Review
Cannabis and psychosis: Have we found the missing links?

https://doi.org/10.1016/j.ajp.2013.03.012Get rights and content

Highlights

  • Epidemiological studies show that cannabis use is associated with a higher risk of developing psychosis.

  • Only a small proportion of cannabis users go on to develop psychosis.

  • Risk factors include heavy cannabis use in young age, genetic vulnerability and environmental stress.

  • Cannabis acts as a component cause of psychosis.

Abstract

Background

The association between cannabis and psychosis has long been a matter of debate, with cannabis widely perceived as a harmless recreational drug.

Methods

Electronic bibliographic databases like PubMed and Google Scholar were searched using the format “(psychosis or schizophrenia or synonyms) and (cannabis or synonyms)”. Cross-linked searches were made taking the lead from key articles. Recent articles and those exploring the genetic factors or gene–environment interaction between cannabis use and psychosis were focussed upon.

Results

Heavy cannabis use at a n young age, in association with genetic liability to psychosis and exposure to environmental stressors like childhood trauma and urban upbringing increases the risk of psychotic outcome in later life.

Conclusion

Cannabis acts as a component cause of psychosis, that is, it increases the risk of psychosis in people with certain genetic or environmental vulnerabilities, though by itself, it is neither a sufficient nor a necessary cause of psychosis. Although significant progress has been made over the last few years, we are yet to find all the missing links. Further work is necessary to identify all the factors that underlie individual vulnerability to cannabis-related psychosis and to elucidate the biological mechanisms underlying this risk.

Introduction

The psychotropic properties of cannabis have been known since time immemorial, but whether cannabis has detrimental effects on health has been a matter of debate. In 1893, Indian Hemp Commission established by the British government concluded in its seven-volume report that there was no evidence of any weight regarding mental and moral injuries from moderate use of cannabis (Kaplan, 1969). Even after the passage of a century, it continued to be widely accepted in the medical fraternity that smoking cannabis did not cause long-term harm to health and cannabis came to be perceived as a drug of recreational use like alcohol and tobacco. However, over the last decade or so, there has been a spate of evidence on the mental health risks of long-term use of cannabis and a number of studies have furthered our understanding of the effects of cannabis on the brain, though it remains to be seen if all the missing links are in place.

There is ample evidence from case reports and surveys of cannabis users in the general population that cannabis can produce acute psychotic symptoms which are transient and recover completely on abstinence (Chopra and Smith, 1974, Keeler et al., 1971, Talbott and Teague, 1969, Thomas, 1996). In relation to this, some researchers proposed that “cannabis-induced psychosis” be considered a distinct diagnostic entity (Mathers and Ghodse, 1992, Rottanburg et al., 1982, Thakore and Shukla, 1976). However, others argued that cannabis-induced psychosis is not clinically different from other psychotic disorders and could be an early sign of schizophrenia rather than a distinct clinical entity (Arendt et al., 2005, McGuire et al., 1994). In further support of this, a population-based cohort study found no difference in familial predisposition to psychotic disorders between patients with cannabis-induced psychosis and those with schizophrenia (Arendt et al., 2008).

Section snippets

Is there an association between cannabis and schizophrenia?

It is well known that regular cannabis use and psychotic disorders such as schizophrenia are associated in the general population (Degenhardt and Hall, 2001, Tien and Anthony, 1990) and heavy cannabis users are over-represented among new cases of schizophrenia (Barbee et al., 1989). However, the strongest evidence that cannabis use may have a causal association with schizophrenia comes from longitudinal studies of large representative samples of the population who have been followed up to see

Can the association be explained by reverse causality?

A possible explanation of the association is that cannabis use is a consequence, rather than a cause, of schizophrenia. Cannabis is known to improve negative and depressive symptoms and may be used to self-medicate symptoms of schizophrenia (Schneier and Siris, 1987). In order to counter this, some longitudinal studies excluded patients with psychotic symptoms at baseline or made statistical adjustments for the same and yet found an increased risk of psychosis in cannabis users (Arseneault et

Impact of cannabis on course of schizophrenia

Negrete et al. (1986) conducted a restrospective study of the relationship between self-reported cannabis use and schizophrenia and found higher rates of positive symptoms, and more hospitalizations among active cannabis users. These relationships persisted after statistical adjustment for age and sex differences between the user groups. In a prospective study over one year of follow-up, Linszen et al. (1994) found that cannabis users relapsed to psychotic symptoms sooner, and had more frequent

Is the association biologically plausible?

Although the epidemiological link between cannabis and psychosis has been investigated extensively, the biological basis of this association remains poorly understood. There is ample indirect evidence for the biological basis in the form of the presence of alterations in the endocannabinoid system in schizophrenia. Studies on schizophrenic patients have shown up-regulation of cannabinoid-1 (CB1) receptors in cortical brain regions such as the dorsolateral prefrontal cortex (Dalton et al., 2011,

Why is it that only a small proportion of cannabis users develop psychosis?

Although there is strong evidence that use of cannabis is associated with a higher risk of psychosis and also that the association is biologically plausible, the fact remains that the vast majority of cannabis users never go on to develop any psychotic symptoms. Some of the factors that influence the development of psychotic symptoms have been elucidated.

Does cannabis also have antipsychotic effects?

Delta-9-tetrahydrocannabinol and cannabidiol are the two major constituents found in cannabis, of which delta-9-tetrahydrocannabinol is the main psychoactive ingredient and is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. Cannabidiol, on the other hand, has been shown to have opposite effects to delta-9-tetrahydrocannabinol and may even have antipsychotic properties. A functional neuroimaging study reported that

Cannabis as a component cause of psychosis

Heavy cannabis use, especially in the adolescence, is likely to increase the risk of psychotic disorder in later life, but by itself it is neither a necessary nor a sufficient cause. That is why, many cannabis users never go on to develop psychosis. It is only some people who have a high genetic liability to psychosis and may also have exposure to environmental stressors like childhood trauma and urban upbringing, who are highly vulnerable to the psychotogenic effects of cannabis, especially

Conclusion

It is now known beyond doubt that cannabis acts as a component cause of psychosis, that is, it increases the risk of psychosis in people with certain genetic or environmental vulnerabilities, though by itself, it is neither a sufficient nor a necessary cause of psychosis. Genetic vulnerability, exposure to cannabis in adolescence, frequent heavy use of cannabis and use of potent forms of cannabis containing higher levels of tetrahydrocannabinol and lower levels of cannabidiol are the important

Funding source

None.

Conflicts of interest

The authors have no conflicts of interest to disclose with this submission.

References (93)

  • J.D. Jentsch et al.

    Repeated exposure to delta 9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat

    Neuroscience Letters

    (1998)
  • S. Kapur et al.

    From dopamine to salience to psychosis—linking biology, pharmacology and phenomenology of psychosis

    Schizophrenia Research

    (2005)
  • R. Kuepper et al.

    Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines

    Schizophrenia Research

    (2010)
  • C.R. Lupica et al.

    Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction

    Neuropharmacology

    (2005)
  • F. Matyas et al.

    Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area

    Neuropharmacology

    (2008)
  • P.K. McGuire et al.

    Cannabis and acute psychosis

    Schizophrenia Research

    (1994)
  • P.K. McGuire et al.

    Morbid risk of schizophrenia for relatives of patients with cannabis associated psychosis

    Schizophrenia Research

    (1995)
  • T.H.M. Moore et al.

    Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review

    Lancet

    (2007)
  • D. Rottanburg et al.

    Cannabis-associated psychosis with hypomanic features

    Lancet

    (1982)
  • H. Thomas

    A community survey of adverse effects of cannabis use

    Drug and Alcohol Dependence

    (1996)
  • D.R. Weinberger

    On the plausibility of “the neurodevelopmental hypothesis” of schizophrenia

    Neuropsychopharmacology

    (1996)
  • D.F. Wong et al.

    Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C] OMAR

    Neuroimage

    (2010)
  • K. Zavitsanou et al.

    Selective antagonist [3H] SR 141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2004)
  • M. Arendt et al.

    Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia

    Archives of General Psychiatry

    (2008)
  • M. Arendt et al.

    Cannabis induced psychosis and subsequent schizophrenia: follow-up study of 535 incident cases

    British Journal of Psychiatry

    (2005)
  • L. Arseneault et al.

    Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study

    British Medical Journal

    (2002)
  • J.G. Barbee et al.

    Alcohol and substance abuse among schizophrenic patients presenting to an emergency psychiatry service

    Journal of Nervous and Mental Disease

    (1989)
  • S. Bhattacharyya et al.

    Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology

    Neuropsychopharmacology

    (2010)
  • S. Bhattacharyya et al.

    Induction of psychosis by {delta}9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing

    Archives of General Psychiatry

    (2012)
  • S. Bhattacharyya et al.

    Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function

    Molecular Psychiatry

    (2012)
  • A. Caballero et al.

    Association of cannabis use during adolescence, prefrontal CB1 receptor signaling, and schizophrenia

    Frontiers in Pharmacology

    (2012)
  • J.F. Cheer et al.

    Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats

    Journal of Neuroscience

    (2004)
  • G.S. Chopra et al.

    Psychotic reactions following cannabis use in East Indians

    Archives of General Psychiatry

    (1974)
  • A. Cougnard et al.

    Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A psychosis proneness–persistence model

    Psychological Medicine

    (2007)
  • D.C. D'Souza et al.

    Cannabis and psychosis/schizophrenia: human studies

    European Archives of Psychiatry and Clinical Neuroscience

    (2009)
  • V.S. Dalton et al.

    Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex

    Neuropsychopharmacology

    (2011)
  • N. De Marchi et al.

    Endocannabinoid signalling in the blood of patients with schizophrenia

    Lipids in Health and Disease

    (2003)
  • L. Degenhardt et al.

    The association between psychosis and problematical drug use among Australian adults: findings from the National Survey of Mental Health and Well-being

    Psychological Medicine

    (2001)
  • L.E. DeLisi

    The effect of cannabis on the brain: can it cause brain anomalies that lead to increased risk for schizophrenia?

    Current Opinion in Psychiatry

    (2008)
  • S.M. Eggan et al.

    Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia

    Archives of General Psychiatry

    (2008)
  • D.M. Fergusson et al.

    Cannabis dependence and psychotic symptoms in young people

    Psychological Medicine

    (2003)
  • D.J. Foti et al.

    Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization

    American Journal of Psychiatry

    (2010)
  • E.D. French et al.

    Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra

    Neuroreport

    (1997)
  • I. Galve-Roperh et al.

    The endocannabinoid system and neurogenesis in health and disease

    Neuroscientist

    (2007)
  • A. Giuffrida et al.

    Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms

    Neuropsychopharmacology

    (2004)
  • A. Gonzalez-Pinto et al.

    Cannabis and first-episode psychosis: different long-term outcomes depending on continued or discontinued use

    Schizophrenia Bulletin

    (2009)
  • Cited by (0)

    View full text