Introduction

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.

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