• CAM-summaries
  • Alternative medical systems
  • Biologically-based practices
    • Boswellia
    • Cannabinoids
      • What are Cannabinoids?
      • How well do Cannabinoids work?
      • Are Cannabinoids safe?
      • Cannabinoids conclusions
    • Essiac
    • Galavit
    • Laetrile
    • Shark cartilage
    • Ukrain
    • Black cohosh
  • Diet & nutrition
  • Energy medicine
  • Manipulative & body-based practices
  • Mind-body medicine
• CAM systematic reviews
• CAM and the law
• Prevalence of CAM use

How well do Cannabinoids work?

Pharmacology

Pharmacokinetics (ref 3, 5) have been intensively investigated. Absorption in the GI-tract is high (90-95%), but due to hepatic first-pass metabolism oral bioavailability ranges only between 5 to 20%. Systemic bioavailability is slightly higher after inhalation, with a considerable interindividual variation (~20% +/-10%). Peak plasma concentrations are seen within minutes after intravenous or inhalative administration and between 2 to 4 hours after oral intake. THC in the plasma is bound to plasma lipoproteins (95 to 99%), less to albumin. As a lipophilic compound, THC is rapidly eliminated from plasma through distribution to highly vascularised tissue and is able to cross the blood-brain-barrier. Subsequently, redistribution to, and accumulation in, body fat can be observed. Peak effects are seen with a lag of 15 to 60 minutes after peak plasma concentration; pharmacologic effects are not correlated with maximum plasma levels (ref 3, 5). Plasma half-life ranges between 28 to 57 hours due to interindividual differences in redistribution from fat tissue. Cannabinoids are metabolised by cytochrome P450 subsystems in the liver and metabolites are excreted in bile and urine over several days with an extensive enterohepatic recirculation.

Biological mechanisms

Two types of cell surface receptors for cannabinoids have been identified in human tissue (CB1 and CB2) (ref 10, 11, 12, 13). Derivates of arachidonic acid, so called endogenous cannabinoids, work as physiologic ligands for both receptor subtypes. The CB1 receptor is predominantly found in tissue of the central, peripheral and autonomous nervous system, with its highest density in the basal ganglia of the brain. The main effect of CB1 receptor stimulation is a decrease in the release of neurotransmitters, such as dopamine, norepinephrine, and serotonin. This receptor subtype mediates the central effects of cannabinoids, such as antiemesis and the alteration of cognitive processes, movement, appetite and pain regulation. The CB2 receptor subtype is mainly expressed in tissue with immunologic function, including peripheral blood leukocytes, bone marrow, spleen, thymus, tonsils, macrophages and mast cells. CB2 receptors mediate the immunomodulative effects of cannabinoids.

In addition to cannabinoid receptors, cannabinoids are probably active by a number of other mechanisms. For example, research suggests that the antiemetic effect might be related to interaction with the 5-HT3A receptor (serotonin receptor) (ref 14).

The appetite-stimulating effect of cannabis products has regularly been reported by recreational users of cannabis drugs and could be confirmed in controlled studies with healthy male volunteers using both smoked cannabis and oral THC (ref 15). The alteration of appetite and food intake has been attributed to the effects of cannabinoids on the central control of food intake, especially in the hypothalamus (ref 10). Evidence has been found that an activation of the CB1 receptor in the central nervous system also inhibits chemically induced vomiting in animals (ref 11). A high density of cannabinoids receptors has been found in the nucleus solitary tract, which is important for the control of emesis. The analgesic effects may be produced by both central and peripheral mechanisms. One theory is that cannabinoids inhibit release of transmitters from primary afferents, another is that they activate descending modulatory pathways (ref 16).

How well does it work for Nausea and emesis?

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

Nausea and emesis induced by chemotherapy

A systematic review (Oxford level of evidence 1) is available establishing the efficacy of cannabinoids against chemotherapy-induced nausea and vomiting (ref 17). 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. Benefit seemed to be more pronounced in medium emetogenic chemotherapy than in low or high emetogenic chemotherapy. However, no trial tested cannabinoids against the modern forms of antiemetic prophylaxis (5-HT3-antagonists and drug combinations including glucocorticoids). Reviewers came to the conclusion 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 cannot be recommended for solitary use.

As cannabinoids act differently from other antiemetic drugs, they might be effective in people whose emesis is not adequately controlled with current treatment options when administered in combination with modern antiemetics. Plasse reports anecdotal evidence that cannabinoids might help against chemotherapy-induced delayed nausea, but no controlled trials have so far been conducted (ref 18).

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 patients (ref 19). 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.

How well does it work in palliative care

Preliminary results of an open dose-finding study (phase I/II) with standardised cannabis extracts (containing a standardised combination of THC and cannabidiol) suggest that cannabinoids might relieve nausea in palliative care (ref 20). However, evidence for the medical cannabinoids dronabinol or nabilone is not available.

How well does it work for Anorexia-cachexia-syndrome?

Several early findings suggested that oral cannabinoids increased appetite in cancer patients, stopped weight loss or even increased body weight (ref 21, 22). In an open phase II study, Nelson (ref 23) investigated the effect of 3x2.5 mg oral THC in 19 patients with various malignancies and tumour-associated anorexia. Thirteen of 18 evaluable patients 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.

Jatoi (ref 24) tested oral dronabinol (2x2.5mg daily) versus the progesterone derivate megestrol versus a combination of both. 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.

Preliminary results are available for the most recent study, a randomised placebo-controlled phase III trial comparing oral THC, oral cannabis extracts and placebo for patients with cancer-related anorexia (ref 25). Outcomes for 216 participants have been reported so far and suggested no difference between treatment arms concerning appetite and overall quality of life. A trend has been found that THC is inferior to placebo and cannabis extract for appetite-stimulation. Hence, recruitment for the study was stopped early.

To summarise, the most recent and rigorous findings from randomised trials suggested no benefit for a treatment with dronabinol for cancer-related anorexia-cachexia syndrome compared to placebo or megestrol acetate.

How well does it work for pain?

Qualitative systematic reviews of randomised-controlled trials investigated the efficacy of cannabinoids in the management of pain (ref 26, 27). Campbell (ref 26) reviewed five studies with n=128 cancer patients that compared oral THC or THC congeners 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. Authors pointed out that all five included studies were rather small (n=10 to n=37) and though no differences in pain control between codeine and cannabinoids were found in four of five studies, dose-limitating adverse effects were a common problem with cannabinoids. Reviewers concluded that there is insufficient evidence to support the introduction of cannabinoids into widespread clinical use as analgesics.

References

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.

5. Grotenhermen,F.(Ed.)(2001): Cannabis und Cannabinoide. Pharmakologie, Toxikologie und therapeutisches Potential. Hans Huber Verlag, Bern.

10. 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.

11. 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.

12. Townsend,D.W., Thayer,S.A., and Brown,D.R. (2002): Cannabinoids throw up a conundrum. Br J Pharmacology, 173:575-577.

13. Brenneisen,R. (2001): Pharmakokinetik. In: Cannabis und Cannabinoide. Pharmakologie, Toxikologie und therapeutisches Potential, edited by F.Grotenhermen, pp. 87-92. Hans Huber Verlag, Bern.

14. Bruera,E. and Castro,M. (2003): Cannabinoids in supportive care: are they necessary? Support Care Cancer, 11:133-134.

15. 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.

16. 16) 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

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. 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.

19. 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.

20. Helwig,S., Fronk,E.-M., Reif,M., Schnelle,M., and Hofmann,J. (2003): Maximally tolerated dose (MTD) of standardized cannabis extract in palliative cancer patients: Preliminary results from an open-label, non-randomized phase I/II trial. IACM 2003 Conference, (Abstract)

21. 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.

22. 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.

23. 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.

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. Strasser,F., Lueftner,D., Possinger,K., Ernst,G., Ruhstaller,T., Meissner,W., Ko,Y.D., Schnelle,M., Reif,M., Cerny,T., and Cannabis-in-Cachexia-Study-Group (2003): Oral cannabis-extract (CE) versus delta-9-tetrahydrocannabinol (THC) for patients with cancer-related anorexis (CRA): A randomized, double-blind, placebo-controlled, multicenter study. IACM 2003 Conference, (Abstract)

26. 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.

27. Azad,S.C. (2003): Sind Cannabinoide eine effektive und sichere Option bei der Schmerzbehandlung? - Ein qualitativer systematischer Überblick. Der Schmerz, 17:63-65.