Cannabis and psychosis

The relationship between cannabis use and psychosis has, in recent decades, become a focus of controversy.^[1] The National Institute of Mental Health has stated that "research has found increasing evidence of a link between marijuana and schizophrenia symptoms."^[2] In a report issued in 2000, the National Academy of Sciences noted that some researchers had proposed a link between cannabis use and schizophrenia, as well as between cannabis use and a unique type of psychosis. They observed that "marijuana use alone—without the influence of additional risk factors—is unlikely to provoke a psychosis that persists longer than intoxication."^[3] Likewise, a number of reviews have concluded that cannabis use only results in a significant increase in risk of psychosis when coupled with additional risk factors, in particular, an underlying genetic vulnerability.^[4][5]

There is evidence that the brains of people with psychosis who previously used cannabis differ from those of healthy individuals with respect to areas such as the cingulate and prefrontal cortex.^[6] Research has consistently found that people with psychosis have higher rates of cannabis use, and that there exists an association between cannabis use and schizophrenia and other forms of psychosis.^[7][8] Some studies have also concluded that cannabis use is associated with an earlier age at onset of schizophrenia.^[7] However, it is less clear whether this association is a result of the specific effects of cannabis use.^[9] Proposed mechanisms by which this possible link could occur include the effects of dronabinol, a pure isomer of THC, and its ability to induce "acute psychotic states," which, in turn, have been called "the early signs of schizophrenia and related disorders."^[10] Further complicating the establishment of causation, another cannabinoid found in cannabis, cannabidiol (CBD), is thought to have antipsychotic properties. CBD has been shown to have anxiolytic properties and inhibit the psychotomimetic effects of THC, yet CBD content varies widely and has rarely been accounted for in epidemiological studies.^[11] It is believed that cannabis' effects on the risk of schizophrenia is especially pronounced among those who begin using the drug early.^[12]

Systematic reviews

• In 2000, a review by researchers from the National Drug and Alcohol Research Centre in Australia examined two hypotheses:

1. That heavy use of cannabis causes "cannabis psychosis," which would never have happened had the patient never used cannabis, and
2. That cannabis use may precipitate, or exacerbate the symptoms of, schizophrenia.

The authors concluded that there was limited evidence to support the first hypothesis, but more support for the second, citing a large prospective study which found a linear relationship between cannabis use before the age of 18 and risk of being diagnosed with schizophrenia over the next 15 years.^[13]

• In 2004, a review was published in the British Journal of Psychiatry which concluded that discouraging cannabis smoking would result in the rate of schizophrenia decreasing by 8%.^[14] Also that year, a review was published in the journal Addiction which reported that "antecedent cannabis use appears to act as a risk factor in the onset of schizophrenia, especially in vulnerable people, but also in people without prior history."^[15]
• In 2005, a review by researchers from Sheba Medical Center in Haifa concluded that while it is true that studies have shown an association between cannabis use and risk of schizophrenia, that this might be explicable not by a causal link between the two, but rather by a deficit in the function of the endocannabinoid system in some people, which puts them at an increased risk of both cannabis use and schizophrenia.^[16]
• In 2007, a review published in the Lancet concluded that "there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life."^[17]
• In 2009, a review was published in the European Archives of Psychiatry and Clinical Neuroscience which found that "Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative, and cognitive symptoms in some healthy individuals."^[18]
• In 2010, the Global burden of disease study found that cannabis use as a risk factor for schizophrenia accounted for an estimated 7,000 disability adjusted life years globally and that "cannabis use as a risk factor for schizophrenia is not a major contributor to population-level disease burden".^[19] Also that year, Italian researchers published an overview of reviews on the subject of cannabis and psychosis in which they noted a consistent association between cannabis use and psychotic symptoms. However, they were unable to draw firm conclusions regarding whether this association was causal.^[20]
• In 2011, a review by researchers from the Schizophrenia Research Institute in Darlinghurst, Australia listed three risk factors for schizophrenia which it considered to be supported by the "highest quality evidence"; cannabis use was one of these factors.^[21]
• In 2013, a review by researchers at the Icahn School of Medicine at Mount Sinai stated that there exists "a strong association between schizophrenia and cannabis use...". They found that cannabis use alone does not predict the transition to subsequent psychiatric illness. Many factors are involved, including genetics, environment, time period of initiation and duration of cannabis use, underlying psychiatric pathology that preceded drug use, and combined use of other psychoactive drugs.^[8]
• In 2014, a review was published in Frontiers in Psychiatry which concluded that "The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence," and that this potential relationship "warrants serious consideration from the point of view of public health policy."^[11]
• A 2014 review said that "Because longitudinal work indicates that cannabis use precedes psychotic symptoms, it seems reasonable to assume a causal relationship" between cannabis and psychosis, but that "more work is needed to address the possibility of gene-environment correlation."^[22]
• A 2016 meta-analysis found that cannabis use increases the risk of psychosis, and that a dose-response relationship exists between the level of cannabis use and risk of psychosis. The analysis was not able to establish a causal link. ^[23] Another meta-analysis published the same year found that cannabis use only predicted transition to psychosis among those who met the criteria for abuse of or dependence on the drug.^[24]

References

1. Wilkinson, Samuel T. (1 July 2013). "Pot-Smoking And the Schizophrenia Connection". Wall Street Journal. Retrieved 5 March 2014.
2. Schizophrenia
3. Mack, Alison; Joy, Janet (2000). Marijuana As Medicine?: The Science Beyond the Controversy. National Academy of Sciences. p. 61.
4. Luzi, S.; Morrison, P. D.; Powell, J.; Di Forti, M.; Murray, R. M. (2008). "What is the mechanism whereby cannabis use increases risk of psychosis?". Neurotoxicity Research 14 (2–3): 105–112. doi:10.1007/BF03033802. PMID 19073418.
5. Henquet, C.; Di Forti, M.; Morrison, P.; Kuepper, R.; Murray, R. M. (2008). "Gene-Environment Interplay Between Cannabis and Psychosis". Schizophrenia Bulletin 34 (6): 1111–1121. doi:10.1093/schbul/sbn108. PMC 2632498. PMID 18723841.
6. Rapp, C; Bugra, H; Riecher-Rössler, A; Tamagni, C; Borgwardt, S (2012). "Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and post mortem studies.". Current pharmaceutical design 18 (32): 5070–80. doi:10.2174/138161212802884861#sthash.KcFwdnpZ.dpuf. PMID 22716152.
7. Large, Matthew; Sharma, Swapnil; Compton, Michael T.; Slade, Tim; Nielssen, Olav (6 June 2011). "Cannabis Use and Earlier Onset of Psychosis". Archives of General Psychiatry 68 (6): 555–61. doi:10.1001/archgenpsychiatry.2011.5. PMID 21300939.
8. Chadwick, B.; Miller, M. L.; Hurd, Y. L. (2013). "Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness". Frontiers in Psychiatry 4: 129. doi:10.3389/fpsyt.2013.00129. PMC 3796318. PMID 24133461.
9. Zammit, S.; Moore, T. H. M.; Lingford-Hughes, A.; Barnes, T. R. E.; Jones, P. B.; Burke, M.; Lewis, G. (31 October 2008). "Effects of cannabis use on outcomes of psychotic disorders: systematic review". The British Journal of Psychiatry 193 (5): 357–363. doi:10.1192/bjp.bp.107.046375. PMID 18978312.
10. van Os J, Kapur S (August 2009). "Schizophrenia" (PDF). Lancet 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
11. Radhakrishnan, Rajiv; Wilkinson, Samuel T.; D’Souza, Deepak Cyril (22 May 2014). "Gone to Pot â€" A Review of the Association between Cannabis and Psychosis". Frontiers in Psychiatry 5. doi:10.3389/fpsyt.2014.00054.
12. Semple, D. M. (1 June 2005). "Book Review: Cannabis as a risk factor for psychosis: systematic review". Journal of Psychopharmacology 19 (2): 187–194. doi:10.1177/0269881105049040. PMID 15871146.
13. Hall, W.; Degenhardt, L. (2000). "Cannabis use and psychosis: A review of clinical and epidemiological evidence". The Australian and New Zealand journal of psychiatry 34 (1): 26–34. doi:10.1046/j.1440-1614.2000.00685.x. PMID 11185941.
14. Arseneault, L.; Cannon, M.; Witton, J.; Murray, R. M. (2004). "Causal association between cannabis and psychosis: Examination of the evidence". The British journal of psychiatry : the journal of mental science 184 (2): 110–117. doi:10.1192/bjp.184.2.110. PMID 14754822.
15. Smit, Filip; Bolier, Linda; Cuijpers, Pim. "Cannabis use and the risk of later schizophrenia: a review". Addiction 99 (4): 425–430. doi:10.1111/j.1360-0443.2004.00683.x.
16. Weiser, M.; Noy, S. (2005). "Interpreting the association between cannabis use and increased risk for schizophrenia". Dialogues in clinical neuroscience 7 (1): 81–85. PMC 3181719. PMID 16060598.
17. Moore, TH; Zammit, S; Lingford-Hughes, A; Barnes, TR; Jones, PB; Burke, M; Lewis, G (July 28, 2007). "Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.". Lancet 370 (9584): 319–28. doi:10.1016/s0140-6736(07)61162-3. PMID 17662880.
18. d’Souza, D. C.; Sewell, R. A.; Ranganathan, M. (2009). "Cannabis and psychosis/schizophrenia: Human studies". European Archives of Psychiatry and Clinical Neuroscience 259 (7): 413–431. doi:10.1007/s00406-009-0024-2. PMC 2864503. PMID 19609589.
19. Degenhardt, L; Ferrari, AJ; Calabria, B; Hall, WD; Norman, RE; McGrath, J; Flaxman, AD; Engell, RE; Freedman, GD; Whiteford, HA; Vos, T (2013). "The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study.". PLOS ONE 8 (10): e76635. doi:10.1371/journal.pone.0076635. PMID 24204649.
20. Minozzi, S; Davoli, M; Bargagli, AM; Amato, L; Vecchi, S; Perucci, CA (May 2010). "An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results.". Drug and alcohol review 29 (3): 304–17. doi:10.1111/j.1465-3362.2009.00132.x. PMID 20565524.
21. Matheson, S. L.; Shepherd, A. M.; Laurens, K. R.; Carr, V. J. (2011). "A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia". Schizophrenia Research 133 (1–3): 133–142. doi:10.1016/j.schres.2011.09.020. PMID 21999904.
22. van Winkel, Ruud; Kuepper, Rebecca (28 March 2014). "Epidemiological, Neurobiological, and Genetic Clues to the Mechanisms Linking Cannabis Use to Risk for Nonaffective Psychosis". Annual Review of Clinical Psychology 10 (1): 767–791. doi:10.1146/annurev-clinpsy-032813-153631.
23. Marconi, A; Di Forti, M; Lewis, CM; Murray, RM; Vassos, E (15 February 2016). "Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis.". Schizophrenia bulletin. PMID 26884547.
24. Kraan, T; Velthorst, E; Koenders, L; Zwaart, K; Ising, HK; van den Berg, D; de Haan, L; van der Gaag, M (March 2016). "Cannabis use and transition to psychosis in individuals at ultra-high risk: review and meta-analysis.". Psychological Medicine 46 (4): 673–81. doi:10.1017/S0033291715002329. PMID 26568030.