Balancing risks and benefits of cannabis on humans: umbrella review of meta-analyses of randomized controlled trials and observational studies.

Marco Solmi*, Marco De Toffol, Jong Yeob Kim, Min Je Choi, Brendon Stubbs, Trevor Thompson, Joseph Firth, Alessandro Miola, Giovanni Croatto, Francesca Baggio, Pierluigi Simonato, Silvia Michelon, Luca Ballan, Björn Gerdle, Francesco Monaco, Paolo Scocco, Valdo Ricca, Giovanni Castellini, Michele Fornaro, Andrea MurruEduard Vieta, Paolo Fusar-Poli

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Objective. To systematically assess credibility/certainty of associations between cannabis/cannabinoids/cannabis-based medicines (CBM) and human health, from observational/ randomized controlled trials (RCTs).
Design. Umbrella review (PRIOR checklist. PROSPERO CRD42018093045).
Data Sources. PubMed/PsychInfo/Embase/manual search (February 9th, 2022).
Eligibility criteria and synthesis of results. Systematic reviews/meta-analysis of observational studies/RCTs reporting on cannabis/cannabinoids/CBM outcomes. Credibility was graded according to convincing/highly suggestive/suggestive/weak/not significant (observational evidence) and GRADE (RCTs).Sensitivity analyses were conducted.
Results. We included 101 meta-analyses (50 meta-analyses of observational studies/215 meta-analytic associations, 51 meta-analyses of RCTs/364 meta-analytic associations) (AMSTAR2=high/moderate/low/critically low in 34/30/32/5 meta-analyses). Regarding RCTs, the following results were supported by high/moderate certainty. In mixed conditions, CBM increased central nervous system (equivalent odds ratio/eOR=2.84, 95%CI=2.16-3.73)/psychological (eOR=3.07, 95%CI=1.79-5.26)/vision related adverse events (AE) (eOR=3.00, 95%CI=1.79-5.03) (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal AE, and somnolence among others (GRADE=moderate). CBD improved 50% reduction of seizures (eOR=0.59, 95%CI=0.38-0.92)/ seizure events (eOR=0.59, 95%CI=0.36-0.96) (GRADE=high), but increased pneumonia, gastrointestinal AE, and somnolence (GRADE=moderate). In chronic pain CBM/cannabinoids reduced pain by 30% (eOR=0.59, 95%CI=0.37-0.93) (GRADE=high), across different condition (n=7), but increasing psychological distress. In epilepsy, CBD increased risk of diarrhoea (eOR=2.25, 95%CI=1.33-3.81)/had no effect on sleep disruption (GRADE=high). CBD reduced seizures across different populations/measures (n=7), improved global impression (n=2), quality of life, but increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic (eOR=5.21, 95%CI=3.36-8.01)/total psychiatric symptoms (eOR=7.49, 95%CI=5.31-10.42) (GRADE=high), negative psychotic symptoms,cognition (n=11) (GRADE=moderate). In healthy subjects, cannabinoids improved pain threshold (eOR=0.74, 95%CI=0.59-0.91)/unpleasantness (eOR=0.60, 95%CI=0.41-0.88) (GRADE=high). In inflammatory bowel disease, cannabinoids improved quality of life (eOR=0.34, 95%CI=0.22-0.53, GRADE=high). In multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). In cancer, cannabinoids improved sleep disturbances, but had gastrointestinal (n=2) and nervous system AE (GRADE=moderate). CBM, CBD, and cannabinoids had poor tolerability across various conditions (GRADE=moderate).
Convincing evidence emerged from observational studies (main/sensitivity analyses); in pregnant women, small for gestational age (eOR=1.61, 95%CI=1.41-1.83)/low birth weight (RR=1.43, 95%CI=1.27-1.62); in drivers, car crash (eOR=1.27, 95%CI=1.21-1.34); in the general population, psychosis (eOR=1.71, 95%CI: 1.47-2.00). Harmful effects on three additional neonatal outcomes (suggestive), four car crash-related outcomes (suggestive=2, highly suggestive=2), eleven outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania (highly suggestive=1, suggestive=10), seven on impaired cognition in healthy cannabis users (highly suggestive=4, suggestive=3) also emerged.
Conclusions: Convincing or converging evidence prompts to avoid cannabis during adolescence and early adulthood, in people prone to/with mental disorders, in pregnancy and before/while driving. Cannabidiol is effective for epilepsy, notably in children, while CBM can be effective in multiple sclerosis, chronic pain, and palliative care, not without adverse events. This work informs individual risk/benefit considerations, knowledge translation efforts impacting policy making, and guidelines across different branches of medicine.
Original languageEnglish
Publication statusAccepted/In press - 10 Jul 2023


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