03. Cannabis-Induced Psychosis: Which Antipsychotics Best Prevent Hospitalization?

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Cannabis-Induced Psychosis: Prevalence and Challenges

Cannabis-induced psychosis is a severe mental disorder whose prevalence has increased substantially over the past few decades. The reasons for this increase are uncertain but may involve increased prevalence of cannabis use and increased potency of available cannabis. Under DSM-5 Diagnostic Criteria, cannabis-induced psychosis must be temporary, that is, symptoms resolve within one month.

However, about 1/3 of patients go on to develop schizophrenia or similar non-affective psychosis within the next several years. Little is known about the optimal treatment for cannabis-induced psychosis. There are no published long-term treatment studies and no medication is FDA approved for this disorder.

Swedish Database Study Tracked Hospitalization

This study by Dr. Mustonen and colleagues evaluated real-world evidence for the effectiveness of various antipsychotic medications in preventing hospitalization after a diagnosis of cannabis-induced psychosis. The investigators took advantage of several comprehensive national databases that cover all residents of Sweden that linked databases for inpatient and outpatient healthcare, prescribed medications and deaths covering July 2005 through December 2023. They used these linked databases to identify a cohort of 1772 individuals with cannabis-induced psychosis. These individuals were followed for 4 to 12 years, a mean of about 8 years. Rates of hospitalization were compared during periods the individual was taking antipsychotic medication versus periods when they were not taking medication. Thus, each individual served as their own control. This within-subject analysis minimized the risk of selection bias from individual differences in genetic background or comorbidity.

Key Findings: Antipsychotics Reduce Hospitalization Risk

The study found that being prescribed an antipsychotic medication significantly reduced the risk of three types of hospitalization:

• Risk of hospitalization for any type of psychotic episode whether substance induced, schizophrenia or unspecified was reduced by about one quarter
• Risk of hospitalization for any substance use disorder was also reduced by about one quarter
• Risk of hospitalization for any medical condition was reduced by almost half. The most common causes in this category were GI, musculoskeletal, neurologic, respiratory, and cardiovascular conditions.

Effectiveness Varied by Antipsychotic and Formulation

Antipsychotic medications varied widely in their effectiveness in reducing hospitalization.

• Aripiprazole and olanzapine significantly reduced hospitalization for psychosis in both oral and long-acting injectable (LAI) formulations.
• The LAIs were particularly effective, reducing hospitalizations for psychosis by about 75%, roughly double the effect of their oral counterparts.
• Oral clozapine was also effective for reducing psychosis-related hospitalizations.

On the other hand, several other commonly used antipsychotics showed no effectiveness in this outcome:

• This included oral or LAI risperidone, quetiapine, and paliperidone for psychosis-related hospitalizations.

When it came to preventing hospitalizations for any substance use disorder, a broader range of antipsychotics were effective:

• Oral and LAI olanzapine
• LAI aripiprazole and paliperidone
• Oral clozapine and risperidone

Unfortunately, the sample sizes were too small to allow for meaningful comparisons among individual antipsychotics for medical hospitalization risk.

Study Applicability and Limitations

The study findings are probably applicable to US clinical populations. Study participants included a broad age range from 16 to over 30 years of age, both men and women and a range of educational, from no high school to college graduate, and socioeconomic levels.

One major difference is the homogeneity of the Swedish population. The study does not report the race or ethnicity of participants presumably because the vast majority were white.

Clinical Takeaway

The bottom line is that treatment with antipsychotic medication prevents future hospitalization for psychosis, substance use disorders and medical conditions in patients with cannabis-induced psychosis

My recommendation is to treat these patients with a long-acting injectable, ideally olanzapine or aripiprazole. For those who cannot tolerate injectables, I recommend oral clozapine.

Abstract

Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis

Antti Mustonen; Heidi Taipale; Alexander Denissoff; Venla Ellilä; Marta Di Forti; Antti Tanskanen; Ellenor Mittendorfer-Rutz; Jari Tiihonen; Solja Niemelä.

Background: Cannabis use is linked to treatment non-adherence and relapses in psychotic disorders. Antipsychotic medication is effective for relapse prevention in primary psychoses, but its effectiveness after cannabis-induced psychosis (CIP) remains unclear.

Aims: To examine the effectiveness of antipsychotic medication for relapse prevention following the first clinically diagnosed CIP.

Method: A cohort of 1772 patients (84.1% men) with incident CIP was identified from the Swedish National Patient and Micro Data for Analyses of Social Insurance registers. The primary outcome was hospitalisation due to any psychotic episode. Drug use data were collected from the Prescribed Drug Register and modelled into drug use periods using the PRE2DUP method. A within-individual Cox regression model was used to study the risk of outcomes during the use of different oral or long-acting injectable (LAI) antipsychotics compared with non-use.

Results: The mean age at first diagnosis was 26.6 years (s.d. = 8.3). Of the cohort, 1343 (75.8%) used antipsychotics and 914 (51.3%) experienced psychosis hospitalisation during the follow-up. Any antipsychotic use was associated with a decreased risk of psychosis hospitalisation (adjusted hazard ratio (aHR) 0.75; 95% CI 0.67-0.84). Specific antipsychotics associated with decreased risk included aripiprazole LAI (aHR 0.27; 95% CI 0.14-0.51), olanzapine LAI (aHR 0.28; 95% CI 0.15-0.53), clozapine (aHR 0.55; 95% CI 0.34-0.90), oral aripiprazole (aHR 0.64; 95% CI 0.45-0.91), antipsychotic polytherapy (aHR 0.74; 95% CI 0.63-0.87) and oral olanzapine (aHR 0.81; 95% CI 0.69-0.94).

Conclusions: In particular, LAIs, clozapine and oral aripiprazole were associated with a decreased risk of psychosis relapse following CIP. Prescribers should consider using more LAIs for better treatment outcomes after CIP.

Keywords: Cannabis; antipsychotics; cannabis-induced psychosis; psychotic disorders; relapse.

Reference

Mustonen, A.; Taipale, H; Denissoff, A.; Ellilä, V.; Di Forti, M.; Tanskanen, A.; Mittendorfer-Rutz, E.; Tiihonen, J.; Niemelä, S. (2025). Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis. Br J Psychiatry. 2025 May 6:1-7.