. 2023 Aug 30:382:e072348.

doi: 10.1136/bmj-2022-072348.

Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies

Marco Solmi^{1

2

3

4

5

6

7}, Marco De Toffol⁸, Jong Yeob Kim⁹, Min Je Choi⁹, Brendon Stubbs^{10

11}, Trevor Thompson¹², Joseph Firth^{13

14}, Alessandro Miola¹⁵, Giovanni Croatto¹⁶, Francesca Baggio¹⁶, Silvia Michelon¹⁷, Luca Ballan¹⁷, Björn Gerdle¹⁸, Francesco Monaco^{19

20}, Pierluigi Simonato²¹, Paolo Scocco²², Valdo Ricca²³, Giovanni Castellini²³, Michele Fornaro²⁴, Andrea Murru²⁵, Eduard Vieta²⁵, Paolo Fusar-Poli^{5

26}, Corrado Barbui²⁷, John P A Ioannidis^{28

29

30}, Andrè F Carvalho³¹, Joaquim Radua³², Christoph U Correll^{7

33

34}, Samuele Cortese^{6

35

36

37

38}, Robin M Murray³⁹, David Castle^{40

41}, Jae Il Shin^{42

43}, Elena Dragioti^{18

44}

Affiliations

¹ Department of Psychiatry, University of Ottawa, Ontario, ON, Canada msolmi@toh.ca.
² On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, ON, Canada.
³ Ottawa Hospital Research Institute, Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada.
⁴ School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Early Psychosis: Interventions and Clinical detection Lab, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK.
⁶ Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, and NHS Trust, Southampton, UK.
⁷ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
⁸ Psychiatry Unit, Veris Delli Ponti Scorrano Hospital, Department of Mental Health, ASL Lecce, Lecce, Italy.
⁹ Yonsei University College of Medicine, Seoul, South Korea.
¹⁰ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹¹ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK.
¹² Centre of Chronic Illness and Ageing, University of Greenwich, London, UK.
¹³ Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
¹⁴ Greater Manchester Mental Health NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹⁵ Neurosciences Department, Padua Neuroscience Center, University of Padua, Italy.
¹⁶ Mental Health Department, AULSS 3 Serenissima, Mestre, Venice, Italy.
¹⁷ Department of Mental Health, AULSS 7 Pedemontana Veneto, Italy.
¹⁸ Pain and Rehabilitation Centre, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
¹⁹ Department of Mental Health, Asl Salerno, Salerno, Italy.
²⁰ European Biomedical Research Institute of Salerno, Salerno, Italy.
²¹ Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.
²² Mental Health Department, ULSS 6 Euganea, Padova, Italy.
²³ Psychiatry Unit, Department of Health Sciences, University of Florence, Florence, Italy.
²⁴ Section of Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy.
²⁵ Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁶ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁷ WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
²⁸ Meta-Research Innovation Center at Stanford, Stanford University, Stanford, CA, USA.
²⁹ Meta-Research Innovation Center Berlin, Berlin Institute of Health, Charité Universitätsmedizin, Berlin, Germany.
³⁰ Departments of Medicine, of Epidemiology and Population Health, of Biomedical Data Science, and of Statistics, Stanford University, Stanford, CA, USA.
³¹ IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
³² Institut d'Investigacions Biomediques August Pi i Sunyer, CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain.
³³ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA.
³⁴ Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
³⁵ Clinical and Experimental Sciences (Central Nervous System and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
³⁶ Solent NHS Trust, Southampton, UK.
³⁷ Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.
³⁸ Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York City, New York, NY, USA.
³⁹ Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College of London, London, UK.
⁴⁰ Department of Psychiatry, University of Tasmania, Sandy Bay, TAS, Australia.
⁴¹ Co-Director, Centre for Mental Health Service Innovation, Department of Health, Tasmania, Australia.
⁴² Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea.
⁴³ Severance Underwood Meta-research Center, Institute of Convergence Science, Yonsei University, Seoul, South Korea.
⁴⁴ Research Laboratory Psychology of Patients, Families and Health Professionals, Department of Nursing, School of Health Sciences, University of Ioannina, Ioannina, Greece.

PMID: 37648266
PMCID: PMC10466434
DOI: 10.1136/bmj-2022-072348

Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies

Marco Solmi et al. BMJ. 2023.

. 2023 Aug 30:382:e072348.

doi: 10.1136/bmj-2022-072348.

Authors

Affiliations

¹ Department of Psychiatry, University of Ottawa, Ontario, ON, Canada msolmi@toh.ca.
² On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, ON, Canada.
³ Ottawa Hospital Research Institute, Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada.
⁴ School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Early Psychosis: Interventions and Clinical detection Lab, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK.
⁶ Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, and NHS Trust, Southampton, UK.
⁷ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
⁸ Psychiatry Unit, Veris Delli Ponti Scorrano Hospital, Department of Mental Health, ASL Lecce, Lecce, Italy.
⁹ Yonsei University College of Medicine, Seoul, South Korea.
¹⁰ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹¹ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK.
¹² Centre of Chronic Illness and Ageing, University of Greenwich, London, UK.
¹³ Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
¹⁴ Greater Manchester Mental Health NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹⁵ Neurosciences Department, Padua Neuroscience Center, University of Padua, Italy.
¹⁶ Mental Health Department, AULSS 3 Serenissima, Mestre, Venice, Italy.
¹⁷ Department of Mental Health, AULSS 7 Pedemontana Veneto, Italy.
¹⁸ Pain and Rehabilitation Centre, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
¹⁹ Department of Mental Health, Asl Salerno, Salerno, Italy.
²⁰ European Biomedical Research Institute of Salerno, Salerno, Italy.
²¹ Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.
²² Mental Health Department, ULSS 6 Euganea, Padova, Italy.
²³ Psychiatry Unit, Department of Health Sciences, University of Florence, Florence, Italy.
²⁴ Section of Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Naples, Italy.
²⁵ Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
²⁶ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
²⁷ WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
²⁸ Meta-Research Innovation Center at Stanford, Stanford University, Stanford, CA, USA.
²⁹ Meta-Research Innovation Center Berlin, Berlin Institute of Health, Charité Universitätsmedizin, Berlin, Germany.
³⁰ Departments of Medicine, of Epidemiology and Population Health, of Biomedical Data Science, and of Statistics, Stanford University, Stanford, CA, USA.
³¹ IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia.
³² Institut d'Investigacions Biomediques August Pi i Sunyer, CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain.
³³ Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA.
³⁴ Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
³⁵ Clinical and Experimental Sciences (Central Nervous System and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
³⁶ Solent NHS Trust, Southampton, UK.
³⁷ Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.
³⁸ Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York City, New York, NY, USA.
³⁹ Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College of London, London, UK.
⁴⁰ Department of Psychiatry, University of Tasmania, Sandy Bay, TAS, Australia.
⁴¹ Co-Director, Centre for Mental Health Service Innovation, Department of Health, Tasmania, Australia.
⁴² Department of Pediatrics, Yonsei University College of Medicine, Seoul, South Korea.
⁴³ Severance Underwood Meta-research Center, Institute of Convergence Science, Yonsei University, Seoul, South Korea.
⁴⁴ Research Laboratory Psychology of Patients, Families and Health Professionals, Department of Nursing, School of Health Sciences, University of Ioannina, Ioannina, Greece.

PMID: 37648266
PMCID: PMC10466434
DOI: 10.1136/bmj-2022-072348

Abstract

Objective: To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs).

Design: Umbrella review.

Data sources: PubMed, PsychInfo, Embase, up to 9 February 2022.

Eligibility criteria for selecting studies: Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted.

Results: 101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 to 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse events, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disruption (GRADE=high), reduced seizures across different populations and measures (n=7), improved global impression (n=2), quality of life, and increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic symptoms (5.21 (3.36 to 8.01)) and total psychiatric symptoms (7.49 (5.31 to 10.42)) (GRADE=high), negative psychotic symptoms, and cognition (n=11) (GRADE=moderate). In healthy people, cannabinoids improved pain threshold (0.74 (0.59 to 0.91)), unpleasantness (0.60 (0.41 to 0.88)) (GRADE=high). For inflammatory bowel disease, cannabinoids improved quality of life (0.34 (0.22 to 0.53) (GRADE=high). For multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). For cancer, cannabinoids improved sleep disruption, but had gastrointestinal adverse events (n=2) (GRADE=moderate). Cannabis based medicines, cannabis, and cannabinoids resulted in poor tolerability across various conditions (GRADE=moderate). Evidence was convincing from observational studies (main and sensitivity analyses) in pregnant women, small for gestational age (1.61 (1.41 to 1.83)), low birth weight (1.43 (1.27 to 1.62)); in drivers, car crash (1.27 (1.21 to 1.34)); and in the general population, psychosis (1.71 (1.47 to 2.00)). Harmful effects were noted for additional neonatal outcomes, outcomes related to car crash, outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania, and impaired cognition in healthy cannabis users (all suggestive to highly suggestive).

Conclusions: Convincing or converging evidence supports avoidance of cannabis during adolescence and early adulthood, in people prone to or with mental health disorders, in pregnancy and before and while driving. Cannabidiol is effective in people with epilepsy. Cannabis based medicines are effective in people with multiple sclerosis, chronic pain, inflammatory bowel disease, and in palliative medicine but not without adverse events.

Study registration: PROSPERO CRD42018093045.

Funding: None.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: MS received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, Otsuka. DC has received grant monies for research from Eli Lilly, Janssen Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, Astra Zeneca, Hospira; Travel Support and Honoraria for Talks and Consultancy from Eli Lilly, Bristol-Myers Squibb, Astra Zeneca, Lundbeck, Janssen Cilag, Pfizer, Organon, Sanofi-Aventis, Wyeth, Hospira, Servier, Seqirus; and is a current or past Advisory Board Member for Lu AA21004: Lundbeck; Varenicline: Pfizer; Asenapine: Lundbeck; Aripiprazole LAI: Lundbeck; Lisdexamfetamine: Shire; Lurasidone: Servier; Brexpiprazole: Lundbeck; Treatment Resistant Depression: LivaNova; Cariprazine: Seqirus. He is founder of the Optimal Health Program, currently operating as Optimal Health Australia; and is part owner of Clarity Healthcare. He is on the scientific advisory of The Mental Health Foundation of Australia. He does not knowingly have stocks or shares in any pharmaceutical company. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Angelini, Biogen, Boehringer-Ingelheim, Celon Pharma, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Janssen, Lundbeck, Novartis, Orion Corporation, Organon, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside of the submitted work. CUC has been a consultant or advisor to or have received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, and LB Pharma.

Figures

**Fig 1**
Study selection flow. References of excluded studies after full text assessment available in supplementary table 3. *One meta-analysis included both observational and randomised controlled trials

**Fig 2**
Moderate and high certainty evidence according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE), from randomised controlled trials on outcomes of cannabis based medications in people with chronic pain, multiple sclerosis, inflammatory bowel disease, and cancer. Only associations for which an eOR was available are displayed. Results are displayed in descending order of level of evidence and effect size. CBM=cannabis based medications eOR=equivalent odds ratio; H=high; M=moderate

**Fig 3**
Moderate and high certainty evidence according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE), from randomised controlled trials on outcomes of cannabis based medications (CBD) in people with epilepsy. Results are displayed in descending order of level of evidence and effect size; only associations for which an eOR was available are displayed. eOR=equivalent odds ratio; H=high; M=moderate

**Fig 4**
Observational meta-analytical associations between cannabis and outcomes in pregnant women, drivers, and people with psychosis supported by convincing, highly suggestive, or suggestive evidence in main or sensitivity analysis. Results are displayed in descending order of level of evidence and effect size; only associations for which an eOR was available are displayed. n=cases; N=population; CE=class of evidence (convincing (I), highly suggestive (II), suggestive (III), weak (IV)); CES=class of evidence after removing the n>1000 cases criterion; eOR=equivalent odds ratio; NR=not reported

**Fig 5**
Observational meta-analytical associations between cannabis and outcomes in the general population and healthy people supported by convincing, highly suggestive, or suggestive evidence in main or sensitivity analysis excluding 1000 cases criterion. Results are displayed in descending order of level of evidence and effect size; only associations for which an eOR was available are displayed. n=cases; N=population; CE=class of evidence (convincing (I), highly suggestive (II), suggestive (III), weak (IV)); CES=class of evidence after removing the n>1000 cases criterion; eOR=equivalent odds ratio; NR=not reported

See this image and copyright information in PMC

Comment in

Benefits and risks of cannabinoids.
Freeman TP, Hall W. Freeman TP, et al. BMJ. 2023 Sep 18;382:2113. doi: 10.1136/bmj.p2113. BMJ. 2023. PMID: 37722728 No abstract available.

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Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies

Affiliations

Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

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LinkOut - more resources

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Medical