitter release in regions such as the hippocampus, endocannabinoid-mediated retrograde signaling has been implicated in numerous forms of short- and long-term synaptic plasticity
including phenomena such as depolarization-induced suppression of inhibition or excitation and
presynaptic forms of long-term depression (LTD).
Recently, other, nonretrograde forms of endocannabinoid signaling have also been observed. In
nucleus accumbens and hippocampus, N-arachidonoylethanolamine acting at transient receptor
potential vanilloid receptor type 1 receptors have been found to modulate postsynaptic forms of
LTD (Chavez et al. 2010, Grueter et al. 2010). And in somatosensory cortex, autocrine signaling
in the form of slow self-inhibition has been demonstrated at GABAergic interneurons, where
2-arachidonoylglycerol activation of postsynaptic CB1 receptors led to a decrease in its excitability
via signaling to a G-protein-coupled inwardly rectifying K+ channel (Bacci et al. 2004, Howlett
et al. 2011, Marinelli et al. 2009).
Because of its powerful role in fine-tuning synaptic neurotransmission, the endocannabinoid
system thus appears to be involved in a wide range of neural functions, including neural development, motor control, cognition, and emotional processing.
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Effects of THC on the Brain
Acute effects. In most individuals, the acute, psychological effects of cannabis include relaxation,
sociability, and euphoria, but anxiety, panic attacks, and paranoia also have been reported (Hall &
Solowij 1998, Murray et al. 2007). Furthermore, cannabis use has been shown to affect cognitive
functioning, in particular mnemonic and executive functioning, as well as psychomotor speed,
both acutely and beyond the period of intoxication (Lundqvist 2005, Ranganathan & D’Souza
2006, Solowij & Battisti 2008).
Behaviorally, the administration of cannabis and THC has been particularly associated with
the induction of psychotomimetic effects, characterized by delusional thinking and hallucinations,
closely resembling the symptoms observed in psychosis and schizophrenia. In a double-blind
placebo-controlled randomized laboratory study on the acute psychotomimetic effects of THC
in 22 healthy cannabis users with average age of 29 years, D’Souza and colleagues (2004) demonstrated that 2.5 mg and 5 mg of intravenously administered THC dose-dependently induced
positive and negative psychotic symptoms as well as perceptual alterations, as measured with the
Positive and Negative Syndrome Scale (PANSS) and the Clinician-Administered Dissociative
Symptom Scale, respectively. THC further impaired neuropsychological functioning, which was
most pronounced in the domains of learning and memory (D’Souza et al. 2004). Similar results
were obtained by Morrison and colleagues (Morrison & Stone 2011, Morrison et al. 2009), who
studied the acute effects of 2.5 mg intravenous THC in 22 healthy males with an average age of
28 years. THC significantly increased scores on the PANSS, including both the positive and negative symptom domain, and worsened performance in the domains of verbal learning, attention,
working memory, and reasoning but not verbal fluency. THC-induced cognitive impairment was
unrelated to increased scores on the PANSS (Morrison & Stone 2011, Morrison et al. 2009).
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Functional neuroimaging studies on the acute effects of THC have demonstrated increased
resting activity in several brain areas, including frontal and temporal regions, and increased activation of frontal and anterior cingulate cortex during cognitive processing (Martin-Santos et al.
2010). Animal studies have furthermore demonstrated that acute administration of THC disrupts
retrograde signaling underlying endocannabinoid-mediated synaptic plasticity in areas involved
in learning and memory, such as nucleus accumbens, amygdala, and hippocampus (Azad et al.
2008, Mato et al. 2004).
Chronic effects. Beyond the period of acute intoxication, cannabis use has been shown to affect
not only psychotic symptoms but also neurocognitive function. Solowij and colleagues (2002)
showed in a multisite study including a total of 102 heavy cannabis users and 33 controls that
cannabis users performed significantly worse than nonusers on a number of tests measuring attention and memory. Furthermore, there was a significant association with duration of use, with
long-term users performing worse than shorter-term users (Solowij et al. 2002). More recently,
deficits in sensory gating (Broyd et al. 2013) and directed attention and cognitive flexibility (Battisti
et al. 2010) were demonstrated in chronic cannabis users. Again, the effects were more pronounced
with longer duration of cannabis use and earlier onset of use, supporting the notion that longterm cannabis use leads to impairments in cognitive functioning that endure beyond the period
of intoxication and worsen with increasing years of use. A study in rats demonstrated that hippocampal synaptic plasticity is disrupted for up to 14 days after THC administration (Hoffman
et al. 2007). Furthermore, it has been shown that rats that were chronically treated with THC
during postnatal days 35 to 45 showed alterations in hippocampal neuroplasticity, including lower
total dendritic length and number and reduced spine density, in adulthood compared to vehicletreated animals (Rubino et al. 2009). Thus, THC seems to affect brain processes by disrupting
endocannabinoid-mediated synaptic plasticity in brain regions that are critical for learning and
memory. Whether the neurocognitive effects of chronic long-term use are reversible is unclear;
some level of neuropsychological impairment has been detected in abstinent users (Meier et al.
2012, Solowij 1995). In patients with psychosis, however, recent meta-analyses reported better
cognition in cannabis-using patients (Rabin et al. 2011, Yücel et al. 2012). It has been hypothesized that persons who develop a psychotic disorder in the absence of cannabis use have greater
neurodevelopmental vulnerability compared to their cannabis-using counterparts who, under the
influence of cannabis may have developed psychosis that they would not have developed in the
absence of use (Yücel et al. 2012).
A systematic review of imaging studies published before January 2009 concluded that the
evidence for structural brain abnormalities in cannabis users was minimal, as only three out of
eight included studies found significant differences between users and controls (Martin-Santos
et al. 2010). Yet more recent evidence does suggest cannabis-related changes in the brain
morphology of chronic users, including reduced hippocampal volume and cerebellar white
matter (Demirakca et al. 2011; Solowij et al. 2011, 2013). Some studies further suggest that these
changes happen dose dependently and are related to early age of onset of use (Arnone et al.
2008, Wilson et al. 2000, Yücel et al. 2008). A study of patients with psychosis, their unaffected
siblings, and healthy controls furthermore revealed decreases in cortical thickness associated with
cannabis use in the patients and the unaffected siblings but not the healthy controls (Habets et al.
2011). This result is in agreement with the widespread idea that familial risk and cannabis use act
synergistically to increase risk for psychosis, and it suggests that increased risk may be mediated
by brain structural alterations. Interestingly, evidence from early animal studies also suggests that
contextual factors such as environmental stress alter the brain’s response to THC (Littleton et al.
1976, MacLean & Littleton 1977, Mokler et al. 1987).
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Effects of CBD on the Human Brain in Interaction with THC
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As mentioned previously in this review, THC and CBD differ in their effects on brain function and
mental health. In line with this, functional neuroimaging studies have demonstrated distinctive
and in part opposing effects of THC and CBD on brain activation during cognitive and emotional
processing in various regions of the brain including the hippocampus, amygdala, temporal and
occipital cortex, and anterior cingulate (Bhattacharyya et al. 2010, 2012; Borgwardt et al. 2008;
Fusar-Poli et al. 2009, 2010; Winton-Brown et al. 2011). Furthermore, pretreatment with CBD
was shown to prevent the behaviorally observed psychotomimetic and anxiogenic effects of THC
(Bhattacharyya et al. 2010, Fusar-Poli et al. 2010), the latter possibly by disrupting the neural
connectivity between amygdala and anterior cingulate cortex (Fusar-Poli et al. 2010). In line with
these findings are the results of a recent laboratory study showing that pretreatment with CBD
inhibited acute THC-induced psychotic symptoms as well as THC-induced cognitive impairment
(Englund et al. 2013). Interestingly, CBD has recently been suggested to also protect against the
long-term effects of THC on brain structure: Compared to nonusing controls, users of highCBD/low-THC strains of cannabis showed a lesser reduction in hippocampal volume than users
of high-THC/low-CBD cannabis preparations (Demirakca et al. 2011).
Cannabis Use and the Dopamine System
Based on animal research showing that THC increases dopamine levels in several regions of
the brain including striatal and prefrontal areas (El Khoury et al. 2012), neurochemical interactions between cannabinoids and dopamine have been hypothesized to constitute a neurobiological
link between cannabis and psychosis (Kuepper et al. 2010, Morrison & Murray 2009). An early
single-photon emission computed tomography study on dopaminergic alterations in schizophrenia by chance found evidence for increased dopamine release in the striatum following cannabis
exposure in a single patient who violated the study protocol by smoking marijuana in-between
two scans (Voruganti et al. 2001). This acute effect of cannabis on striatal dopamine release was
later replicated by Bossong and colleagues (2009), who administered 8 mg of pulmonary THC to
seven healthy males with recreational cannabis use. Using positron emission tomography (PET)
and [11 C]raclopride, the researchers observed an up to 4.1% decrease in nondisplaceable binding
potential (BPND ) in the THC condition compared to placebo condition. The effect was most
pronounced in ventral striatum, dorsal putamen, and caudate nucleus. In contrast, Stokes and colleagues (2009) as well as Barkus and colleagues (2011), who investigated acute effects of THC on
striatal dopamine neurotransmission using PET in combination with [11 C]raclopride and singlephoton emission tomography with [123 I]IBZM, respectively, did not observe significant dopamine
release after the experimental THC challenge. Yet significant decreases in BPND measured with
PET and [11 C]raclopride were observed in cortical brain regions, in particular in right middle
frontal gyrus, left superior frontal gyrus, and left superior temporal gyrus (Stokes et al. 2010).
Recently, acute THC-induced dopamine response was measured for the first time in patients with
psychotic disorder, unaffected first-degree relatives, and healthy controls, who were all frequent
cannabis users (Kuepper et al. 2013). In line with most previous findings, no dopamine release
associated with the administration of THC was detected in healthy controls. Yet in patients and
relatives, THC did induce significant amounts of dopamine release, most pronounced in the caudate nucleus. Although the sample size was small (seven patients, eight relatives, and nine healthy
controls), this study provides further preliminary evidence for an interaction between THC and
familial liability for psychosis from the neurobiological perspective.
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Other studies have investigated the involvement of the dopamine system in the effects of
cannabis use by examining different parameters of dopamine neurotransmission in chronic
cannabis users. Stokes and colleagues (2012) measured the availability of striatal dopamine D2-like
receptors in 10 cannabis users and 10 controls. They did not find any difference in BPND between
cannabis users and nonusers. Neither did BPND correlate with lifetime frequency of cannabis use
(Stokes et al. 2012). Bloomfield and colleagues (2013) investigated presynaptic dopamine synthesis
capacity—a parameter that has been found to be increased in schizophrenia and prodromal states
(Egerton et al. 2013, Howes et al. 2012)—in 19 regular cannabis users. However, cannabis use
was not associated with elevated striatal dopamine synthesis capacity. In fact, the opposite was
found. Dopamine synthesis capacity was negatively correlated with cannabis use, and cannabis
users showed reduced dopamine synthesis capacity in associative and limbic striatum (Bloomfield
et al. 2013). Two other studies examined dopamine release in response to a psychosocial stress
challenge and a pharmacological amphetamine challenge, respectively, in chronic cannabis users
and nonusing controls (Mizrahi et al. 2013, Urban et al. 2012). Both studies reported negative
results; that is, a history of cannabis use was not associated with increased dopamine release in
response to either amphetamine (Urban et al. 2012) or psychosocial stress (Mizrahi et al. 2013).
INSIGHTS FROM GENETIC STUDIES
A final source of information on the link between psychosis and cannabis is genetic studies,
which may be particularly helpful in explaining why some individuals develop psychosis following
cannabis use while most do not. Genetic factors are assumed to play a pivotal role in determining
sensitivity to the psychosis-inducing effects of cannabis. When the effect of an environmental
factor is influenced by genetic factors, this is usually referred to as gene-environment interaction
(van Winkel et al. 2010) (Figure 1). Most commonly, this takes the form of increased risk after
exposure to an environmental risk factor in those with genetic predisposition, versus a small to
absent increase in risk after environmental exposure in those without a genetic predisposition (a
quantitative or fan-shaped interaction). It is also possible, however, that the environmental factor
has opposite effects dependent on the underlying genotype, which is referred to as a qualitative or
cross-over interaction. Gene-environment interaction can be examined at the omnibus level using
an overall measure of genetic risk, such as familial loading, psychometric risk, or polygenic risk
scores derived from genome-wide association studies (Purcell et al. 2009), or at the level of specific
genes or single-nucleotide polymorphisms (SNPs). Usually, the possibility of gene-environment
interaction is examined at the omnibus level before hypotheses relating to specific genetic markers
are tested (Decoster et al. 2012). The use of familial risk as a proxy of psychosis liability is based
on the observation that the risk to develop a psychotic disorder increases as the degree of genetic
affinity with an affected family member increases. In addition to familial risk, some researchers
have used psychometric psychosis liability as a proxy for the underlying genetic vulnerability. Psychometric psychosis liability refers to the level of subtle psychotic experiences, which are seen as
the behavioral expression of genetic vulnerability in unaffected individuals. Earlier research argues
that psychometric psychosis liability in the general population reflects a genetic liability that is
consistent with the genetic vulnerability in patients (Decoster et al. 2012). However, this approach
assumes early, subtle psychotic experiences to be the result of only genetic predisposition, which is
unlikely. Furthermore, it cannot take into account underlying genetic heterogeneity and assumes
genetic risk to be equal across different individuals with these experiences. Therefore, we focus
on studies using familial risk as the measure of genetic loading; for an overview of studies using
psychometric risk as the measure of genetic loading, see Decoster et al. (2012).
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Evidence for G×E: Omnibus Approach Using Familial Risk
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A number of studies have investigated whether unaffected individuals who have a family member
with psychosis are more sensitive to the effects of cannabis use than are healthy controls. Hollis
and colleagues (2008) compared mental health functioning in relation to cannabis use in three
groups of young people: 36 nonpsychotic siblings of patients with schizophrenia, 25 patients with
ADHD, and 72 healthy controls. In this study, an association between cannabis use and schizotypal
symptoms was specific for the group at familial risk for psychosis, suggesting that this subgroup was
particularly vulnerable to the detrimental effects of cannabis use (Hollis et al. 2008). In addition,
the Genetic Risk and Outcome in Psychosis (GROUP) Investigation (2011) demonstrated an
increased sensitivity to the psychosis-inducing effects of cannabis associated with familial risk for
psychosis, using a sibling-control and cross-sibling design (participants included 1,120 patients
with psychotic disorder, 1,057 siblings of these patients, and 590 community controls) [Genetic
Risk Outcome Psychos. (GROUP) Investig. 2011]. These results were recently supported by novel
patient-sibling (978 pairs; 1,723 observations) and parent-sibling (669 pairs; 1,222 observations)
analyses of the same sample, using data from the baseline assessment as well as the three-year
follow-up assessment, which showed that the familial correlation in psychosis-related experiences
was significantly stronger in siblings exposed to cannabis use [van Winkel & Genetic Risk Outcome
Psychos. (GROUP) Investig. 2013].
Candidate Gene Studies
Caspi and colleagues were the first to report an interaction between cannabis use and a specific
genetic marker in its effect on the risk for psychotic disorder (Caspi et al. 2005). Their study
focused on a functional polymorphism (Val158Met or rs4680) in the catechol-O-methyltransferase
(COMT ) gene. COMT is an enzymatic inactivator of dopamine and other monoamines and is
essential for dopamine signaling in the prefrontal cortex. The Val allele is associated with a 40%
higher enzyme activity (Chen et al. 2004). The authors reported that the COMT polymorphism
moderated the risk of developing schizophreniform disorder at age 26 following adolescent-onset
cannabis use in a birth cohort of 1,037 individuals, with Val carriers displaying a more than
10 times higher risk (Caspi et al. 2005). Since its original publication, this study has been cited
more than 500 times (Web of Science; accessed July 1, 2013), and researchers from different groups
worldwide have attempted to replicate this finding, with mixed results (Decoster et al. 2012).
To put these observations into perspective, a recent critical review by Duncan & Keller (2011) of
observational studies in the field of candidate gene-environment interactions (cG×E) in psychiatry
should be considered. Duncan and Keller compared the rate of positive (i.e., significant) results
among studies reporting novel findings to the rate among replication attempts, following the
reasoning that replication attempts should have a higher rate of significant findings because both
positive and negative findings should be of interest to the general public, whereas for novel reports,
significant results will be most publishable (Duncan & Keller 2011). However, the observed pattern
was opposite of the one expected: 96% of novel cG×E reports were significant in comparison
with 27% of replication attempts, which is strongly suggestive of publication bias. Second, the
authors considered the sample sizes of replication efforts: In the absence of publication bias, larger
sample sizes should provide more statistical power than smaller ones and thus should be more
likely to produce significant findings (assuming the same effect size). Again, the observed pattern
was the exact opposite: the median sample size of the 10 positive replication attempts was 154 in
comparison with 377 for the negative replication attempts, which suggests that larger replication
attempts were published irrespective of the results (significant or not), whereas smaller studies
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were preferentially published when they yielded significant results. A third consideration is the
definition of what constitutes replication: In a series of simulations of genetic associations, Sullivan
(2007) showed that the rate of false-positive findings can be very high (up to 96%) when using broad
definitions of replication, whereas when using precise definitions, false discovery rates were much
lower, especially in combination with more stringent levels of statistical significance. Therefore,
in considering the evidence base for a particular cG×E, Duncan & Keller (2011) conclude that
it is important that only direct replications are considered; only when a cG×E is supported by
a number of direct replications can indirect replications help to gauge the generalizability of the
original finding.
Given this conclusion, we distinguish between studies that attempt to directly replicate the original finding of Caspi and colleagues (replication studies) and studies examining COMT×cannabis
interaction in other phenotypes relevant to psychosis (validation studies). The results are sobering:
Whereas almost all of the validation studies report significant interaction, there is not a single attempt at replication showing significant replication in the expected direction (Table 1). Recently,
groups from Spain and the Netherlands have independently reported a three-way interaction
between cannabis use, childhood adversity, and the COMT Val158Met genotype using epidemiological designs (Alemany et al. 2014, Vinkers et al. 2013). The Dutch group also reported results
from an attempt at replication; although this attempt failed in terms of statistical significance, the
effect was in the same direction (Vinkers et al. 2013).
A few papers have examined possible interactions with candidate markers other than COMT
Val158Met. Given the recommendations of Duncan & Keller (2011), we consider only genetic
markers for which human observational studies assessing possible effects on the clinical disorder phenotype are available. Zammit and colleagues (2007) used a case-only design to examine a possible interaction between cannabis use and two other SNPs in COMT (rs737865 and
rs165599) as well as an interaction between cannabis and rs1049353 in the CNR1 gene. There was
no evidence for gene-environment interaction for any of these SNPs (Zammit et al. 2007), nor
was evidence found that COMT Val158Met interacts with cannabis use, as reported in Table 1.
van Winkel and the GROUP investigators examined a broader selection of a priori defined candidate genes including 152 SNPs selected from 42 candidate genes (including COMT Val158Met)
[van Winkel & Genetic Risk Outcome Psychos. (GROUP) Investig. 2011]. They first examined interactions between these markers and recent cannabis use in 740 unaffected siblings of patients with
schizophrenia, following the reasoning that a number of disease-related confounding mechanisms
may be reduced by studying the effects of recent use in individuals at risk, such as stress associated
with emerging psychotic symptoms, changes in patterns of use, or treatment with antipsychotics,
whereas the clinical relevance of identified interactions may be subsequently confirmed by selective follow-up in the patients [van Winkel & Genetic Risk Outcome Psychos. (GROUP) Investig.
2011]. Three SNPs showed evidence for interaction with cannabis at the Bonferroni threshold
of statistical significance in the unaffected siblings, situated in AKT1 (two SNPs) and LRRTM1
(one SNP). Follow-up of these SNPs in the patients confirmed the presence of gene-environment
interaction between rs2494732 in AKT1 and cannabis using case-only (801 patients with psychotic disorder), case-sibling, and case-control (419 unrelated controls) designs. Compared to
those with the T/T genotype, individuals with a C/C genotype displayed a twofold-increased risk
of being diagnosed with a psychotic disorder after having used cannabis [van Winkel & Genetic
Risk Outcome Psychos. (GROUP) Investig. 2011]. A recent case-control study of an independent sample of 489 patients and 278 controls from the United Kingdom supported an interaction
between rs2494732 in AKT1 and cannabis (Di Forti et al. 2012); indirect evidence supporting
this interaction was also found at the level of AKT1-dependent prefrontal functioning under the
influence of cannabis, as measured by the Continuous Performance Test (van Winkel et al. 2011).
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Table 1 Studies following up the finding of COMT Val158Met interaction with cannabis on phenotypes relevant to
psychosis, distinguishing between direct replication studies and indirect validation studies
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Replication
studies
Indirect validation in
humans
Outcome
Indirect validation in
animal models
Outcome
Outcome
Zammit et al.
(2007) case-only
study
Negative
Henquet (2006)
Acute effects of
experimental cannabis
exposure on psychotic
symptoms and cognition
Positiveb
O’Thuathaigh (2010)
COMT KO mice exposed
to THC: impact on
behavioral phenotypes
Negatived
Kantrowitz (2009)
case-only study
Negative
Henquet (2009)
Psychotic symptoms after
cannabis use in daily life
Positiveb
O’Thuathaigh (2012)
COMT KO mice exposed
to cannabinoid
WIN55212: impact on
behavioral phenotypes and
prepulse inhibition
Negatived
Gutiérrez (2009)
case-control
study
Negative
Pelayo-Teran (2010)
Age at onset of psychosis
and duration of untreated
psychosis
Positivec
Behan (2012)
COMT KO mice exposed
to THC: impact on
dopamine cell size in VTA,
CB1R expression in
hippocampus, and
parvalbumin cell size in
prefrontal cortex
Negatived
Costas (2011)
case-only study
Negativea
Estrada (2011)
Age at onset of psychosis
Positive
–
–
Zammit (2011)
birth cohort study
Negative
van Winkel & Genetic Risk
Outcome Psychos.
(GROUP) Investig. (2011)
Subclinical symptoms in
unaffected siblings
following recent cannabis
use
Negative
–
–
–
–
Verdejo-Garcia (2013)
Executive functioning in
cannabis users versus
healthy controls
Positive
–
–
–
–
Batalla (2013)
Structural magnetic
resonance imaging study in
cannabis users and controls
Positive
–
–
a
The authors found a significant association but with opposite directionality (association with the Met rather than the Val allele).
Conditional on psychometric psychosis liability.
c
Genotype differences were significantly different in nonusers but not in users of cannabis.
d
COMT KO mice were consistently (and significantly) more vulnerable to the adverse effects of cannabinoids than wild-type mice, in contrast to
expectations (the Val allele in humans is associated with higher enzymatic function, whereas COMT KO leads to loss of enzymatic function).
Abbreviations: CB1R, cannabinoid receptor 1; COMT, catechol-O-methyltransferase; KO, knockout; THC, tetrahydrocannabinol; VTA, ventral
tegmental area.
b
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Table 2 Studies following up the finding of AKT1 rs2494732 interaction with cannabis on phenotypes relevant to
psychosis, distinguishing between direct replication studies and indirect validation studies
Replication studies
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Di Forti et al. (2012)
case-control study
Outcome
Positive
Indirect validation in humans
Outcome
Indirect
validation in
animal models
Outcome
van Winkel & Genetic Risk Outcome
Psychos. (GROUP) Investig. (2011)
Subclinical symptoms in unaffected
siblings following recent cannabis use
Positive
–
–
van Winkel et al. (2011)
Cognition (assessed with Cognitive
Performance Test) in patients with
psychotic disorder
Positive
–
–
Nevertheless, further efforts at replication and indirect validation are necessary because the currently available evidence base is still relatively small (Table 2).
FACTS, CONTROVERSIES, AND MYTHS IN THE
CANNABIS-PSYCHOSIS RELATIONSHIP
A large body of work relevant to the cannabis-psychosis relationship has been published; the
present review focuses on studies in the field of epidemiology, neurobiology, and genetics. What
are the most important and reliable findings from this literature that may help to gain further
insight in the underlying mechanisms relating cannabis to psychosis? In order to answer this question, we graded the available evidence using the number of studies published and the consistency
of the reported results as well as the degree to which different research fields (i.e., epidemiological,
neurobiological, and genetics) converge on similar findings (Table 3). This categorization could
then be used as different pieces of the puzzle, which can be combined into a developmental model
relating cannabis use to risk of psychosis (Figure 2).
Compiling the Evidence
Cannabis use is associated with psychosis, but most people do not develop psychosis following
(prolonged periods of ) cannabis use. A first factor that needs to be considered is the type of
cannabis that is consumed, in particular the balance between THC and CBD in the different
available varieties, as there is good evidence that the THC/CBD ratio is an important factor in
determining the psychotogenic properties of cannabis (evidence grade A).
Furthermore, a number of robust findings indicate the existence of vulnerable subpopulations
and/or time windows. Observational studies, as well as experimental animal studies, have shown
that adolescence is a particularly vulnerable period in terms of the psychosis-inducing effects of
cannabis (evidence grade A+). Although on average the duration of cannabis use is longer in
people who start using at a younger age, there is good evidence from long-term observational
studies, as well as studies in adult animals, that duration of use per se is not responsible for the
particularly strong association with cannabis use in adolescence. In addition, observational and
animal studies have shown that subgroups exposed to early life stress, such as growing up in an
urban environment or exposure to childhood trauma, or, in rats, experiencing isolation and food
deprivation, increases vulnerability to the effects of cannabis (evidence grade B). Finally, familial
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NB
NB
NB
G, NB
G, NB
G
−
−
−
++
+/−
+
Cannabis use impacts dopamine D2 receptor availability
Cannabis use is associated with increased dopamine synthesis capacity
Cannabis use is associated with increased striatal dopamine response to
a challenge with amphetamine or stress
Individuals at familial risk are more sensitive to the psychosis-inducing
effects of cannabis
COMT Val158Met is an important genetic risk factor for
cannabis-induced psychosis
AKT1 rs2494732 is an important genetic risk factor for
cannabis-induced psychosis
B
C
A
D
D
D
C
C
C
C
C
C
C
A+
A
B
a
Statements were rated independently by the authors of the present review for their consistency of evidence, evidence from multiple fields of investigation, and grade of evidence. In the case of
disagreements, categorizations were discussed until consensus was reached.
b
Definitions applied: +++, considerable number of studies with consistent results; ++, considerable number of studies with largely consistent results or a reasonable number of studies (more
than three) with consistent results; +, a small number of studies (at least two) with consistent results or a reasonable number of studies (more than three) with largely consistent results; +/−,
several studies available but with mixed results or only one study reporting a given finding; −, no positive evidence available.
c
Definitions applied: A+, consistent evidence from several studies and multiple fields; A, consistent evidence from multiple studies from one field of investigation and absence of conflicting
evidence from other fields; B, consistent evidence from some studies in one or more fields of investigation; C, conflicting evidence within one field of investigation or between different fields of
investigation, or only one study available reporting a significant finding; D, most studies reporting negative results in one or more fields of investigation.
Abbreviations: CBD, cannabidiol; COMT, catechol-O-methyltransferase; KO, knockout; THC, tetrahydrocannabinol.
NB
NB
+/−
+/−
Cannabis use induces striatal dopamine release in individuals at familial
risk for psychosis
Cannabis use is associated with specific brain tissue loss in cerebellum
Cannabis use induces striatal dopamine release
NB
NB
+/−
+/−
Cannabis use is associated with specific brain tissue loss in hippocampus
NB
NB
+/−
+/−
Cannabis use is associated with brain tissue loss, especially in
individuals at familial risk for psychosis
E, NB
+/−
Cannabis has enduring negative effects on cognition, even in the
absence of current use
A+
A
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Cannabis use is associated with generalized brain tissue loss
NB
E, NB
+++
+
There is a synergistic interaction between early life stress and cannabis
use to increase psychosis risk
+++
E, NB
++
The balance between THC and CBD is a critical factor
Cannabis affects cognitive ability in the short term
E, NB
E, NB
+++
The younger the age at onset of use, the higher the risk
Evidence
gradec
ARI
THC interferes with processes regulating synaptic plasticity
Evidence from multiple fields of investigation:
epidemiology (E), neurobiology (NB), genetics (G)
Consistency of
evidenceb
Statement
Table 3 Facts, controversies, and myths relevant to the association between cannabis use and psychosisa
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a
Synaptic
plasticity
Minimal or no structural
or functional changes
Critical neurodevelopment
Cannabis use
15
20
25
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Age
b
Environmental
risk
Familial
risk
?
Synaptic
plasticity
Increased striatal
dopamine release?
Structural brain changes?
Psychosis
Critical neurodevelopment
Cannabis use
15
20
25
Age
Figure 2
(a) Typical timeline of a person for whom cannabis use is relatively benign. Cannabis use (indicated by the green bar) is initiated after
the most critical time window in adolescence, where important neurodevelopmental processes take place (indicated by the blue bar).
Tetrahydrocannabinol (THC) exposure is moderate in terms of relatively low TCH/cannabidiol (CBD) ratio and/or frequency and
duration of exposure. In the absence of high genetic risk and in the absence of environmental risk factors such as childhood trauma, this
type of exposure to cannabis in most cases does not lead to psychotic outcomes, and long-term alterations of brain structure and
cognition are probably minimal or absent. (b) Typical timeline of a person for whom cannabis use may be a causal factor in the
development of psychotic disorder. Cannabis use (indicated by the green bar) is initiated before or during the most critical time window
in adolescence, where important neurodevelopmental processes take place (indicated by the blue bar). THC exposure is severe (as
indicated by the more intense color of the green bar) in terms of a relatively high THC/CBD ratio and/or greater frequency and
duration of exposure. This type of exposure in itself may already lead to onset of psychotic symptoms, and this effect may be even more
pronounced in the presence of familial/genetic or environmental risk. There is preliminary evidence that in such vulnerable subgroups,
neurodevelopment brain processes may go awry, leading to brain alterations associated with psychosis, such as sensitization of striatal
dopamine release and selective (e.g., hippocampal) or generalized structural alterations. It is not known whether familial and
environmental risk exert their hypothesized effects via inducing more intense alterations in synaptic plasticity following cannabis use
(dashed red arrows) or via an increased sensitivity to structural or functional alterations associated with cannabis-induced changes in
synaptic plasticity (solid red arrows).
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and genetic factors (evidence grade A), possibly including the AKT1 rs2494732 polymorphism
(evidence grade B), are contributing factors in determining sensitivity to the psychosis-inducing
effects of cannabis.
Although these findings identify vulnerable subgroups, which may give indirect hints about
the underlying biology of cannabis-induced psychosis, studies trying to tie cannabis use to specific
biological mechanisms have been largely unsuccessful. Currently no robust evidence indicates
that cannabis use leads to abnormalities in dopaminergic neurotransmission or to generalized or
specific brain tissue loss. What has been established is that administration of THC interferes
with processes regulating synaptic plasticity (evidence grade A). Authors have hypothesized how
disruption of synaptic plasticity by THC may induce developmental brain alterations that ultimately may lead to psychosis (Bossong & Niesink 2010, Morrison & Murray 2009). Bossong
& Niesink (2010) propose that exposure to THC in adolescence disrupts the normal process of
fine-tuning of glutamate and GABA release by the endocannabinoid system, thereby adversely
impacting brain maturational processes occurring in adolescence, especially with regard to prefrontal neural circuitries. Another theory is based on the observation that dopamine, adenosine,
and the endocannabinoid system work together to gate input from the cortex to the striatum,
thus regulating implicit learning. Given the essential role of striatal endocannabinoid signaling
in habit formation and implicit learning, excessive stimulation of the endocannabinoid system by
THC might favor connections between logically unrelated ideas, ultimately resulting in delusion
formation (Morrison & Murray 2009).
These theories link disruption of the long-term potentiation/LTD balance caused by excessive stimulation of the endocannabinoid system to processes of adolescent brain maturation and
dopamine-dependent striatal learning. Although these theories are appealing, human studies have
failed to consistently show a disruption of dopamine neurotransmission or developmental brain
alterations associated with the use of cannabis (Table 3). It is important to note, however, that
these studies have typically been conducted in healthy adult volunteers with limited previous exposure to cannabis, or in long-term cannabis users without frank psychotic symptoms, whereas the
epidemiological evidence suggests that such processes mainly occur in certain vulnerable subpopulations (Figure 2). The few studies that have been conducted in such populations are suggestive
of (a) significant dopamine release following administration of THC in persons at familial risk for
schizophrenia (patients as well as their first-degree relatives) but not in healthy controls (Kuepper
et al. 2013) and (b) significantly reduced cortical thickness associated with a history of cannabis
use in persons at familial risk but not in healthy controls (Habets et al. 2011).
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
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CP10CH28-vanWinkel
Recommendations for Future Research
The above findings indicate a number of gaps in knowledge that are in need of further scientific
investigation. A first important aspect is the possible correlation between genetic risk for psychosis
and exposure to cannabis. Although it seems unlikely that gene-environment correlation entirely
explains the association between cannabis and psychosis, examination of this issue is necessary
before causality can be more confidently assumed.
In addition, a better understanding of the exact mechanisms through which THC and CBD
act on the endocannabinoid system, and how this in turn affects adolescent brain development and
brain function, is necessary. The actions of CBD in particular remain insufficiently understood.
Although having only low affinity for the CB1 and CB2 receptor, CBD seems be a powerful
antagonist of CB1 and CB2 receptor agonists (Pertwee 2008). Preliminary data further suggest
that CBD may exert its effects by inhibiting reuptake of the endogenous cannabinoid anandamide
(Mechoulam et al. 2002, Pertwee 2008).
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The results also suggest that specific examination of vulnerable subgroups—be it based on genetic risk or on environmental risk—may yield valuable information on differential vulnerability to
long-term brain alterations relevant for psychosis. Central to possible long-term brain alterations
may be THC-induced changes of synaptic plasticity; how these processes are influenced by genetic
risk or early childhood exposure to relevant stressors is likely to be very important (Figure 2).
Likewise, further delineation of the time window in which these changes take place is likely to
provide valuable information.
DISCLOSURE STATEMENT
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
LITERATURE CITED
Alemany S, Arias B, Fatjo-Vilas M, Villa H, Moya J, et al. 2014. Psychosis-inducing effects of cannabis are
related to both childhood abuse and COMT genotypes. Acta Psychiatr. Scand. 129:54–62
Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, et al. 2012. Modulation of L-alphalysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids.
J. Biol. Chem. 287:91–104
Arnold JC, Boucher AA, Karl T. 2012. The yin and yang of cannabis-induced psychosis: the actions of (9)tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia. Curr. Pharm. Des. 18:5113–30
Arnone D, Barrick TR, Chengappa S, Mackay CE, Clark CA, Abou-Saleh MT. 2008. Corpus callosum damage
in heavy marijuana use: preliminary evidence from diffusion tensor tractography and tract-based spatial
statistics. NeuroImage 41:1067–74
Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. 2002. Cannabis use in adolescence and
risk for adult psychosis: longitudinal prospective study. BMJ 325:1212–13
Azad SC, Kurz J, Marsicano G, Lutz B, Zieglgansberger W, Rammes G. 2008. Activation of CB1 specifically
located on GABAergic interneurons inhibits LTD in the lateral amygdala. Learn. Mem. 15:143–52
Bacci A, Huguenard JR, Prince DA. 2004. Long-lasting self-inhibition of neocortical interneurons mediated
by endocannabinoids. Nature 431:312–16
Barkus E, Morrison PD, Vuletic D, Dickson JC, Ell PJ, et al. 2011. Does intravenous 9-tetrahydrocannabinol
increase dopamine release? A SPET study. J. Psychopharmacol. 25:1462–68
Batalla A, Soriano-Mas C, Lopez-Sola M, Torrens M, Crippa JA, et al. 2013. Modulation of brain structure
by catechol-o-methyltransferase Val(158)Met polymorphism in chronic cannabis users. Addict. Biol. In
press. doi:10.1111/adb.12027
Battisti RA, Roodenrys S, Johnstone SJ, Pesa N, Hermens DF, Solowij N. 2010. Chronic cannabis users show
altered neurophysiological functioning on Stroop task conflict resolution. Psychopharmacology 212:613–24
Behan A, Hryniewiecka M, O’Tuathaigh CM, Kinsella A, Cannon M, et al. 2012. Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic,
endocannabinoid and GABAergic pathways. Neuropsychopharmacology 37:1773–83
Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, et al. 2012. Induction of psychosis by 9tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience
processing. Arch. Gen. Psychiatry 69:27–36
Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, et al. 2010. Opposite effects
of -9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–74
Bloomfield MA, Morgan CJ, Egerton A, Kapur S, Curran HV, Howes OD. 2013. Dopaminergic function in
cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol. Psychiatry. In press
Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, et al. 2008. Neural basis of -9tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 64:966–73
www.annualreviews.org • Cannabis Use and Psychosis
785
ARI
12 February 2014
14:36
Bossong MG, Niesink RJ. 2010. Adolescent brain maturation, the endogenous cannabinoid system and the
neurobiology of cannabis-induced schizophrenia. Prog. Neurobiol. 92:370–85
Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schuit RC, et al. 2009. Delta 9-tetrahydrocannabinol
induces dopamine release in the human striatum. Neuropsychopharmacology 34:759–66
Broyd SJ, Greenwood LM, Croft RJ, Dalecki A, Todd J, et al. 2013. Chronic effects of cannabis on sensory
gating. Int. J. Psychophysiol. 89:381–89
Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, et al. 2005. Moderation of the effect of adolescent-onset
cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene:
longitudinal evidence of a gene X environment interaction. Biol. Psychiatry 57:1117–27
Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y. 2012. Endocannabinoid signaling and synaptic function. Neuron 76:70–81
Chavez AE, Chiu CQ, Castillo PE. 2010. TRPV1 activation by endogenous anandamide triggers postsynaptic
long-term depression in dentate gyrus. Nat. Neurosci. 13:1511–18
Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, et al. 2004. Functional analysis of genetic variation in
catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem
human brain. Am. J. Hum. Genet. 75:807–21
Chevaleyre V, Takahashi KA, Castillo PE. 2006. Endocannabinoid-mediated synaptic plasticity in the CNS.
Annu. Rev. Neurosci. 29:37–76
Costas J, Sanjuan J, Ramos-Rios R, Paz E, Agra S, et al. 2011. Interaction between COMT haplotypes and
cannabis in schizophrenia: a case-only study in two samples from Spain. Schizophr. Res. 127:22–27
Cougnard A, Marcelis M, Myin-Germeys I, De Graaf R, Vollebergh W, et al. 2007. Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A
psychosis proneness-persistence model. Psychol. Med. 37:513–27
Cross-Disord. Group Psychiatr. Genomics Consort., Smoller JW, Craddock N, Kendler KS, Lee PH, et al.
2013. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide
analysis. Lancet 381:1371–79
D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, et al. 2004. The psychotomimetic effects
of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558–72
Decoster J, Van Os J, Myin-Germeys I, De Hert M, van Winkel R. 2012. Genetic variation underlying
psychosis-inducing effects of cannabis: critical review and future directions. Curr. Pharm. Des. 18:5015–
23
Demirakca T, Sartorius A, Ende G, Meyer N, Welzel H, et al. 2011. Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend. 114:242–45
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, et al. 1992. Isolation and structure of a brain
constituent that binds to the cannabinoid receptor. Science 258:1946–49
Di Forti M, Iyegbe C, Sallis H, Kolliakou A, Falcone A, et al. 2012. Confirmation that the AKT1 (rs2494732)
genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 72:811–16
Dominguez MD, Wichers M, Lieb R, Wittchen HU, van Os J. 2011. Evidence that onset of clinical psychosis
is an outcome of progressively more persistent subclinical psychotic experiences: an 8-year cohort study.
Schizophr. Bull. 37:84–93
Duncan LE, Keller MC. 2011. A critical review of the first 10 years of candidate gene-by-environment
interaction research in psychiatry. Am. J. Psychiatry 168:1041–49
Egerton A, Chaddock CA, Winton-Brown TT, Bloomfield MA, Bhattacharyya S, et al. 2013. Presynaptic
striatal dopamine dysfunction in people at ultra-high risk for psychosis: findings in a second cohort. Biol.
Psychiatry 74:106–12
Ehrenreich H, Rinn T, Kunert HJ, Moeller MR, Poser W, et al. 1999. Specific attentional dysfunction in
adults following early start of cannabis use. Psychopharmacology 142:295–301
El Khoury MA, Gorgievski V, Moutsimilli L, Giros B, Tzavara ET. 2012. Interactions between the cannabinoid and dopaminergic systems: evidence from animal studies. Prog. Neuropsychopharmacol. Biol. Psychiatry
38:36–50
Englund A, Morrison PD, Nottage J, Hague D, Kane F, et al. 2013. Cannabidiol inhibits THC-elicited
paranoid symptoms and hippocampal-dependent memory impairment. J. Psychopharmacol. 27:19–27
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
CP10CH28-vanWinkel
786
van Winkel
·
Kuepper
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
CP10CH28-vanWinkel
ARI
12 February 2014
14:36
Estrada G, Fatjó-Vilas M, Muñoz MJ, Pulido G, Miñano MJ, et al. 2011. Cannabis use and age at onset of
psychosis: further evidence of interaction with COMT Val158Met polymorphism. Acta Psychiatr. Scand.
123:485–92
Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC. 2005. Cannabis use predicts
future psychotic symptoms, and vice versa. Addiction 100:612–18
Fergusson DM, Horwood LJ, Swain-Campbell NR. 2003. Cannabis dependence and psychotic symptoms in
young people. Psychol. Med. 33:15–21
Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, et al. 2010. Modulation of effective connectivity
during emotional processing by 9-tetrahydrocannabinol and cannabidiol. Int. J. Neuropsychopharmacol.
13:421–32
Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, et al. 2009. Distinct effects of 9tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry 66:95–105
Genetic Risk Outcome Psychos. (GROUP) Investig. 2011. Evidence that familial liability for psychosis is
expressed as differential sensitivity to cannabis: an analysis of patient-sibling and sibling-control pairs.
Arch. Gen. Psychiatry 68:138–47
Grueter BA, Brasnjo G, Malenka RC. 2010. Postsynaptic TRPV1 triggers cell type–specific long-term depression in the nucleus accumbens. Nat. Neurosci. 13:1519–25
Gutiérrez B, Rivera M, Obel L, McKenney K, Martı́nez-Leal R, et al. 2009. Variability in the COMT gene
and modification of the risk of schizophrenia conferred by cannabis consumption. Rev. Psiquiatr. Salud
Ment. 2:89–94
Habets P, Marcelis M, Gronenschild E, Drukker M, van Os J. 2011. Reduced cortical thickness as an outcome
of differential sensitivity to environmental risks in schizophrenia. Biol. Psychiatry 69:487–94
Hall W, Solowij N. 1998. Adverse effects of cannabis. Lancet 352:1611–16
Harley M, Kelleher I, Clarke M, Lynch F, Arseneault L, et al. 2010. Cannabis use and childhood trauma
interact additively to increase the risk of psychotic symptoms in adolescence. Psychol. Med. 40:1627–34
Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, et al. 2005a. Prospective cohort study of cannabis
use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330:11–14
Henquet C, Murray R, Linszen D, van Os J. 2005b. The environment and schizophrenia: the role of cannabis
use. Schizophr. Bull. 31:608–12
Henquet C, Rosa A, Delespaul P, Papiol S, Fananas L, et al. 2009. COMT ValMet moderation of cannabisinduced psychosis: a momentary assessment study of “switching on” hallucinations in the flow of daily
life. Acta Psychiatr. Scand. 119:156–60
Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L, et al. 2006. An experimental study of catechol-omethyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis
and cognition. Neuropsychopharmacology 31:2748–57
Hoffman AF, Oz M, Yang R, Lichtman AH, Lupica CR. 2007. Opposing actions of chronic 9 tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn. Mem.
14:63–74
Hollis C, Groom MJ, Das D, Calton T, Bates AT, et al. 2008. Different psychological effects of cannabis
use in adolescents at genetic high risk for schizophrenia and with attention deficit/hyperactivity disorder
(ADHD). Schizophr. Res. 105:216–23
Houston JE, Murphy J, Adamson G, Stringer M, Shevlin M. 2008. Childhood sexual abuse, early cannabis
use, and psychosis: testing an interaction model based on the National Comorbidity Survey. Schizophr.
Bull. 34:580–85
Houston JE, Murphy J, Shevlin M, Adamson G. 2011. Cannabis use and psychosis: re-visiting the role of
childhood trauma. Psychol. Med. 41:2339–48
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, et al. 2012. The nature of dopamine dysfunction in
schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69:776–86
Howlett AC, Reggio PH, Childers SR, Hampson RE, Ulloa NM, Deutsch DG. 2011. Endocannabinoid tone
versus constitutive activity of cannabinoid receptors. Br. J. Pharmacol. 163:1329–43
Kantrowitz JT, Nolan KA, Sen S, Simen A, Lachman HM, Bowers M. 2009. Adolescent cannabis use, psychosis
and catechol-O-methyltransferase genotype in African Americans and Caucasians. Psychiatr. Q. 80:213–18
www.annualreviews.org • Cannabis Use and Psychosis
787
ARI
12 February 2014
14:36
Klugmann M, Klippenstein V, Leweke FM, Spanagel R, Schneider M. 2011. Cannabinoid exposure in pubertal
rats increases spontaneous ethanol consumption and NMDA receptor associated protein levels. Int. J.
Neuropsychopharmacol. 14:505–17
Konings M, Bak M, Hanssen M, van Os J, Krabbendam L. 2006. Validity and reliability of the CAPE: a selfreport instrument for the measurement of psychotic experiences in the general population. Acta Psychiatr.
Scand. 114:55–61
Konings M, Henquet C, Maharajh HD, Hutchinson G, Van Os J. 2008. Early exposure to cannabis and risk
for psychosis in young adolescents in Trinidad. Acta Psychiatr. Scand. 118:209–13
Konings M, Stefanis N, Kuepper R, de Graaf R, ten Have M, et al. 2012. Replication in two independent
population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk. Psychol. Med. 42:149–59
Kuepper R, Ceccarini J, Lataster J, Van Os J, Van Kroonenburgh M, et al. 2013. Delta-9tetrahydrocannabinol-induced dopamine release as a function of psychosis risk:18 F-fallypride positron
emission tomography study. PLoS ONE 8:e70378
Kuepper R, Henquet C, Lieb R, Wittchen HU, van Os J. 2011a. Non-replication of interaction between
cannabis use and trauma in predicting psychosis. Schizophr. Res. 131:262–63
Kuepper R, Morrison PD, van Os J, Murray RM, Kenis G, Henquet C. 2010. Does dopamine mediate the
psychosis-inducing effects of cannabis? A review and integration of findings across disciplines. Schizophr.
Res. 121:107–17
Kuepper R, van Os J, Lieb R, Wittchen HU, Henquet C. 2011b. Do cannabis and urbanicity co-participate
in causing psychosis? Evidence from a 10-year follow-up cohort study. Psychol. Med. 41:2121–9
Kuepper R, van Os J, Lieb R, Wittchen HU, Hofler M, Henquet C. 2011c. Continued cannabis use and risk
of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ 342:d738
Littleton JM, MacLean KI, Brownlee G. 1976. Proceedings: alterations in dopamine uptake in rat corpus striatum induced by combinations of stress and delta8-tetrahydrocannabinol (delta8-THC). Br. J. Pharmacol.
56:370P
Lopez-Moreno JA, Gonzalez-Cuevas G, Moreno G, Navarro M. 2008. The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their
repercussions in behavioral addiction. Addict. Biol. 13:160–87
Lundqvist T. 2005. Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin
with regard to attention, memory and executive functions. Pharmacol. Biochem. Behav. 81:319–30
Mackie K. 2005. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb.
Exp. Pharmacol. 168:299–325
MacLean KI, Littleton JM. 1977. Environmental stress as a factor in the response of rat brain catecholamine
metabolism to delta8-tetrahydrocannabinol. Eur. J. Pharmacol. 41:171–82
Marinelli S, Pacioni S, Cannich A, Marsicano G, Bacci A. 2009. Self-modulation of neocortical pyramidal
neurons by endocannabinoids. Nat. Neurosci. 12:1488–90
Martin-Santos R, Fagundo AB, Crippa JA, Atakan Z, Bhattacharyya S, et al. 2010. Neuroimaging in cannabis
use: a systematic review of the literature. Psychol. Med. 40:383–98
Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, Manzoni OJ. 2004. A single in-vivo exposure to delta
9 THC blocks endocannabinoid-mediated synaptic plasticity. Nat. Neurosci. 7:585–86
McGrath J, Welham J, Scott J, Varghese D, Degenhardt L, et al. 2010. Association between cannabis use and
psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch. Gen. Psychiatry
67:440–47
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, et al. 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol.
50:83–90
Mechoulam R, Parker LA, Gallily R. 2002. Cannabidiol: an overview of some pharmacological aspects. J. Clin.
Pharmacol. 42:11–19S
Meier MH, Caspi A, Ambler A, Harrington H, Houts R, et al. 2012. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Natl. Acad. Sci. USA 109:E2657–64
Mizrahi R, Suridjan I, Kenk M, George TP, Wilson A, et al. 2013. Dopamine response to psychosocial stress
in chronic cannabis users: a PET study with [(11)C]-(+)-PHNO. Neuropsychopharmacology 38:673–82
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
CP10CH28-vanWinkel
788
van Winkel
·
Kuepper
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
CP10CH28-vanWinkel
ARI
12 February 2014
14:36
Mokler DJ, Robinson SE, Johnson JH, Hong JS, Rosecrans JA. 1987. Neonatal administration of delta-9tetrahydrocannabinol (THC) alters the neurochemical response to stress in the adult Fischer-344 rat.
Neurotoxicol. Teratol. 9:321–27
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, et al. 2007. Cannabis use and risk of
psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–28
Morgan CJ, Curran HV. 2008. Effects of cannabidiol on schizophrenia-like symptoms in people who use
cannabis. Br. J. Psychiatry 192:306–7
Morgan CJ, Gardener C, Schafer G, Swan S, Demarchi C, et al. 2012. Sub-chronic impact of cannabinoids
in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol. Med.
42:391–400
Morgan CJ, Schafer G, Freeman TP, Curran HV. 2010. Impact of cannabidiol on the acute memory and
psychotomimetic effects of smoked cannabis: naturalistic study [corrected]. Br. J. Psychiatry 197:285–90
Morrison PD, Murray RM. 2009. From real-world events to psychosis: the emerging neuropharmacology of
delusions. Schizophr. Bull. 35:668–74
Morrison PD, Stone JM. 2011. Synthetic delta-9-tetrahydrocannabinol elicits schizophrenia-like negative
symptoms which are distinct from sedation. Hum. Psychopharmacol. 26:77–80
Morrison PD, Zois V, McKeown DA, Lee TD, Holt DW, et al. 2009. The acute effects of synthetic intravenous
Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol. Med. 39:1607–16
Murphy J, Houston JE, Shevlin M, Adamson G. 2013. Childhood sexual trauma, cannabis use and psychosis:
statistically controlling for pre-trauma psychosis and psychopathology. Soc. Psychiatry Psychiatr. Epidemiol.
48:853–61
Murray RM, Morrison PD, Henquet C, Di Forti M. 2007. Cannabis, the mind and society: the hash realities.
Nat. Rev. 8:885–95
Ohno-Shosaku T, Tanimura A, Hashimotodani Y, Kano M. 2012. Endocannabinoids and retrograde modulation of synaptic transmission. Neuroscientist 18:119–32
O’Tuathaigh CM, Clarke G, Walsh JJ, Desbonnet L, Petit E, et al. 2012. Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. Int.
J. Neuropsychopharmacol. 15:1331–42
O’Tuathaigh CM, Hryniewiecka M, Behan A, Tighe O, Coughlan C, et al. 2010. Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other
phenotypes. Neuropsychopharmacology 35:2262–73
Pelayo-Teran JM, Perez-Iglesias R, Mata I, Carrasco-Marin E, Vazquez-Barquero JL, Crespo-Facorro B.
2010. Catechol-O-methyltransferase (COMT) Val158Met variations and cannabis use in first-episode
non-affective psychosis: clinical-onset implications. Psychiatr. Res. 179:291–96
Pertwee RG. 1997. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74:129–80
Pertwee RG. 2008. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 153:199–215
Pertwee RG. 2010. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 17:1360–81
Pistis M, Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL. 2004. Adolescent exposure to cannabinoids
induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol.
Psychiatry 56:86–94
Pope HG Jr, Gruber AJ, Hudson JI, Cohane G, Huestis MA, Yurgelun-Todd D. 2003. Early-onset cannabis
use and cognitive deficits: What is the nature of the association? Drug Alcohol Depend. 69:303–10
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. 2009. Common polygenic variation
contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52
Rabin RA, Zakzanis KK, George TP. 2011. The effects of cannabis use on neurocognition in schizophrenia:
a meta-analysis. Schizophr. Res. 128:111–16
Ranganathan M, D’Souza DC. 2006. The acute effects of cannabinoids on memory in humans: a review.
Psychopharmacology 188:425–44
Realini N, Rubino T, Parolaro D. 2009. Neurobiological alterations at adult age triggered by adolescent
exposure to cannabinoids. Pharmacol. Res. 60:132–38
www.annualreviews.org • Cannabis Use and Psychosis
789
ARI
12 February 2014
14:36
Rubino T, Realini N, Braida D, Guidi S, Capurro V, et al. 2009. Changes in hippocampal morphology
and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in
adulthood. Hippocampus 19:763–72
Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, et al. 2007. The orphan receptor GPR55 is a
novel cannabinoid receptor. Br. J. Pharmacol. 152:1092–101
Schneider M, Drews E, Koch M. 2005. Behavioral effects in adult rats of chronic prepubertal treatment with
the cannabinoid receptor agonist WIN 55,212–2. Behav. Pharmacol. 16:447–54
Schneider M, Koch M. 2003. Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats.
Neuropsychopharmacology 28:1760–69
Schneider M, Koch M. 2007. The effect of chronic peripubertal cannabinoid treatment on deficient object
recognition memory in rats after neonatal mPFC lesion. Eur. Neuropsychopharmacol. 17:180–86
Schneider M, Schomig E, Leweke FM. 2008. Acute and chronic cannabinoid treatment differentially affects
recognition memory and social behavior in pubertal and adult rats. Addict. Biol. 13:345–57
Schubart CD, Boks MP, Breetvelt EJ, van Gastel WA, Groenwold RH, et al. 2011a. Association between
cannabis and psychiatric hospitalization. Acta Psychiatr. Scand. 123:368–75
Schubart CD, Sommer IE, van Gastel WA, Goetgebuer RL, Kahn RS, Boks MP. 2011b. Cannabis with high
cannabidiol content is associated with fewer psychotic experiences. Schizophr. Res. 130:216–21
Smith MJ, Barch DM, Wolf T, Mamah D, Csernansky JG. 2008. Elevated rates of substance use disorders in
non-psychotic siblings of individuals with schizophrenia. Schizophr. Res. 106:294–99
Solowij N. 1995. Do cognitive impairments recover following cessation of cannabis use? Life Sci. 56:2119–26
Solowij N, Battisti R. 2008. The chronic effects of cannabis on memory in humans: a review. Curr. Drug Abuse
Rev. 1:81–98
Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, et al. 2002. Cognitive functioning of long-term
heavy cannabis users seeking treatment. JAMA 287:1123–31
Solowij N, Walterfang M, Lubman DI, Whittle S, Lorenzetti V, et al. 2013. Alteration to hippocampal shape
in cannabis users with and without schizophrenia. Schizophr. Res. 143:179–84
Solowij N, Yücel M, Respondek C, Whittle S, Lindsay E, et al. 2011. Cerebellar white-matter changes in
cannabis users with and without schizophrenia. Psychol. Med. 41:2349–59
Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. 2004. Early adolescent cannabis
exposure and positive and negative dimensions of psychosis. Addiction 99:1333–41
Stokes PR, Egerton A, Watson B, Reid A, Breen G, et al. 2010. Significant decreases in frontal and temporal
[11C]-raclopride binding after THC challenge. NeuroImage 52:1521–27
Stokes PR, Egerton A, Watson B, Reid A, Lappin J, et al. 2012. History of cannabis use is not associated with
alterations in striatal dopamine D2/D3 receptor availability. J. Psychopharmacol. 26:144–49
Stokes PR, Mehta MA, Curran HV, Breen G, Grasby PM. 2009. Can recreational doses of THC produce
significant dopamine release in the human striatum? NeuroImage 48:186–90
Stowkowy J, Addington J. 2013. Predictors of a clinical high risk status among individuals with a family history
of psychosis. Schizophr. Res. 147:281–86
Sullivan PF. 2007. Spurious genetic associations. Biol. Psychiatry 61:1121–26
Urban NB, Slifstein M, Thompson JL, Xu X, Girgis RR, et al. 2012. Dopamine release in chronic cannabis
users: a [11c]raclopride positron emission tomography study. Biol. Psychiatry 71:677–83
van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. 2009. A systematic review and metaanalysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model
of psychotic disorder. Psychol. Med. 39:179–95
van Os J, Rutten BP, Poulton R. 2008. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr. Bull. 34:1066–82
van Winkel R, Esquivel G, Kenis G, Wichers M, Collip D, et al. 2010. Genome-wide findings in schizophrenia
and the role of gene-environment interplay. CNS Neurosci. Ther. 16:e185–92
van Winkel R, Genetic Risk Outcome Psychos. (GROUP) Investig. 2011. Family-based analysis of genetic
variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch.
Gen. Psychiatry 68:148–57
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
by University of Dayton on 08/12/14. For personal use only.
CP10CH28-vanWinkel
790
van Winkel
·
Kuepper
Annu. Rev. Clin. Psychol. 2014.10:767-791. Downloaded from www.annualreviews.org
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ARI
12 February 2014
14:36
van Winkel R, Genetic Risk Outcome Psychos. (GROUP) Investig. 2013. Family-based study examining moderation of familial correlation in psychosis-related experiences by the environment. Manuscr. submitted
van Winkel R, van Beveren JM, Genetic Risk Outcome Psychos. (GROUP) Investig. 2011. AKT1 moderation
of cannabis-induced cognitive alterations in psychotic disorder. Neuropsychopharmacology 36:2529–37
Veling W, Mackenbach JP, van Os J, Hoek HW. 2008. Cannabis use and genetic predisposition for schizophrenia: a case-control study. Psychol. Med. 38:1251–56
Verdejo-Garcia A, Beatriz Fagundo A, Cuenca A, Rodriguez J, Cuyas E, et al. 2013. COMT Val158Met and
5-HTTLPR genetic polymorphisms moderate executive control in cannabis users. Neuropsychopharmacology 38:1598–606
Vinkers C, Van Gastel WA, Schubart CD, Van Eijk K, Luykx J, et al. 2013. The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val158Met polymorphism.
Schizophr. Res. 150:303–11
Voruganti LN, Slomka P, Zabel P, Mattar A, Awad AG. 2001. Cannabis induced dopamine release: an in-vivo
SPECT study. Psychiatry Res. 107:173–77
Wegener N, Koch M. 2009. Behavioural disturbances and altered Fos protein expression in adult rats after
chronic pubertal cannabinoid treatment. Brain Res. 1253:81–91
Wilson W, Mathew R, Turkington T, Hawk T, Coleman RE, Provenzale J. 2000. Brain morphological changes
and early marijuana use: a magnetic resonance and positron emission tomography study. J. Addict. Dis.
19:1–22
Winton-Brown TT, Allen P, Bhattacharyya S, Borgwardt SJ, Fusar-Poli P, et al. 2011. Modulation of auditory
and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology 36:1340–48
Yücel M, Bora E, Lubman DI, Solowij N, Brewer WJ, et al. 2012. The impact of cannabis use on cognitive
functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a firstepisode sample. Schizophr. Bull. 38:316–30
Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, et al. 2008. Regional brain abnormalities associated
with long-term heavy cannabis use. Arch. Gen. Psychiatry 65:694–701
Zammit S, Owen M, Evans J, Heron J, Lewis G. 2011. Cannabis, COMT and psychotic experiences. Br. J.
Psychiatry 199:380–85
Zammit S, Spurlock G, Williams H, Norton N, Williams N, et al. 2007. Genotype effects of CHRNA7, CNR1
and COMT in schizophrenia: interactions with tobacco and cannabis use. Br. J. Psychiatry 191:402–7
Zuardi AW, Crippa JA, Hallak JE, Bhattacharyya S, Atakan Z, et al. 2012. A critical review of the antipsychotic
effects of cannabidiol: 30 years of a translational investigation. Curr. Pharm. Des. 18:5131–40
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Volume 10, 2014
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Advances in Cognitive Theory and Therapy: The Generic
Cognitive Model
Aaron T. Beck and Emily A.P. Haigh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
The Cycle of Classification: DSM-I Through DSM-5
Roger K. Blashfield, Jared W. Keeley, Elizabeth H. Flanagan,
and Shannon R. Miles p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
The Internship Imbalance in Professional Psychology: Current Status
and Future Prospects
Robert L. Hatcher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p53
Exploratory Structural Equation Modeling: An Integration of the Best
Features of Exploratory and Confirmatory Factor Analysis
Herbert W. Marsh, Alexandre J.S. Morin, Philip D. Parker,
and Gurvinder Kaur p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p85
The Reliability of Clinical Diagnoses: State of the Art
Helena Chmura Kraemer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111
Thin-Slice Judgments in the Clinical Context
Michael L. Slepian, Kathleen R. Bogart, and Nalini Ambady p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Attenuated Psychosis Syndrome: Ready for DSM-5.1?
P. Fusar-Poli, W.T. Carpenter, S.W. Woods, and T.H. McGlashan p p p p p p p p p p p p p p p p p p p 155
From Kanner to DSM-5: Autism as an Evolving Diagnostic Concept
Fred R. Volkmar and James C. McPartland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 193
Development of Clinical Practice Guidelines
Steven D. Hollon, Patricia A. Areán, Michelle G. Craske, Kermit A. Crawford,
Daniel R. Kivlahan, Jeffrey J. Magnavita, Thomas H. Ollendick,
Thomas L. Sexton, Bonnie Spring, Lynn F. Bufka, Daniel I. Galper,
and Howard Kurtzman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 213
Overview of Meta-Analyses of the Prevention of Mental Health,
Substance Use, and Conduct Problems
Irwin Sandler, Sharlene A. Wolchik, Gracelyn Cruden, Nicole E. Mahrer,
Soyeon Ahn, Ahnalee Brincks, and C. Hendricks Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 243
vii
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Improving Care for Depression and Suicide Risk in Adolescents:
Innovative Strategies for Bringing Treatments to Community
Settings
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The Contribution of Cultural Competence to Evidence-Based Care
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and Caitlin A. Smith p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 305
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How to Use the New DSM-5 Somatic Symptom Disorder Diagnosis
in Research and Practice: A Critical Evaluation and a Proposal for
Modifications
Winfried Rief and Alexandra Martin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Antidepressant Use in Pregnant and Postpartum Women
Kimberly A. Yonkers, Katherine A. Blackwell, Janis Glover,
and Ariadna Forray p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Depression, Stress, and Anhedonia: Toward a Synthesis and
Integrated Model
Diego A. Pizzagalli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
Excess Early Mortality in Schizophrenia
Thomas Munk Laursen, Merete Nordentoft, and Preben Bo Mortensen p p p p p p p p p p p p p p p p 425
Antecedents of Personality Disorder in Childhood and Adolescence:
Toward an Integrative Developmental Model
Filip De Fruyt and Barbara De Clercq p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
The Role of the DSM-5 Personality Trait Model in Moving Toward a
Quantitative and Empirically Based Approach to Classifying
Personality and Psychopathology
Robert F. Krueger and Kristian E. Markon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 477
Early-Starting Conduct Problems: Intersection of Conduct Problems
and Poverty
Daniel S. Shaw and Elizabeth C. Shelleby p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 503
How to Understand Divergent Views on Bipolar Disorder in Youth
Gabrielle A. Carlson and Daniel N. Klein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
Impulsive and Compulsive Behaviors in Parkinson’s Disease
B.B. Averbeck, S.S. O’Sullivan, and A. Djamshidian p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553
Emotional and Behavioral Symptoms in Neurodegenerative Disease:
A Model for Studying the Neural Bases of Psychopathology
Robert W. Levenson, Virginia E. Sturm, and Claudia M. Haase p p p p p p p p p p p p p p p p p p p p p p p 581
viii
Contents
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Attention-Deficit/Hyperactivity Disorder and Risk of Substance Use
Disorder: Developmental Considerations, Potential Pathways, and
Opportunities for Research
Brooke S.G. Molina and William E. Pelham Jr. p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 607
The Behavioral Economics of Substance Abuse Disorders:
Reinforcement Pathologies and Their Repair
Warren K. Bickel, Matthew W. Johnson, Mikhail N. Koffarnus,
James MacKillop, and James G. Murphy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 641
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The Role of Sleep in Emotional Brain Function
Andrea N. Goldstein and Matthew P. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 679
Justice Policy Reform for High-Risk Juveniles: Using Science to
Achieve Large-Scale Crime Reduction
Jennifer L. Skeem, Elizabeth Scott, and Edward P. Mulvey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 709
Drug Approval and Drug Effectiveness
Glen I. Spielmans and Irving Kirsch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 741
Epidemiological, Neurobiological, and Genetic Clues to the
Mechanisms Linking Cannabis Use to Risk for Nonaffective
Psychosis
Ruud van Winkel and Rebecca Kuepper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 767
Indexes
Cumulative Index of Contributing Authors, Volumes 1–10 p p p p p p p p p p p p p p p p p p p p p p p p p p p p 793
Cumulative Index of Articles Titles, Volumes 1–10 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 797
Errata
An online log of corrections to Annual Review of Clinical Psychology articles may be
found at http://www.annualreviews.org/errata/clinpsy
Contents
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Annual Reviews
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New From Annual Reviews:
Annual Review of Organizational Psychology and Organizational Behavior
Volume 1 • March 2014 • Online & In Print • http://orgpsych.annualreviews.org
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The Annual Review of Organizational Psychology and Organizational Behavior is devoted to publishing reviews of
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strategic HR, cross-cultural issues, work attitudes, entrepreneurship, affect and emotion, organizational change
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Table of Contents:
• An Ounce of Prevention Is Worth a Pound of Cure: Improving
Research Quality Before Data Collection, Herman Aguinis,
Robert J. Vandenberg
• Burnout and Work Engagement: The JD-R Approach,
Arnold B. Bakker, Evangelia Demerouti,
Ana Isabel Sanz-Vergel
• Compassion at Work, Jane E. Dutton, Kristina M. Workman,
Ashley E. Hardin
• Constructively Managing Conflict in Organizations,
Dean Tjosvold, Alfred S.H. Wong, Nancy Yi Feng Chen
• Coworkers Behaving Badly: The Impact of Coworker Deviant
Behavior upon Individual Employees, Sandra L. Robinson,
Wei Wang, Christian Kiewitz
• Delineating and Reviewing the Role of Newcomer Capital in
Organizational Socialization, Talya N. Bauer, Berrin Erdogan
• Emotional Intelligence in Organizations, Stéphane Côté
• Employee Voice and Silence, Elizabeth W. Morrison
• Intercultural Competence, Kwok Leung, Soon Ang,
Mei Ling Tan
• Learning in the Twenty-First-Century Workplace,
Raymond A. Noe, Alena D.M. Clarke, Howard J. Klein
• Pay Dispersion, Jason D. Shaw
• Personality and Cognitive Ability as Predictors of Effective
Performance at Work, Neal Schmitt
• Perspectives on Power in Organizations, Cameron Anderson,
Sebastien Brion
• Psychological Safety: The History, Renaissance, and Future
of an Interpersonal Construct, Amy C. Edmondson, Zhike Lei
• Research on Workplace Creativity: A Review and Redirection,
Jing Zhou, Inga J. Hoever
• Talent Management: Conceptual Approaches and Practical
Challenges, Peter Cappelli, JR Keller
• The Contemporary Career: A Work–Home Perspective,
Jeffrey H. Greenhaus, Ellen Ernst Kossek
• The Fascinating Psychological Microfoundations of Strategy
and Competitive Advantage, Robert E. Ployhart,
Donald Hale, Jr.
• The Psychology of Entrepreneurship, Michael Frese,
Michael M. Gielnik
• The Story of Why We Stay: A Review of Job Embeddedness,
Thomas William Lee, Tyler C. Burch, Terence R. Mitchell
• What Was, What Is, and What May Be in OP/OB,
Lyman W. Porter, Benjamin Schneider
• Where Global and Virtual Meet: The Value of Examining
the Intersection of These Elements in Twenty-First-Century
Teams, Cristina B. Gibson, Laura Huang, Bradley L. Kirkman,
Debra L. Shapiro
• Work–Family Boundary Dynamics, Tammy D. Allen,
Eunae Cho, Laurenz L. Meier
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New From Annual Reviews:
Annual Review of Statistics and Its Application
Volume 1 • Online January 2014 • http://statistics.annualreviews.org
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Editor: Stephen E. Fienberg, Carnegie Mellon University
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The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as
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table of contents:
• What Is Statistics? Stephen E. Fienberg
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• The Role of Statistics in the Discovery of a Higgs Boson,
David A. van Dyk
• Breaking Bad: Two Decades of Life-Course Data Analysis
in Criminology, Developmental Psychology, and Beyond,
Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca
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• Statistics and Climate, Peter Guttorp
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Radu V. Craiu, Jeffrey S. Rosenthal
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• Structured Regularizers for High-Dimensional Problems:
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