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Cannabinoids in Multiple Sclerosis: is it time to take the lid off the pot?

http://www.veritasmedicine.com/d_home.cfm?type=WU&did=121&cid=72576

03/14/2003
Amit Bar-Or, M.D.
Neurologist and Neuroimmunologist, McGill University and the Montreal Neurological Institute

Extracts of the plant Cannabis sativa, including cannabis (a.k.a. marijuana) and other cannabinoids, have long since been proclaimed to have potential as medical therapeutics. However, concerns over their safety as well as efficacy have led to caution when considering legislature of these compounds. In recent years, there has been an accumulation of pre-clinical research into cannabinoids (including studies in the laboratory and in animal models of human diseases) that has generated renewed interest in this diverse family of compounds (1).

Based on animal model studies, including studies in the commonly used animal model of multiple sclerosis (EAE), natural as well as synthetic cannabinoids may have a role in reducing pain perception, decreasing spasticity and tremors, and alleviating nausea and vomiting. Reports suggesting that these compounds may act as anti-inflammatory agents, and studies suggesting that they may reduce the production of toxic substances in the brain (such as glutamate or oxygen radicals) have prompted researchers to investigate their potential in neuroprotection. For example, various cannabinoids appear to rescue dying neurons in experimental models of acute neuronal injury, such as stroke or trauma (2). Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential therapeutic agents, while avoiding their potential risks.

Humans have cannabinoid receptors in the central and peripheral nervous system, although the functions of these receptors, and the roles of natural substances that may bind to these receptors, remain unclear. Cannabis has been used recreationally because of the euphoria that it produces. Reported adverse side effects have included slowed thought process, decreased retention of memories, anxiety, panic attacks, and even paranoia. Physical side effects may also include dry mouth, blurred vision, rapid or irregular heart beat and decreased blood pressure. Interestingly, at least two naturally occurring cannabinoid receptors have been described (CB1 and CB2). Many of the available cannabinoids appear to interact with both these receptors. However, it appears that the adverse psychological effects of cannabinoids are largely mediated through binding to the CB1 receptor. Researchers are now exploring strategies that might enable cannabinoids to preferentially interact with the CB2 and not the CB1 receptors. This could serve to maximize the separation between the sought-after therapeutic effects and the unwanted side effects of these drugs.

In the United Kingdom (UK) physicians were able to prescribe cannabis up to 1971, and in a 1994 survey 74% of UK doctors wanted cannabis to be available again by prescription. Similar sentiments have been voiced by both patients and medical teams in North America. The debate has included both the natural chemicals that act on cannabinoid receptors and the synthetic cannabinoids. The synthetic nabilone is legally available in several countries where its license is largely restricted for use in nausea and vomiting induced by chemotherapy (mostly for patients with cancer). A particularly potent cannabinoid, Delta-9-tetrahydrocannabinol (THC), is available in the United States to help increase appetite in patients with HIV wasting illness. In Canada, while the Canadian Medical Association has not formally endorsed the medical use of cannabis, an Ontario court recently ruled that preventing individuals suffering from intractable conditions from having access to this agent is unconstitutional. There have been recent reports of a government supported and regulated facility that has been developed to produce ‘Medicinal Marijuana’ - or ‘Marihuana’ (the h is for health).

Until recently, the majority of the evidence that cannabinoids may have a role in reducing pain or alleviating other symptoms in humans, has been either anecdotal (personal reports, questionnaires), or from small series of case-reports. However, several controlled trials comparing cannabis to other established analgesics or to placebo, have been emerging in the last few years. In a recent review of such trials (3), mostly carried out with rather small numbers of patients, it was reported that THC and nabilone can produce some relief from symptoms of spasticity, pain, tremor, and the need to void frequently, in patients with multiple sclerosis (8 trials) or spinal cord injury (1 trial).

In one recent study, Wade and colleagues reported on a controlled trial to determine whether cannabis extracts can improve intractable pain symptoms (4). Twenty-four patients (including 18 with MS and 4 with spinal cord injury) were given either THC, cannabidiol (CBD), a combination of the two, or matched placebo. Patients recorded their own symptoms, well-being and intoxication scores on a daily basis. At the end of each two-week period an independent observer rated the severity and frequency of their symptoms and recorded adverse events. The study found that pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were also improved in some patients with these symptoms. Three patients had transient drops in blood pressure and symptoms of intoxication.

Larger scale studies are underway. Possibly the most ambitious is a 660-patient trial, taking place in over 30 medical centers around the world. In this study, supported by the Medical Research Council, patients are assigned to one of several groups: some are taking capsules containing the whole cannabis; others are being given THC, and a final group is being given a placebo. The trial is one-year long and the results are expected by late Spring 2003.

References

1. Croxford, JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 17(3):179-202, 2003.

2. Grundy, RL. The therapeutic potential of the cannabinoids in neuroprotection. Expert Opinion on Investigational Drugs. 11(10):1365-74, 2002.

3. Pertwee, RG. Cannabinoids and multiple sclerosis. Pharmacology & Therapeutics. 95(2):165-74, 2002.

4. Wade, DT, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation. 17(1):21-9, 2003.

This information was last reviewed March 14, 2003.
 

© 2003 Veritas Medicine