Written by Gabriele Dennert and the CAM-Cancer Consortium.
Updated November 25, 2011

Cannabinoids

Does it work ?

Do cannabinoids work for therapy-induced nausea and emesis?

Nausea and vomiting are severe and distressing adverse effects of many chemo- and radiotherapeutic treatments. Palliative care patients also complain frequently of nausea that impairs their quality of life.

Nausea and emesis induced by chemotherapy

Systematic reviews

A systematic review is available establishing the efficacy of cannabinoids against chemotherapy-induced nausea and vomiting17. These findings were replicated in another systematic review with meta-analysis18. Thirty randomised-controlled trials were included in this review investigating oral dronabinol, oral nabilone and intramuscular levonantradol in comparison to placebo and antiemetics available in the 1980s (prochlorperazine, metoclopramide, thiethylperazine, haloperidol, domperidone, alizapride). Cannabinoids showed a significantly better control of chemotherapy-induced nausea and vomiting than placebo/control medication, and were preferred for future chemotherapy cycles by two out of three patients in cross-over trials. Benefits seemed to be more pronounced in medium emetogenic chemotherapy than in low or high emetogenic chemotherapy. However, none of the included trials tested cannabinoids against the modern forms of antiemetic prophylaxis (5-HT3-antagonists, NK1-receptor antagonists and drug combinations including glucocorticoids). The authors concluded that in selected patients, cannabinoids may be useful as mood-enhancing adjuvants for the control of chemotherapy-related sickness, but considering the availability of well-investigated modern drug combinations for antiemetic prophylaxis, cannabinoids could not be recommended for solitary or first-line use.

A recent systematic review on antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in children identified four randomised controlled trials, which were not meta-analysed due to study heterogeneity19. Cochrane authors concluded that cannabinoids “are probably effective, but produce high levels of side effects” (p.14) and no clear route, schedule or dose recommendation could be identified from the included studies.

Controlled trials

As cannabinoids act differently from other antiemetic drugs, they might be effective when administered in combination with modern antiemetics in people whose emesis is not adequately controlled with current treatment options. Plasse reports anecdotal evidence that cannabinoids might help against chemotherapy-induced delayed nausea20. One randomised, placebo-controlled trial investigated the efficacy of dronabinol alone or in combination with ondansetron for the prevention of delayed chemotherapy-induced nausea and vomiting21. Sixty-four participants receiving moderate to high emetogenic chemotherapy were randomised to one of four intervention groups. All participants received dexamethasone plus ondansetron before chemotherapy, the three active intervention groups received additional dronabinol on the day of chemotherapy and either dronabinol, ondansetron or both on the following four days after chemotherapy. Results suggested that dronabinol was equally effective as ondansetron for the prevention of delayed chemotherapy induced nausea and vomiting. Acute chemotherapy induced nausea and vomiting on the first day of chemotherapy was reduced in the three groups receiving additive dronabinol compared to the standard treatment alone (dexamethasone + ondansetron). However, this trial failed to recruit the necessary number of participants for a valid evaluation and findings need to be replicated in a larger study with comparable intervention groups at baseline to further elucidate the potential benefits of additive dronabinol.

Nausea and emesis induced by radiotherapy

One double-blind randomised cross-over trial compared nabilone and metoclopramid for the prevention of radiotherapy-induced nausea in 40 patients22. Findings suggested no difference in the antiemetic effect of 2mg nabilone compared to 30mg metoclopramid, but adverse reactions were more severe in the nabilone group.

Do cannabinoids work for anorexia-cachexia-syndrome?

Clinical studies

Strasser et colleagues conducted a randomised placebo-controlled phase III trial and compared oral THC, oral cannabis extracts and placebo for patients with cancer-related anorexia23. Two hundred and forty-three adults with advanced cancer (54% men) were randomly assigned to THC/cannabidiol (2.5mg/1mg), THC alone (2.5 mg) or placebo orally daily for 6 weeks. The results showed significant unspecific (placebo) effects on symptom control, but no substance-specific benefit of cannabinoids over placebo on appetite or overall quality of life (primary study end points), or mood or nausea (secondary end points). Recruitment for this study was terminated early because of insufficient differences between study arms.

Jatoi24 tested oral dronabinol (2.5mg twice a day + placebo) versus the progesterone derivate megestrol (plus placebo) versus both agents. 469 patients with advanced cancer and weight loss participated in this double-blind randomised trial. Megestrol acetate had better outcomes (appetite, food intake, body weight) than dronabinol, while the combination was not more effective than megestrol alone.

A small placebo-controlled randomised trial investigated THC (2.5 mg/day) in 46 patients with advanced cancer25. Per-protocol analyses of 21 patients found a subjectively increased appetite and taste perception in the THC group, but no differences in total caloric intake between both groups.

Case series / reports

Several findings suggested that oral cannabinoids increased appetite in cancer patients, stopped weight loss or even increased body weight26,27. In an open phase II study, Nelson investigated the effect of 3x2.5 mg oral THC in 19 patients with various malignancies and tumour-associated anorexia28. Thirteen of 18 patients that could be evaluated reported a subjective improvement in appetite. Body weight was measured in six patients and after four weeks was increased in three patients, not changed in two and decreased in one.

To summarise, the most recent and rigorous findings from randomised trials suggested no benefit of treatment with dronabinol/THC alone or in combination with cannabidiol for cancer-related anorexia-cachexia syndrome compared with placebo or megestrol acetate. Recent reviews on the treatment of cancer cachexia support a multimodal approach with different, newer medications29,30.

Do cannabinoids work for pain?

Systematic reviews

A systematic review of randomised clinical trials investigated the efficacy of cannabinoids in the management of pain31. Campbell reviewed five studies with a total of 128 cancer patients comparing oral THC or a THC congener (benzopyranopyridine) to placebo, codeine or a barbiturate. Results were contradictory and cannabinoids were found to be equally or more effective than placebo, and less or equally effective as codeine. Studies were rather small (n=10 to n=37) and dose-limitating adverse effects were a common. Reviewers concluded that there is insufficient evidence to support the introduction of cannabinoids into widespread clinical use as analgesics.

Clinical studies

Two phase II randomised double-blind controlled trials investigated the use of cannabinoids in participants with advanced cancer32,33. Both trials used cannabinoid preparations as oral sprays in comparison to placebo sprays as add-on medication to opioids in participants with intractable cancer pain.

The first trial compared two cannabis extracts (Sativex© and Tetranabinex©) versus placebo for pain control32. A statistically significant improvement of pain (as measured in a pain score) due to cancer unresponsive to opioids was seen for Sativex©, but not for Tetranabinex© compared to placebo (177 participants).

Results of the second trial have so far only been published as a press report: Statistically significant differences from placebo in pain scores were reported for Sativex© at three different doses in this dose-finding study. A phase III trial is under way33.
Maida34 conducted a prospective observational study comparing advanced cancer patients who were treated with or without nabilone in a specialized palliative care center. 112 patients were prescribed or not prescribed nabilone at their physicians’ discretion based on the presence of physical symptoms including pain. Pain and nausea improved in the nabilone group. The uncontrolled study design, however, does not allow to causally attribute these observed findings to nabilone as they might also be related to bias or unspecific effects.

Citation Gabriele Dennert, CAM-Cancer Consortium. Cannabinoids [online document]. http://www.cam-cancer.org/CAM-Summaries/Herbal-products/Cannabinoids. November 25, 2011.

References

  1. Grotenhermen,F. (2003): Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet, 42:327-360.
  2. Guy,G.W., Whittle,B.A., Robson,P.J.(2004): The medicinal uses of cannabis and cannabinoids. Pharmaceutical Press, London.
  3. Walsh,D., Nelson,K.A., and Mahmoud,F.A. (2003): Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer, 11:137-143.
  4. Mutschler,E., Geisslinger,G. , Kroemer, H.K., Schäfer-Korting,M. (Eds.) (2001): Mutschler Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.
  5. Cota,D., Marsicano,G., Lutz,B., Vicennati,V., Stalla,G.K., Pasquali,R., and Pagotto,U. (2003): Endogenous cannabinoid system as a modulator of food intake. Int J Obesity, 27:289-301.
  6. Martin,B.R. and Wiley,J.L. (2004): Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol, 2:305-314.
  7. Townsend,D.W., Thayer,S.A., and Brown,D.R. (2002): Cannabinoids throw up a conundrum. Br J Pharmacology, 173:575-577.
  8. Brenneisen,R. (2001): Pharmakokinetik. In: Cannabis und Cannabinoide. Pharmakologie, Toxikologie und therapeutisches Potential, edited by F.Grotenhermen, pp. 87-92. Hans Huber Verlag, Bern.
  9. Bruera,E. and Castro,M. (2003): Cannabinoids in supportive care: are they necessary? Support Care Cancer, 11:133-134.
  10. Robson,P.J. and Guy,G.W. (2004): Clinical studies of cannabis-based medicines. In: The medicinal uses of cannabis and cannabinoids, edited by G.W.Guy, et al, pp. 229-269. Pharmaceutical Press, London.
  11. Svendsen,K.B., Jensen,T.S., and Bach,F.W. (2004): Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ, 329:253
  12. Grotenhermen,F.(Ed.)(2001): Cannabis und Cannabinoide. Pharmakologie, Toxikologie und therapeutisches Potential. Hans Huber Verlag, Bern.
  13. Russo,E. (2004): History of cannabis as a medicine. In: The medicinal uses of cannabis and cannabinoids, edited by G.W.Guy, et al, pp. 1-16. Pharmaceutical Press, London.
  14. Ware,M.A., Adams,H., and Guy,G.W. (2005): The medicinal use of cannabis in the UK: results of a nationwide survey. Int J Clin Pract., 59:291-295.
  15. Gorter,R.W., Butorac,M., Cobian,E.P., and van der,S.W. (2005): Medical use of cannabis in the Netherlands. Neurology, 64:917-919.
  16. www.acmed.org [International Organization for Cannabis as Medicine] (accessed 21/10/2011)
  17. Tramer,M.R., Carroll,D., Campbell,F.A., Reynolds,D.J.M., Moore,R.A., and McQuay,H.J. (2001): Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ, 1-8.
  18. Machado Rocha,F.C., Stefano,S.C., de Cassia Haiek,R., Rosa Oliviera,L.M.Q., da Silveira,D.X. (2008): Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care, 17:431-443.
  19. Phillips, R.S., Gopaul, S., Gibson, F., Houghton, E., Craig, J.V., Light, K., Pizer, B. (2010): Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database of systematic reviews 2010, Issue 9, Art. No. CD007786. DOI: 10.1002/14651858.CD007786.pub2
  20. Plasse,T. (2001): Antiemetische Effekte. In: Cannabis und Cannabinoide. Pharmakologie, Toxikologie und therapeutisches Potential, edited by F.Grotenhermen, pp. 187-210. Hans Huber Verlag, Bern.
  21. Meiri,E., Jhangiani,H., Vredenburg,J.J., Barbato,L.M., Carter,F.J., Yang,H.M., Baranowski,V. (2007): Efficacy of dronabinol alone and in combination with ondansetron versus ondasetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opinion, 23:533-543.
  22. Priestman,S.G., Priestman,T.J., and Canney,P.A. (1987): A double-blind randomised cross-over comparison of nabilone and metoclopramide in the control of radiation-induced nausea. Clinical Radiology, 38:543-544.
  23. Strasser,F., Lueftner,D., Possinger,K., Ernst,G., Ruhstaller,T., Meissner,W., Ko,Y.D., Schnelle,M., Reif,M., Cerny,T. (2006): Comparison of orally administered cannabis extract with 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, 24:3394-3400.
  24. Jatoi,A., Windschitl,H.E., Loprinzi,C.L., Sloan,J.A., Dakhil,S.R., Mailliard,J.A., Pundaleeka,S., Kardinal,C.G., Fitch,T.R., Krook,J.E., Novotny,P.J., and Christensen,B. (2002): Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol, 20:567-573.
  25. Brisbois, T. D., de Kock, I. H., Watanabe, S. M., Mirhosseinie, M., Kamoureux, D. C., Chasen, M., MacDonald, N., Baracos, V. E., Wismer, W. V. (2011): Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo controlled pilot trial. Annals of Oncology; 22: 2086-2093.
  26. Regelson,W., Butler,J.R., Schulz,J., Kirk,T., Peek,L., Green,M.L., and Zalis,M.O. (1976): Tetrahydrocannabinol as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In: The pharmacology of marihuana: A monograph of the National Institute of Drug Abuse, edited by M.C.Braude, et al, pp. 763-776. Raven, New York.
  27. Plasse,T.F., Gorter,R.W., Krasnow,S.H., Lane,M., Shepard,K.V., and Wadleigh,R.G. (1991): Recent clinical experience with dronabinol. Pharmacol Biochem Behav, 40:695-700.
  28. Nelson,K., Walsh,D., Deeter,P., and Sheehan,F. (1994): A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J Palliat Care, 10:14-18.
  29. Tazi, E., Errihani, H. (2010): Treatment of cachexia in oncology. Indian Journal of Palliative Care, 16(3): 129-137.
  30. Madeddu, C., Mantovani, G. (2009): An update on promising agents for the treatment of cancer cachexia. Current opinion in supportive & palliative care; 3(4): 258-262.
  31. Campbell,F.A., TramSr,D., Carroll,D., Reynolds,D.J.M., Moore,R.A., and McQuay,H.J. (2001): Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ, 323:1-6.
  32. Johnson, J.R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E.D., Potts, R., Fallon, M.T. (2010): 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. Journal of Pain & Symptom Management 39: 167-79.
  33. GW Pharmaceuticals (2010): Phase IIb Cancer Pain Trial Data. http://www.gwpharm.com/ Phase IIb Cancer Pain Trial Data.aspx (accessed on 18/10/2011)
  34. Maida,V., Ennis,M., Irani,S. Corbo,M. Dlozhykhov,M. (2008): Adjunctive nabilone in cancer pain and symptom management: A prospective observational study using propensity scorino. Supp Oncol, 6:119-124.
  35. Radbruch,L. and Nauck,F. (2004): Cannabinoide in der Behandlung von Übelkeit und Erbrechen. Schmerz, 18:306-310.
  36. Hall,W., Christie,M., and Currow,D. (2005): Cannabinoids and cancer: causation, remediation, and palliation. Lancet Oncol, 6:35-42.
  37. Notcutt,W. (2004): Cannabis in the treatment of chronic pain. In: The medicinal uses of cannabis and cannabinoids , edited by G.W.Guy, et al, pp. 271-299. Pharmaceutical Press, London.
  38. Rossato,M., Ion,P.F., Ferigo,M., Clari,G., and Foresta,C. (2005): Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J Clin Endocrinol Metab, 90:984-991.
  39. Slatkin, N.E. (2007): Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: Beyong prevention of acute emesis. J Support Oncol, 5(suppl 3): 1-9.
Legal notice
The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused because anyone relies on the information.