Cannabis and Cannabinoids (Marijuana)

• A very weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward higher risk of oral cancer among people using cannabis (marijuana) the equivalent of 1 joint per day for 1 year or more compared to no use in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 2 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies with low strength of evidence¹Ghasemiesfe M, Barrow B, Leonard S, Keyhani S, Korenstein D. Association between marijuana use and risk of cancer: a systematic review and meta-analysis. JAMA Network Open. 2019 Nov 1;2(11):e1916318.
• No evidence of an effect on risk of head and neck cancer among people ever using cannabis (marijuana) compared to no use in a meta-analysis of 6 observational studies²Carvalho MF, Dourado MR et al. Head and neck cancer among marijuana users: a meta-analysis of matched case-control studies. Archives of Oral Biology. 2015 Dec;60(12):1750-5.
• Higher risk of HPV-16-positive head and neck squamous cell carcinomas, but not HPV-16-negative carcinomas, among people with increasing intensity of cannabis (marijuana) use compared to no use in a mid-sized observational study³Gillison ML, D’Souza G et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. Journal of the National Cancer Instititue. 2008 Mar 19;100(6):407-20.

• Weak associations between cannabis smoking and lung cancer among people who never smoked tobacco in a pooled analysis of observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies⁴Zhang LR, Morgenstern H et al; Cannabis and Respiratory Disease Research Group of New Zealand. Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. International Journal of Cancer. 2015 Feb 15;136(4):894-903.
• Increased risk of squamous cell carcinoma among people with single nucleotide polymorphisms associated with lifetime cannabis use compared to people without the polymorphisms in a very large observational study⁵Baumeister SE, Baurecht H et al; International Lung Cancer Consortium. Cannabis use, pulmonary function, and lung cancer susceptibility: a mendelian randomization study. Journal of Thoracic Oncology. 2021 Jul;16(7):1127-1135.

• Higher risk of testicular germ cell tumor (TGCT) and nonseminoma TGCT among people reporting use of cannabis (marijuana) for more than 10 years compared to no use, but no evidence of an effect with fewer years of use or regarding seminoma TGCT, in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 3 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods studies with low strength of evidence⁶Ghasemiesfe M, Barrow B, Leonard S, Keyhani S, Korenstein D. Association between marijuana use and risk of cancer: a systematic review and meta-analysis. JAMA Network Open. 2019 Nov 1;2(11):e1916318.
• Higher risk of nonseminoma testicular germ cell tumors among people reporting cannabis (marijuana) use compared to no use in a meta-analysis of 4 observational studies⁷Song A, Myung NK et al. Incident testicular cancer in relation to using marijuana and smoking tobacco: a systematic review and meta-analysis of epidemiologic studies. Urologic Oncology: Seminars and Original Investigations. 2020 Jul;38(7):642.e1-642.e9.
• Higher risk of testicular germ cell tumor, and especially nonseminoma development, among people with current, chronic, or frequent cannabis use compared to no use in a meta-analysis of 3 observational studies⁸Gurney J, Shaw C, Stanley J, Signal V, Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer. 2015 Nov 11;15:897.

• Substantially shorter time to tumor progression and overall survival, and a worse marker of immune function (lymphocyte count) among people with advanced cancer initiating immunotherapy using cannabis compared to no cannabis in a mid-sized observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study; better survival was also associated with the presence immune-related side effects (adverse events)⁹Bar-Sela G, Cohen I et al. Cannabis consumption used by cancer patients during immunotherapy correlates with poor clinical outcome. Cancers (Basel). 2020 Aug 28;12(9):2447.
• Substantially lower response to immunotherapy (nivolumab), but no evidence of an effect on progression-free or overall survival, among people with advanced cancers—melanoma, non-small cell lung cancer, or renal clear cell carcinoma—using cannabis compared to no cannabis in a mid-sized observational study; the percentages of THC and CBD in the cannabis had no impact on this effect¹⁰Taha T, Meiri D et al. Cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies. Oncologist. 2019 Apr;24(4):549-554.

• Higher rate of withdrawal from treatment due to adverse side effects among people treated with THC for pain compared to controls, with a higher likelihood of withdrawal among people treated with THC extracted from cannabis compared to synthetic THC, in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 5 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹⁷McDonagh MS, Morasco BJ et al. Cannabis-based products for chronic pain: a systematic review. Annals of Internal Medicine. 2022 Jun 7.
• Pharmaceutical cannabinoids were less tolerated and less safe than placebo and conventional antiemetics in treating chemotherapy-induced nausea and vomiting (moderate quality evidence).¹⁸Tafelski S, Häuser W, Schäfer M. Efficacy, tolerability, and safety of cannabinoids for chemotherapy-induced nausea and vomiting—a systematic review of systematic reviews. Schmerz. 2016;30:14-24.

• Slightly higher risk of short-term cognitive impairment and impaired attention among people with chronic pain or cancer treated with oral cannabis compared to placebo in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 32 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹⁹Wang L, Hong PJ et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034.

• Slightly higher risk of drowsiness among people with chronic pain or cancer treated with oral cannabis compared to placebo in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 32 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁰Wang L, Hong PJ et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034.
• Higher risk of sedation among people treated with high-THC cannabinoids compared to controls in a meta-analysis of 3 RCTs²¹McDonagh MS, Morasco BJ et al. Cannabis-based products for chronic pain: a systematic review. Annals of Internal Medicine. 2022 Jun 7.
• Higher rates of sedation among people with chemotherapy-induced nausea and vomiting treated with oral cannabis compared to placebo or other treatments in meta-analyses of 3 or 4 RCTs²²Chow R, Valdez C, Chow N, et al. Oral cannabinoid for the prophylaxis of chemotherapy-induced nausea and vomiting—a systematic review and meta-analysis. Supportive Care in Cancer. 2020;28:2095-2103.
• A higher incidence of moderate or severe cannabinoid-related adverse events including sedation, but no serious adverse events—and participants preferred cannabis to placebo—among people with refractory chemotherapy-induced nausea and vomiting treated with 1 cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) 3 times daily, from days -1 to 5 compared to placebo in a small RCT²³Grimison P, Mersiades A, Kirby A, et al. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial. Annals of Oncology. 2020;31:1553-1560.

• Slightly higher risk of nausea and vomiting among people with chronic pain or cancer treated with oral cannabis compared to placebo in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 32 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects²⁴Wang L, Hong PJ et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034.
• Higher risk of nausea and vomiting but no evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on constipation among people with chronic cancer pain when adding cannabis to prescription opioids compared to opioids alone in a meta-analysis of 5 RCTs²⁵Noori A, Miroshnychenko A et al. Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies. BMJ Open. 2021 Jul 28;11(7):e047717.
• Risk of cannabinoid hyperemesis syndrome, a syndrome of cyclic vomiting associated with cannabis use, in a review of 183 studies²⁶Sorensen CJ, DeSanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment-a systematic review. Journal of Medical Toxicology. 2017 Mar;13(1):71-87.
• More gastrointestinal side effects but not serious adverse events among people treated with medical cannabis compared to placebo in a meta-analysis of 5 RCTs of low quality²⁷Häuser W, Welsch P, Klose P, Radbruch L, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain : a systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019 Oct;33(5):424-436. English

General nervous system side effects: Preliminary evidence of nervous system side effects among people treated with medical cannabis

• More nervous system side effects but not serious adverse events or psychiatric side effects among people treated with medical cannabis compared to placebo in a meta-analysisa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 5 RCTsrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects of low quality²⁸Häuser W, Welsch P, Klose P, Radbruch L, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain : a systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019 Oct;33(5):424-436. English
• No evidence of an effect on the occurrence of psychiatric diseases such as hallucinations or psychosis among people with cancer treated with cannabis or cannabinoids compared to placebo in meta-analyses of 9 RCTs and 9 controlled trialsa study design in which people are assigned to either an experimental group or a control group to compare the outcomes from different treatment; assignment is not random, and so this is not as strong a study design as a randomized controlled trial, but still stronger than an uncontrolled trial of low quality²⁹Mücke M, Carter C et al. Cannabinoide in der palliativen Versorgung: Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit [Cannabinoids in palliative care: systematic review and meta-analysis of efficacy, tolerability and safety]. Schmerz. 2016 Feb;30(1):25-36. German; Mücke M, Weier M. Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of Cachexia, Sarcopenia and Muscle. 2018 Apr;9(2):220-234.

Euphoria: good evidence of euphoria among people using cannabinoids

• Increased risks of euphoria among people using THC/CBD (between cheek and gum—oromucosal), THC (oromucosal), and SCT (inhalation) in a large systematic review of 25 RCTs³⁰Rabgay K, Waranuch N et al. The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: a systematic review and network meta-analysis. Journal of the American Pharmacists Association. 2020 Jan-Feb;60(1):225-234.e6.
• Higher risk of dysphoria, euphoria, ‘feeling high’, and sedation among people receiving chemotherapy with cannabinoids compared with prochlorperazine in a meta-analysis of 7 RCTs of low quality³¹Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews. 2015 Nov 12;2015(11):CD009464.

Dysphoria: modest evidence of higher rates of dysphoria among people treated with cannabis for chemotherapy-induced nausea and vomiting

• Higher rates of dysphoria among people with chemotherapy-induced nausea and vomiting treated with oral cannabis compared to placeboa pill, medicine, or procedure—thought to be both harmless and ineffective—prescribed for the psychological benefit to the patient or as a sham treatment in a study to allow a comparison to a therapy of interest or other treatments in meta-analyses of 3 or 4 RCTs³²Chow R, Valdez C, Chow N, et al. Oral cannabinoid for the prophylaxis of chemotherapy-induced nausea and vomiting—a systematic review and meta-analysis. Supportive Care in Cancer. 2020;28:2095-2103.

Dizziness or disorientation: modest and somewhat conflicting evidence of higher risk of dizziness  or disorientation among people treated with oral cannabis

• Higher risk of dizziness among people with chronic pain or cancer treated with oral cannabis compared to placebo in a meta-analysis of 32 RCTs³³Wang L, Hong PJ et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034.
• Increased risks of dizziness with cannabis use compared to placebo in a large meta-analysis of well-designed RCTs³⁴Whiting PF, Wolff RF et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73.
• Higher risk of dizziness during chemotherapy among people treated with cannabinoids compared with prochlorperazine in a meta-analysis of 7 RCTs of low quality³⁵Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews. 2015 Nov 12;2015(11):CD009464.
• Higher risk of dizziness (3 RCTs) among people treated with high-THC cannabinoids compared to controls in meta-analyses³⁶McDonagh MS, Morasco BJ et al. Cannabis-based products for chronic pain: a systematic review. Annals of Internal Medicine. 2022 Jun 7.
• A higher incidence of moderate or severe cannabinoid-related adverse events including disorientation, but no serious adverse events—and participants preferred cannabis to placebo—among people with refractory chemotherapy-induced nausea and vomiting treated with 1 cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) 3 times daily, from days -1 to 5 compared to placebo in a small RCT³⁷Grimison P, Mersiades A, Kirby A, et al. Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial. Annals of Oncology. 2020;31:1553-1560.
• No effect on the risk of dizziness among people with cancer treated with cannabis or cannabinoids compared to placebo in a meta-analyses of 9 RCTs and 9 controlled trials of low quality³⁸Mücke M, Carter C et al. Cannabinoide in der palliativen Versorgung: Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit [Cannabinoids in palliative care: systematic review and meta-analysis of efficacy, tolerability and safety]. Schmerz. 2016 Feb;30(1):25-36. German; Mücke M, Weier M. Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of Cachexia, Sarcopenia and Muscle. 2018 Apr;9(2):220-234.

• Harm to the tissues that both surround and support the teeth (periodontium) among people who smoke cannabis in a review of clinical studies³⁹Keboa MT, Enriquez N, Martel M, Nicolau B, Macdonald ME. Oral health implications of cannabis smoking: a rapid evidence review. Journal of the Canadian Dental Association. 2020 Jan;86:k2.