Cannabis and Cannabinoids (PDQ®) Health Professional Version

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“This complementary and alternative medicine (CAM) information summary provides an overview of the use of Cannabis and its components as a treatment for people with cancer-related symptoms caused by the disease itself or its treatment.

This summary contains the following key information:

  • Cannabis has been used for medicinal purposes for thousands of years.
  • By federal law, the possession of Cannabis, also known as marijuana, is illegal in the United States; however, a growing number of states and the District of Columbia have enacted laws to legalize its medical use.
  • The U.S. Food and Drug Administration has not approved Cannabis as a treatment for cancer or any other medical condition.
  • Chemical components of Cannabis, called cannabinoids, activate specific receptors found throughout the body to produce pharmacologic effects, particularly in the central nervous system and the immune system.
  • Commercially available cannabinoids, such as dronabinol and nabilone, are approved drugs for the treatment of cancer-related side effects.
  • Cannabinoids may have benefits in the treatment of cancer-related side effects.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ CAM information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

General Information

Cannabis, also known as marijuana, originated in Central Asia but is grown worldwide today. In the United States, it is a controlled substance and is classified as a Schedule I agent (a drug with increased potential for abuse and no known medical use). TheCannabis plant produces a resin containing psychoactive compounds called cannabinoids. The highest concentration of cannabinoids is found in the female flowers of the plant.[1] Clinical trials conducted on medicinal Cannabis are limited. The U.S. Food and Drug Administration (FDA) has not approved the use of Cannabis as a treatment for any medical condition. To conductclinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA.

The potential benefits of medicinal Cannabis for people living with cancer include antiemetic effects, appetite stimulation, pain relief, and improved sleep. Although few relevant surveys of practice patterns exist, it appears that physicians caring for cancer patients in the United States who recommend medicinal Cannabis predominantly do so for symptom management.[2] A growing number of pediatric patients are seeking symptom relief with Cannabis or cannabinoid treatment, although studies are limited.

Cannabinoids are a group of terpenophenolic compounds found in Cannabis species (e.g., Cannabis sativa L.). This summary will review the role of Cannabis and the cannabinoids in the treatment of people with cancer and disease-related or treatment-relatedside effects.

References

  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed]
  2. Doblin RE, Kleiman MA: Marijuana as antiemetic medicine: a survey of oncologists’ experiences and attitudes. J Clin Oncol 9 (7): 1314-9, 1991. [PubMed]

History

Cannabis use for medicinal purposes dates back at least 3,000 years.[1–5] It was introduced into Western medicine in the 1840s by W.B. O’Shaughnessy, a surgeon who learned of its medicinal properties while working in India for the British East Indies Company. Its use was promoted for reported analgesic, sedative, anti-inflammatory, antispasmodic, and anticonvulsant effects.

In 1937, the U.S. Treasury Department introduced the Marihuana Tax Act. This Act imposed a levy of $1 per ounce for medicinal use of Cannabis and $100 per ounce for recreational use. Physicians in the United States were the principal opponents of the Act. The American Medical Association (AMA) opposed the Act because physicians were required to pay a special tax for prescribingCannabis, use special order forms to procure it, and keep special records concerning its professional use. In addition, the AMA believed that objective evidence that Cannabis was harmful was lacking and that passage of the Act would impede further research into its medicinal worth.[6] In 1942, Cannabis was removed from the U.S. Pharmacopoeia because of persistent concerns about its potential to cause harm.[2,3]

In 1951, Congress passed the Boggs Act, which for the first time, included Cannabis with narcotic drugs. In 1970, with the passage of the Controlled Substances Act, marijuana was classified as a Schedule I drug. Drugs in this category are distinguished as having no accepted medicinal use. Other Schedule I substances include heroin, LSD, mescaline, and methaqualone.

Despite its designation as having no medicinal use, Cannabis was distributed to patients by the U.S. government on a case-by-case basis under the Compassionate Use Investigational New Drug program established in 1978. Distribution of Cannabis through this program was discontinued in 1992.[1–4] Although federal law prohibits the use of Cannabis, figure 1 below shows the states and territories that permit its use for certain medical conditions.

Figure 1

Figure

Figure 1. Cannabis map.

The main psychoactive constituent of Cannabis was identified as delta-9-tetrahydrocannabinol (THC). In 1986, synthetic delta-9-THC in sesame oil was licensed and approved for the treatment of chemotherapy-associated nausea and vomiting under the genericname dronabinol. Clinical trials determined that dronabinol was as effective as or better than other antiemetic agents available at the time.[7] Dronabinol was also studied for its ability to stimulate weight gain in patients with AIDS in the late 1980s. Thus, the indications were expanded to include treatment of anorexia associated with human immunodeficiency virus infection in 1992.Clinical trial results showed no statistically significant weight gain, although patients reported an improvement in appetite.[8,9]

Within the past 20 years, the neurobiology of cannabinoids has been analyzed.[10–13] The first cannabinoid receptor, CB1, was identified in the brain in 1988. A second cannabinoid receptor, CB2, was identified in 1993. The highest expression of CB2receptors is located on B lymphocytes and natural killer cells, suggesting a possible role in immunity. Endogenous cannabinoids (endocannabinoids) have been identified and appear to have a role in, for example, pain modulation, control of movement, feeding behavior, and memory.[11]

Nabiximols, a THC:cannabidiol extract, is approved in Canada (under the Notice of Compliance with Conditions) for symptomatic relief of pain in advanced cancer and multiple sclerosis.[14] Canada, New Zealand, and some countries in Europe also approve nabiximols for spasticity of multiple sclerosis, a common symptom that may include muscle stiffness, reduced mobility, and pain, and for which existing therapy is unsatisfactory.

References

  1. Abel EL: Marihuana, The First Twelve Thousand Years. New York: Plenum Press, 1980. Also available online. Last accessed July 16, 2015.
  2. Joy JE, Watson SJ, Benson JA, eds.: Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press, 1999. Also available online. Last accessed July 16, 2015.
  3. Mack A, Joy J: Marijuana As Medicine? The Science Beyond the Controversy. Washington, DC: National Academy Press, 2001. Also available online. Last accessed July 16, 2015.
  4. Booth M: Cannabis: A History. New York, NY: St Martin’s Press, 2003.
  5. Russo EB, Jiang HE, Li X, et al.: Phytochemical and genetic analyses of ancient cannabis from Central Asia. J Exp Bot 59 (15): 4171-82, 2008. [PMC free article] [PubMed]
  6. Schaffer Library of Drug Policy: The Marihuana Tax Act of 1937: Taxation of Marihuana. Washington, DC: House of Representatives, Committee on Ways and Means, 1937. Available online. Last accessed July 16, 2015.
  7. Sallan SE, Zinberg NE, Frei E 3rd: Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293 (16): 795-7, 1975. [PubMed]
  8. Gorter R, Seefried M, Volberding P: Dronabinol effects on weight in patients with HIV infection. AIDS 6 (1): 127, 1992. [PubMed]
  9. 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]
  10. Devane WA, Dysarz FA 3rd, Johnson MR, et al.: Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34 (5): 605-13, 1988. [PubMed]
  11. Devane WA, Hanus L, Breuer A, et al.: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258 (5090): 1946-9, 1992. [PubMed]
  12. Pertwee RG, Howlett AC, Abood ME, et al.: International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev 62 (4): 588-631, 2010. [PMC free article] [PubMed]
  13. Felder CC, Glass M: Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol 38: 179-200, 1998. [PubMed]
  14. Howard P, Twycross R, Shuster J, et al.: Cannabinoids. J Pain Symptom Manage 46 (1): 142-9, 2013. [PubMed]

Laboratory/Animal/Preclinical Studies

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis species (e.g.,Cannabis sativa L.) .[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to havesignificant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types oftumors.[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 lungadenocarcinoma 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 inglioma 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 theviability 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 innon-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 andestrogen 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 experimentalsystem, 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 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 ofcolorectal cancer has been developed.[27–30]

CBD may also enhance uptake of cytotoxic drugs into malignant cells. Activation of the transient receptor potential vanilloid type 2 (TRPV2) has been shown to inhibit proliferation of human glioblastoma multiforme cells and overcome resistance to thechemotherapy agent carmustine.[31] 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.[13,32]

Appetite Stimulation

Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetiteand 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.[33] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[34]

Analgesia

Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. 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 brainthat regulate nociceptive processing.[35] 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 endogenouscannabinoids in the modulation of pain has been obtained.[36,37]

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.[38–40] 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.[41]

References

  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed]
  2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press, 2002.
  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]
  4. Bifulco M, Laezza C, Pisanti S, et al.: Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148 (2): 123-35, 2006. [PMC free article] [PubMed]
  5. Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al.: Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61 (15): 5784-9, 2001. [PubMed]
  6. McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100 (2): 627-34, 2002. [PubMed]
  7. Casanova ML, Blázquez C, Martínez-Palacio J, et al.: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111 (1): 43-50, 2003. [PMC free article] [PubMed]
  8. Blázquez C, González-Feria L, Alvarez L, et al.: Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64 (16): 5617-23, 2004. [PubMed]
  9. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PubMed]
  10. Blázquez C, Casanova ML, Planas A, et al.: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17 (3): 529-31, 2003. [PubMed]
  11. Vaccani A, Massi P, Colombo A, et al.: Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144 (8): 1032-6, 2005. [PMC free article] [PubMed]
  12. Ramer R, Bublitz K, Freimuth N, et al.: Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J 26 (4): 1535-48, 2012. [PubMed]
  13. Velasco G, Sánchez C, Guzmán M: Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12 (6): 436-44, 2012. [PubMed]
  14. Cridge BJ, Rosengren RJ: Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag Res 5: 301-13, 2013. [PMC free article] [PubMed]
  15. Vara D, Salazar M, Olea-Herrero N, et al.: Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18 (7): 1099-111, 2011. [PMC free article] [PubMed]
  16. Preet A, Qamri Z, Nasser MW, et al.: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4 (1): 65-75, 2011. [PMC free article] [PubMed]
  17. Nasser MW, Qamri Z, Deol YS, et al.: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6 (9): e23901, 2011. [PMC free article] [PubMed]
  18. Shrivastava A, Kuzontkoski PM, Groopman JE, et al.: Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 10 (7): 1161-72, 2011. [PubMed]
  19. Caffarel MM, Andradas C, Mira E, et al.: Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer 9: 196, 2010. [PMC free article] [PubMed]
  20. McAllister SD, Murase R, Christian RT, et al.: Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129 (1): 37-47, 2011. [PMC free article] [PubMed]
  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]
  22. Romano B, Borrelli F, Pagano E, et al.: Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine 21 (5): 631-9, 2014. [PubMed]
  23. Preet A, Ganju RK, Groopman JE: Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27 (3): 339-46, 2008. [PubMed]
  24. Zhu LX, Sharma S, Stolina M, et al.: Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165 (1): 373-80, 2000. [PubMed]
  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]
  26. Massa F, Marsicano G, Hermann H, et al.: The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113 (8): 1202-9, 2004. [PMC free article] [PubMed]
  27. Patsos HA, Hicks DJ, Greenhough A, et al.: Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem Soc Trans 33 (Pt 4): 712-4, 2005. [PubMed]
  28. Liu WM, Fowler DW, Dalgleish AG: Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5 (4): 281-7, 2010. [PubMed]
  29. Malfitano AM, Ciaglia E, Gangemi G, et al.: Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15 (3): 297-308, 2011. [PubMed]
  30. Sarfaraz S, Adhami VM, Syed DN, et al.: Cannabinoids for cancer treatment: progress and promise. Cancer Res 68 (2): 339-42, 2008. [PubMed]
  31. Nabissi M, Morelli MB, Santoni M, et al.: Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34 (1): 48-57, 2013. [PubMed]
  32. 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]
  33. Mechoulam R, Berry EM, Avraham Y, et al.: Endocannabinoids, feeding and suckling–from our perspective. Int J Obes (Lond) 30 (Suppl 1): S24-8, 2006. [PubMed]
  34. Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PubMed]
  35. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PubMed]
  36. Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PubMed]
  37. Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PMC free article] [PubMed]
  38. Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PMC free article] [PubMed]
  39. Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PMC free article] [PubMed]
  40. Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PubMed]
  41. Khasabova IA, Gielissen J, Chandiramani A, et al.: CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22 (5-6): 607-16, 2011. [PMC free article] [PubMed]

Human/Clinical Studies

Cannabis Pharmacology

When Cannabis is ingested by mouth, 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. When 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 drugsconcomitant with medicinal Cannabis taken in the form of an herbal tea for 15 consecutive days, starting 12 days before the secondtreatment.[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–solublecannabinoids.

Cancer Risk

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

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.[5]

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.[6]

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 and found no positive associations with any cancer type (oral, pharyngeal, laryngeal, lung, or esophagus) when adjusting for several confounders, including cigarette smoking.[7]

A systematic review assessing 19 studies that evaluated premalignant or malignant lung lesions in persons 18 years or older who inhaled marijuana concluded that observational studies failed to demonstrate statistically significant associations between marijuana inhalation and lung cancer after adjusting for tobacco use.[8]

Epidemiologic 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 cases, 356 tongue cases, and 7,639 controls. Compared with those who never smoked Cannabis, Cannabis smokers had an elevated risk of oropharyngeal cancers and a reduced risk of tongue cancer. These study results both reflect the inconsistent effects of cannabinoids on cancerincidence noted in previous studies and suggest that more work needs to be done to understand the potential role of human papillomavirus infection.[9]

With a hypothesis that chronic marijuana use produces adverse effects on the human endocrine and reproductive systems, the association between marijuana use and incidence of testicular germ cell tumors (TGCTs) has been examined.[10–12] Three population-based case-control studies report an association between marijuana use and elevated risk of TGCTs, especiallynonseminoma or mixed-histology tumors.[10–12] However, the sample sizes in these studies were inadequate to address marijuanadose by addressing associations with respect to recency, frequency, and duration of use. These early reports of marijuana use and TGCTs establish 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 betweenCannabis 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, 0.33–1.00).[13]

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 epidemiologic evidence of a link between marijuana use andcancer is still inconclusive.[14]

Cancer Treatment

No clinical trials of Cannabis as a treatment for cancer in humans were identified in a PubMed search; however, a single, small study of intratumoral injection of delta-9-THC in patients with recurrent glioblastoma multiforme reported potential antitumoral activity.[15,16]

Antiemetic Effect

Cannabinoids

Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting (N/V) remain distressing side effectsfor cancer patients and their families. Dronabinol, a synthetically produced delta-9-THC, was approved in the United States in 1986 as an antiemetic to be used in cancer chemotherapy. Nabilone, a synthetic derivative of delta-9-THC, was first approved in Canada in 1982 and is now also available in the United States.[17] Both dronabinol and nabilone have been approved by the U.S. Food and Drug Administration for the treatment of N/V associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic therapy. Numerous clinical trials and meta-analyses have shown that dronabinol and nabilone are effective in the treatment of N/V induced by chemotherapy.[18–21] The National Comprehensive Cancer Network Guidelines recommend cannabinoids as breakthrough treatment for chemotherapy-related N/V.

One systematic review studied 30 randomized comparisons of delta-9-THC preparations with placebo or other antiemetics from which data on efficacy and harm were available.[22] Oral nabilone, oral dronabinol, and intramuscular levonantradol (a syntheticanalog of dronabinol) were tested. Inhaled Cannabis trials were not included. Among all 1,366 patients included in the review, cannabinoids were found to be more effective than the conventional antiemetics prochlorperazine, metoclopramide, chlorpromazine,thiethylperazine, haloperidol, domperidone, and alizapride. Cannabinoids, however, were not more effective for patients receiving very low or very high emetogenic chemotherapy. Side effects included a feeling of being high, euphoria, sedation or drowsiness, dizziness, dysphoria or depression, hallucinations, paranoia, and hypotension.[22] Newer antiemetics (e.g., 5-HT3 receptorantagonists) have not been directly compared with Cannabis or cannabinoids in cancer patients.

Another analysis of 15 controlled studies compared nabilone with placebo or available antiemetic drugs.[23] Among 600 cancerpatients, nabilone was found to be superior to prochlorperazine, domperidone, and alizapride, with nabilone favored for continuous use.

(Refer to the Cannabis section in the PDQ summary on Nausea and Vomiting for more information.)

Cannabis

Three trials have evaluated the efficacy of inhaled marijuana in chemotherapy-induced N/V.[24–26] In two of the studies, inhaledCannabis was made available only after dronabinol failure. In the first trial, no antiemetic effect was achieved with marijuana in patients receiving cyclophosphamide or doxorubicin,[24] but in the second trial, a statistically significant superior antiemetic effect of inhaled Cannabis versus placebo was found among patients receiving high-dose methotrexate.[25] The third trial was a randomized, double-blind, placebo-controlled, cross-over trial involving 20 adults in which both inhaled marijuana and oral THC were evaluated. One-quarter of the patients reported a favorable antiemetic response to the cannabinoid therapies. This latter study was reported in abstract form in 1984. A full report, detailing the methods and outcomes apparently has not been published, which limits a thorough interpretation of the significance of these findings.[26]

Appetite Stimulation

Anorexia, early satiety, weight loss, and cachexia are problems experienced by cancer patients. Such patients are faced not only with the disfigurement associated with wasting but also with an inability to engage in the social interaction of meals.

Cannabinoids

Three controlled trials demonstrated that oral THC has variable effects on appetite stimulation and weight loss in patients with advanced malignancies and human immunodeficiency virus (HIV) infection.[23] One study evaluated whether dronabinol alone or with megestrol acetate was greater, less, or equal in efficacy to megestrol acetate alone for managing cancer-associated anorexia.[27] In this randomized, double-blind study of 469 adults with advanced cancer and weight loss, patients received 2.5 mg of oral THC twice daily, 800 mg of oral megestrol daily, or both. Appetite increased by 75% in the megestrol group and weight increased by 11%, compared with a 49% increase in appetite and a 3% increase in weight in the oral THC group after 8 to 11 weeks oftreatment. These two differences were statistically significant. Furthermore, the combined therapy did not offer additional benefits beyond those provided by megestrol acetate alone. The authors concluded that dronabinol did little to promote appetite or weight gain in advanced cancer patients compared with megestrol acetate. However, a smaller, placebo-controlled trial of dronabinol in cancer patients demonstrated improved and enhanced chemosensory perception in the cannabinoid group—food tasted better, appetite increased, and the proportion of calories consumed as protein was greater than in the placebo recipients.[28]

In a randomized clinical trial, researchers compared the safety and effectiveness of orally administered Cannabis extract (2.5 mg THC and 1 mg cannabidinol), THC (2.5 mg), or placebo for the treatment of cancer-related anorexia-cachexia in 243 patients with advanced cancer who received treatment twice daily for 6 weeks. Results demonstrated that although these agents were well tolerated by these patients, no differences were observed in patient appetite or quality of life among the three groups at this dose level and duration of intervention.[29]

Another clinical trial that involved 139 patients with HIV or AIDS and weight loss found that, compared with placebo, oral dronabinolwas associated with a statistically significant increase in appetite after 4 to 6 weeks of treatment. Patients receiving dronabinol tended to have weight stabilization, whereas patients receiving placebo continued to lose weight.[30]

Cannabis

In trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase in caloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods.[31,32] No published studies have explored the effect of inhaled Cannabis on appetite in cancer patients.

Analgesia

Cannabinoids

Pain management improves a patient’s quality of life throughout all stages of cancer. Through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists, the mechanisms of cannabinoid-induced analgesia have been analyzed. The CB1 receptor is found in the central nervous system (CNS) and in peripheral nerve terminals.[33] CB2 receptors are located mainly in peripheral tissue and are expressed in only low amounts in the CNS. Whereas only CB1 agonists exert analgesicactivity in the CNS, both CB1 and CB2 agonists have analgesic activity in peripheral tissue.[34,35]

Cancer pain results from inflammation, invasion of bone or other pain-sensitive structures, or nerve injury. When cancer pain is severe and persistent, it is often resistant to treatment with opioids.

Two studies examined the effects of oral delta-9-THC on cancer pain. The first, a double-blind placebo-controlled study involving ten patients, measured both pain intensity and pain relief.[36] It was reported that 15 mg and 20 mg doses of the cannabinoid delta-9-THC were associated with substantial analgesic effects, with antiemetic effects and appetite stimulation.

In a follow-up, single-dose study involving 36 patients, it was reported that 10 mg doses of delta-9-THC produced analgesic effects during a 7-hour observation period that were comparable to 60 mg doses of codeine, and 20 mg doses of delta-9-THC induced effects equivalent to 120 mg doses of codeine.[37] Higher doses of THC were found to be more sedative than codeine.

Another study examined the effects of a whole-plant extract with controlled cannabinoid content in an oromucosal spray. In a multicenter, double-blind, placebo-controlled study, the THC:cannabidiol nabiximols (THC:CBD) extract and THC extract alone were compared in the analgesic management of patients with advanced cancer and with moderate-to-severe cancer-related pain. Patients were assigned to one of three treatment groups: THC:CBD extract, THC extract, or placebo. The researchers concluded that the THC:CBD extract was efficacious for pain relief in advanced cancer patients whose pain was not fully relieved by strong opioids.[38] In a randomized, placebo-controlled, graded-dose trial, opioid-treated cancer patients with poorly controlled chronic pain demonstrated significantly better control of pain and sleep disruption with THC:CBD oromucosal spray at lower doses (1–4 and 6–10 sprays/day), compared with placebo. Adverse events were dose related, with only the high-dose group (11–16 sprays/day) comparing unfavorably with the placebo arm. These studies provide promising evidence of an “adjuvant analgesic” effect of THC:CBD in this opioid-refractory patient population and may provide an opportunity to address this significant clinical challenge.[39] An open-label extension study of 43 patients who had participated in the randomized trial found that some patients continued to obtain relief of their cancer-related pain with long-term use of the THC:CBD oromucosal spray without increasing their dose of the spray or the dose of their other analgesics.[40]

A randomized, placebo-controlled, crossover pilot study of nabiximols in 16 patients with chemotherapy-induced neuropathic pain showed no significant difference between the treatment and placebo groups. A responder analysis, however, demonstrated that five patients reported a reduction in their pain of at least 2 points, suggesting that a larger follow-up study may be warranted.[41]

An observational study assessed the effectiveness of nabilone in advanced cancer patients who were experiencing pain and othersymptoms (anorexia, depression, and anxiety). The researchers reported that patients who used nabilone experienced improved management of pain, nausea, anxiety, and distress when compared with untreated patients. Nabilone was also associated with a decreased use of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, gabapentin, dexamethasone,metoclopramide, and ondansetron.[42]

Cannabis

Animal studies have suggested a synergistic analgesic effect when cannabinoids are combined with opioids. The results from one pharmacokinetic interaction study have been reported. In this study, 21 patients with chronic pain were administered vaporizedCannabis along with sustained-release morphine or oxycodone for 5 days.[43] The patients who received vaporized Cannabis and sustained-release morphine had a statistically significant decrease in their mean pain score over the 5-day period; those who received vaporized Cannabis and oxycodone did not. These findings should be verified by further studies before recommendations favoring such an approach are warranted in general clinical practice.

Neuropathic pain is a symptom cancer patients may experience, especially if treated with platinum-based chemotherapy ortaxanes. To date, no clinical trial has examined the effectiveness of cannabinoid preparations in the treatment of chemotherapy-induced neuropathic pain.

Two randomized controlled trials of inhaled Cannabis in patients with peripheral neuropathy or neuropathic pain of various etiologies found that pain was reduced in patients who received inhaled Cannabis, compared with those who received placebo.[44,45] Two additional trials of inhaled Cannabis have also demonstrated the benefit of Cannabis over placebo in HIV-associated neuropathic pain.[46,47]

Anxiety and Sleep

Cannabis

Patients often experience mood elevation after exposure to Cannabis, depending on their prior experience. In a five-patient case series of inhaled marijuana that examined the analgesic effects of THC, it was reported that patients administered THC had improved mood, improved sense of well-being, and less anxiety.[48]

Another common effect of Cannabis is sleepiness. In a trial of a sublingual spray, a Cannabis-based mixture was able to improvesleep quality.[49] A small placebo-controlled study of dronabinol in cancer patients with altered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[28]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for cancer CAM clinical trials on dronabinol, marijuana, nabiximols, nabilone andcannabidiol that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

References

  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed]
  2. Agurell S, Halldin M, Lindgren JE, et al.: Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38 (1): 21-43, 1986. [PubMed]
  3. Yamamoto I, Watanabe K, Narimatsu S, et al.: Recent advances in the metabolism of cannabinoids. Int J Biochem Cell Biol 27 (8): 741-6, 1995. [PubMed]
  4. Engels FK, de Jong FA, Sparreboom A, et al.: Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist 12 (3): 291-300, 2007. [PubMed]
  5. Berthiller J, Straif K, Boniol M, et al.: Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol 3 (12): 1398-403, 2008. [PubMed]
  6. Sidney S, Quesenberry CP Jr, Friedman GD, et al.: Marijuana use and cancer incidence (California, United States). Cancer Causes Control 8 (5): 722-8, 1997. [PubMed]
  7. Hashibe M, Morgenstern H, Cui Y, et al.: Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev 15 (10): 1829-34, 2006. [PubMed]
  8. Mehra R, Moore BA, Crothers K, et al.: The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med 166 (13): 1359-67, 2006. [PubMed]
  9. Marks MA, Chaturvedi AK, Kelsey K, et al.: Association of marijuana smoking with oropharyngeal and oral tongue cancers: pooled analysis from the INHANCE consortium. Cancer Epidemiol Biomarkers Prev 23 (1): 160-71, 2014. [PMC free article] [PubMed]
  10. Daling JR, Doody DR, Sun X, et al.: Association of marijuana use and the incidence of testicular germ cell tumors. Cancer 115 (6): 1215-23, 2009. [PMC free article] [PubMed]
  11. Trabert B, Sigurdson AJ, Sweeney AM, et al.: Marijuana use and testicular germ cell tumors. Cancer 117 (4): 848-53, 2011. [PMC free article] [PubMed]
  12. Lacson JC, Carroll JD, Tuazon E, et al.: Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer 118 (21): 5374-83, 2012. [PMC free article] [PubMed]
  13. Thomas AA, Wallner LP, Quinn VP, et al.: Association between cannabis use and the risk of bladder cancer: results from the California Men’s Health Study. Urology 85 (2): 388-92, 2015. [PubMed]
  14. Health Canada: Marihuana (Marijuana, Cannabis): Dried Plant for Administration by Ingestion or Other Means. Ottawa, Canada: Health Canada, 2010. Available online. Last accessed July 16, 2015.
  15. Guzmán M, Duarte MJ, Blázquez C, et al.: A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer 95 (2): 197-203, 2006. [PMC free article] [PubMed]
  16. Velasco G, Sánchez C, Guzmán M: Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 12 (6): 436-44, 2012. [PubMed]
  17. 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]
  18. Ahmedzai S, Carlyle DL, Calder IT, et al.: Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer 48 (5): 657-63, 1983. [PMC free article] [PubMed]
  19. Chan HS, Correia JA, MacLeod SM: Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 79 (6): 946-52, 1987. [PubMed]
  20. Johansson R, Kilkku P, Groenroos M: A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev 9 (Suppl B): 25-33, 1982. [PubMed]
  21. Niiranen A, Mattson K: A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin Oncol 8 (4): 336-40, 1985. [PubMed]
  22. Tramèr MR, Carroll D, Campbell FA, et al.: Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323 (7303): 16-21, 2001. [PMC free article] [PubMed]
  23. Ben Amar M: Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 105 (1-2): 1-25, 2006. [PubMed]
  24. Chang AE, Shiling DJ, Stillman RC, et al.: A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 47 (7): 1746-51, 1981. [PubMed]
  25. Chang AE, Shiling DJ, Stillman RC, et al.: Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann Intern Med 91 (6): 819-24, 1979. [PubMed]
  26. Levitt M, Faiman C, Hawks R, et al.: Randomized double blind comparison of delta-9-tetrahydrocannabinol and marijuana as chemotherapy antiemetics. [Abstract] Proceedings of the American Society of Clinical Oncology 3: A-C354, 91, 1984.
  27. Jatoi A, Windschitl HE, Loprinzi CL, et al.: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 20 (2): 567-73, 2002. [PubMed]
  28. Brisbois TD, de Kock IH, Watanabe SM, et al.: Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol 22 (9): 2086-93, 2011. [PubMed]
  29. Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 24 (21): 3394-400, 2006. [PubMed]
  30. 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]
  31. Foltin RW, Brady JV, Fischman MW: Behavioral analysis of marijuana effects on food intake in humans. Pharmacol Biochem Behav 25 (3): 577-82, 1986. [PubMed]
  32. Foltin RW, Fischman MW, Byrne MF: Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11 (1): 1-14, 1988. [PubMed]
  33. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PubMed]
  34. Calignano A, La Rana G, Giuffrida A, et al.: Control of pain initiation by endogenous cannabinoids. Nature 394 (6690): 277-81, 1998. [PubMed]
  35. Fields HL, Meng ID: Watching the pot boil. Nat Med 4 (9): 1008-9, 1998. [PubMed]
  36. Noyes R Jr, Brunk SF, Baram DA, et al.: Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15 (2-3): 139-43, 1975 Feb-Mar. [PubMed]
  37. Noyes R Jr, Brunk SF, Avery DA, et al.: The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18 (1): 84-9, 1975. [PubMed]
  38. Johnson JR, Burnell-Nugent M, Lossignol D, et al.: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39 (2): 167-79, 2010. [PubMed]
  39. Portenoy RK, Ganae-Motan ED, Allende S, et al.: Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13 (5): 438-49, 2012. [PubMed]
  40. Johnson JR, Lossignol D, Burnell-Nugent M, et al.: An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage 46 (2): 207-18, 2013. [PubMed]
  41. Lynch ME, Cesar-Rittenberg P, Hohmann AG: A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47 (1): 166-73, 2014. [PubMed]
  42. Maida V, Ennis M, Irani S, et al.: Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol 6 (3): 119-24, 2008. [PubMed]
  43. Abrams DI, Couey P, Shade SB, et al.: Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90 (6): 844-51, 2011. [PubMed]
  44. Wilsey B, Marcotte T, Deutsch R, et al.: Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 14 (2): 136-48, 2013. [PMC free article] [PubMed]
  45. Wilsey B, Marcotte T, Tsodikov A, et al.: A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 9 (6): 506-21, 2008. [PubMed]
  46. Abrams DI, Jay CA, Shade SB, et al.: Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 68 (7): 515-21, 2007. [PubMed]
  47. Ellis RJ, Toperoff W, Vaida F, et al.: Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 34 (3): 672-80, 2009. [PMC free article] [PubMed]
  48. Noyes R Jr, Baram DA: Cannabis analgesia. Compr Psychiatry 15 (6): 531-5, 1974 Nov-Dec. [PubMed]
  49. Russo EB, Guy GW, Robson PJ: Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 4 (8): 1729-43, 2007. [PubMed]

Adverse Effects

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 tissuesthroughout the body, not just in the central nervous system, and adverse effects include tachycardia, hypotension, conjunctivalinjection, bronchodilation, muscle relaxation, and 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.

Since Cannabis smoke contains many of the same components as tobacco smoke, there are valid concerns about the adversepulmonary effects of inhaled Cannabis. A longitudinal study in a noncancer population evaluated repeated measurements ofpulmonary function over 20 years in 5,115 men and women whose smoking histories were known.[5] 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]).

References

  1. Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PubMed]
  2. Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: 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]
  4. Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PubMed]
  5. 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] [PubMed]

Summary of the Evidence for Cannabis and Cannabinoids

To assist readers in evaluating the results of human studies of complementary and alternative medicine (CAM) treatments for people with cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. An overall level of evidence score cannot be assigned to cannabinoids because there has been insufficient clinical research to date. For an explanation of possible scores and additional information about levels of evidence analysis of CAMtreatments for people with cancer, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

Cannabinoids

Cannabis

  • There have been only three small clinical trials on the use of Cannabis in cancer patients. All three studies assessedantiemetic activity but each explored a different patient population and chemotherapy regimen. One study demonstrated no effect, the second study showed a positive effect versus placebo, and the report of the third study did not provide enough information to characterize the overall outcome as positive or neutral. Consequently, there are insufficient data to provide an overall level of evidence assessment for the use of Cannabis for chemotherapy-induced N/V. Apparently, there are no published data on the use of Cannabis for other cancer-related or cancer treatment–related symptoms.
  • An increasing number of trials are evaluating the oromucosal administration of whole Cannabis plant extract with fixed concentrations of cannabinoid components.
  • At present, there is insufficient evidence to recommend inhaling Cannabis as a treatment for cancer-related symptoms or cancer treatment–related side effects.”
Logo of National Cancer Institute (US)
“Cannabis and Cannabinoids (PDQ®) Health Professional Version: 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. Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death”  http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032740/

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