Examining Sex-Specific Associations Between Schizophrenia and Cannabis Use Disorder

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CASE VIGNETTE

“Mr Smith” is an African American male aged 42 years with a history of cannabis use disorder (CUD) and chronic schizophrenia. He started smoking cannabis almost every day when he was 20. At 22, he was in a motor vehicle accident while under the influence of substances and experienced a head injury. Several months later, he was hospitalized for a first episode of psychosis and was started on antipsychotic medication.

For the past 15 years, Mr Smith has been maintained on a long-acting injectable antipsychotic and is adherent with appointments. He tends to get paranoid during stressful times, but has not had any subsequent psychiatric hospitalizations. However, he has continued to use cannabis regularly—daily to weekly—for more than 20 years. Although he worked prior to the onset of his psychotic disorder, he has since been chronically unemployed. He lives at home with his parents, has never married, and does not have children. He remains precontemplative regarding the need for treatment for CUD.

Cannabis is a frequently used psychoactive substance. The potency of cannabis, as measured by the percentage of the psychoactive component Δ-9-tetrahydrocannabinol (THC), is increasing in the United States¹ and in Denmark,² with a corresponding increase in the prevalence of CUD. There is evidence that THC use may trigger or worsen the clinical course of schizophrenia.³ In Denmark, parallel to the increased concentration of THC, the schizophrenia population-attributable risk fraction (PARF)—or the reduction in disease that would occur if exposure to a risk factor were eliminated—for CUD has increased 3- to 4-fold over the past 20 years.⁴

There is growing evidence that the relationship between CUD and schizophrenia varies by sex.⁵ Males with early heavy or frequent cannabis use have an earlier onset of psychosis.⁶ Males also have a younger age of onset of CUD.⁷ The increased incidence of schizophrenia in males in comparison with females has been postulated to reflect these data on cannabis use.

The Current Study

Hjorthøj and colleagues⁸ investigated sex-specific associations between CUD and schizophrenia over time in a Danish nationwide, register-based cohort study, using the unique identification number in the Civil Registration System. The authors included all individuals born before 2006 who were alive and aged 16 to 49 years at some point between 1972 and 2021.

Data on psychiatric disorders were obtained from the Psychiatric Central Research Register and the National Patient Register. Both schizophrenia and CUD were identified in these registers and defined based on ICD-8 and ICD-10 codes. Data on other psychiatric disorders, as well as alcohol and other substance use disorders, were obtained from the same registers. Data were also available on sex, parental history of psychiatric and substance use disorders, and whether the individual was Danish-born.

Data were analyzed using Cox proportional hazards regression, using alcohol and substance use disorders as time-varying covariate, with an interaction term between CUD and sex. The PARFs for the entire cohort and males and females were calculated separately. The PARFs for each study year were estimated to examine time trends, including the average annual percentage changes in PARFs of CUD in schizophrenia between 1972 and 2021. Lastly, the investigators used Poisson regression and evaluated the potential 3-way interaction effect between CUD, sex, and age on the incidence of schizophrenia.

The study examined 6.9 million individuals, including 45,327 cases of schizophrenia. The cohort was 51% male and 91% Danish-born. After controlling for potential confounding factors, the adjusted HR (aHR) for individuals with CUD to receive a diagnosis of schizophrenia was 2.3 (95% CI, 2.2-2.4), with a significant interaction between sex and CUD. The aHR for CUD on schizophrenia was significantly higher in males than in females (aHR = 2.4 vs 2.0, respectively). There was evidence for a time trend in males, with the annual aHR increasing gradually from ~2 to ~3, with no such trend in females.

Between 1972 and 2021, the annual average change in the PARFs of CUD on the incidence of schizophrenia was 4.8% in males and 3.2% in females. If causality is assumed, this implies that about 15% of recent cases of schizophrenia in males would have been prevented with the absence of CUD, compared with 4% in females.

In the Poisson regression models, the interaction between CUD, sex, and age was significant. In males, the highest adjusted incidence rate ratio (aIRR) of CUD on schizophrenia was in those aged 16 to 20 years (aIRR = 3.84), which was more than twice that of females aged 16 to 20 years (aIRR = 1.81).

Study Conclusions

The investigators found evidence in a nationwide, register-based cohort study for a stronger association between CUD and schizophrenia in males. They also found that strong PARFs of CUD in schizophrenia for males consistently increased between 1972 and 2021. Assuming causality, 15% of recent cases of schizophrenia in males, vs 4% in females, would have been prevented in the absence of CUD. In young males aged 16 to 20 years, this proportion could be as high as 25% to 30%.

Study strengths include the use of nationwide registers and the large cumulative sample size with significant longitudinal follow-up. Study limitations include the absence of specific clinical information on schizophrenia and CUD, potential residual confounding factors, and the absence of genetic information.

The Bottom Line

Young males appear to be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, approximately 20% of cases of schizophrenia in young males might be prevented by eliminating CUD. Study findings highlight the importance of early detection and treatment of CUD.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. ElSohly MA, Chandra S, Radwan M, et al. A comprehensive review of cannabis potency in the United States in the last decade. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6(6):603-606.

2. Freeman TP, Groshkova T, Cunningham A, et al. Increasing potency and price of cannabis in Europe, 2006-16. Addiction. 2019;114(6):1015-1023.

3. Volkow ND, Swanson JM, Evins AE, et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry. 2016;73(3):292-297.

4. Hjorthøj C, Posselt CM, Nordentoft M. Development over time of the population-attributable risk fraction for cannabis use disorder in schizophrenia in Denmark. JAMA Psychiatry. 2021;78(9):1013-1019.

5. Arranz B, Safont G, Corripio I, et al. Substance use in patients with first-episode psychosis: is gender relevant? J Dual Diagn. 2015;11(3-4):153-160.

6. Han B, Compton WM, Einstein EB, Volkow ND. Associations of suicidality trends with cannabis use as a function of sex and depression status. JAMA Netw Open. 2021;4(6):e2113025.

7. Haberstick BC, Young SE, Zeiger JS, et al. Prevalence and correlates of alcohol and cannabis use disorders in the United States: results from the national longitudinal study of adolescent health. Drug Alcohol Depend. 2014;136:158-161.

8. Hjorthøj C, Compton W, Starzer M, et al. Association between cannabis use disorder and schizophrenia stronger in young males than in females. Psychol Med. Published online May 4, 2023.