Cannabis, or marijuana, has been consumed by humans for centuries and remains one of the most widely and commonly used illicit substances. Recently, there has been renewed interest in the association between cannabis use and psychosis. The purpose of this article is to review the evidence supporting and refuting the association between cannabis exposure and psychotic disorders, including schizophrenia.
As far back as 1845, Dr. Jacques- Joseph Moreau de Tours described psychotic phenomena with hashish use as:[A]cute psychotic reactions, generally lasting but a few hours, but occasionally as long as a week; the reaction seemed doserelated and its main features included paranoid ideation, illusions, hallucinations, delusions, depersonalization, confusion, restlessness and excitement. There can be delirium, disorientation and marked clouding of consciousness.
In 1964, Gaoni and Mechoulam identified δ-9 tetrahydrocannabinol (δ-9-THC) as the principal psychoactive ingredient of cannabis.
The identification and cloning of a brain cannabinoid receptor (CB-1) in 1990 provided a jump start to renewed research on cannabinoids (Matsuda et al., 1990). Most of the psychoactive effects of cannabis are believed to be mediated by CB-1 receptors where δ-9-THC is a modest affinity (Ki=35 nmol to 80 nmol) low intrinsic activity partial agonist. A peripheral receptor later named CB-2 was identified in splenic tissue (Munro et al., 1993). Recent evidence suggests the presence of other brain cannabinoid receptors. The presence of cannabinoid receptors led to the logical search for endogenous cannabinoid receptor ligands, culminating in the discovery of anandamide and 2-arachidonoyl glycerol, two of the better known endogenous cannabinoids or endocannabinoids. Cannabinoid-1 receptors are distributed with high density in the cerebral cortex, particularly the frontal regions, basal ganglia, hippocampus, anterior cingulate cortex and cerebellum (Glass et al., 1997; Herkenham et al., 1990), brain regions that are relevant to their known effects. Further, these are also regions that have been implicated in the putative neural circuitry of psychosis. The primary effect of cannabinoids is the modulation of neurotransmitter release via 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 been implicated in the pathophysiology of psychosis.
The effects of herbal cannabis are a composite of a number of cannabinoid compounds, terpenoids and flavonoids. Thus, cannabidiol, a constituent of herbal cannabis, may offset some δ-9-THC effects (Zuardi et al., 1995). The ratio of the constituents of herbal cannabis varies, and this may result in important differences in its net effect.
Emerging data suggest an association between cannabis exposure and the development of schizophrenia (Table). Interest in the association between cannabis and schizophrenia received a major boost from the Swedish Conscript study, a large historical, longitudinal cohort study of all Swedes conscripted in 1969-1970 (Andreasson et al., 1987). Since Sweden mandates military service, 97% of males aged 18 to 20 years were included. Individuals who at age 18 reported having used cannabis >50 times were six times more likely than nonusers to have been diagnosed with schizophrenia in the ensuing 15 years. Adjusting for other relevant risk factors, including psychiatric diagnosis other than psychosis at conscription, reduced but did not eliminate the higher risk (odds ratio [OR]=2.3) of schizophrenia conferred by cannabis use.
A reanalysis and extension of the same Swedish conscript cohort reconfirmed that those who were heavy cannabis users by the age of 18 were 6.7 times more likely than nonusers to be hospitalized for schizophrenia 27 years later (Zammit et al., 2002). The OR for cannabis use and schizophrenia remained significant (1.2), albeit lower than in the original study, despite adjusting for a number of confounds, including low IQ and stimulant use. Further, the finding of an increased risk of schizophrenia conferred by cannabis use persisted after controlling for the possibility that cannabis use was a consequence of prodromal manifestations of psychosis.
