Scoping Review and Meta-Analysis Suggests that Cannabis Use May Reduce Cancer Risk in the United States
Thomas M. Clark
Cannabis and Cannabinoid Research, 2021, Volume 6, Number 5, 413-434.
Doi : 10.1089/can.2019.0095
Introduction:Cannabis smoke contains carcinogens similar to tobacco, in addition to compounds with antitumor activity. Cannabis use reduces the risk of obesity and cannabinoids inhibit chronic inflammation, known causes of cancer. The net effect of Cannabis use on cancer risk is not known.
Objective: To examine the association between Cannabis use and cancer risk in the United States.
Methods: Identify and analyze published data on cancer risk in Cannabis users.
Results: A total of 55 data points, consisting of risk ratios of cancer in Cannabis users and nonusers, were identified from 34 studies. Of these, 5 did not contain data essential for inclusion in the meta-analysis. The remaining data showed a nonsignificant trend to an association with reduced risk (relative risk [RR]=0.90, p>0.06, N=50) although heterogeneity is high (I2=72.4%). Removal of data with high risk of selection bias (defined as those from North Africa and those that failed to adjust for tobacco) and data with high risk of performance bias (defined as those with fewer than 20 cases or controls among Cannabis users) resulted in an RR <1.0 (RR=0.86, p<0.017, N=24) and large effect size (Hedges g=0.66), but did not decrease heterogeneity (I2=74.9). Of all cancer sites, only testicular cancer showed an RR value >1, although this was not significant and had a negligible effect size (RR=1.12, p=0.3, Hedges g=0.02). Following removal of testicular cancers the remaining data showed a decrease in risk (RR=0.87, p<0.025, N=41). Cancers of the head and neck showed a negative association with cancer risk (RR=0.83, p<0.05), with a large effect size (Hedges g=0.55), but high heterogeneity (I2=79.2%). RR did not reach statistical significance in the remaining cancer site categories (lung, testicular, obesity-associated, other). The data are consistent with a negative association between Cannabis use and nontesticular cancer, but there is low confidence in this result due to high heterogeneity and a paucity of data for many cancer types.
The impact of Cannabis use on cancer risk is of considerable interest. Cancer is a leading cause of death in the United States and around the world. In the United States alone, >1.7 million diagnoses and 607,000 deaths are projected from cancer in 2019 (Ref.1) and cancer deaths were responsible for $94.4 billion in lost earnings in 2015 (Ref.2). The real costs are much higher than this, however, because even cancer patients who will make a full recovery face lengthy, expensive, and stressful treatment regimens.
The pharmacological activity of Cannabis is primarily due to the presence of phytocannabinoids, a group of lipid-soluble chemicals. These act by mimicking the cannabinoids produced by the endocannabinoid system (ECs), an important physiological signaling system. The cellular and physiological actions of cannabinoids arise from interaction with a variety of widely distributed receptor types, of which cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 have received the greatest attention.3
The ECs appears to be dysregulated by the modern American diet. In particular, emerging evidence suggests that an elevated dietary ratio of omega-6/omega-3 fatty acids may lead to excess production of the endocannabinoid signals N-arachidonoylethanolamide and 2-arachidonoylglycerol, leading to overstimulation of CB1 and contributing in turn to the emerging epidemic of obesity, metabolic syndrome, and associated diseases.4–6 CB1 is also stimulated by the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in Cannabis.
Paradoxically, however, acute stimulation of CB1 is associated with weight gain and antagonists of CB1 increase metabolic rates,4–6 yet Cannabis users show decreased body mass index (BMI) relative to nonusers.4 This may be due to downregulation of CB1 in Cannabis users, which would desensitize the ECs and counteract the impact of the modern American diet on weight gain.4
Cannabis has both protumor and antitumor actions. Which effect predominates in Cannabis users? Cannabis is emerging as a palliative option for cancer patients.7–14 Medical Cannabis use reduces opioid use,8–11 counteracts multiple side effects of chemotherapy, improves mood and outlook, and provides relief from insomnia.12–14 If Cannabis causes cancer, these therapeutic benefits might be offset in cancer patients by stimulation of existing tumors or creation of new neoplasms. However, if Cannabis reduces cancer risk, the case for inclusion of Cannabis in therapeutic cancer care strategies is augmented. In addition, if moderate, adult Cannabis use is found to reduce risk of cancer, a leading cause of death, this information must be included in estimates of its impact on public health.
Tumorigenic activity of Cannabis
Cannabis has several tumorigenic properties, manifested when smoked. Cannabis smoke contains carcinogens similar to those in tobacco smoke, including tar and polycyclic aromatic hydrocarbons, and these may be at higher concentration than in tobacco smoke.15,16 Users who smoke Cannabis heavily have histological changes, including inflammation, in the lungs and airways resembling those prestaging the initiation of tobacco-related lung cancer.17 Sharing of joints or pipes is hypothesized to increase risk of human papilloma virus exposure, a significant cause of oral and other cancers.18 Furthermore, although cannabinoids usually inhibit cancer cells in vitro and in mouse models,3 they stimulate growth of some cancer cell lines in laboratory studies.19
Antitumor activity of Cannabis
Actions that reduce cancer risk include reduced risk of obesity and diabetes mellitus (DM), and inhibition of inflammation by cannabinoids. In addition, in laboratory studies, cannabinoids and other compounds in Cannabis directly inhibit cancer initiation, growth, and spread at the cellular level.