Evidence-Based Reviews

Cannabis, synthetic cannabinoids, and psychosis risk: What the evidence says

Current Psychiatry. 2011 September;10(9):49-58

Research suggests marijuana may be a ‘component cause’ of psychosis.

References

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2. Zammit S, Moore TH, Lingford-Hughes A, et al. Effects of cannabis use on outcomes of psychotic disorders: systematic review. Br J Psychiatry. 2008;193(5):357-363.

3. Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006;39(4):421-429.

4. Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20(5):683-686.

5. Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192(4):306-307.

6. Schwarcz G, Karajgi B, McCarthy R. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can improve the symptoms of schizophrenia. J Clin Psychopharmacol. 2009;29(3):255-258.

7. Schwarcz G, Karajgi B. Improvement in refractory psychosis with dronabinol: four case reports. J Clin Psychiatry. 2010;71(11):1552-1553.

8. D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558-1572.

9. Morrison PD, Zois V, McKeown DA, et al. The acute effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol Med. 2009;39(10):1607-1616.

10. Favrat B, Ménétrey A, Augsburger M, et al. Two cases of “cannabis acute psychosis” following the administration of oral cannabis. BMC Psychiatry. 2005;5:17.-

11. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-328

12. Minozzi S, Davoli M, Bargagli AM, et al. An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. Drug Alcohol Rev. 2010;29(3):304-317.

13. Andréasson S, Allebeck P, Engström A, et al. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987;2(8574):1483-1486

14. Zammit S, Allebeck P, Andreasson S, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325(7374):1199.-

15. Arseneault L, Cannon M, Poulton R, et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325(7374):1212-1213

16. van Os J, Bak M, Hanssen M, et al. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002;156(4):319-327

17. Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychol Med. 2003;33(1):15-21

18. 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(7481):11.-

19. Kuepper R, van Os J, Lieb R, et al. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ. 2011;342:d738.-

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22. D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005;57(6):594-608

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Over the past 50 years, anecdotal reports linking cannabis sativa (marijuana) and psychosis have been steadily accumulating, giving rise to the notion of “cannabis psychosis.” Despite this historic connection, marijuana often is regarded as a “soft drug” with few harmful effects. However, this benign view is now being revised, along with mounting research demonstrating a clear association between cannabis and psychosis.

In this article, I review evidence on marijuana’s impact on the risk of developing psychotic disorders, as well as the potential contributions of “medical” marijuana and other legally available products containing synthetic cannabinoids to psychosis risk.

Cannabis use and psychosis

Cannabis use has a largely deleterious effect on patients with psychotic disorders, and typically is associated with relapse, poor treatment adherence, and worsening psychotic symptoms.^1,2 There is, however, evidence that some patients with schizophrenia might benefit from treatment with cannabidiol,^3-5 another constituent of marijuana, as well as delta-9-tetrahydrocannabinol (Δ-9-THC), the principle psychoactive constituent of cannabis.^6,7

Clinical Point

Three meta-analyses have concluded cannabis use is associated with an increased risk of psychosis

The acute psychotic potential of cannabis has been demonstrated by studies that documented psychotic symptoms (eg, hallucinations, paranoid delusions, derealization) in a dose-dependent manner among healthy volunteers administered Δ-9-THC under experimental conditions.^8-10 Various cross-sectional epidemiologic studies also have revealed an association between cannabis use and acute or chronic psychosis.^11,12

In the absence of definitive evidence from randomized, long-term, placebo-controlled trials, the strongest evidence of a connection between cannabis use and development of a psychotic disorder comes from prospective, longitudinal cohort studies. In the past 15 years, new evidence has emerged from 7 such studies that cumulatively provide strong support for an association between cannabis use as an adolescent or young adult and a greater risk for developing a psychotic disorder such as schizophrenia.^13-19 These longitudinal studies surveyed for self-reported cannabis use before psychosis onset and controlled for a variety of potential confounding factors (eg, other drug use and demographic, social, and psychological variables). Three meta-analyses of these and other studies concluded an increased risk of psychosis is associated with cannabis use, with an odds ratio of 1.4 to 2.9 (meaning the risk of developing psychosis with any history of cannabis use is up to 3-fold higher compared with those who did not use cannabis).^11,20,21 In addition, this association appears to be dose-related, with increasing amounts of cannabis use linked to greater risk—1 study found an odds ratio of 7 for psychosis among daily cannabis users.¹⁶

There are several ways to explain the link between cannabis use and psychosis, and a causal relationship has not yet been firmly established (Table 1).^{1-7,11-19,21-25} Current evidence supports that cannabis is a “component cause” of chronic psychosis, meaning although neither necessary nor sufficient, cannabis use at a young age increases the likelihood of developing schizophrenia or other psychotic disorders.²⁶ This risk may be greatest for young persons with some psychosis vulnerability (eg, those with attenuated psychotic symptoms).^16,18

Clinical Point

The magnitude of psychosis risk tied to cannabis use is modest and most users do not develop psychosis

The overall magnitude of risk appears to be modest, and cannabis use is only 1 of myriad factors that increase the risk of psychosis.²⁷ Furthermore, most cannabis users do not develop psychosis. However, the risk associated with cannabis occurs during a vulnerable time of development and is modifiable. Based on conservative estimates, 8% of emergent schizophrenia cases and 14% of more broadly defined emergent psychosis cases could be prevented if it were possible to eliminate cannabis use among young people.^11,26 Therefore, reducing cannabis use among young people vulnerable to psychosis should be a clinical and public health priority.

Table 1

Hypotheses linking cannabis and psychosis

Hypothesis	Strength of evidence	Evidence for	Evidence against
Cannabis does not cause chronic psychosis	Weak	No randomized controlled trials Other possible explanations (demographic/socioeconomic, trauma, other drug use) Possible reverse causality (psychosis leads to cannabis use) Possible publication bias (negative evidence not published)	Controlled (cross-sectional and longitudinal cohort) studies consistently show an association^11-19 Longitudinal studies include risk calculations adjusted for confounding variables^13-19 Publication bias not found in meta-analyses^11,21
Cannabis can cause schizophrenia	Equivocal	Cannabis use precedes the onset of schizophrenia in longitudinal studies^13-19	The incidence of schizophrenia has not been clearly increasing as expected with increasing cannabis use^11,21
Cannabis worsens existing psychotic disorders	Strong	Cannabis is associated with increased symptoms, relapse, and treatment nonadherence among those with schizophrenia^1,2 Patients with schizophrenia are more vulnerable to cannabis-induced psychosis under experimental conditions²²	Cannabidiol and Δ-9-THC improve symptoms in some patients with schizophrenia^3-7
Cannabis increases the risk of chronic psychosis among vulnerable individuals	Strong	For patients with schizophrenia, a history of cannabis use is associated with illness onset 2 to 3 years earlier compared with non-users²³ Cannabis use is a risk factor for conversion to psychosis in some studies of prodromal schizophrenia²⁴	Cannabis use is not always a risk factor for conversion to psychosis in studies of prodromal schizophrenia²⁵
Δ-9-THC: delta-9-tetrahydrocannabinol