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There are several potential psychological harms of cannabis use (Box). The link between cannabis and psychosis remains the most intriguing. Specifically, cannabis has been noted to cause psychotic-like symptoms during intoxication, to lead to a "cannabis psychosis", to increase the relative risk of schizophrenia, and to affect the clinical course of established schizophrenia.¹¹ Population studies, such as the Epidemiologic Catchment Area study in the United States, confirm an association between cannabis use and psychotic symptoms. In this study, daily marijuana use over a year was associated with a 2.4-times greater risk of psychotic experiences, while any use was associated with a 1.3-times greater risk for self-reported psychotic experiences when compared with non-users. The relative risk for daily users remained significant after adjustment for other substance abuse and baseline psychiatric diagnoses.¹²

• a "toxic psychosis", in which psychotic symptoms are associated with confusion. This generally occurs after ingestion of large amounts of cannabis in someone with no significant psychiatric history, and recovery is usually rapid with abstinence;¹³ and

• a functional psychosis occurring without confusion (exacerbation of schizophrenia, and schizophreniform psychoses). The case for a true functional psychosis caused by cannabis is more vexed than the case for a "toxic psychosis", with various authors describing a heterogeneous clinical picture, often with manic features.¹⁴

The better-designed studies suggest that it is, in fact, hard to delineate a specific functional cannabis psychosis. McGuire and colleagues examined all patients presenting with psychotic symptoms at two London hospitals, comparing those with positive and negative results on urinary cannabinoid screening.¹⁵ Using structured interviews, they found a similar spread of diagnoses and illness onset among case and control patients, with similar numbers of first admissions and symptom profiles.

Does cannabis cause schizophrenia? Perhaps the more worrying question is whether cannabis causes chronic psychosis, particularly schizophrenia. The work of Andreasson and others examined this question in a cohort of male Swedish conscripts, followed up through a national psychiatric case register.¹⁶ They found that having used cannabis between one and 10 times at conscription increased the relative risk of schizophrenia to 1.3, the risk rising to 6.0 for those who had used cannabis on 50 or more occasions. However, this relative risk was reduced after adjustment for factors which independently contributed to the risk of schizophrenia. While this study provides some of the strongest evidence for a link between cannabis and psychosis, methodological concerns have been raised. These include the temporal gap between self-reported cannabis use at conscription and later schizophrenia, the potential confounding role of other substance use (particularly as amphetamines were a major drug of abuse during the study period), the adequacy of psychological assessment at conscription, and the reliability of self-reported drug use at conscription.³

Nevertheless, the association between cannabis use and schizophrenia is strengthened by studies which demonstrate that cannabis is widely used among people with schizophrenia. A recent study in Newcastle examined substance use in all outpatients with schizophrenia, finding 29.9% of subjects had some use of cannabis in their lifetime, with 7.7% and 28.3% of subjects having lifetime diagnoses of cannabis abuse and dependence, respectively.¹⁷ Notably, alcohol was more commonly used than cannabis, while amphetamines were the third most commonly used substance.

A number of hypotheses have been proposed to explain the prevalence of cannabis use in schizophrenia. Apart from the causation/precipitation role, it has been suggested that cannabis is used as self-medication for psychotic or dysphoric symptoms, or to ameliorate the side effects of antipsychotic drugs. Alternatively, the relationship may reflect the common peaks of onset of schizophrenia and cannabis use (particularly as prevalence samples are seldom compared with age- or sex-matched general population controls), or the role of underlying factors such as demographic differences.

How might cannabis use affect established schizophrenia? Clinical intuition suggests that cannabis has an adverse effect on the clinical course, a view supported by some well-designed studies. Linszen and colleagues studied 93 subjects with schizophrenia prospectively over a year, finding a higher rate of relapse in the cannabis-users than in the non-users, with a differential risk of relapse according to level of cannabis use.¹⁸ This effect persisted after adjustment for age, sex, age at first hospital admission, and alcohol use. However, this study was limited by the failure to consider the role of polysubstance use, reliance on self-report alone, and the gross measure of compliance used. Data from the Epidemiologic Catchment Area study also support a relationship between an alcohol- or cannabis-use disorder and a higher risk for hospitalisation in those with schizophrenia over a year.¹⁹ However, in this study, substance use covaried with depressive rather than psychotic symptoms, suggesting a complex relationship between substance use and symptoms in schizophrenia.

Confounding issues: The relationship between cannabis and psychosis is thus far from straightforward. Cannabis is rarely the only substance used. Other factors, such as personality, may confound the relationship. One study found higher rates of schizotypy in volunteer cannabis users, raising the possibility that the relationship between cannabis and psychosis is mediated by a premorbid "psychosis prone" personality.²⁰ Mueser and colleagues have identified antisocial personality as a common factor underlying both schizophrenia and substance-use disorders.²¹ Methodological concerns, such as the failure to assess and control for use of other substances and reliance on the case-study method, make it difficult to draw firm conclusions in this area.

Such discoveries have encouraged some researchers to speak of a "cannabinoid hypothesis" of schizophrenia, likening the cognitive deficits of schizophrenia to those induced temporarily by -9-tetrahydrocannabinol. Indeed, a recent study found higher levels of two endogenous cannabinoids in cerebrospinal fluid in 10 patients with schizophrenia compared with 11 non-psychotic control patients.²⁵ The authors suggested this may represent the response of the cannabinoid system to dopamine imbalance, or may reflect an underlying pathogenic "hypercannabinergic" state. This intriguing result can be viewed as preliminary only, because of the small number of subjects and the paucity of information about possible confounding factors, particularly substance use. The role of cannabinoids is being investigated in other neurological conditions, including Huntington's chorea and Tourette's syndrome. Such theories, while appealing, remain purely speculative. A hundred years have passed since the Indian Hemp Drugs Commission. The research that has followed confirms an association between cannabis and psychosis, but the nature of the connection remains elusive. We clearly see a need for further carefully controlled, prospective clinical studies, as well as insights from neuroscience, to clarify whether the relationship is causal or, in fact, due to factors common to both cannabis and psychosis. However, in the meantime, we believe it is important to inform young people with psychosis of the possible impact of ongoing cannabis use on their symptoms, particularly on the risk of relapse.

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University of Sydney Academic Psychiatry, Royal North Shore Hospital, Sydney, NSW.
Christopher C Tennant, MD, FRANZCP, Professor of Psychiatry.

Reprints will not be available from the authors.
Correspondence: Professor C C Tennant, University of Sydney Academic Psychiatry, Royal North Shore Hospital, St Leonards, NSW 2065.
tennant@med.usyd.edu.au

©MJA 2000
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