ReviewCannabinoids in medicine: A review of their therapeutic potential
Introduction
Originating from Central Asia, cannabis is one of the oldest psychotropic drugs known to humanity. The beginnings of its use by humans are difficult to trace, because it was cultivated and consumed long before the appearance of writing. According to archeological discoveries, it has been known in China at least since the Neolithic period, around 4000 BC (McKim, 2000).
There are several species of cannabis. The most relevant are Cannabis sativa, Cannabis indica and Cannabis ruderalis. Cannabis sativa, the largest variety, grows in both tropical and temperate climates. The two main preparations derived from cannabis are marijuana and hashish. Marijuana is a Mexican term initially attributed to cheap tobacco but referring today to the dried leaves and flowers of the hemp plant. Hashish, the Arabic name for Indian hemp, is the viscous resin of the plant (Ben Amar and Léonard, 2002).
The Emperor of China, Shen Nung, also the discoverer of tea and ephedrine, is considered to be the first to have described the properties and therapeutic uses of cannabis in his compendium of Chinese medicinal herbs written in 2737 BC (Li, 1974). Soon afterwards, the plant was cultivated for its fibre, seeds, recreational consumption and use in medicine. It then spread to India from China (Mechoulam, 1986).
In 1839, William O'Shaughnessy, a British physician and surgeon working in India, discovered the analgesic, appetite stimulant, antiemetic, muscle relaxant and anticonvulsant properties of cannabis. The publication of his observations quickly led to the expansion of the medical use of cannabis (O'Shaugnessy, 1838–1840). It was even prescribed to Queen Victoria for relief of dysmenorrhea (Baker et al., 2003).
In 1854, cannabis is listed in the United States Dispensatory (Robson, 2001). It is sold freely in pharmacies of Western countries. It would be available in the British Pharmacopoeia in extract and tincture form for over 100 years (Iversen, 2000).
However, after prohibition of alcohol was lifted, the American authorities condemned the use of cannabis, making it responsible for insanity, moral and intellectual deterioration, violence and various crimes. Thus, in 1937, under pressure from the Federal Bureau of Narcotics and against the advice of the American Medical Association, the U.S. Government introduced the Marihuana Tax Act: a tax of $1 per ounce was collected when marijuana was used for medical purposes and $100 per ounce when it was used for unapproved purposes (Solomon, 1968, Carter et al., 2004). In 1942, cannabis was removed from the United States Pharmacopoeia, thus losing its therapeutic legitimacy (Fankhauser, 2002).
Great Britain and most European countries banned cannabis by adopting the 1971 Convention on Psychotropic Substances instituted by the United Nations.
Cannabis contains more than 460 known chemicals, more than 60 of which are grouped under the name cannabinoids (Ben Amar, 2004). The major psychoactive ingredient of cannabis is delta-9-tetrahydrocannabinol, commonly known as THC. Other cannabinoids present in Indian hemp include delta-8-tetrahydrocannabinol (Δ8THC), cannabinol (CBN), cannabidiol (CBD), cannabicyclol (CBL), cannabichromene (CBC) and cannabigerol (CBG), but they are present in small quantities and have no significant psychotropic effects compared to THC (Smith, 1998, McKim, 2000). However, they may have an impact on the product's overall effect (Ashton, 2001). Cannabinoids exert their actions by binding to specific receptors: the CB1 cannabinoid receptors, discovered by Devane et al. (1988), then cloned by Matsuda et al. (1990) and the CB2 cannabinoid receptors, identified by Munro et al. (1993). Both cannabinoid receptors are part of the G-protein coupled class and their activation results in inhibition of adenylate cyclase activity. The identification of agonists (anandamide and 2-arachidonylglycerol, the most studied endocannabinoids, participate in the regulation of neurotransmission) and antagonists of these receptors has stimulated interest in the medical uses of cannabis (Baker et al., 2003, Iversen, 2003, Di Marzo et al., 2004).
Despite its illegality, patients have continued to obtain cannabis on the black market for self-medication. In 1978, in response to the success of a lawsuit filed by a glaucoma patient (Robert Randall) who had begun treating himself by smoking marijuana after losing a substantial part of his vision, the U.S. Government created a compassionate program for medical marijuana: 20 people suffering from debilitating diseases legally received marijuana cigarettes from the National Institute on Drug Abuse (NIDA), after approval by the Food and Drug Administration (FDA). This program was closed to new candidates in 1991 by President Bush, but still recently seven people continued to receive their marijuana (Mirken, 2004).
In Canada, 14 years after the 1988 arrest of Terrance Parker (an Ontario patient who had discovered that marijuana consumption relieved his epileptic attacks, contrary to conventional drugs) and 1 year after the Ontario Court of Appeal ruled that discretionary regulation of marijuana use for medical purposes was contrary to the principles of the Canadian Charter of Rights and Freedoms, the Government of Canada decided to draft new regulations (Hoey, 2001). Thus, since July 30, 2001, the Marihuana Medical Access Regulations (MMAR) allow Canadian patients suffering from a serious disease to be eligible for therapeutic marijuana consumption. As of April 2005, 821 people were thus authorized to possess marijuana for medical purposes and 363 physicians had supported a request for authorization of possession (Health Canada, 2005).
The therapeutic applications of cannabis and its derivatives have been studied by various world bodies, including the Scientific Committee of the House of Lords in Great Britain (1998), the Institute of Medicine in the United States (1999) and the Senate Special Committee on Illegal Drugs in Canada (Nolin et al., 2002). Since 2003, medicinal cannabis, in standard cannabinoid concentrations, is sold in pharmacies in the Netherlands by medical prescription (Gorter et al., 2005). It is presently available in two dosages: cannabis flos, variety Bedrocan, containing 18% dronabinol and 0.8% cannabidiol and cannabis flos, variety Bedrobinol, containing 13% dronabinol and 0.2% cannabidiol (Office of Medicinal Cannabis, 2005). Various Western countries have authorized and conducted clinical trials on cannabis and its derivatives. Thus, for example, since 1999, Health Canada, in collaboration with the Canadian Institutes of Health Research, has established a Medical Marihuana Research Program (Health Canada/CIHR, 1999).
To date, there are a multitude of anecdotal reports and a certain number of clinical trials evaluating the therapeutic applications of cannabis and its derivatives. This review reports on the most current data available on the therapeutic potential of cannabinoids.
Section snippets
Methodology
A systematic search was performed in Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human.
After initial sorting, all articles and reviews including clinical protocols or a summary of the literature evaluating the therapeutic potential of cannabinoids in humans were
Results
The meta-analysis identified 10 pathologies in which controlled studies on cannabinoids have been published: nausea and vomiting associated with cancer chemotherapy, loss of appetite, pain, multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy, glaucoma, Parkinson disease and dystonia.
Discussion
The summary of the clinical trials conducted with nabilone and dronabinol reveals that these two cannabinoids have a significant antiemetic efficacy, generally equivalent or superior to that of first-generation antiemetic drugs to relieve nausea and vomiting associated with cancer chemotherapy. Unfortunately, this interest has largely faded since the marketing of new, more potent and less toxic antiemetic drugs. Thus, the existing oral formulations are not recommended as first-line antiemetics.
Conclusion
The progress achieved over the past 15 years in understanding the action mechanisms of THC and other cannabinoids has revived the therapeutic interest in these substances.
The relaxation of the regulatory norms for therapeutic cannabis and the accomplishment of a greater number of controlled clinical trials make it possible to affirm that cannabinoids exhibit an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, as well
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