Neurotherapeutics (2015) 12:816–824

DOI 10.1007/s13311-015-0382-6

REVIEW

Cannabinoids and Schizophrenia: Risks

Published online: 27 August 2015

Abstract A convergence of evidence shows that use of Can- the role of CBD and other CBD-based compounds in treating
nabis sativa is associated with increased risk of developing psychotic disorders will require further human research.
psychotic disorders, including schizophrenia, and earlier age
at which psychotic symptoms first manifest. Cannabis expo- Key Words Cannabinoids . schizophrenia . psychosis .
sure during adolescence is most strongly associated with the cannabidiol . cannabis . endocannabinoid
onset of psychosis amongst those who are particularly vulner-
able, such as those who have been exposed to child abuse and
those with family histories of schizophrenia. Schizophrenia Introduction
that develops after cannabis use may have a unique clinical
phenotype, and several genetic polymorphisms may modulate Schizophrenia is a chronic and often disabling developmental
the relationship between cannabis use and psychosis. The brain disease that affects approximately 1 % of the population
endocannabinoid system has been implicated in psychosis over the course of life [1], and is characterized by positive
both related and unrelated to cannabis exposure, and studying symptoms (delusions, hallucinations, and disorganized think-
this system holds potential to increase understanding of the ing), negative symptoms (social withdrawal, amotivation, and
pathophysiology of schizophrenia. Anandamide signaling in affective flattening), deficits in cognition (memory, executive
the central nervous system may be particularly important. Δ9- functioning, and processing speed), and a decline in social and
Tetrahydrocannabinol in cannabis can cause symptoms of occupational functioning [2]. While significant advances have
schizophrenia when acutely administered, and cannabidiol been made in understanding the neurobiology of schizophre-
(CBD), another compound in cannabis, can counter many of nia, and effective treatments have been developed for positive
these effects. CBD may have therapeutic potential for the symptoms, the goal of reversing disability associated with
treatment of psychosis following cannabis use, as well as cognitive deficits and amotivation has not been realized.
schizophrenia, possibly with better tolerability than current Cannabis sativa is the most commonly used illicit sub-
antipsychotic treatments. CBD may also have anti- stance globally, and its main psychoactive component, Δ9-
inflammatory and neuroprotective properties. Establishing tetrahydrocannabinol (THC), has been widely recognized for
its ability to cause acute psychotic symptoms and cognitive
impairment similar to schizophrenia [3, 4]. Cannabis is also
the most commonly abused illicit substance amongst people
Electronic supplementary material The online version of this article
(doi:10.1007/s13311-015-0382-6) contains supplementary material, with schizophrenia, and there is substantial evidence that con-
which is available to authorized users. tinued use after a schizophrenia diagnosis is associated with
worsening psychotic symptoms, relapse, and decreased func-
* Donald C. Goff tioning over time [4, 5]. Furthermore, epidemiologic evidence
Donald.Goff@nyumc.org has accumulated implicating cannabis use as an important
environmental risk factor for developing schizophrenia. In
1
Department of Psychiatry, New York University Langone Medical 1987, Andreasson et al. [6] reported that heavy cannabis use
Center, New York, NY, USA was associated with a 6-fold increase in risk for schizophrenia,
Cannabinoids and Schizophrenia 817

based on a 15-year follow-up of Swedish military conscripts. have preceded onset of illness. Interestingly, the relationship
Debate has since ensued over whether this association is caus- between cannabis use and age of onset did not differ between
al. A greater understanding of the endocannabinoid system schizophrenia and affective psychosis, suggesting a lack of
(ECS) and its links to psychosis has the potential to generate specificity for schizophrenia. In a study of 625 patients with
new insights into the neurobiological causes of schizophrenia, a first episode of psychosis, subjects whose substance use was
and to open up novel and more efficacious treatment options restricted to cannabis had an earlier age of onset of psychosis,
for this debilitating illness. but only if cannabis use started before the age of 14 years [12].
Here, we first review the evidence for cannabis use as a Whereas the effect of cannabis use before the age of 14 years
causal factor for the development of schizophrenia. Next, we on age of psychosis onset was small, in the entire sample the
review the biology of the ECS as it pertains to psychosis. age of onset of cannabis strongly predicted age of onset of
Finally, we review preliminary evidence for the use of psychosis, accounting for 25 % of the variance of age of ill-
cannabinoid-based compounds in the treatment of psychosis, ness onset. Similarly, in a sample of 997 subjects, Stefanis
and identify potential future research directions for the field. et al. [13] found that onset of cannabis use preceded onset of
psychosis on average by 7–8 years regardless of the age at
which cannabis use began. This finding is not consistent with
Cannabis and Schizophrenia the widely held view that adolescence is a unique develop-
mental period of vulnerability to cannabis, but rather that early
Evidence for a relationship between cannabis use and risk for exposure to cannabis predicts early onset of illness in part
psychosis has been replicated frequently. An analysis of re- because the temporal onset of the 2 are related, regardless of
sults from 35 studies revealed a pooled odds ratio of 1.4 for the age at which cannabis use starts. Two longitudinal cohort
risk of developing psychosis in individuals with any history of studies utilized repeated assessments during adolescence and
cannabis exposure and an odds ratio of 2.1 among individuals young adulthood to examine the temporal relationship be-
with histories of more frequent use [7]. In addition, a relation- tween cannabis use and psychosis [14, 15]. Although the
ship between the age of initiation of cannabis use and age of numbers of individuals with psychosis were small, both stud-
onset of psychosis has also been well documented, with most ies found a bidirectional relationship, such that early psychotic
studies finding that cannabis use precedes onset of psychosis symptoms predicted later cannabis use and vice versa,
and that the amount of cannabis exposure in adolescence may supporting both a causal relationship and a self-medication
be the strongest determinant of this association [4]. However, hypothesis, or the existence of a third factor. In contrast,
several issues have complicated interpretation of these find- Henquet et al. [16] prospectively followed 2437 adolescents
ings, including the role of comorbid substance use, of male and young adults for 4 years and found that low levels of
sex (which is associated with higher rates of cannabis use and psychotic symptoms in combination with cannabis use pre-
earlier age of onset of schizophrenia), of lower socioeconomic dicted onset of psychosis; the risk of psychosis correlated with
status, and of the potentially poor reliability of self-reported the frequency of cannabis use. However, low levels of psy-
histories of past cannabis use. In addition, rather than a causal chotic symptoms did not predict subsequent initiation of can-
association, it is possible that cannabis use may represent self- nabis use in participants who were abstinent at baseline. The
medication of early symptoms of a psychotic diathesis (e.g., issue of confounding socioenvironmental factors was ad-
anxiety) or that both the predilection for early use of cannabis dressed by McGrath et al. [17], who used sibling pairs in a
and the risk for psychosis are related to a third factor [8]. For study that corroborated the relationship between duration of
example, the high rates of cigarette smoking in individuals cannabis use and risk of psychosis [17]. Duration since first
with schizophrenia represents a strong association, which is cannabis use and subsequent psychosis-related outcome mea-
not viewed as causal, but rather is interpreted as reflecting a sures remained significant within sibling pairs, suggesting that
third factor, dysregulation of nicotinic acetycholine transmis- this relationship is less likely to be explained entirely by un-
sion in schizophrenia [9]. Consistent with this model, schizo- measured confounding.
phrenia risk alleles have been linked both to risk for cannabis The fact that only a very small minority of cannabis users
use and the quantity of use among the general population [10]. develop schizophrenia, as well as the absence of an increase in
In a meta-analysis that included 83 studies and 22,000 in- the incidence of psychosis commensurate with the recent
dividuals with psychotic disorders, substance use was signif- population-level increase in cannabis use, suggest that the ep-
icantly associated with an earlier onset of psychosis (by a idemiologic association between the 2 might be based on con-
mean of 2.7 years), after controlling for sex [11]. Alcohol founding factors and/or reverse causation [18, 19]. Arguing in
use did not predict age of onset, whereas the relationship of support of a causal relationship is the consistently replicated
other substances of abuse to age of onset could not be deter- evidence in different populations that cannabis use precedes
mined, nor were the authors of the meta-analysis able to re- psychotic symptoms [20, 21], there is a dose effect [16], and
strict subjects to those for whom cannabis use was known to there are coherent, plausible biological mechanisms [4, 22, 23].
818 Manseau and Goff

However, cannabis use does not meet the specificity or strength psychosis [35], and fewer soft signs of neurologic dysfunction
criteria for causality in that it is neither necessary nor sufficient [36, 37] than those who developed schizophrenia in the ab-
to cause persistent psychosis in the general population. In sum- sence of cannabis exposure. The findings related to cognitive
mary, frequent cannabis use clearly is associated with subse- functioning have been replicated in both first episode and more
quent risk for psychotic disorders, particularly schizophrenia. chronic populations of people with psychotic illness [33]. Ex-
However, though highly suggestive, it is not possible from the planations for these results have included the idea that disrup-
available evidence to conclude that this relationship is causal. tion of the ECS by exogenous cannabinoids (i.e., THC) during
Rather, based on available evidence, one can only conclude that a critical developmental period may interact with specific bio-
a relationship exists between heavy, early cannabis use and logical vulnerabilities when psychosis develops following can-
psychosis—a causal link may occur in either direction. As ran- nabis use, whereas those who develop schizophrenia without
domized experiments are not possible, natural experiments in cannabis exposure may develop the illness along a different
which cannabis use is increased or decreased at a population pathway of neurobiological vulnerability.
level by legalization or by prevention programs may help ad- Regardless of how important cannabis use is in causing the
dress the issue of causality. onset of schizophrenia, it is fairly clear that continued canna-
bis use after diagnosis is associated with more severe positive
Vulnerability Factors symptoms and decreased functioning in both first episode and
more chronically ill people with schizophrenia [5], and that
There are a number of specific factors that convey increased discontinuing cannabis use improves mood and anxiety symp-
risk of developing a psychotic disorder after cannabis expo- toms [38], psychotic symptoms [39], and psychosocial func-
sure. A family history of schizophrenia has been shown to tioning [38].
increase the risk of psychosis following cannabis exposure
[24, 25]. For example, one study comparing 54 cannabis- Gene-by-Environment Interactions
using patients with schizophrenia to 71 patients who did not
use cannabis found cannabis-using patients to have higher Four genes have emerged as possibly modulating the risk of
rates of psychosis in their family histories, especially if can- developing a psychotic illness following exposure to canna-
nabis use preceded their psychotic symptoms [24]. Another bis, in increasing order of replication in the literature: the
population registry-based study found that family history of brain-derived neurotrophic factor (BDNF) gene, the cannabi-
schizophrenia increased both the risk of schizophrenia and of noid receptor 1 (CNR1) gene, the catechol O-
acute cannabis-induced psychosis [25]. A history of child methyltransferase (COMT) gene, and AKT1 [40]. A single
abuse (including sexual, physical, and/or emotional abuse) nucleotide polymorphism (SNP) of the gene encoding brain-
or neglect also increases the risk of developing schizophrenia derived neurotrophic factor, Val66Met (rs6265), has been
after cannabis use [26–31]. Two large, population-based, lon- shown to moderate the relationship between cannabis use
gitudinal studies, in Greece and the Netherlands, both repli- and age of onset of psychosis. The interaction may be limited
cated findings that childhood maltreatment and cannabis use to females for unknown reasons; female cannabis users who
precede and are independently associated with increased risk carry the Val/Val polymorphism displayed psychotic symp-
of later psychosis, and that the combination of the 2 risk fac- toms on average 7 years earlier than female Met carriers
tors is synergistically associated with an increased risk of psy- [41]. CNR1 encodes the cannabinoid receptor 1 (CB1R),
chosis [28]. Finally, being born in and growing up in an urban which is widespread throughout the central nervous system
environment is positively associated with the combination of (CNS), including the brain. In a functional magnetic reso-
cannabis use and psychosis. For instance, a large prospective nance imaging study of working memory in healthy subjects,
study in and around Munich, Germany, found that the in- those carrying a G allele in a SNP (rs1406977) of CNR1 as-
creased risk of psychosis following cannabis use was much sociated with lower receptor expression levels in the prefrontal
greater for those who grew up in the city of Munich than for cortex who also had a history of cannabis use demonstrated
those raised in surrounding rural areas [32]. decreased working memory and abnormally increased ventro-
One might expect that those vulnerable to developing medial prefrontal connectivity than those with AA alleles, as
schizophrenia after cannabis exposure would have greater well as to those with a G allele but no history of cannabis use
baseline neurological and cognitive deficits than those less vul- [42]. A variation of CNRI involving AAT triplet repeats has
nerable. However, the opposite seems to be true. Those who been associated with a “hebephrenic” type of schizophrenia,
develop schizophrenia following cannabis use tend to have characterized by prominent negative symptoms and disorga-
more severe positive psychotic symptoms [24], fewer negative nization [43, 44]. Catechol O-methyltransferase is one of the
psychotic symptoms [24], fewer cognitive deficits [33], better enzymes responsible for degrading catecholamines, including
premorbid functioning [34], acute onset of psychosis without a dopamine. A Val158Met SNP (rs4680) in COMT has been
prodromal period [34], a shorter duration of untreated found to increase the risk of schizophrenia amongst people
Cannabinoids and Schizophrenia 819

with premorbid cannabis use [45], although this finding has receptor 55, and peroxisome proliferator-activated receptors α
not been consistently replicated [46]. The Val/Val genotype and γ [53]. CB1R expression is high in brain areas with a
has also been associated with increased symptom severity in greater density of dopaminergic neurons, such as frontal re-
individuals with schizophrenia who are using cannabis [45]. gions, basal ganglia, cerebellum, hippocampus, amygdala,
Two studies found a 3-way interaction between the COMT and substantia nigra, and interactions between the
SNP, cannabis use, and a history of child abuse. Carriers of endocannabinoid and dopaminergic systems have been thought
the COMT Val/Val genotype who were exposed to both child- to play a role in the relationships between cannabinoids and
hood abuse and cannabis had more severe psychotic symp- psychosis [54]. CB1R are expressed on GABA-ergic and glu-
toms, whereas amongst carriers of a Met allele, childhood tamatergic axon terminals in the hippocampus where they mod-
abuse was associated with more severe psychotic symptoms ulate long-term potentiation, which is involved in memory and
in noncannabis users [26, 27]. AKT1 encodes for a protein plasticity [55]. The effect of CB1R agonists on long-term po-
kinase involved in second messenger transduction at the tentiation may be biphasic, producing enhancement at low con-
CB1R, and has also been implicated in increasing the risk centrations and inhibition at higher concentrations; vanilloid
for psychosis in cannabis users. An SNP (rs2494732) has been receptors, which are co-localized with CB1R, may play a role
associated with a greatly increased risk of developing a psy- in this modulatory function [56].
chotic disorder amongst cannabis users: compared with T/T Although 2-AG may be more plentiful in the CNS, ananda-
carriers, C/C carriers demonstrated 7-fold odds of developing mide has received particular attention in the literature linking
psychosis [47]. In a study examining potential mechanisms the ECS to psychosis [57]. Anandamide was found to be ele-
behind this gene-by-cannabis exposure interaction, it was vated in the cerebrospinal fluid (CSF) of people experiencing
found that subjects with schizophrenia carrying the C/C geno- prodromal symptoms of schizophrenia compared with healthy
type with premorbid cannabis use performed worse on cogni- controls, but lower anandamide levels correlated with a greater
tive measures of sustained attention as than C/C genotype risk of transition to psychosis within the prodromal population
subjects without premorbid cannabis use, even after long- [58]. Furthermore, anandamide has been found to be elevated
term abstinence from cannabis. T/T carriers with cannabis in the CSF of people experiencing both chronic and acute psy-
use performed as well or better than T/T carriers without can- chotic symptoms relative to healthy controls [59, 60]. In turn,
nabis use, suggesting a differential effect on brain functioning amongst those with psychosis, CSF anandamide levels are in-
and psychosis risk of cannabis use depending on underlying versely related to the severity of psychotic symptoms [59].
genetic vulnerability [48]. These findings have been interpreted as indicating that ananda-
mide may be part of a natural compensatory mechanism for
psychosis in the brain, such that it is elevated in response to
The ECS and Psychosis onset of psychosis, and the degree of elevation determines the
degree of antipsychotic buffering—an interpretation that re-
The ECS comprises 2 cannabinoid receptors, CB1R in the CNS mains highly speculative. CSF anandamide levels decrease
and CB2R in the periphery [49]; 2 main endogenous ligands, when people with psychosis are treated with typical antipsy-
anandamide and arachidonoylglycerol (2-AG) [50]; 2 main chotic medications with high dopaminergic blockade, but not
endocannabinoid synthesizing enzymes, N-acyl phosphatidyl- when they are treated with newer atypical agents with propor-
ethanolamine phospholipase and diacylglycerol lipase; and 2 tionally greater serotonergic antagonism [59]. People with
degradation enzymes, fatty acid amide hydrolase and schizophrenia and a history of chronic cannabis use do not have
monoacylglycerol lipase [51]. The system is involved in com- elevation in CSF anandamide levels [61], suggesting that can-
plex regulation of emotion, reward, and cognition, and has been nabis use may suppress the brain’s natural ability to temper a
implicated in both inflammatory and neuroprotective processes psychotic process, and pointing towards a potential biological
[51]. 2-AG is a full agonist at both CB1R and CB2R, whereas mechanism underlying the cannabis–psychosis link in vulner-
anandamide is a partial agonist at CB1R. Both 2-AG and anan- able individuals. In healthy volunteers who regularly use can-
damide are retrograde messengers; they are released postsyn- nabis, CSF anandamide levels are decreased and 2-AG levels
aptically and act presynaptically to inhibit release of many ex- are increased compared with infrequent cannabis users [62]. In
citatory and inhibitory neurotransmitters, including dopamine, addition, amongst cannabis users, CSF anandamide levels are
glutamate, and γ-aminobutyric acid (GABA) [52]. Several oth- inversely correlated with persisting psychotic symptoms when
er molecules also act at cannabinoid receptors, including N- cannabis-free, and higher CSF anandamide levels are associat-
arachidonoyl-dopamine, noladin ether, oleamide, N- ed with a lower risk of psychotic symptoms acutely following
oleoylethanolamide, N-palmitoylethanolamide, and cannabis use [62].
virodhamine. In addition, endocannabinoids may also modu- In summary, these complex and seemingly contradictory
late neuroplasticity and exert other effects by acting at transient findings can be parsed into a compelling and plausible, albeit
receptor potential vanilloid 1channels, G protein-coupled still preliminary and speculative, biological mechanism for
820 Manseau and Goff

how the ECS relates to psychosis. Higher levels of CB1R, serious adverse effects on mood. Rimonabant has been shown
such as via the full agonist endocannabinoid 2-AG or through to normalize psychotic-like behaviors in animal models of
exogenous cannabinoids such as THC, may directly and indi- schizophrenia [72, 73]. In a small, 16-week, placebo-con-
rectly (e.g., via affecting GABAergic transmission) contribute trolled, double-blind, randomized trial of 15 obese patients with
to dopaminergic dysregulation in brain areas important to psy- schizophrenia, which was terminated when rimonabant was
chosis, such as frontal cortical areas and the hippocampus withdrawn from the European market, rimonabant 20 mg per
[63]. Anandamide may play an important regulatory role in day decreased anxiety, depression and hostility compared with
this system, possibly through its partial agonism at the CB1R placebo, but did not improve negative symptoms or psychosis
and/or by affecting neuroplasticity. Because anandamide [74]. In addition, rimonabant improved a probabilistic test of
seems to rise in psychosis, which then, in turn, correlates with reward learning, but performance was inferior to placebo on a
a reduction in psychotic symptoms, it could be part of a neg- standard cognitive test battery [75].
ative feedback system on psychotic processes in the brain. Another important constituent of cannabis is cannabidiol
Exogenous cannabinoid exposure may, over time, dysregulate (CBD), which has very low affinity for and may be a weak
or attenuate this natural antipsychotic compensatory system. partial agonist at the CB1R. CBD also inhibits the reuptake
and degradation of anandamide, thereby increasing ananda-
mide levels in the CNS [76]. This may have important impli-
Cannabinoids and Treatment cations in that anandamide has recently been found to modu-
late synaptic neuroplasticity via activity at transient receptor
THC, the primary psychoactive constituent of cannabis, is a potential vanilloid type 1 receptors [77, 78]. As it has been
partial agonist at the CB1R. THC increases extracellular dopa- more widely studied, and because of its greater therapeutic
mine and glutamate and decreases GABA concentrations in the promise, we focus more attention on CBD.
prefrontal cortex [63]. THC binds more tightly to the receptor
and dissociates more slowly than natural endogenous ligands. CBD
Psychotomimetic effects of THC are well established, and in-
clude paranoia, grandiosity, disorganization, and alterations in Whereas CBD is very well tolerated and has few psychoactive
sensory perception. When administered to healthy subjects in a effects on its own [79], it counteracts several effects of THC
laboratory setting, THC produced positive and negative psy- and other CB1R agonists in healthy subjects [80], including
chotic symptoms, euphoria, anxiety, and impairments in atten- anxiety, euphoria, and psychosis [3, 73, 81]. CBD has also
tion, working memory, and verbal recall [64, 65]. People with been shown to attenuate THC-induced memory impairment
schizophrenia exhibit more severe psychotic symptoms in re- [80]. However, in mice and rats, CBD inhibits metabolism of
sponse to THC than healthy controls [66]. Findings have been THC, so that pretreatment with CBD can increase brain con-
mixed as to whether antipsychotics attenuate the psychotomi- centrations of THC and thereby potentiate its behavioral ef-
metic effects of THC in healthy subjects [67, 68], and chronic fects [82]. In a series of functional magnetic resonance imag-
antipsychotic treatment does not fully protect individuals with ing experiments in which CBD and THC were administered to
schizophrenia from symptom exacerbation after THC exposure healthy human subjects, the 2 compounds produced largely
[66]. Forms of cannabis that contain a higher THC content, opposite patterns of activation during tasks involving memo-
such as the “skunk-like” or sinsemilla cannabis, commonly ry, emotional processing, salience, and response inhibition in
used in theUK, have been shown to cause more severe psy- key brain regions implicated in schizophrenia, such as the
chotic symptoms and increase the risk for schizophrenia to a striatum, prefrontal cortex, and hippocampus [3, 81]. There
greater degree [69, 70]. More recently, synthetic cannabinoids, is also evidence that using cannabis with a higher CBD/
which consist of an array of compounds, many of which are full THC ratio is associated with a lower risk of psychotic disor-
agonists at the CB1R, have been associated with severe, acute ders, subthreshold psychotic symptoms, and cognitive chang-
psychosis, and agitation, among a host of other physical and es related to psychosis [3], from both studies analyzing THC
psychological problems [71]. Because of the ability of THC to and CBD concentrations in hair samples [83, 84], and from a
induce a psychotic syndrome, as well as evidence associating study analyzing the content of the cannabis that subjects re-
cannabis use with the development of schizophrenia, the po- ported regularly using [85]. Cannabis users have been found
tential antipsychotic properties of cannabinoid-based com- to have evidence for neurotoxicity in the prefrontal cortex
pounds that may counter the effects of THC have engendered based on lower levels of N-acetylaspartic acid measured by
great interest. One of the most commonly studied compounds proton magnetic spectroscopy, which reflects neuronal integ-
has been rimonabant, a CB1R antagonist, initially released in rity [86]. A higher ratio of CBD to THC concentrations in hair
the European Union as an anorectic for the treatment of obesity, samples of cannabis users was associated with higher levels of
but not approved by the Food and Drug Administration and N-acetylaspartic acid in the putamen/globus pallidus region
pulled from European Union markets owing to potentially [86], as well as larger hippocampal volume [87, 88].
Cannabinoids and Schizophrenia 821

The potential antipsychotic properties of CBD independent and synthetic cannabinoids can provoke symptoms of schizo-
of cannabis use have garnered increasing attention recently. phrenia in healthy subjects and exacerbate symptoms in pa-
Preclinical animal studies have shown that CBD normalizes tients with schizophrenia. THC has multiple actions that could
behaviors in rodent models for schizophrenia [72, 89], such as disrupt brain development in vulnerable adolescents, includ-
social interaction and performance on novel object recogni- ing impairment of neuroplasticity, dysregulation of dopamine
tion tests. In one study, psychotic-like behaviors induced in and glutamate signaling, and, possibly, neurotoxicity. Al-
mice through N-methyl-D-aspartate receptor antagonism with though still highly speculative, it is an intriguing hypothesis
the phencyclidine-like drug, dizocilpine (MK-801), were nor- that cannabis use in adolescence could contribute to the onset
malized by either clozapine or CBD administration [90]. CBD of a distinct form of schizophrenia which differs from the
also normalized markers of glial cell dysfunction and inflam- cannabis-independent neurodevelopmental pathway to
mation induced by N-methyl-D-aspartate receptor antagonist schizophrenia characterized by more gradual onset, greater
administration, suggesting that CBD may have anti- cognitive impairment, and functional disability. CBD attenu-
inflammatory and neuroprotective properties [90]. ates many of the adverse effects of THC, including psychosis
Five published clinical studies have examined the antipsy- and some elements of cognitive impairment. CBD may also
chotic effects of CBD in humans. In 1995, Zuardi et al. [91] be neuroprotective, based on observations of individuals using
published a case report in which a patient with treatment- cannabis with high or low relative concentrations of CBD.
resistant schizophrenia was administered up to 1500 mg orally Whereas simultaneous administration of CBD and THC ap-
per day of CBD for 26 days, with symptomatic improvement pears to protect against THC toxicity in humans, rodent stud-
and no adverse effects. In a follow-up report, the same group ies have found that pretreatment with CBD can potentiate
studied the effects of up to 1280 mg orally per day of CBD for THC effects by inhibiting its metabolism. This potential com-
4 weeks in 3 patients with treatment-resistant psychosis. Only plication therefore requires study in humans, as it could have
1 of the 3 patients improved, but none had adverse effects important implications for administration of CBD in cannabis
[92]. In another study, CBD up to 600 mg orally per day for users. Many potential clinical and preventive strategies follow
6 weeks significantly reduced psychotic symptoms in 6 pa- from the accumulated literature. Increasing decriminalization
tients with Parkinson’s disease and was well tolerated [93]. and legalization of cannabis may present opportunities to in-
Hallak et al. studied the acute effects of CBD on selective vestigate ways to reduce the harm of cannabis use through
attention, as well as electrodermal responsiveness to auditory regulation. For example, government regulators might moni-
stimuli, in 28 medication-free schizophrenic patients. They tor the ratio of CBD to THC in cannabis products, allowing
found no differences on any measure between patients who researchers to determine whether requiring an increased ratio
received a single oral dose of CBD 300 mg, CBD 600 mg, or of CBD to THC might reduce the risk of harm in vulnerable
placebo [94]. Finally, the largest clinical study of the effects of individuals. It is also possible that biomarkers, such as CSF
CBD on psychosis to date was a 4-week, double-blind, ran- anandamide or genetic profiling based on AKT1, COMT, or
domized trial comparing CBD, up to 800 mg per day (n=20), CNR1 might identify individuals at high risk for or early in the
to the antipsychotic amisulpride (n=19). Both groups signifi- course of psychosis who might benefit from CBD or other
cantly improved on ratings of positive and negative symptoms endocannabinoid-targeted interventions and may even not re-
with no significant differences between treatment groups. quire chronic antipsychotic treatment. Whether CBD might
However, the CBD group experienced significantly fewer side represent a general alternative or augmentative therapeutic
effects, including prolactin elevations, extrapyramidal symp- strategy for patients with schizophrenia will require much ad-
toms, and weight gain [76]. Further analysis showed that CBD ditional research.
treatment led to a significant increase in serum anandamide
levels, which correlated with improvement in symptoms [76].
Required Author Forms Disclosure forms provided by the authors are
If replicated in larger samples, such findings could suggest
available with the online version of this article.
that CBD may have significant antipsychotic properties with
superior tolerability to currently available antipsychotic drugs
[73]. However, further larger scale, placebo-controlled trials
are needed to determine whether CBD would make an effec- References
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