Psychiatric Times.
No. 4
Gone to Pot: The Association Between Cannabis and Psychosis
By Asif R. Malik, MD, and Deepak Cyril D'Souza, MD |
April 1, 2006
Several recent prospective cohort
studies complement studies using a
historical approach. In a general population
birth cohort study of 1,037 people
born in Dunedin, New Zealand, and
followed through age 26, individuals
using cannabis at ages 15 and 18,
compared to nonusers, had higher rates
of both psychotic symptoms at age 26
(even after controlling for psychotic
symptoms) and schizophreniform disorder
predating the onset of cannabis use
(Arseneault et al., 2002). Similarly,
cohort studies from elsewhere have also
reported a dose-response relationship
in the increased risk of psychosis with
cannabis exposure (Ferdinand et al.,
2005a; Fergusson et al., 2003; Henquet
et al., 2005; Stefanis et al., 2004; van
Os et al., 2002; Weiser et al., 2002).
Several studies of patients during their
first-break psychosis suggested that
cannabis use precedes or is coincident
with the first psychotic break in patients
with schizophrenia (Allebeck et al.,
1993; Hambrecht and Hafner, 2000).
Are these data sufficient to constitute
a 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 plausibility
are some of the criteria that have
been used to establish disease causality
(Aiello and Larson, 2002).
Several studies reviewed here provided
evidence of a dose-response relationship
between cannabis exposure
and the risk of psychosis. Most studies
also provided evidence of direction by
showing that the association between
cannabis use and psychosis persists
even after controlling for many potential
confounding variables such as IQ,
education, urbanicity, marital status and
previous psychotic symptoms. With
regard to temporality, several studies
suggested that cannabis use precedes
or coincides with the onset of psychosis.
Further, there is also evidence that
cannabis use may be associated with a
lower age of schizophrenia onset (Green
et al., 2004; Linszen et al., 1994). There
is evidence for both the specificity of
exposure (i.e., cannabis [Arseneault et
al., 2002; Ferdinand et al., 2005a, 2005b;
Zammit et al., 2002]) and specificity of
the outcome (i.e., psychosis [Arseneault
et al., 2002; Stefanis et al., 2004]).
Experimental evidence from laboratory
studies suggested that cannabinoids can
induce transient short-lived psychosis
in healthy individuals (D’Souza et al.,
2004; Leweke et al., 2000). Further, relative
to controls, patients with schizophrenia
have been shown to be more
vulnerable to the psychotomimetic
effects of δ-9-THC (D’Souza et al.,
2005). While it is out of the scope of
this review, the interactions between
cannabinoid receptor function and dopamine(Drug information on dopamine), glutamate and γ-aminobutyric
acid receptor function provide
potential mechanisms by which
cannabis may “cause” psychosis (as
reviewed in D’Souza et al., 2004, 2005).
One of the most obvious genetic risk
factors for psychosis is a family history
of psychosis. In a case-control study,
cannabis users admitted for schizophrenia
had a significantly greater familial
risk of schizophrenia than patients
with schizophrenia without cannabis use
(McGuire et al., 1995). Consistent with
these findings, data from the Edinburgh
High Risk project showed that frequent
cannabis use conferred a sixfold higher
risk of schizophrenia in individuals with
a family history of schizophrenia (Miller
et al., 2001). Recently, a polymorphism
of the catechol-O-methyltransferase
gene has been reported to modulate the
risk 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 receptor
system dysfunction contributes to
the pathophysiology of schizophrenia. Thus, it is possible that cannabinoid
receptor dysfunction is the substrate that
links cannabis exposure and psychosis.
Finally, if cannabis causes psychosis
in and of itself, then one would expect
that any increase in the rates of cannabis
use would be associated with increased
rates of psychosis. However, in some areas
where cannabis use has clearly increased
(e.g., Australia), there has not been a
commensurate increase in the rate of
psychotic disorders (Degenhardt et al.,
2003). Further, one might also expect that
if the age of initiation of cannabis use
decreases, there should also be a decrease
in the age of onset of psychotic disorders.
We are unaware of such evidence.
In conclusion, there is evidence for
an association between cannabis and
psychosis. It is clear that cannabinoids
can cause acute transient psychotic
symptoms or an acute psychosis. Also
it is clear that cannabis can exacerbate
psychosis in individuals with an established
psychotic disorder. However,
whether cannabis causes a persistent
de novo psychosis independent of any
other risk factors is not supported by the
existing literature. More likely, cannabis
is a component cause that interacts with
other factors (e.g., genetic risk) to induce
psychosis.
Nevertheless, in the absence of known
causes of schizophrenia, the role of
component causes such as cannabis use
remains important and warrants further
study. Finally, studying the role of exogenous
cannabinoids in the development
of psychosis will need to be complemented
by further studying a possible
role of endocannabinoid dysfunction in
the pathophysiology of psychosis.
Dr Malik is a fourth year resident in psychiatry
and Dr D'Souza is associate professor of
psychiatry, both at Yale University School of
Medicine, New Haven, Conn.
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