The Marijuana Receptors: A New Medical Target?

Banned by the U.S. government and legalized by other nations, praised by some college students and disdained by others, marijuana is an issue of contention not only in policy writing but also in the medical sphere. The endocannabinoid system — which regulates the psychoactive effects of marijuana — is emerging as a new medical target in pain research and many other areas, such as weight loss and neurological disorders. However, the stigma associated with cannabis and cannabinoids leave scientists and doctors in a controversial conundrum.

Although the endocannabinoid system (ECS) is a relatively “young” discovery in the world of signaling systems (the term “endocannabinoid” was coined in the mid-1990s), it is surprisingly heavily involved with a number of our bodily functions and pathological conditions. This elaborate network of receptors and proteins — which includes endocannabinoids, enzymes, and the cannabinoid receptors CB1 and CB2 — plays major roles in our immune function, autonomic nerve function, memory, stress response, and appetite. Research even demonstrates a clear relationship between altered endocannabinoid signaling with cancer, cardiovascular disorders, eating disorders, and psychiatric and neurological disorders.

Enticed by the system’s powerful role in regulating cravings, mood, pain, and memory, drug designers have endeavored to develop drugs that can improve one’s physical and mental health despite much controversy. While some researchers have been successful, others point out gaps in our knowledge and understanding of the system. In 2006, the pharmaceutical company Sanofi-Aventis began selling a new weight-loss drug, Rimonabant, that worked by targeting CB1 receptors and reducing patients’ appetites. Within six months, however, the company had received more than 900 reports of side effects, such as depression and nausea, and the drug was then pulled from the market. Studies later linked the existence of a previously undiscovered second receptor, CB2, to these effects.

The ECS is responsible for appetite and award-seeking behavior. Courtesy of BBC Science Features.

“It’s against the propagation of life in the long run to interfere with the central components of appetite,” asserts Dr. Tamas Horvath, who serves as Chair of the Section of Comparative Medicine and works as a Professor of Neurobiology and Obstetrics, Gynecology, and Reproductive Sciences at the Yale School of Medicine. For this reason, the development of such drugs that target ECS receptors has raised ethical controversies; when we try to manipulate a system as widespread and effective as the ECS without sufficient understanding, we can end up with a broad spectrum of unintended effects. “It is virtually impossible to selectively interfere with either a brain region or a peripheral organ such as the liver, without having any other impact on other tissues,” Horvath adds.

Other pharmaceutical companies have tried to develop powerful painkillers that imitate how the active ingredient in marijuana, delta-9-tetrahydrocannabinol (THC), reacts with receptors in the body’s endocannabinoid system. The British company GW Pharmaceuticals is one of these companies currently seeking FDA approval for their marijuana mouth spray, Sativex. GW Pharmaceuticals is attempting to quell concerns of recreational drug abuse by utilizing only two cannabinoid compounds that could counterbalance each other: THC and CBD (cannabidiol). While THC would activate CB1 receptors for pain relief, CBD is believed to suppress the “high” feeling that comes as a side effect of THC. The company also advertises that Sativex, as a mouth spray, takes at least an hour to start producing an effect — a time period too long to be easily abused by drug users.

Sativex is the first medicine to be naturally derived from plant extracts of the cannabis sativa plant. Image courtesy of Inpharm.

Although the FDA has set strict guidelines regarding cannabinoid pharmaceutical drugs, there is evidence that a policy shift may soon allow more of these drugs to appear on the market. In the 1980s, Marinol and Cesamet, two drugs based on synthetic cannabinoids, were approved for alleviating the nausea and vomiting for patients undergoing chemotherapy and for stimulating the appetite of patients with AIDS. Further trials for these drugs have concentrated on movement disorders such as Parkinson’s syndrome, chronic pain, dystonia, and multiple sclerosis. Despite claims that these drugs are based on synthetic compounds and have low risk of physical or mental dependence, concerns still exist over whether such cannabinoid-based drugs could or would still be abused for recreational use.

While developing new drugs targeting the ECS can bring about groundbreaking medical treatments, the extensive and highly integrated nature of the ECS has made it very difficult to avoid negatively affecting the other parts of body. The quest and urge to better understand the endocannabinoid system needs to be tackled before we can begin to see the ECS as a common medical target.