Cannabis sativa is an annual flowering herb native to East Asia, but is now cultivated around the world. Its uses as a source of industrial fiber, seed oil, and as a recreational agent date back thousands of years across cultures. It has also been employed in traditional medicine as an analgesic, hypnotic, and hallucinogenic, as a sedative, and for reducing inflammation. Preparations containing flowers (marijuana) and leaves; hashish derived from the resinous extract of the plant are consumed orally; by smoking in cigarettes, cigars, pipes, water pipes, or “blunts” (cannabis rolled in the tobacco-leaf wrapper from a cigar); or by vaporizing. Cannabis tinctures, teas, ointments, and oil-based extracts that can be mixed into food products are also popular. It is currently the most widely used illicit agent by more than 147 million people worldwide ⁽¹⁾, and the common route of consumption is via inhalation. Because of the potential for high abuse and dependence, and its classification as a Schedule I agent by the Controlled Substances Act in 1970, cannabis use is a controversial subject in the US.

Pharmacologic investigations over the last few decades revealed cannabinoids (terpenoids) to be the active constituents. Delta-9-tetrahydrocannabinol (THC) is the chief psychoactive component whereas cannabidiol (CBD) is a major secondary non-psychoactive cannabinoid, and may modulate the effects of THC. It has antipsychotic, anticonvulsive, and anxiolytic effects. When co-administered, CBD was reported to mitigate the adverse psychotropic and cardiovascular effects associated with THC ⁽²⁾.

Cannabis has been studied for its utility in treating pain, symptoms of neurological disorders, AIDS and cancer.
A systematic review reported significant relief from pain due to neuropathy, fibromyalgia, rheumatoid arthritis, and mixed chronic pain following cannabinoid use compared to placebo ⁽³⁾ but another review determined placebo as a contributor to pain reductions ⁽⁷³⁾. In addition, a 4-year prospective study involving 1,514 patients with chronic non-cancer pain did not find evidence that cannabis use decreased pain severity or interference, or exerted an opioid-sparing effect ⁽⁴⁾. 

In a Cochrane review of four trials involving 48 epileptic patients, short-term CBD use was reported to be well tolerated with no adverse effects, but limited evidence precluded definitive conclusions to be reached on efficacy ⁽⁵⁾. Newer randomized studies of patients with either Lennox-Gastaut syndrome or Dravet syndrome, both rare forms of epilepsy, reported effectiveness of Epidiolex, an oral CBD solution, for reducing the frequency of seizures ⁽⁶⁾. This is now an FDA-approved drug ⁽⁷⁾. Additionally, data indicate benefits of cannabinoids for treating spasticity and neuropathic pain in multiple sclerosis (MS) patients ⁽⁸⁾. The American Academy of Neurology issued a Summary of Systematic Reviews for Clinicians indicating that oral cannabis extract is effective in reducing patient-reported spasticity scores and central pain or painful spasms associated with MS ⁽⁹⁾.

Conclusions from a large, comprehensive review of 79 trials (6462 subjects) indicate low-quality evidence to address weight gain from HIV infection, sleep disorders, increasing appetite, and for Tourette syndrome, along with elevated risk of short-term adverse effects ⁽¹⁰⁾. The evidence for recommending cannabinoids to treat symptoms of dyskinesia, Parkinson’s and Huntington’s diseases, irritable bowel syndrome, and addiction has been deemed unavailable or insufficient ⁽¹¹⁾.

In oncology settings, preclinical findings from 34 studies suggest selective cytotoxic effects of cannabinoids against glioma cells (sparing normal brain cells) via apoptosis, toxicity, autophagy and necrosis ⁽¹²⁾. A clinical study of 9 patients with recurrent glioblastoma multiforme receiving chemotherapy did not find any benefit with intratumoral THC, but it was well tolerated ⁽¹³⁾. Data from another study involving 21 glioblastoma patients, in which oromucosal whole plant extract nabiximols (contains THC +CBD) was used, have yet to be published ⁽¹⁴⁾. In addition, a cannabinoid resin extract was reported to affect dose-dependent disease control in a patient with acute lymphoblastic leukemia ⁽²⁰⁾.  But a retrospective observational study showed that concomitant use of cannabis during immunotherapy with nivolumab was associated with reduction in tumor response rate in patients with advanced melanoma, non-small-cell lung cancer, and renal clear cell carcinoma. Progression-free survival and overall survival remained unaffected ⁽²¹⁾.

For symptom management, systematic reviews ^(10) (15) show that patients who used cannabis-based products experienced less chemo-induced nausea and vomiting compared to those on placebo group or on antiemetics. The differences were not statistically significant and adverse effects including “feeling high,” dizziness, sedation, and dysphoria were reported, resulting in a high dropout rate.  Noteworthy are the 2017 American Society of Clinical Oncology (ASCO) guidelines on antiemetics that recommend dronabinol and nabilone for nausea and vomiting, which is resistant to standard therapy ⁽¹⁶⁾.

Findings on effectiveness of cannabis against cancer pain are encouraging. Data from four trials indicate reductions in pain with orally administered THC and with nabiximols spray in advanced cancer patients ⁽¹⁷⁾. In addition, incorporating medical cannabis early in the treatment as opposed to delayed start resulted in decreased opioid use along with improved pain control in this population ⁽⁷¹⁾. Cannabis has also been investigated for its role in ameliorating cancer-related anorexia-cachexia syndrome (CACS), but neither cannabis extract nor THC were found useful in a randomized trial of patients with advanced cancer ⁽¹⁸⁾. Additional case reports suggest that dronabinol may be useful for managing persistent symptomatic paraneoplastic night sweats in cancer patients ⁽¹⁹⁾. In a randomized uncontrolled study, THC-containing medicinal cannabis was found to improve sleep, functional well-being, and quality of life in patients with high grade gliomas ⁽⁶⁷⁾.

Although some data suggest potential benefits, cannabis remains a contentious issue because non-medical use is associated with high risk of addiction, especially when used from an early age ^(22) (23); dependence ⁽²⁴⁾; adverse effects ⁽²⁵⁾; and with withdrawal syndrome (irritability, sleeping difficulties, dysphoria, craving, and anxiety) ⁽²⁶⁾ that makes cessation tough, eventually leading to relapse. Cannabis use was also reported to elevate the risk of creating false memories ⁽⁶²⁾.

It is also important to note that synthetic cannabinoid drugs cause more serious adverse effects compared to natural cannabis, and include respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation and cognitive impairment ⁽²⁷⁾.

Some studies suggest utility of nicotine patch in decreasing negative affect-related withdrawal symptoms in individuals with cannabis use disorder ⁽⁶³⁾; and in patients with cannabis dependence, nabiximols combined with psychosocial interventions reduced cannabis use ⁽⁵⁸⁾. However, an incentive-based intervention was ineffective in individuals with early psychosis and problematic cannabis use ⁽⁵⁹⁾.

Despite the controversy surrounding cannabis use, California became the first state to legalize it for “medical use” in 1996. As of May 2021, it is available in 35 more states and the District of Columbia (DC) as a medicinal agent, with 16 states and DC also allowing recreational use. Current indications that qualify for medical cannabis use include cancer symptoms, non-cancer pain, glaucoma, AIDS, epilepsy, and MS. However, cannabis use remains illegal under federal law. Following a review of available scientific evidence, the Institute of Medicine ⁽²⁸⁾, and the National Academies of Sciences, Engineering, and Medicine recommend that further research be done to develop a comprehensive understanding of the health effects of cannabis ⁽¹¹⁾, which can inform medical cannabis policy. Barriers to research include regulatory issues that involve the FDA, Drug Enforcement Administration, National Institute on Drug Abuse, and Institutional Review Boards; procuring cannabis for studies; and methodological challenges of establishing an acceptable route of administration and standardized doses ⁽²⁹⁾.

With the growing popularity of cannabis among cancer patients, it is important that oncology providers be aware of emerging data so they can counsel patients about its use ⁽⁷²⁾. Oncology guidelines recommend against using cannabis and/or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Whether cannabis and/or cannabinoids improve any supportive care outcomes, with the exception of chemo-induced nausea and vomiting, is also uncertain ^{(74) (75) (79)}. Additionally, a systematic review determined that rigorous evidence is lacking to inform the dosing, safety, and efficacy of cannabinoids in children with cancer ⁽⁷⁶⁾.