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This is your preliminary warning about a weight–loss drug called Rimonabant that works by blocking cannabinoid receptors in the brain. Scientists from Sanofi, France’s biggest pharmaceutical company, announced favorable clinical–trial results at this year’s meeting of the International Cannabinoid Research Society and expect FDA approval to market Rimonabant within a year.
Cannabinoid receptors are proteins on the surface of certain cells to which certain compounds bind, setting off molecular cascades within the cells that produce effects in the body such as reduced inflammation, increased appetite, etc. Two kinds of cannabinoid receptors have been discovered — CB1, highly concentrated in the brain and central nervous system, and CB2, found mainly in tissues associated with the immune system.
There are three different kinds of cannabinoids, or chemical "agonists" that activate the cannabinoid receptors. They are, in order of evolutionary appearance: compounds made in the body for purposes of neurotransmission, compounds unique to the cannabis plant (the most famous being delta–9 THC), and compounds made in the lab — synthetics — developed in recent decades.
The cannabinoids made in the body are called "endocannabinoids" (just as the body’s endogenous morphine–like chemicals are called "endorphins"). The first to be identified, by Raphael Mechoulam and William Devane in 1992, was named "anandamide" after the Sanskrit word for "bliss." It has since been learned that endocannabinoids help regulate the cardiovascular, digestive, endocrine, excretory, immunological, nervous, reproductive, and respiratory systems.
Rimonabant is an "antagonist" drug that engages the CB1 receptors so they can’t be activated. Originally called SR–141716, it was developed by Sanofi in the early ’90s as a research tool. If a given effect is blocked by SR–141716, that effect is said to be mediated by CB1 receptors. Rimonabant is SR–141716 redefined as a "therapeutic drug" that counteracts unwanted effects — like overeating — mediated by the cannabinoid receptor system.
In a talk at the ICRS meeting entitled "Clinical Results with Rimonabant in Obesity," Sanofi researcher Gerard Le Fur reported that the drug had done well in phase–three clinical trials involving 13,000 patients. The trials were conducted at numerous sites in the U.S. Obese patients were treated with Rimonabant for 52 weeks. "Over 72% of patients at 1 year showed a weight loss of greater than 5 percent, with over 44% showing a weight loss of greater than 10%," according to Le Fur. "There was also an increase in HDL–cholesterol values, a reduction in triglyceride values and reductions in glucose and insulin values… The general tolerance of the compound was excellent."
But the advent of Rimonabant troubles California doctors who have made a specialty of monitoring their patients’ cannabis use, as well as some scientists who are studying the basic nature of the cannabinoid system. Jeffrey Hergenrather, MD, of Sebastopol — one of the few clinicians to attend the ICRS meeting, which was held in Paestum, Italy, in late June — says "We are only now be becoming aware of the modulating effects the cannabinoids have on the body and mind. The consequences of interfering with the cannabinoid receptor system have not been evaluated in normal human physiology."
Le Fur and other Sanofi researchers were asked how a drug could block the CB1 receptor system without adversely affecting mood, sleep, pain relief, and other CB1–mediated aspects of well–being. The answers were vague — other neurotransmitters may play compensatory roles. We were told that no pattern of adverse effects had been observed during the clinical trials, and that such effects are probably so rare that they won’t be detectable until Rimonabant has been used by millions of people over a period of years.
The developer of another antagonist drug, a rival of Sanofi’s, claimed that Rimonabant induced "food aversion" in five percent of the test subjects. Le Fur responded that obesity was such a widespread and serious health problem that five percent seems like an acceptable rate of anorexia. Other criticisms and misgivings were only whispered. A multiple sclerosis specialist told of a case in which Rimonabant apparently caused an immediate, extreme exacerbation. A physician wondered — since the body’s own cannabinoids have neuroprotectant and anti–oxidant functions — if Rimonabant users would be at increased risk for stroke and cancer. But the negative remarks were anecdotal or speculative; the positive data belonged to Sanofi.
Le Fur and two colleagues accepted the ICRS’s 2004 achievement award on behalf of their company. It was presented by Mechoulam, the grand old man of the field. who observed that Sanofi had shown great foresight in developing a weight–loss drug in the late 1990s, because it has since swallowed up two much larger drug companies, Synthelabo and Aventis.
From the perspective of the scientists in the ICRS — mainly employees of universities or pharmaceutical companies who get funding from the U.S. National Institute on Drug Abuse– it’s a win–win–win to honor Sanofi for developing CB–receptor antagonists as "new therapeutic drugs." NIDA is eager to sponsor research involving cannabinoid antagonists. A lot will be learned about the cannabinoid system, its mechanism of action, etc. And a therapeutic effect is a therapeutic effect, whether it’s produced by activating or blocking the cannabinoid receptors.
But common sense and a few cautious clinicians say DANGER DANGER DANGER. CB1 receptors are concentrated in the cerebellum and the basal ganglia (responsible for motor control, which may help explain why marijuana eases muscle spasticity in disorders like multiple sclerosis), the hippocampus (responsible for storage of short–term memory), and the limbic system (emotional control).
Although other neurotransmitters may play compensatory roles when the cannabinoid receptors are blocked, the longterm impacts will not be known until years after Sanofi gets approval to market Rimonabant to the slimness–loving masses. Before marketing commences, says Hergenrather, "It would be ethical to design longitudinal studies to assess the consequences of interfering with the cannabinoid system."
Other uses for cannabinoid–antagonist drugs are being studied with active encouragement from NIDA. Walter Fratta of the University of Cagliari gave a paper in Paestum proposing antagonists "as therapeutic agents to prevent relapse to heroin abuse." Carl Lupica of NIDA discussed Rimonabant as a "potential treatment" for food, alcohol and nicotine cravings. "It is also clear that marijuana craving may be successfully treated by this drug," according to Lupica.
Alas, this was supposed to be the year that G.W. Pharmaceuticals won the ICRS achievement award. G.W. is the British firm that in 1998 got government approval to develop and test an extract of the cannabis plant which it formulated as an oral spray and dubbed "Sativex." Clinical trials of Sativex as a treatment for neuropathic pain, multiple sclerosis and other conditions were conducted and favorable results reported to the regulators. Bayer agreed to market Sativex in Europe when the approval came through. G.W. generously made Sativex and other plant extracts with different cannabinoid contents available to investigators who previously could experiment only with NIDA–weed or synthetics.
But the marketing approval that Guy said he expected by the end of 2003, and then by spring ’04, has yet to be granted. So he and his associates had to walk a bit of a tightrope in Paestum, reassuring all concerned that Sativex certainly will get approved, while not risking any more misstatements about when.
Guy cited favorable data produced in recent trials of Sativex as a treatment for pain in rheumatoid arthritis and spasticity in multiple sclerosis. Unfortunately, in the U.K. as in the U.S., favorable trial results can count for less than the establishment connections of the doctors who conduct them. And so the British regulatory authorities continue to ponder G.W.’s dossier, while the banquet at this year’s ICRS meeting was hosted by Sanofi.