Cannabinoids for Medical Use: A Systematic Review and Meta-analysis

Whiting, Penny F.; Wolff, Robert F.; Deshpande, Sohan; Di Nisio, Marcello; Duffy, Steven; Hernandez, Adrian V.; Keurentjes, J. Christiaan; Lang, Shona; Misso, Kate; Ryder, Steve; Schmidlkofer, Simone; Westwood, Marie; Kleijnen, Jos

doi:10.1001/jama.2015.6358

Cited by 2,169Cannabis and Cannabinoid ResearchNausea and vomiting managementComplementary and Alternative Medicine Studies

Cannabinoids for Medical Use: A Systematic Review and Meta-analysis

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Whiting, Penny F., Wolff, Robert F., Deshpande, Sohan, Di Nisio, Marcello, Duffy, Steven, Hernandez, Adrian V., Keurentjes, J. Christiaan, Lang, Shona +5 more·2015·JAMA

DOI 10.1001/jama.2015.6358

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Abstract

IMPORTANCE: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES: Twenty-eight databases from inception to April 2015. STUDY SELECTION: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. RESULTS: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. CONCLUSIONS AND RELEVANCE: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

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Mild to moderate central nervous or gastro-intestinal side effects are more common with cannabinoids than with placebo, but severe side effects are rare.
“Mild to moderate central nervous or gastro-intestinal side effects are more common with cannabinoids than with placebo but severe side effects are rare [13].”
From Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits (2025) · cites this paper as [13]
The Adverse Events section and Table 3 report higher odds of gastrointestinal and nervous-system adverse events with cannabinoids than with placebo. The paper does not establish that these events were mild to moderate or that severe events were rare; it instead reports increased odds of serious adverse events (OR 1.41, 95% CI 1.04–1.92). Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Medical uses of THC-based cannabinoids are associated with an increased risk of short-term adverse effects, but severe side effects are rare.
“Medical uses of THC-based cannabinoids are associated with an increased risk of short-term adverse effects, but severe side effects are rare [13].”
From Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits (2025) · cites this paper as [13]
The Discussion reports an increased risk of short-term adverse events with medical cannabinoids. The Adverse Events section also reports an increased risk of serious adverse events; it does not establish that they are rare. The review covers cannabinoids generally, not only THC-based products. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Previous systematic reviews have been limited in their coverage of all relevant diseases and primarily ignored that medical cannabinoid products differ in their pharmacology.
“Previous systematic reviews have been limited in their coverage of all relevant diseases, but most importantly primarily ignored the fact that medical cannabinoid products—a term that encompasses all plant-derived and synthetic derivatives—differ in their pharmacology [1–5].”
From Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications. (2022) · cites this paper as [3]
The Strengths and Weaknesses section (page unavailable) says almost all previous reviews focused on single indications, supporting the claim that their disease coverage was limited. It says this review stratified analyses by cannabinoid type, but does not say previous reviews primarily ignored pharmacological differences between products. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Data analysis using SMD allowed the inclusion of a large variety of measurements and allowed inclusion of many more RCTs for all relevant medical indications than in a previous extensive meta-analysis.
“Finally, data analysis using SMD allowed the inclusion of a large variety of measurements in the evaluation of the outcomes and allowed us to include many more RCTs for all relevant medical indications than in a previous extensive meta-analysis [3].”
From Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications. (2022) · cites this paper as [3]
Efforts to self-manage depression with cannabis are increasing despite lack of evidence that cannabinoids are effective for this purpose, and prospectively cannabis worsens the course of depressive disorders.
“Evidence suggests that efforts to selfmanage depression with cannabis are increasing [71][72][73][74][75] (also Aaron L. Sarvet, MPH, written communication, January 2, 2018) despite lack of evidence that cannabinoids are effective for this purpose 76,77 ; prospectively, cannabis worsens the course of depressive disorders.78”
From Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States (2018) · cites this paper as [75]

Several clinical studies have demonstrated analgesic effects of cannabinoids in human disease states, including pain associated with diabetes, chemotherapy, multiple sclerosis, and fibromyalgia.
“Several clinical studies have demonstrated the analgesic effects of cannabinoids in human disease states, including pain associated with diabetes, chemotherapy, multiple sclerosis, and fibromyalgia (Lynch and Ware, 2015;Whiting et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Whiting et al, 2015
A comprehensive meta-analysis shows that medicinal cannabis and cannabinoids effectively alleviate different types of pain, such as neuropathic, fibromyalgia, multiple sclerosis, cancer, diabetic neuropathy, refractory pain due to multiple sclerosis or other neurological conditions, rheumatoid arthritis, noncancer pain, central pain, musculoskeletal problems, and chemotherapy-induced pain.
“A comprehensive meta-analysis shows that medicinal cannabis and cannabinoids effectively alleviate different types of pain, such as neuropathic, fibromyalgia, multiple sclerosis, cancer, diabetic neuropathy, refractory pain due to multiple sclerosis or other neurological conditions, rheumatoid arthritis, noncancer pain, central pain, musculoskeletal problems, and chemotherapy-induced pain (Whiting”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Whiting et al, 2015
Cannabimimetic side effects, including drowsiness or fatigue, dizziness, dry mouth, nausea, and cognitive effects, have been reported with medical cannabis.
“Although several studies show that 'medical cannabis' can improve various types of pain, cannabimimetic side effects, which include drowsiness or fatigue, dizziness, dry mouth, nausea, and cognitive effects, have also been reported (Whiting et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Whiting et al, 2015

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Authors: Whiting, P. F., Wolff, R. F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A. V., Keurentjes, J. C., Lang, S., Misso, K., Ryder, S., Schmidlkofer, S., Westwood, M., & Kleijnen, J.
Affiliations: University Hospitals Bristol NHS Foundation Trust (GB)
Kleijnen Systematic Reviews (United Kingdom) (GB)
Department of Medical, Oral, and Biotechnological Sciences, University “G. D'Annunzio” of Chieti-Pescara, Chieti, Italy5Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
Medical School, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru7Health Outcomes and Clinical Epidemiology Section, Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
Radboud University Medical Center (NL)
Institut für Epidemiologie und kongenitale Erkrankungen, Cepicon GmbH, Hamburg, Germany
Maastricht University (NL)
ORCID: Whiting, Penny F.
Wolff, Robert F.
Deshpande, Sohan
Duffy, Steven
Lang, Shona
Misso, Kate
Ryder, Steve
Westwood, Marie
Kleijnen, Jos
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2015-06-23
Volume: 313
Issue: 24
Pages: 2456
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2015.6358
OpenAlex: W2120227293
Semantic Scholar: 029bce497e0633eb2a7895cfd3b315f9c462dd5f
Cited by: 2,169
References: 137
Citations by year: 2026: 119 · 2025: 166 · 2024: 168 · 2023: 200 · 2022: 220 · 2021: 262 · 2020: 272 · 2019: 230 · 2018: 209 · 2017: 159 · 2016: 131 · 2015: 33
FWCI: 22.34
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion, other-oa)
Bristol Research (University of Bristol) (publishedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Data Archiving and Networked Services (DANS) (submittedVersion)
Americanae (AECID Library) (submittedVersion, other-oa)
Research Publications (Maastricht University) (submittedVersion, other-oa)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
Explore Bristol Research (submittedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Surgery › Nausea and vomiting management
Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
Keywords: cannabinoids, medical cannabis, nausea and vomiting, chemotherapy-induced nausea, chronic pain, spasticity, multiple sclerosis, depression, anxiety, sleep disorders, psychosis, glaucoma, Tourette syndrome, adverse events, quality of life, activities of daily living, risk of bias, placebo comparison
MeSH terms: Anorexia, Mental Disorders, Cannabinoids, Tourette Syndrome, Glaucoma, Humans, Muscle Spasticity, Nausea, Randomized Controlled Trials as Topic, Chronic Pain, Medical Marijuana

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