Growing the evidence base for medical cannabis

Research in the medical marijuana field is burgeoning as various governments consider changing policy in favour of legalizing the marijuana plant Cannabis sativa. Like any modern research effort, the "gold standard" for assessing a new treatment for efficacy compares the treatment to a placebo group. However, controlling for the placebo effects of marijuana may be extremely difficult and several confounds must be carefully considered by researchers in this field.

Broadly, the placebo effect is an improvement in health or behaviour which engulfs a biopsychosocial phenomenon attributable to the placebo and treatment context (1). On the psychosocial end of the placebo effect spectrum, "the meaning effect" is a similar notion that pertains to the meaning attached to the treatment, as well as the setting and the context surrounding the medical encounter (2). On the psychobiological end of the spectrum, researchers highlight the central role of expectation, suggestion, and conditioning in placebo-related phenomena (3). New treatments are compared to placebos because placebo effects are very strong - oftentimes stronger than the effects of the treatment in question.

When it comes to marijuana, several placebo effects come into play. Marijuana has a distinct smell and taste, which may elicit classical conditioning responses. Placebo science research holds strong evidence for the effect of classical conditioning related to odour and taste: caffeine- associated stimuli like the smell and taste of coffee, for example, is shown to increase skin conductance responses and startle eyeblink reflexes in the absence of caffeine (4, 5). In addition, visual cues associated with smoking marijuana such as cigarettes, smoke, or lighters may elicit the placebo effect and still remain a factor in even the most well- controlled recent studies (6, 7).

The method of marijuana administration and dose in new trials can carry powerful placebo effects. Will the marijuana be inhaled, injected, administered topically or sublingually? Placebo science demonstrates that placebo injections work better than placebo pills (8), and that four placebos work better than two (9). The strength of the effect of marijuana may differ greatly depending on the method of administration. To date, medical marijuana research spans several routes of administration including injections of the psychoactive ingredient delta-9- tetrahydrocannabinol (THC) (10), oral THC capsule (11) or spray (12), as well as smoking a marijuana pipe (7) or cigarette (6). These differing methods of administration will each carry their own placebo effects; grouping such findings together should be avoided.

There is a way to overcome the interference between treatment and placebo effects of marijuana. We can take these lessons from placebo analgesia studies. Studies comparing hidden treatments (for example, using a computer controlled infusion machine that is pre-programmed to dispense medication at a desired time) with open administration (where medication is given overtly by a physician or nurse) can eliminate the placebo component by making the patient unaware that a medical therapy is being carried out. Patients in this study design do not know that the drug is being injected, therefore eliminating expectations of a therapeutic response. Indeed, a trial conducted by Benedetti et al. (13) showed that a CCK antagonist induced stronger analgesia than a placebo, suggesting that it was a good analgesic. However, this conclusion proved to be erroneous because a hidden injection of the same CCK antagonist was totally ineffective, showing that it had no intrinsic analgesic pharmacodynamic action, but instead, it enhanced placebo-activated release of endogenous opioids (14, 15). If similar studies are replicated with THC, researchers may be able to elucidate the pain relieving properties of marijuana's primary psychoactive ingredient.

The marijuana research field is new. Standardized methods need to be developed so that researchers can properly evaluate the effectiveness of this treatment for various disorders. Controlling for the powerful placebo effects of marijuana will bring the scientific community one step closer to identifying which conditions this treatment may be most useful for, and how it is best administered.

References

1. Kirsch I. Hidden administration as ethical alternatives to the balanced placebo design. Prevention & Treatment. 2003;6(1).

2. Moerman DE. Meaning, medicine, and the "placebo effect". Cambridge, U.K. ; New York: Cambridge University Press; 2002.

3. Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. The Journal of Neuroscience. 2003;23(10):4315-23.

4. Flaten MA, Blumenthal TD. Caffeine-associated stimuli elicit conditioned responses: an experimental model of the placebo effect. Psychopharmacology. 1999;145(1):105-12.

5. Mikalsen A, Bertelsen B, Flaten M. Effects of caffeine, caffeine- associated stimuli, and caffeine-related information on physiological and psychological arousal. Psychopharmacology. 2001;157(4):373-80.

6. Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. The Journal of Pain. 2008;9(6):506-21.

7. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journal. 2010;182(14):E694-E701.

8. Chaput De Saintonge DM, Herxheimer A. Harnessing placebo effects in health care. Lancet. 1994;344(8928):995-8.

9. De Craen AJM, Moerman DE, Heisterkamp SH, Tytgat GNJ, Tijssen JGP, Kleijnen J. Placebo effect in the treatment of duodenal ulcer. British Journal of Clinical Pharmacology. 1999;48(6):853-60.

10. D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biological Psychiatry. 2005;57(6):594-608.

11. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004 2004-07-29 21:55:16;329(7460):253.

12. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812-9.

13. Benedetti F, Amanzio M, Maggi G. Potentiation of placebo analgesia by proglumide. The Lancet. 1995;346(8984):1231.

14. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta J-K. Neurobiological Mechanisms of the Placebo Effect. The Journal of Neuroscience. 2005 November 9, 2005;25(45):10390-402.

15. Benedetti F, Maggi G, Lopiano L, Lanotte M, Rainero I, Vighetti S, et al. Open versus hidden medical treatments: The patient's knowledge about a therapy affects the therapy outcome. Prevention & Treatment. [Journal; Peer Reviewed Journal]. 2003 Jun;6(1).

Conflict of Interest:

None declared