Cannabis use and subsequent onset of manic symptoms and bipolar disorder: A systematic review and meta-analysis.

Sanjuan-Ortiz C.; Querol P.; Aymerich C.; Laherran N.; Ditlevsen F.; Navalón P.; Rojo-Bofill L.; Young A.; Arango C.; Sharma A. et al. · Journal of affective disorders · 2026

**Background & Methods** This PRISMA/MOOSE-compliant systematic review and meta-analysis examined longitudinal observational studies from PubMed and Web of Science (inception to October 2025) comparing cannabis-exposed versus unexposed individuals without prior bipolar disorder to assess subsequent bipolar disorder (BD) and manic/hypomanic symptom development. Nineteen studies were included involving 6,960,517 participants (mean age 23.8±11.8 years; 49% female), with study quality assessed using the Newcastle-Ottawa Scale (NOS scores 6-9, indicating good to high methodological rigor). **Key Findings** • Cannabis use was associated with a 2.46-fold increased risk of incident bipolar disorder (95% CI=1.57-3.84; 8 studies; N=206,572), representing a significant and clinically meaningful elevation in risk. • Cannabis use demonstrated a 2.11-fold increased risk of subsequent manic/hypomanic symptoms (95% CI=1.07-4.18; 6 studies; N=57,243), with outcome-specific analysis enabling differentiation between full BD diagnosis and symptom-level manifestations. • Moderator analyses identified significant clinical and methodological heterogeneity sources, suggesting that cannabis effects on bipolar-spectrum outcomes vary by study characteristics and population factors. **Dosage & Administration** Not reported. The review examined cannabis exposure as a binary variable (users vs. non-users) without specifying frequency, duration, potency, or route of administration. **Safety & Adverse Effects** The review focuses on psychiatric outcomes rather than direct adverse effects. Cannabis use is identified as a risk factor for bipolar-spectrum disorders, representing a significant mental health safety concern rather than traditional adverse effects. **Evidence Quality** Strengths include large pooled sample size, outcome-specific meta-analyses separating BD diagnosis from manic symptoms, registered protocol reducing bias, and consistent methodological quality. Limitations include reliance on observational studies precluding causal inference, potential confounding by unmeasured variables, heterogeneity in outcome assessment across studies, and inability to determine dose-response relationships. The review demonstrates moderate-to-strong evidence at the systematic review level but cannot establish causation. Findings support cannabis as a potential modifiable risk factor warranting preventive intervention strategies, particularly in at-risk populations.

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