Individuals who are psychosis-prone may be more likely to have a psychotic outcome (both acute and long-term) following exposure to cannabis. Psychosis-proneness may be defined on the basis of a psychometric measure or by family history of psychotic disorder. Cannabis exposure has been shown to be associated with higher rates of psychotic outcomes in individuals with higher scores on measures of psychosis-proneness [19
]. Similarly, individuals with a high risk for developing psychosis (either because of family history or prodromal symptoms) have higher rates of psychotic outcomes associated with cannabis use [15
]. McGuire [150
] reported that that individuals who developed acute psychosis after cannabis exposure were more likely to have a positive family history of schizophrenia than patients who screened negative for cannabis use. Recently Arendt [15
] showed that risk of psychiatric disorders in first-degree relatives of individuals treated for cannabis-induced psychosis were the same as in those of individuals treated for schizophrenia, suggesting that cannabis causes psychotic symptoms mainly in those who are predisposed to psychosis.
Corcoran et al. [41
] prospectively followed 32 cases of prodromal psychosis for up to 2 years and found that these cases had significantly more perceptual disturbances and worse functioning during epochs of increased cannabis use. They concluded that the use of cannabis was a risk factor for the exacerbation of subthreshold psychotic symptoms (perceptual aberrations) in these high-risk cases. Similarly, Cadenhead et al. [119
] reported that in a sample of individuals with a high risk for developing psychosis, those individuals with cannabis use were ten times more likely to convert to psychosis than individuals without cannabis use. This interaction of psychosis-proneness and cannabis exposure has also been observed in an experimental approach—in a controlled laboratory study, Henquet [94
] showed that psychosis-proneness influenced the effects of Δ9
-THC on cognition and psychosis.
Several models have been proposed to explain the interaction between cannabis exposure and psychosis-proneness. It may be that the psychosis-prone individuals are attracted to using cannabis (an association model), or that cannabis use increases psychosis-proneness (a causal model), or that there is another factor that causes both psychosis-proneness and cannabis use (an indicator-variable model) [91
]. While cannabis users tend to exhibit higher psychosis-proneness scores in some [54
] but not all studies [55
], psychosis-prone individuals are not more likely to use cannabis [92
]. Recently, Veling et al. [227
] showed that individuals with schizophrenia had higher rates of cannabis use than either their siblings or controls, while their siblings had similar rates of cannabis use to controls, suggesting (1) that cannabis use predicted schizophrenia and (2) that risk for developing schizophrenia did not confer a higher risk for cannabis use.
Psychosis-proneness may in part have a genetic basis. A number of recent studies illustrate how specific genetic factors moderate the effect of cannabis exposure on the risk for psychosis [91
-methyltransferase (COMT) is the enzyme that degrades DA, epinephrine, and norepinephrine. COMT is critical in the breakdown of DA in the prefrontal cortex. A functional polymorphism of the COMT gene results in two common allelic variants, the valine (Val), and the methionine (Met) allele, associated with high versus low enzyme activity, respectively. Increased COMT activity associated with the Val allele may result in a combination of reduced DA neurotransmission in the prefrontal cortex (cognitive deficits) and subsequent increased levels of mesolimbic DA signaling (psychosis). In a longitudinal birth cohort study (n
> 1,000), adolescents homozygous for the COMT Val108/158
Met allele were most likely to exhibit psychotic symptoms or develop schizophrenia if they used cannabis [31
]. Similarly, in a randomized, double-blind, placebo-controlled study, carriers of the Val allele were more sensitive to Δ9
-THC-induced psychotomimetic and amnestic effects than Met carriers, but this was conditional on psychometric evidence of psychosis-proneness [94
]. Unlike Caspi et al. [31
], Zammit et al. [240
] failed to find evidence supporting differential effects of cannabis use on psychosis risk according to variation of the COMT gene.
The neuregulin 1 gene (Nrg1) has been implicated in schizophrenia. Nrg1 has a role in the expression and activation of neurotransmitter receptors, including the NMDA, GABA, and acetylcholine receptors [171
], and is relevant to several schizophrenia-related neurodevelopmental processes (reviewed in [163
]). A number of studies have identified associations between Nrg1 haplotypes and schizophrenia in various populations [53
]. Heterozygous deletion of Nrg1 has been shown to increase sensitivity of mice to the behavioral effects of cannabinoids, especially under conditions of stress [25
]. These mice also showed greater increases in prepulse inhibition (PPI), a marker for sensorimotor gating known to be impaired in schizophrenia, following Δ9
-THC administration [25
The cannabinoid receptor gene (CNR1) is thought to modulate the striatal response to rewarding stimuli [32
] and polymorphisms of this gene are associated with alcoholism and intravenous drug use in humans [39
]. A variety of CNR1 polymorphisms have been studied for associations with schizophrenia, with mixed results [33
]. However, in a case-only design Zammit et al. [240
] failed to find an effect of a CNR1 polymorphism on schizophrenia between those who did not use cannabis and those who claimed to have used cannabis at least 1 year prior to illness onset.
Several other genes relevant to schizophrenia and the mechanism of action of cannabinoids will also need to be studied. For example, as discussed earlier, there are extensive interactions between endocannabinoid and GABA systems. Thus, whether there are any interactions between cannabis exposure and variations in genes that regulate GABA on the risk of psychosis will be important to study.