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
As far back as 1845, Dr. Jacques-
Joseph Moreau de Tours described
psychotic phenomena with hashish
[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,
restlessness and excitement.
There can be delirium, disorientation
and marked clouding of
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
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
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