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Is cannabis use psychotogenic?
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The Lancet Jan 21, 2006; 367:193-195
Wayne Hall
School of Population Health, University of Queensland, Herston, Queensland, 4006 Australia
Cannabis use and psychotic symptoms are associated, but the nature of the association is controversial.1 Some argue that the link shows that cannabis use precipitates psychosis in vulnerable individuals,2 while others say the relation is either because of uncontrolled confounding3,4 or because cannabis is used to medicate symptoms of early psychosis.1,5
A 15-year prospective study of cannabis use and schizophrenia in 50_465 Swedish conscripts6 found a dose-response relation between the risk of schizophrenia and the frequency of cannabis use by age 18 years. The risks were lower after statistical adjustment for confounding variables (a psychiatric diagnosis at age 18 years, parental divorce) but the association remained statistically significant. A 27-year follow-up of this cohort found a dose-response relation between cannabis use at baseline and the risk of schizophrenia during follow-up.5 The relation persisted after controlling for potential confounders, including psychiatric symptoms at baseline (OR 2-5, 95% CI 1-2-5-1) for those who had used cannabis 50 or more times).
These findings are supported by a 3-year longitudinal study by van Os and colleagues in a community sample of 4848 young people in the Netherlands.7 The sample was assessed at baseline for cannabis and other drug use and psychotic symptoms with a computerised diagnostic interview. A diagnosis of psychosis was validated by a telephone interview with a psychiatrist or psychologist and a consensus clinical judgment on whether the disorder was serious enough to need psychiatric care. The frequency of cannabis use at baseline predicted a dose-dependent increased risk of psychotic symptoms during follow-up in individuals without psychiatric symptoms at baseline. The relation persisted when the effects of other drugs were controlled for (OR 3-5, 95% CI 1-6-7-4). The estimated attributable risk of cannabis use for psychosis was 13% for symptoms and 50% for disorders that required psychiatric treatment.
Henquet and colleages8 did a 4-year follow up of 2437 adolescents and young adults in Munich. They found a dose-response relation between self-reported cannabis use at baseline and the likelihood of reporting psychotic symptoms. Young people who reported psychotic symptoms at baseline were more likely to report psychotic symptoms at follow-up if they used cannabis than peers who did not.
These results are supported by two smaller birth-cohorts from New Zealand. Arseneault and colleagues9 prospectively studied the relation between adolescent cannabis use and psychosis in 759 individuals. They found a relation between cannabis use by age 15 years and an increased risk of psychotic symptoms by age 26 years. The relation did not change when other drug use was controlled for, but was no longer statistically significant after adjustment for self-reported psychotic symptoms at age 11 years. Onset of cannabis use at age 15 years was related to psychosis (OR 4-5 95% CI 1-1-18-2). This was no longer statistically significant after controlling for a history of psychotic symptoms at age 11 years but the 95% CI around the odds ratio of 3-1 was consistent with a decrease of 30% or an increase of 133% (OR 3-1, 95% CI 0-7-13-3).
Fergusson and co-authors10 assessed the relation between cannabis dependence at age 18 years and psychotic symptoms reported at age 21 years in a Christchurch birth cohort. Cannabis dependence at age 18 years predicted an increased risk of psychotic symptoms at age 21 years (OR 2-3, 95% CI 1-7-3-2). The association was smaller but still significant after adjustment for self-reported psychotic symptoms at the previous assessment, other drug use and other psychiatric disorders (OR 1-8 95% CI 1-2-2-6).
The self-medication hypothesis was not supported by Van Os', Henquet's or Fergusson's studies because they found no relation between early psychotic symptoms and risk of cannabis use. These negative results are supported by Verdoux and colleagues11 who examined the temporal relation between cannabis use and psychotic symptoms. A 14-year longitudinal study in the Netherlands12 found that cannabis use in people without psychotic symptoms predicted an increased risk of psychotic symptoms at follow up (hazard ratio [HR] 2-8 95% CI 1-8-4-4). They also found that reports of psychotic symptoms at baseline predicted an increased risk of later cannabis use (HR 1-7, 95% CI 1-1-2-6). There was, however, no control for confounders other than age and sex in either relation.
There is evidence to support the biological plausibility of a causal relation between cannabis and psychosis. First, in animals, the cannabinoid system interacts with the dopamine system, and disturbances in the dopamine system have been implicated in the biological bases of psychosis.13 Second, in a double-blind provocation study,14 intravenous delta-9-tetrahydrocannabinol provokes dose-dependent positive and negative psychotic symptoms in people with schizophrenia. Third, an interaction between cannabis use and a polymorphism of the catechol-o-methyltransferase gene that codes for dopamine has been reported.15 Individuals who were homozygous for the polymorphism and used cannabis were 10-9 (95% CI 2-2-54-1) times more likely to have a schizophreniform disorder than peers with the polymorphism who did not use cannabis. Young adults who did not have this polymorphism and used cannabis were not at increased risk of psychosis (OR 1-1, 95% CI 0-2-5-4).
Four of five recent reviews2,3,16-18 have concluded that cannabis use is a contributory cause of psychosis (table). It seems most likely that cannabis produces psychotic disorders in individuals who are vulnerable to psychosis as shown by a history of unusual experiences that may be in part genetically mediated. The interaction between cannabis use and vulnerability would explain: first, why the risk of psychosis in cannabis users is only increased 2-3 times; second, why there have not been large increases in the incidence of psychoses in line with the rise in rates of cannabis use in young adults in recent decades;19 and third, why the age of onset of schizophreniform disorders might be earlier in cannabis users.20,21
The major challenges for health educators will be in finding credible ways of communicating with young people about the significance of cannabis use that might increase the overall lifetime risk of developing schizophrenia from 0-7 in 1000 to 1-4 in 1000.22 The risk is probably higher in those who are vulnerable in ways that are still difficult to specify, apart from a family history of psychosis or a personal history of unusual experiences.
References
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4. Mirken B, Earleywine M. The cannabis and psychosis connection questioned: a comment on Fergusson et al. 2005. Addiction 2005; 100: 714-715[author reply 715-16].
5. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 2002; 325: 1199-1201.
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7. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156: 319-327.
8. Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 2005; 330: 11.
9. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 2002; 325: 1212-1213.
10. Fergusson DM, Horwood JL, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychol Med 2003; 33: 15-21.
11. Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen J. Cannabis use and the expression of psychosis vulnerability in daily life. Eur Psychiatry 2002; 17: 180S.
12. Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction 2005; 100: 612-618.
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14. D'Souza DC, Cho HS, Perry EB, Krystal JH. Cannabinoid emodelf psychosis, dopamine-cannabinoid interactions and implications for schizophrenia In: Castle D, Murray R, eds. Marijuana and madness: psychiatry and neurobiology. Cambridge: Cambridge University Press, 2004: 142-165.
15. Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene x environment interaction. Biol Psychiatry 2005; 57: 1117-1127.
16. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 2005; 19: 187-194.
17. Smit F, Bolier L, Cuijpers P. Cannabis use and the risk of later schizophrenia: a review. Addiction 2004; 99: 425-430.
18. Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull 2005; 31: 60812.
19. Degenhardt L, Hall WD, Lynskey M. Testing hypotheses about the relationship between cannabis use and psychosis. Drug Alcohol Depend 2003; 71: 37-48.
20. Arendt M, Rosenberg R, Foldager L, Perto G, Munk-Jorgensen P. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Br J Psychiatry 2005; 187: 510-515.
21. Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW, Kahn RS. Cannabis use and age at onset of schizophrenia. Am J Psychiatry 2004; 161: 501-506.
22. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med 2005; 2: e141.
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