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1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed: 8972919]
2. Abrams DI: Integrating cannabis into clinical cancer care. Curr Oncol 23 (2): S8-S14, 2016. [PMC free article: PMC4791148] [PubMed: 27022315]
3. Brasky TM, Newton AM, Conroy S, et al.: Marijuana and Cannabidiol Use Prevalence and Symptom Management Among Patients with Cancer. Cancer Res Commun 3 (9): 1917-1926, 2023. [PMC free article: PMC10515742] [PubMed: 37772996]
4. Doblin RE, Kleiman MA: Marijuana as antiemetic medicine: a survey of oncologists' experiences and attitudes. J Clin Oncol 9 (7): 1314-9, 1991. [PubMed: 2045870]
5. Ellison GL, Alejandro Salicrup L, Freedman AN, et al.: The National Cancer Institute and Cannabis and Cannabinoids Research. J Natl Cancer Inst Monogr 2021 (58): 35-38, 2021. [PMC free article: PMC8783594] [PubMed: 34850895]
6. Sexton M, Garcia JM, Jatoi A, et al.: The Management of Cancer Symptoms and Treatment-Induced Side Effects With Cannabis or Cannabinoids. J Natl Cancer Inst Monogr 2021 (58): 86-98, 2021. [PMC free article: PMC8848503] [PubMed: 34850897]
7. Cooper ZD, Abrams DI, Gust S, et al.: Challenges for Clinical Cannabis and Cannabinoid Research in the United States. J Natl Cancer Inst Monogr 2021 (58): 114-122, 2021. [PMC free article: PMC8783595] [PubMed: 34850896]
8. Braun IM, Abrams DI, Blansky SE, et al.: Cannabis and the Cancer Patient. J Natl Cancer Inst Monogr 2021 (58): 68-77, 2021. [PubMed: 34850899]
9. Ward SJ, Lichtman AH, Piomelli D, et al.: Cannabinoids and Cancer Chemotherapy-Associated Adverse Effects. J Natl Cancer Inst Monogr 2021 (58): 78-85, 2021. [PMC free article: PMC8848502] [PubMed: 34850893]
10. McAllister SD, Abood ME, Califano J, et al.: Cannabinoid Cancer Biology and Prevention. J Natl Cancer Inst Monogr 2021 (58): 99-106, 2021. [PubMed: 34850900]
11. Abrams DI, Velasco G, Twelves C, et al.: Cancer Treatment: Preclinical & Clinical. J Natl Cancer Inst Monogr 2021 (58): 107-113, 2021. [PubMed: 34850894]

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Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo.[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] Two reviews summarize the molecular mechanisms of action of cannabinoids as antitumor agents.[13,14] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. For example, these compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats, while they protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[9]

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in HCC.[15] Both agents reduced the viability of HCC cells in vitro and demonstrated antitumor effects in HCC subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]

An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic mammary cells.[18] Other studies have also shown the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer.[19,20]

CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[21] In this experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In a subsequent study, the investigators found that the antiproliferative effect of CBD was counteracted by selective CB1 but not CB2 receptor antagonists, suggesting an involvement of CB1 receptors.[22]

Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression in tumor cells has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[23] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[24,25]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[26] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[27-30]

CBD may also enhance uptake of cytotoxic drugs into malignant cells. Activation of transient receptor potential vanilloid type 2 (TRPV2) has been shown to inhibit proliferation of human glioblastoma multiforme cells and overcome resistance to the chemotherapy agent carmustine.[31] One study showed that coadministration of THC and CBD over single-agent usage had greater antiproliferative activity in an in vitro study with multiple human glioblastoma multiforme cell lines.[32] In an in vitro model, CBD increased TRPV2 activation and increased uptake of cytotoxic drugs, leading to apoptosis of glioma cells without affecting normal human astrocytes. This suggests that coadministration of CBD with cytotoxic agents may increase drug uptake and potentiate cell death in human glioma cells. Also, CBD together with THC may enhance the antitumor activity of classic chemotherapeutic drugs such as temozolomide in some mouse models of cancer.[13,33] A meta-analysis of 34 in vitro and in vivo studies of cannabinoids in glioma reported that all but one study confirmed that cannabinoids selectively kill tumor cells.[34]

Antiemetic Effects

Preclinical research suggests that emetic circuitry is tonically controlled by endocannabinoids. The antiemetic action of cannabinoids is believed to be mediated via interaction with the 5-hydroxytryptamine 3 (5-HT3) receptor. CB1 receptors and 5-HT3 receptors are colocalized on gamma-aminobutyric acid (GABA)-ergic neurons, where they have opposite effects on GABA release.[35] There also may be direct inhibition of 5-HT3 gated ion currents through non–CB1 receptor pathways. CB1 receptor antagonists have been shown to elicit emesis in the least shrew that is reversed by cannabinoid agonists.[36] The involvement of CB1 receptor in emesis prevention has been shown by the ability of CB1 antagonists to reverse the effects of THC and other synthetic cannabinoid CB1 agonists in suppressing vomiting caused by cisplatin in the house musk shrew and lithium chloride in the least shrew. In the latter model, CBD was also shown to be efficacious.[37,38]

Appetite Stimulation

Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[39] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[40]

Analgesia

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. Cannabinoids produce analgesia through supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways.[41] The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[42] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[43,44]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[45-47] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[48]

Cannabinoids have been shown to prevent chemotherapy-induced neuropathy in animal models exposed to paclitaxel, vincristine, or cisplatin.[49-51]

Anxiety and Sleep

The endocannabinoid system is believed to be centrally involved in the regulation of mood and the extinction of aversive memories. Animal studies have shown CBD to have anxiolytic properties. It was shown in rats that these anxiolytic properties are mediated through unknown mechanisms.[52] Anxiolytic effects of CBD have been shown in several animal models.[53,54]

The endocannabinoid system has also been shown to play a key role in the modulation of the sleep-waking cycle in rats.[55,56]

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3. National Toxicology Program: NTP toxicology and carcinogenesis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No. 1972-08-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 446: 1-317, 1996. [PubMed: 12594529]
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21. Aviello G, Romano B, Borrelli F, et al.: Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl) 90 (8): 925-34, 2012. [PubMed: 22231745]
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25. McKallip RJ, Nagarkatti M, Nagarkatti PS: Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174 (6): 3281-9, 2005. [PubMed: 15749859]
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32. Marcu JP, Christian RT, Lau D, et al.: Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9 (1): 180-9, 2010. [PMC free article: PMC2806496] [PubMed: 20053780]
33. Torres S, Lorente M, Rodríguez-Fornés F, et al.: A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10 (1): 90-103, 2011. [PubMed: 21220494]
34. Rocha FC, Dos Santos Júnior JG, Stefano SC, et al.: Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol 116 (1): 11-24, 2014. [PubMed: 24142199]
35. Pacher P, Bátkai S, Kunos G: The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58 (3): 389-462, 2006. [PMC free article: PMC2241751] [PubMed: 16968947]
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Cannabis Pharmacology

When oral Cannabis is ingested, there is a low (6%–20%) and variable oral bioavailability.[1,2] Peak plasma concentrations of delta-9-tetrahydrocannabinol (THC) occur after 1 to 6 hours and remain elevated with a terminal half-life of 20 to 30 hours. Taken by mouth, delta-9-THC is initially metabolized in the liver to 11-OH-THC, a potent psychoactive metabolite. Inhaled cannabinoids are rapidly absorbed into the bloodstream with a peak concentration in 2 to 10 minutes, declining rapidly for a period of 30 minutes and with less generation of the psychoactive 11-OH metabolite.

Cannabinoids are known to interact with the hepatic cytochrome P450 enzyme system.[3,4] In one study, 24 cancer patients were treated with intravenous irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal Cannabis taken in the form of an herbal tea for 15 consecutive days, starting 12 days before the second treatment.[4] The administration of Cannabis did not significantly influence exposure to and clearance of irinotecan or docetaxel, although the herbal tea route of administration may not reproduce the effects of inhalation or oral ingestion of fat-soluble cannabinoids.

Highly concentrated THC or cannabidiol (CBD) oil extracts are illegally promoted as potential cancer cures.[5] These oils have not been evaluated in any clinical trials for anticancer activity or safety. Because CBD is a potential inhibitor of certain cytochrome P450 enzymes, highly concentrated CBD oils used concurrently with conventional therapies that are metabolized by these enzymes could potentially increase toxicity or decrease the effectiveness of these therapies.[6,7]

Additionally, multiple reliability and quality concerns have been raised about Cannabis analytical labs, alleging the inflation of cannabinoids content in different Cannabis products. One study showed major inconsistencies in reported THC content because of an insufficient stabilization of sample preparation and testing methods.[8]

Cancer Risk

A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with Cannabis smoking.

A pooled analysis of three case-cohort studies of men in northwestern Africa (430 cases and 778 controls) showed a significantly increased risk of lung cancer among tobacco smokers who also inhaled Cannabis.[9]

A large, retrospective cohort study of 64,855 men aged 15 to 49 years from the United States found that Cannabis use was not associated with tobacco-related cancers and a number of other common malignancies. However, the study did find that, among nonsmokers of tobacco, ever having used Cannabis was associated with an increased risk of prostate cancer.[10]

A population-based case-control study of 611 lung cancer patients revealed that chronic low Cannabis exposure was not associated with an increased risk of lung cancer or other upper aerodigestive tract cancers. The study also found no positive associations with any cancer type (oral, pharyngeal, laryngeal, lung, or esophageal) when adjusting for several confounders, including cigarette smoking.[11]

A systematic review of 19 studies evaluating premalignant or malignant lung lesions in people 18 years or older who inhaled Cannabis concluded that observational studies failed to demonstrate a statistically significant association between Cannabis inhalation and lung cancer after adjusting for tobacco use.[12] In the review of the published meta-analyses, the National Academies of Sciences, Engineering, and Medicine (NASEM) report concluded that there was moderate evidence of no statistical association between Cannabis smoking and the incidence of lung cancer.[13]

Epidemiological studies examining one association of Cannabis use with head and neck squamous cell carcinomas have also been inconsistent in their findings. A pooled analysis of nine case-control studies from the U.S./Latin American International Head and Neck Cancer Epidemiology (INHANCE) Consortium included information from 1,921 oropharyngeal cancer cases, 356 tongue cancer cases, and 7,639 controls. The study found that Cannabis smokers had an elevated risk of oropharyngeal cancers and a reduced risk of tongue cancer compared with those who never smoked Cannabis. These study results both reflect the inconsistent effects of cannabinoids on cancer incidence noted in previous studies and suggest that more research is needed to understand the potential role of human papillomavirus infection.[14] A systematic review and meta-analysis of nine case-control studies involving 13,931 participants also concluded that there was insufficient evidence to demonstrate a positive or negative association between Cannabis smoking and the incidence of head and neck cancers.[15]

Stimulated by the hypothesis that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems, the association between Cannabis use and incidence of testicular germ cell tumors (TGCTs) has been examined.[16-18] Three population-based case-control studies reported an association between Cannabis use and elevated risk of TGCTs, especially nonseminoma or mixed-histology tumors.[16-18] However, the sample sizes in these studies were inadequate to address Cannabis dose by addressing associations among recency, frequency, and duration of use. In a study of 49,343 Swedish men aged 19 to 21 years enrolled in the military between 1969 and 1970, participants were asked at the time of conscription about their use of Cannabis and were followed up for 42 years.[19] This study found no significant correlation between “ever” Cannabis use and the development of testicular cancer, but it did find that “heavy” Cannabis use (more than 50 times in a lifetime) was associated with a 2.5-fold increased risk. Limitations of the study were that it relied on indirect assessment of Cannabis use, and no information was collected on Cannabis use after the conscription-assessment period or on whether the testicular cancers were seminoma or nonseminoma subtypes. These reports established the need for larger, well-powered, prospective studies, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCTs.

An analysis of 84,170 participants in the California Men’s Health Study was performed to investigate the association between Cannabis use and the incidence of bladder cancer. During 16 years of follow-up, 89 Cannabis users (0.3%) developed bladder cancer compared with 190 (0.4%) of the men who did not report Cannabis use (P < .001). After adjusting for age, race, ethnicity, and body mass index, Cannabis use was associated with a 45% reduction in bladder cancer incidence (hazard ratio, 0.55; 95% confidence interval [CI], 0.33–1.00).[20]

A comprehensive Health Canada monograph on marijuana concluded that while there are many cellular and molecular studies that provide strong evidence that inhaled marijuana is carcinogenic, the epidemiological evidence of a link between marijuana use and cancer is still inconclusive.[21]

Patterns of Cannabis Use Among Cancer Patients

A cross-sectional survey of cancer patients seen at the Seattle Cancer Care Alliance was conducted over a 6-week period between 2015 and 2016.[22] In Washington State, Cannabis was legalized for medicinal use in 1998 and for recreational use in 2012. Of the 2,737 possible participants, 936 (34%) completed the anonymous questionnaire. Twenty-four percent of patients considered themselves active Cannabis users. Similar numbers of patients inhaled (70%) or used edibles (70%), with dual use (40%) being common. Non–mutually exclusive reasons for Cannabis use were physical symptoms (75%), neuropsychiatric symptoms (63%), recreational use/enjoyment (35%), and treatment of cancer (26%). The physical symptoms most commonly cited were pain, nausea, and loss of appetite. Most patients (74%) stated that they would prefer to obtain information about Cannabis from their cancer team, but less than 15% reported receiving information from their cancer physician or nurse.

Data from 2,970 Israeli cancer patients who used government-issued Cannabis were collected over a 6-month period to assess for improvement in baseline symptoms.[23] The most improved symptoms from baseline include the following:

• Nausea and vomiting (91.0%).
• Sleep disorders (87.5%).
• Restlessness (87.5%).
• Anxiety and depression (84.2%).
• Pruritus (82.1%).
• Headaches (81.4%).

Before treatment initiation, 52.9% of patients reported pain scores in the 8 to 10 range, while only 4.6% of patients reported this intensity at the 6-month assessment time point. It is difficult to assess from the observational data if the improvements were caused by the Cannabis or the cancer treatment.[23] Similarly, a study of a subset of cancer patients in the Minnesota medical Cannabis program explored changes in the severity of eight symptoms (i.e., anxiety, appetite loss, depression, disturbed sleep, fatigue, nausea, pain, and vomiting) experienced by these patients.[24]. Significant symptomatic improvements were noted (38.4%–56.2%) in patients with each symptom. Because of the observational and uncontrolled nature of this study, the findings are not generalizable, but as the authors suggested, may be useful in designing more rigorous research studies in the future.

Forty-two percent of women (257 of 612) with a diagnosis of breast cancer within the past 5 years who participated in an anonymous online survey reported using Cannabis for the relief of symptoms, particularly pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea and vomiting (46%).[25] Among Cannabis users, 79% used Cannabis during their cancer treatment, and 75% reported that Cannabis was extremely or very helpful for relieving symptoms. Forty-nine percent of Cannabis users felt that Cannabis could be useful in treating the cancer itself. Only 39% of the participants reported discussing Cannabis use with their physicians.

Cancer patients turn to medical Cannabis use even in states where it has not been legalized. Researchers from the Medical University of South Carolina conducted a survey study that explored the prevalence, patterns, and motivations behind Cannabis use among cancer patients and survivors in a state without legal access to Cannabis as of 2023.[26] Despite the absence of legal access, a significant proportion of participants reported using Cannabis for symptom management including pain, nausea, and other symptoms. Moreover, participants reported improvements in mood, sleep, and overall better quality of life. This study gives insight into why many cancer patients and survivors use Cannabis for symptom management, highlighting the importance of understanding and addressing patient' needs even in states with no legal access to Cannabis.

Cancer Treatment

No ongoing clinical trials of Cannabis as a treatment for cancer in humans were identified in a PubMed search. The first published trial of any cannabinoid in patients with cancer was a small pilot study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme, which demonstrated no significant clinical benefit.[27,28] A small double-blind exploratory phase IB study, conducted in the United Kingdom, used nabiximols, a 1:1 ratio of THC:CBD in a Cannabis-based medicinal extract oromucosal spray, in conjunction with dose-dense temozolomide in treating patients with recurrent glioblastoma multiforme.[29][Level of evidence: 1iA] Of the 27 patients enrolled, 6 were part of an open-label group and 21 were part of a randomized group (12 treated with nabiximols and 9 treated with placebo). Progression-free survival at 6 months was seen in 33% of patients in both arms of the study. However, at 1 year, 83.3% of the patients who received nabiximols were alive compared with 44.4% of those who received placebo (P = .042). The investigators cautioned that this early-phase study was not powered for a survival endpoint. Overall survival rates at 2 years continued to favor the nabiximols arm (50%) compared with the placebo arm (22%) (these rates included results for the 6 patients in the open-label group who received nabiximols).[29]

In a 2016 consecutive case series study, nine patients with varying stages of brain tumors, including six with glioblastoma multiforme, received CBD 200 mg twice daily in addition to surgical excision and chemoradiation.[30][Level of evidence: 3iiiA] The authors reported that all but one of the cohort remained alive at the time of publication. However, the heterogeneity of the brain tumor patients probably contributed to the findings.

Another Israeli group postulated that the anti-inflammatory and immunosuppressive effects of CBD might make it a valuable adjunct in the treatment of acute graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation. The authors investigated CBD 300 mg/d in addition to standard GVHD prophylaxis in 48 adult patients who had undergone a transplant, predominantly for acute leukemia or myelodysplastic syndrome (NCT01385124 and NCT01596075).[31] The combination of CBD with standard GVHD prophylaxis was found to be safe. Compared with 101 historical controls treated with standard prophylaxis, patients who received CBD appeared to have a lower incidence of grade II to grade IV GVHD, suggesting that a randomized controlled trial (RCT) is warranted.

Clinical data regarding Cannabis as an anticancer agent in pediatric use is limited to a few case reports.[32,33]

Antiemetic Effect

Appetite Stimulation

Patients with cancer may experience anorexia, early satiety, weight loss, and cachexia. Such patients face not only the disfigurement associated with wasting but also cannot engage in the social interaction of meals.

Analgesia

Anxiety and Sleep

Symptom Management With Cannabidiol

A randomized, double-blind, placebo-controlled trial (n = 144) assessed the impact of oral cannabidiol oil (50–200 mg three times a day) on the total symptom distress score (TSDS), a measure of overall cancer symptom burden.[76] All patients received baseline care from palliative care specialists. No significant difference was found in the median TSDS between the two arms at the two assessment points (day 14 and day 28). This study had several limitations, including heterogeneity of the patient population, low symptom burden of patients at baseline, and a high level of patient withdrawals from both study arms.

Pediatric Population and Cannabis and Cannabinoid Medicinal Use

A growing number of pediatric patients are seeking symptom relief with Cannabis or cannabinoid treatment, although studies are limited.[77] The American Academy of Pediatrics has not endorsed Cannabis and cannabinoid use because of concerns about brain development.

A retrospective study from Israel of 50 pediatric oncology patients who were prescribed medicinal Cannabis over an 8-year period reported that the most common indications included the following:[78]

• Nausea and vomiting.
• Depressed mood.
• Sleep disturbances.
• Poor appetite and weight loss.
• Pain.

Most of the patients (n = 30) received Cannabis in the form of oral oil drops, with some of the older children inhaling vaporized Cannabis or combining inhalation with oral oils. Structured interviews with the parents, and their child when appropriate, revealed that 40 participants (80%) reported a high level of general satisfaction with the use of Cannabis with infrequent short-term side effects.[78] Survey studies revealed that most responding pediatricians in the United States and Canada supported the use of medical Cannabis for symptom management in pediatric patients with cancer.[79,80]

Clinical Studies of Cannabis and Cannabinoids

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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79. Oberoi S, Protudjer JLP, Rapoport A, et al.: Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer. Cancer Rep (Hoboken) 5 (9): e1551, 2022. [PMC free article: PMC9458513] [PubMed: 34672127]
80. Ananth P, Ma C, Al-Sayegh H, et al.: Provider Perspectives on Use of Medical Marijuana in Children With Cancer. Pediatrics 141 (1): , 2018. [PMC free article: PMC5744275] [PubMed: 29233937]
81. Beal JE, Olson R, Laubenstein L, et al.: Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10 (2): 89-97, 1995. [PubMed: 7730690]

Cannabis and Cannabinoids

Because cannabinoid receptors, unlike opioid receptors, are not located in the brainstem areas controlling respiration, lethal overdoses from Cannabis and cannabinoids do not occur.[1-4] However, cannabinoid receptors are present in other tissues throughout the body, not just in the central nervous system, and adverse effects include the following:

• Tachycardia.
• Hypotension.
• Conjunctival injection.
• Bronchodilation.
• Muscle relaxation.
• Decreased gastrointestinal motility.

Although cannabinoids are considered by some to be addictive drugs, their addictive potential is considerably lower than that of other prescribed agents or substances of abuse.[2,4] The brain develops a tolerance to cannabinoids.

Withdrawal symptoms such as irritability, insomnia with sleep electroencephalogram disturbance, restlessness, hot flashes, and, rarely, nausea and cramping have been observed. However, these symptoms appear to be mild compared with withdrawal symptoms associated with opiates or benzodiazepines, and the symptoms usually dissipate after a few days.

Unlike other commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate (half-life 1–3 days), so even abrupt cessation of cannabinoid intake is not associated with rapid declines in plasma concentrations that would precipitate severe or abrupt withdrawal symptoms or drug cravings.

Cannabidiol (CBD) is an inhibitor of cytochrome P450 isoforms in vitro. Because many anticancer therapies are metabolized by these enzymes, highly concentrated CBD oils used concurrently could potentially increase the toxicity or decrease the effectiveness of these therapies.[5-7]

Since Cannabis smoke contains many of the same components as tobacco smoke, there are valid concerns about the adverse pulmonary effects of inhaled Cannabis. A longitudinal study in a noncancer population evaluated repeated measurements of pulmonary function over 20 years in 5,115 men and women whose smoking histories were known.[8] While tobacco exposure was associated with decreased pulmonary function, the investigators concluded that occasional and low-cumulative Cannabis use was not associated with adverse effects on pulmonary function (forced expiratory volume in the first second of expiration [FEV1] and forced vital capacity [FVC]).

Interactions With Conventional Cancer Therapies

The potential for cytochrome P450 interactions with highly concentrated oil preparations of delta-9-tetrahydrocannabinol and/or cannabidiol is a concern.[9] Few pharmacokinetic interaction studies have been conducted with Cannabis or cannabinoids and conventional cancer therapies. There is insufficient clinical evidence and concern to support the belief that relatively small amounts of active cannabinoids can substantially impact metabolism of relatively large doses of chemotherapy drugs.

An Israeli retrospective observational study assessed the impact of Cannabis use during nivolumab immunotherapy.[10] One hundred forty patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma received the checkpoint inhibitor nivolumab (89 patients received nivolumab alone and 51 patients received nivolumab plus Cannabis). In a multivariate model, Cannabis was the only significant factor that reduced the response rate to immunotherapy (37.5% in patients who received nivolumab alone compared with 15.9% in patients who received nivolumab plus Cannabis [odds ratio, 3.13; 95% confidence interval, 1.24–8.1; P = .016]). There was no difference in progression-free survival or overall survival. A subsequent prospective observational study from the same investigators followed 102 patients with metastatic cancers initiating immunotherapy.[11][Level of evidence: 2Dii] Sixty-eight patients received immunotherapy alone while 34 patients used Cannabis during immunotherapy. Over half of the patients in each group had stage IV non-small cell lung cancer. Cannabis users were less likely to receive immunotherapy as a first-line intervention (24%) compared with nonusers (46%) (P = .03). Cannabis users showed a significantly lower percentage of clinical benefit (39% of Cannabis users with complete or partial responses or stable disease compared with 59% of nonusers [P = .035]). In this analysis, the median time to tumor progression was 3.4 months in Cannabis users compared with 13.1 months in nonusers and the overall survival was 6.4 months in Cannabis users compared with 28.5 months in nonusers. The investigators also noted that Cannabis users reported a lower rate of overall treatment-related adverse experiences compared with nonusers, with fewer immune-related adverse events (P = .057). The investigators postulated that this finding may be related to the possible immunosuppressive effects of Cannabis and concluded that Cannabis consumption should be carefully considered in patients with advanced malignancies who are treated with immunotherapy. Limitations noted by the authors that may be confounders in this analysis include the observational nature of the study, the relatively small sample size, and the high heterogeneity of the participants.

References

1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed: 8972919]
2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. The Haworth Press, 2002.
3. Sutton IR, Daeninck P: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec. [PubMed: 17136871]
4. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PubMed: 14570037]
5. Yamaori S, Okamoto Y, Yamamoto I, et al.: Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39 (11): 2049-56, 2011. [PubMed: 21821735]
6. Jiang R, Yamaori S, Okamoto Y, et al.: Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28 (4): 332-8, 2013. [PubMed: 23318708]
7. Guedon M, Le Bozec A, Brugel M, et al.: Cannabidiol-drug interaction in cancer patients: A retrospective study in a real-life setting. Br J Clin Pharmacol 89 (7): 2322-2328, 2023. [PubMed: 36849134]
8. Pletcher MJ, Vittinghoff E, Kalhan R, et al.: Association between marijuana exposure and pulmonary function over 20 years. JAMA 307 (2): 173-81, 2012. [PMC free article: PMC3840897] [PubMed: 22235088]
9. Kocis PT, Vrana KE: Delta-9-tetrahydrocannabinol and cannabidiol drug-drug interactions. Med Cannabis Cannabinoids 3 (1): 61-73, 2020. [PMC free article: PMC8489344] [PubMed: 34676340]
10. Taha T, Meiri D, Talhamy S, et al.: Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies. Oncologist 24 (4): 549-554, 2019. [PMC free article: PMC6459234] [PubMed: 30670598]
11. Bar-Sela G, Cohen I, Campisi-Pinto S, et al.: Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers (Basel) 12 (9): , 2020. [PMC free article: PMC7563978] [PubMed: 32872248]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Cannabis and cannabinoids in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cannabis and Cannabinoids. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389198]

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