Neurobiology of CIP
Cannabis is considered an environmental risk factor that increases the odds of psychotic episodes, and longer exposure is associated with greater risk of psychosis in a dose-dependent fashion. The drug acts as a stressor that leads to the emergence and persistence of psychosis. While a number of factors play a role in the mechanism by which consumption produces psychosis, the primary psychoactive ingredient is considered to be delta 9-tetrahydrocannabinol (delta9-THC). Properties of delta9-THC include a long half-life (up to 30 days to eliminate the long-acting THC metabolite carboxy-THC from urine) and high lipophilicity, which may contribute to CIP.
During acute consumption, cannabis causes an increase in the synthesis and release of dopamine as well as increased reuptake inhibition, similar to the process that occurs during stimulant use. Consequently, patients with CIP are found to have elevated peripheral dopamine metabolite products.
Findings from a study that examined presynaptic dopaminergic function in patients who have experienced CIP indicate that dopamine synthesis in the striatum has an inverse relationship with cannabis use. Long-term users had reduced dopamine synthesis, although no association was seen between dopaminergic function and CIP.6 This observation may provide insight into a future treatment hypothesis for CIP because it implies a different mechanism of psychosis compared with schizophrenia. As cannabis may not induce the same dopaminergic alterations seen in schizophrenia, CIP may require alternative approaches—most notably addressing associated cannabis use disorder.
Polymorphisms at several genes linked to dopamine metabolism may moderate the effects of CIP. The catechol-o-methyltransferase (COMT Val 158Met) genotype has been linked to increased hallucinations in cannabis users.7 Homozygous and heterozygous genetic compositions (Met/Met, Val/Met, Val/Val) for COMT Val 158Met have been studied in patients with CIP and suggest that the presence of Val/Val and Val/Met genotypes produces a substantial increase in psychosis in relation to cannabis use. This suggests that carriers of the Val allele are most vulnerable to CIP attacks.
There has been much controversy surrounding the validity of a CIP diagnosis and whether it is a distinct clinical entity or an early manifestation of schizophrenia. In patients being treated for schizophrenia, those with a history of CIP had an earlier onset of schizophrenia than patients who never used cannabis.8 Evidence suggests an association between patients who have received treatment for CIP and later development of schizophrenia spectrum disorder. However, it has been difficult to distinguish whether CIP is an early manifestation of schizophrenia or a catalyst. Nonetheless, there is a clear association between the 2 disorders.
Dr. Grewal is a recent MD graduate of Avalon University School of Medicine in Willemstad, Curaçao. Dr. George is Chief of Addictions at the Centre for Addiction and Mental Health (CAMH) and Professor and Director of the Division of Brain and Therapeutics in the Department of Psychiatry at the University of Toronto. Dr. George’s research is supported by the Canadian Institutes of Health Research (CIHR), the CAMH Foundation, and the National Institute on Drug Abuse (NIDA).
Dr. Grewal reports no conflict of interest concerning the subject matter of this article. Dr. George reports that he is a consultant to Novartis, the American College of Neuropsychology, and the Canadian Center for Substance Use and Addiction.
1. Fischer B, Imtiaz Z, Rudzinski K, Rehm J. Crude estimates of cannabis-attributable mortality and morbidity in Canada–implications for public health focused intervention priorities. J Public Health. 2015;38:183-188.
2. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. The DAWN Report: Highlights of the 2011 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD; February 22, 2013.
3. Washington Poison Center. Toxic Trends Report: 2015 Annual Cannabis Report. http://www.wapc.org/toxic-trends/marijuana-and-you/2015annualcannabisreport/. Accessed June 9, 2017.
4. Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016;68:71-75.
5. Brauser D. Cannabis-related ED visits rise in states with legalized use. Medscape. December 16, 2014. http://www.medscape.com/viewarticle/836663. Accessed June 9, 2017.
6. Bloomfield MA, Morgan CJ, Egerton A, et al. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol Psychiatry. 2014;75:470-478.
7. Henquet C, Rosa A, Delespaul P, et al. COMT Val158Met moderation of cannabis-induced psychosis: a momentary assessment study of ‘switching on’ hallucinations in the flow of daily life. Acta Psychiatr Scand. 2009;119:156-160.
8. Arendt M, Rosenberg R, Foldager L, et al. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Br J Psychiatry. 2005;187:510-515.
9. Rottanburg D, Robins AH, Ben-Arie O, et al. Cannabis-associated psychosis with hypomanic features. Lancet. 1983;320:1364-1366.
10. Perera T, Webler R. Cannabis-induced psychosis and an antipsychotic-induced seizure: a case report. Prim Care Companion CNS Disord. 2017;19(1). doi: 10.4088/PCC.16l01993.
11. Leweke F, Emrich M, Hinderk M. Carbamazepine as an adjunct in the treatment of schizophrenia-like psychosis related to cannabis abuse. Int Clin Psychopharmacol. 1999;14:37-39.
12. de Haan L, Linszen DH, Lenior ME, et al. Duration of untreated psychosis and outcome of schizophrenia: delay in intensive psychosocial treatment versus delay in treatment with antipsychotic medication. Schizophr Bull. 2003;29:341-348.
13. Bonsack C, Gibellini Manetti S, Favrod J, et al. Motivational intervention to reduce cannabis use in young people with psychosis: a randomized controlled trial. Psychother Psychosom. 2011;80:287-297.