Cancer.gov | Human Clinical Studies

Human/Clinical Studies

Cannabis Pharmacology
Cancer Risk
Cancer Treatment
Antiemetic Effect
Cannabinoids
Cannabis
Appetite Stimulation
Cannabinoids
Cannabis
Analgesia
Cannabinoids
Cannabis
Anxiety and Sleep
Cannabis
Current Clinical Trials

Cannabis Pharmacology

When Cannabis is ingested by mouth, there is a low (6%–20%) and variable oral bioavailability.[1,2] Peakplasma 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 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.

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 thatCannabis 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, pharyngeallaryngeal, 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]

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 and cancer is still inconclusive.[9]

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.[10]

Antiemetic Effect

Cannabinoids

Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting (N/V) remain distressing side effects for cancer patients and their families. Dronabinol was approved in the United States in 1986 as an antiemetic to be used in cancer chemotherapy. Nabilone, another synthetic derivative of delta-9-THC, was first approved in Canada in 1982 and is now also available in the United States.[11] 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. Numerousclinical trials and meta-analyses have shown that dronabinol and nabilone are effective in the treatment of N/V induced by chemotherapy.[1215] The National Comprehensive Cancer Network Guidelines Exit Disclaimer 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.[16] Oral nabilone, oral dronabinol, andintramuscular levonantradol (a synthetic analog 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 prochlorperazinemetoclopramide, chlorpromazine, thiethylperazinehaloperidol, 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, euphoriasedation or drowsiness, dizziness, dysphoria or depressionhallucinationsparanoia, and hypotension.[16] Newer antiemetics (e.g., 5-HT3 receptor antagonists) 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.[17] Among 600 cancer patients, 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.[1820] In two of the studies, inhaled Cannabis was made available only after dronabinol failure. In the first trial, no antiemetic effect was achieved with marijuana in patients receiving cyclophosphamide or doxorubicin,[18] but in the second trial, a statistically significant superior antiemetic effect of inhaled Cannabis versus placebo was found among patients receiving high-dose methotrexate.[19] The third trial was a randomized, double-blindplacebo-controlledcross-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.[20]

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

Two 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.[17] 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.[21] 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 of treatment. 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.[22]

Another clinical trial that involved 139 patients with HIV or AIDS and weight loss found that, compared with placebo, oral dronabinol was 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.[23]

Cannabis

In trials conducted in the 1980s that involved healthy control subjects, inhaling Cannabis led to an increase incaloric intake, mainly in the form of between-meal snacks, with increased intakes of fatty and sweet foods.[24,25] 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.[26] CB2 receptors are located mainly in peripheral tissue and are expressed in only low amounts in the CNS. Whereas only CB1 agonists exert analgesic activity in the CNS, both CB1 and CB2 agonists have analgesic activity in peripheral tissue.[27,28]

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.[29] 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.[30] 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 (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.[31]

An observational study assessed the effectiveness of nabilone in advanced cancer patients who were experiencing pain and other symptoms (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 antidepressantsgabapentindexamethasone, metoclopramide, andondansetron.[32]

Cannabis

Animal studies have suggested a synergistic analgesic effect when cannabinoids are combined with opioids. Preliminary study results in humans suggest that the addition of vaporized Cannabis to a stable regimen of sustained-released oxycodone or morphine sulfate yields increased pain relief despite lower plasma concentrations of the opioids after Cannabis administration.[33]

Neuropathic pain is a symptom cancer patients may experience, especially if treated with platinum-basedchemotherapy or taxanes. A randomized controlled trial of inhaled Cannabis compared with placebo in 50 patients with HIV-related peripheral neuropathy found that pain was reduced by more than 30% in 52% of patients in the Cannabis group and in 24% of patients in the placebo group. This difference was statistically significant.[34] To date, no clinical trial has examined the effectiveness of cannabinoid preparations in the treatment of chemotherapy-induced neuropathic pain.

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.[35]

Another common effect of Cannabis is sleepiness. In a trial of a sublingual spray, a Cannabis-based mixture was able to improve sleep quality.[36] A small placebo-controlled study of dronabinol in cancer patients withaltered chemosensory perception also noted increased quality of sleep and relaxation in THC-treated patients.[22]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for cancer CAM clinical trials on dronabinolmarijuananabiximols andnabilone 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 Abstract]
  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 Abstract]
  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 Abstract]
  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 Abstract]
  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 Abstract]
  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 Abstract]
  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 Abstract]
  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 Abstract]
  9. Health Canada.: Marihuana (Marijuana, Cannabis): Dried Plant for Administration by Ingestion or Other Means. Ottawa, Canada: Health Canada, 2010. Available online Exit Disclaimer. Last accessed October 21, 2011.
  10. 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.  [PUBMED Abstract]
  11. 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 Abstract]
  12. 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.  [PUBMED Abstract]
  13. 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 Abstract]
  14. 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 Abstract]
  15. 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 Abstract]
  16. 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.  [PUBMED Abstract]
  17. Ben Amar M: Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 105 (1-2): 1-25, 2006.  [PUBMED Abstract]
  18. 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 Abstract]
  19. 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 Abstract]
  20. 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.
  21. 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 Abstract]
  22. 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 Abstract]
  23. 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 Abstract]
  24. 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 Abstract]
  25. 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 Abstract]
  26. Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999.  [PUBMED Abstract]
  27. Calignano A, La Rana G, Giuffrida A, et al.: Control of pain initiation by endogenous cannabinoids. Nature 394 (6690): 277-81, 1998.  [PUBMED Abstract]
  28. Fields HL, Meng ID: Watching the pot boil. Nat Med 4 (9): 1008-9, 1998.  [PUBMED Abstract]
  29. 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 Abstract]
  30. 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 Abstract]
  31. 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 Abstract]
  32. 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 Abstract]
  33. Abrams DI, Couey P, Shade SB, et al.: Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90 (6): 844-51, 2011.  [PUBMED Abstract]
  34. 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 Abstract]
  35. Noyes R Jr, Baram DA: Cannabis analgesia. Compr Psychiatry 15 (6): 531-5, 1974 Nov-Dec.  [PUBMED Abstract]
  36. 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 Abstract]
  1. No trackbacks yet.

You must be logged in to post a comment.
%d bloggers like this: