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Cannabis, or marijuana, has been consumed by humans for centuriesand remains one of the most widely and commonly used illicitsubstances. The authors review the evidence supporting and refutingthe association between cannabis exposure and psychotic disorders.
Cannabis, or marijuana, has beenconsumed by humans for centuriesand remains one of themost widely and commonly used illicitsubstances. Recently, there has beenrenewed interest in the associationbetween cannabis use and psychosis.The purpose of this article is to reviewthe evidence supporting and refutingthe association between cannabis exposureand psychotic disorders, includingschizophrenia.
As far back as 1845, Dr. Jacques-Joseph Moreau de Tours describedpsychotic phenomena with hashishuse as:
[A]cute psychotic reactions,generally lasting but a few hours,but occasionally as long as aweek; the reaction seemed doserelatedand its main featuresincluded paranoid ideation, illusions,hallucinations, delusions,depersonalization, confusion,restlessness and excitement.There can be delirium, disorientationand marked clouding ofconsciousness.
In 1964, Gaoni and Mechoulamidentified δ-9 tetrahydrocannabinol (δ-9-THC) as the principal psychoactiveingredient of cannabis.
The identification and cloning of abrain cannabinoid receptor (CB-1) in1990 provided a jump start to renewedresearch on cannabinoids (Matsuda etal., 1990). Most of the psychoactiveeffects of cannabis are believed to bemediated by CB-1 receptors where δ-9-THC is a modest affinity (Ki=35nmol to 80 nmol) low intrinsic activitypartial agonist. A peripheral receptorlater named CB-2 was identified insplenic tissue (Munro et al., 1993).Recent evidence suggests the presenceof other brain cannabinoid receptors.The presence of cannabinoid receptorsled to the logical search for endogenouscannabinoid receptor ligands,culminating in the discovery of anandamideand 2-arachidonoyl glycerol,two of the better known endogenouscannabinoids or endocannabinoids.Cannabinoid-1 receptors are distributedwith high density in the cerebral cortex,particularly the frontal regions, basalganglia, hippocampus, anterior cingulatecortex and cerebellum (Glass et al.,1997; Herkenham et al., 1990), brainregions that are relevant to their known effects. Further, these are also regionsthat have been implicated in the putativeneural circuitry of psychosis. Theprimary effect of cannabinoids is themodulation of neurotransmitter releasevia activation of presynaptic CB1-Rs(reviewed in Demuth and Molleman,in press; Freund et al., 2003). Of note,some of these neurotransmitters (eg,dopamine and glutamate) have beenimplicated in the pathophysiology ofpsychosis.
The effects of herbal cannabis are acomposite of a number of cannabinoidcompounds, terpenoids and flavonoids.Thus, cannabidiol, a constituent ofherbal cannabis, may offset some δ-9-THC effects (Zuardi et al., 1995). Theratio of the constituents of herbalcannabis varies, and this may result inimportant differences in its net effect.
Emerging data suggest an associationbetween cannabis exposure and thedevelopment of schizophrenia (Table).Interest in the association betweencannabis and schizophrenia received amajor boost from the Swedish Conscriptstudy, a large historical, longitudinalcohort study of all Swedes conscriptedin 1969-1970 (Andreasson et al., 1987).Since Sweden mandates military service,97% of males aged 18 to 20 yearswere included. Individuals who at age18 reported having used cannabis >50times were six times more likely thannonusers to have been diagnosed withschizophrenia in the ensuing 15 years.Adjusting for other relevant risk factors,including psychiatric diagnosis otherthan psychosis at conscription, reducedbut did not eliminate the higher risk(odds ratio [OR]=2.3) of schizophreniaconferred by cannabis use.
A reanalysis and extension of thesame Swedish conscript cohort reconfirmedthat those who were heavy cannabisusers by the age of 18 were 6.7times more likely than nonusers to behospitalized for schizophrenia 27 yearslater (Zammit et al., 2002). The OR forcannabis use and schizophrenia remainedsignificant (1.2), albeit lowerthan in the original study, despite adjustingfor a number of confounds, includinglow IQ and stimulant use. Further,the finding of an increased risk of schizophreniaconferred by cannabis usepersisted after controlling for the possibilitythat cannabis use was a consequenceof prodromal manifestations ofpsychosis.
Several recent prospective cohortstudies complement studies using ahistorical approach. In a general populationbirth cohort study of 1,037 peopleborn in Dunedin, New Zealand, andfollowed through age 26, individualsusing cannabis at ages 15 and 18,compared to nonusers, had higher ratesof both psychotic symptoms at age 26(even after controlling for psychoticsymptoms) and schizophreniform disorderpredating the onset of cannabis use(Arseneault et al., 2002). Similarly,cohort studies from elsewhere have alsoreported a dose-response relationshipin the increased risk of psychosis withcannabis exposure (Ferdinand et al.,2005a; Fergusson et al., 2003; Henquetet al., 2005; Stefanis et al., 2004; vanOs et al., 2002; Weiser et al., 2002).Several studies of patients during theirfirst-break psychosis suggested thatcannabis use precedes or is coincidentwith the first psychotic break in patientswith schizophrenia (Allebeck et al.,1993; Hambrecht and Hafner, 2000).
Are these data sufficient to constitutea causal relationship? And if so,how strong is the association? Temporality,strength, association, direction,dose-response or biological gradient, consistency, specificity, coherence,experimental evidence, and plausibilityare some of the criteria that havebeen used to establish disease causality(Aiello and Larson, 2002).
Several studies reviewed here providedevidence of a dose-response relationshipbetween cannabis exposureand the risk of psychosis. Most studiesalso provided evidence of direction byshowing that the association betweencannabis use and psychosis persistseven after controlling for many potentialconfounding variables such as IQ,education, urbanicity, marital status andprevious psychotic symptoms. Withregard to temporality, several studiessuggested that cannabis use precedesor coincides with the onset of psychosis.Further, there is also evidence thatcannabis use may be associated with alower age of schizophrenia onset (Greenet al., 2004; Linszen et al., 1994). Thereis evidence for both the specificity ofexposure (i.e., cannabis [Arseneault etal., 2002; Ferdinand et al., 2005a, 2005b;Zammit et al., 2002]) and specificity ofthe outcome (i.e., psychosis [Arseneaultet al., 2002; Stefanis et al., 2004]).Experimental evidence from laboratorystudies suggested that cannabinoids caninduce transient short-lived psychosisin healthy individuals (D'Souza et al.,2004; Leweke et al., 2000). Further, relativeto controls, patients with schizophreniahave been shown to be morevulnerable to the psychotomimeticeffects of δ-9-THC (D'Souza et al.,2005). While it is out of the scope ofthis review, the interactions betweencannabinoid receptor function anddopamine, glutamate and γ-aminobutyricacid receptor function providepotential mechanisms by whichcannabis may "cause" psychosis (asreviewed in D'Souza et al., 2004, 2005).
One of the most obvious genetic riskfactors for psychosis is a family historyof psychosis. In a case-control study,cannabis users admitted for schizophreniahad a significantly greater familialrisk of schizophrenia than patientswith schizophrenia without cannabis use(McGuire et al., 1995). Consistent withthese findings, data from the EdinburghHigh Risk project showed that frequentcannabis use conferred a sixfold higherrisk of schizophrenia in individuals witha family history of schizophrenia (Milleret al., 2001). Recently, a polymorphismof the catechol-O-methyltransferasegene has been reported to modulate therisk of schizophrenia conferred by cannabis(Caspi et al., 2005).
Emerging findings from postmortem(Dean et al., 2001; Zavitsanou et al.,2004), neurochemical (Leweke et al.,1999) and genetic (Ujike et al., 2002)studies suggested cannabinoid receptorsystem dysfunction contributes tothe pathophysiology of schizophrenia. Thus, it is possible that cannabinoidreceptor dysfunction is the substrate thatlinks cannabis exposure and psychosis.
Finally, if cannabis causes psychosisin and of itself, then one would expectthat any increase in the rates of cannabisuse would be associated with increasedrates of psychosis. However, in some areaswhere cannabis use has clearly increased(e.g., Australia), there has not been acommensurate increase in the rate ofpsychotic disorders (Degenhardt et al.,2003). Further, one might also expect thatif the age of initiation of cannabis usedecreases, there should also be a decreasein the age of onset of psychotic disorders.We are unaware of such evidence.
In conclusion, there is evidence foran association between cannabis andpsychosis. It is clear that cannabinoidscan cause acute transient psychoticsymptoms or an acute psychosis. Alsoit is clear that cannabis can exacerbatepsychosis in individuals with an establishedpsychotic disorder. However,whether cannabis causes a persistentde novo psychosis independent of anyother risk factors is not supported by theexisting literature. More likely, cannabisis a component cause that interacts withother factors (e.g., genetic risk) to inducepsychosis.
Nevertheless, in the absence of knowncauses of schizophrenia, the role ofcomponent causes such as cannabis useremains important and warrants furtherstudy. Finally, studying the role of exogenouscannabinoids in the developmentof psychosis will need to be complementedby further studying a possiblerole of endocannabinoid dysfunction inthe pathophysiology of psychosis.
Dr Malik is a fourth year resident in psychiatryand Dr D'Souza is associate professor ofpsychiatry, both at Yale University School ofMedicine, New Haven, Conn.
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