Cannabinoids and Psychosis
Introduction
… acute psychotic reactions, generally lasting but a few hours, but occasionally as long as a week; the reaction seemed dose related 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 ‘Du Haschisch et d l'alientation mentale’ J. J. Moreau de Tours (1845) (Moreau, 1973).
An association between cannabis and psychosis has long been recognized. However, recent advances in the understanding of cannabinoid receptor function have renewed in the association between cannabis and psychosis. In addition to epidemiological studies, there are case reports of psychosis following cannabis use, reports of psychosis in surveys of cannabis users from community samples, and pharmacological studies with various cannabinoid compounds. These data are relevant to an exogenous hypothesis according to which the consumption of cannabinoid compounds is associated with psychotic disorders. We also suggest an endogenous hypothesis according to which brain cannabinoid receptor (CB1) dysfunction may contribute to the pathophysiology of psychosis and/or schizophrenia, and further, that the putative CB1 receptor dysfunction maybe unrelated to the consumption of cannabinoid compounds. These two hypotheses are by no means mutually exclusive, and may in fact interact.
The data supporting an association between cannabis consumption and the manifestation of psychotic symptoms in humans is now reviewed. However, a review of the literature will not be complete without a discussion about the constituents of cannabis. The principal active ingredient of cannabis is delta‐9‐tetrahydrocannabinol (Δ‐9‐THC). However, in addition to Δ‐9‐THC, herbal cannabis contains nearly 70 cannabinoid compounds, including cannabidiol (CBD), Δ‐8‐tetrahydrocannabinol, cannabinol, cannabigerol, and also terpenoids and flavonoids (Elsohly and Slade, 2005). These constituent compounds may modulate the effects of Δ‐9‐THC and may also have “entourage” effects (Mechoulam 1999, Russo 2003). The principal active metabolite of Δ‐9‐THC, 11‐hydroxy‐THC is more potent than Δ‐9‐THC. The time course of 11‐hydroxy‐THC blood levels correlates well with the psychological effects of inhaled and oral Δ‐9‐HC reviewed in Agurell et al. (1986). CBD may offset some Δ‐9‐THC effects by its anxiolytic effects (Guimaraes 1994, Zuardi 1982), antipsychotic‐like effects (Zuardi 1991, Zuardi 1995, Zuardi 2006), and may block the conversion of Δ‐9‐THC to the more psychoactive 11‐hydroxy‐THC (Bornheim et al., 1995). Therefore, the net effect of herbal cannabis is a composite of its constituents. The CBD content of cannabis varies greatly and some samples of cannabis have been reported to be devoid of CBD (Pitts 1990, Pitts 1992). Thus, a relatively lower CBD content of cannabis has been implicated in the occurrence of psychotic and anxiety reactions with cannabis use (Solomons 1989, Solomons 1990). An example is South African cannabis, also known as dagga, which has very low levels of CBD compared to other varieties of cannabis obtained elsewhere. Naturalistic studies suggest an association between dagga consumption and high rates of psychotic symptom (Solomons 1989, Solomons 1990).
There are some data from studies with synthetic cannabinoids including dronabinol, nabilone, and levonantradol that are informative about the psychotic adverse effects of cannabinoids (Fig. 1). Dronabinol is synthetic Δ‐9‐THC. The 9‐trans‐ketocannabinoid Nabilone (Cesamet®) is a synthetic analogue of Δ‐9‐THC that was developed as an antiemetic and is available in Europe and Canada. Levonantradol, also a synthetic cannabinoid, was developed as an analgesic agent but abandoned because of a high incidence of intolerable behavioral side effects.
Evidence for an association between cannabis and psychosis comes from several sources, including case series of psychosis following cannabis use, autobiographical accounts, and surveys of cannabis users in the general population, epidemiological studies, and pharmacological studies with various cannabinoid compounds.
Section snippets
Autobiographical Accounts
There are several exquisitely detailed autobiographical accounts of the effects of cannabinoids. In perhaps one of the first detailed accounts of cannabis effects, Moreau de Tours (1845) described acute, transient, dose‐related psychotic reactions lasting hours to days following hashish use (Moreau, 1973). The reaction was characterized by paranoid ideation, illusions, hallucinations, delusions, depersonalization, confusion, restlessness, and excitement. Among other effects of cannabis,
Epidemiological Studies
Epidemiological studies have provided the major contribution to the evidence supporting an association between cannabis and psychosis (Table II). The study that first brought significant attention to the topic was a large historical, longitudinal cohort study of all Swedes conscripted between 1969 and 1970 (Andreasson et al., 1987). Since Sweden mandates military service, 97% of males aged 18–20 years were included. The relationship between self‐reported cannabis use at the time of conscription
Pharmacological Studies
In order to better interpret the pharmacological studies, it would be essential to understand some of the pharmacokinetic issues relevant to cannabis and Δ‐9‐THC. The pharmacokinetics and effects of Δ‐9‐THC vary as a function of route of administration. Herbal cannabis and cannabinoid compounds are typically consumed during recreational use by the inhaled or oral route. However, cannabinoids have also been administered for therapeutic or experimental purposes by the intravenous, rectal,
Cannabis and Psychosis: Causality
Some of the criteria that have been used to establish disease causality include temporality, strength of the association, direction, dose–response or biological gradient, consistency, specificity, coherence, strength of the relationship, experimental evidence, and biologic plausibility (Aiello 2002, Hill 1965).
Most studies provide evidence of direction by showing that the association between cannabis use and psychosis persists even after controlling for many potential confounding variables such
Cannabinoid Receptor Dysfunction and Psychotic Disorders
Emerging findings from postmortem (Dean 2001, Zavitsanou 2004), neurochemical (Giuffrida 2004, Leweke 1999a), and genetic (Ujike et al., 2002) studies suggest that cannabinoid receptor system dysfunction that may contribute to the pathophysiology of schizophrenia.
Leweke et al. (1999a) and colleagues were the first to suggest altered cannabinoid receptor function in schizophrenia. Levels of anandamide, 2‐AG, palmitoylethanolamide (PEA), and a noncannabinoid acylethanolamide, oleylethanolamide
Summary and Conclusions
Cannabinoids can induce acute transient psychotic symptoms or an acute psychosis in some individuals. What makes some individuals vulnerable to cannabinoid‐related psychosis is unclear. Cannabinoids can also exacerbate psychosis in individuals with an established psychotic disorder, and these exacerbations may last beyond the period of intoxication. Less clear is whether cannabis causes a persistent de novo psychosis. The available evidence meets many but not all the criteria for causality,
Acknowledgments
The author wishes to acknowledge support from the (1) Department of Veterans Affairs (Schizophrenia Biological Research Center), (2) National Institute of Mental Health (R01MH61019–02 to DCD), (3) National Institute of Drug Abuse (RO1DA12382–01), (4) Stanley Medical Research Institute, and (5) Donaghue Foundation.
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