Targeting Craving Shows Therapeutic Potential


by Brenda Patoine

May, 2006

A new weight-loss drug illustrates both the promise and problem with tackling cravings, such as for food or nicotine, via the brain’s endogenous cannabinoid system. The promise is fueled by a growing body of evidence from laboratory and clinical studies that indicate the cannabinoid system is intricately involved in the control of appetite, feeding behavior, and body weight.

The potential problem is that the cannabinoid system, by modulating how signals are transmitted between nerve cells, also affects a host of other physiological functions body- and brain-wide. These functions range from reward and motivation to mood and anxiety, pain, and memory.

As a result, a therapy that tweaks the system to achieve one goal has the potential to produce unwanted effects. But that has not stopped pharmaceutical companies from earnestly pursuing “cannabinoid modulators,” dozens of which are now being tested in clinical trials and preclinical studies.

This emerging class of drugs is the first fruit of a burgeoning research sector aimed at understanding the many actions of endogenous cannabinoids, naturally occurring chemicals that serve physiological purposes. These new drugs try to take advantage of the receptors that bind the active chemical in hemp (cannabis), the plant from which marijuana is derived. As is the case with endogenous opioids, which are chemically similar to opiate drugs, the receptors’ function is to recognize a naturally occurring substance, allowing for the pursuit of pharmacological therapies.

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Cannabinoid modulators, which alter nerve cell signaling and affect craving, may hold promise as a treatment for obesity. Scientists are cautious, however. © Getty Images

Focus on Obesity

Obesity represents a first target of cannabinoid modulators. But the sheer size of the market for a diet drug—an estimated 65 percent of Americans are overweight or obese—combined with the safety problems of previous weight-loss remedies, has some experts concerned.

Some go so far as to question whether drugs are the right approach to weight loss at all. While taking a pill to lose those extra pounds may appeal to many people struggling with their weight (a fact not lost on pharmaceutical companies eager to tap this vast market), finding a “magic bullet” that safely and effectively quells appetite or melts away fat is unlikely.

So far, all attempts to do so have failed, and high hopes born from basic science findings have been dashed time and again. In the mid 1990s, for instance, many people thought the diet miracle was imminent based on the discovery of the gene for leptin, a signaling factor in fat tissue that seemed to be critical for healthy weight maintenance.

Mice genetically engineered to lack leptin quickly became obese. If leptin deficiency caused obesity in animals, the thinking went, then perhaps increasing leptin levels could reverse obesity. A lot of people thought leptin held the solution to getting a handle on weight control.

It turned out not to be so simple. The neurological and peripheral systems that regulate “energy homeostasis,” the balance of caloric intake vs. energy expenditure, are incredibly complex and multi-layered. From an evolutionary perspective, adequate food intake is arguably the most critical factor in survival, so nature built a redundant series of checks and balances to ensure the health of a given species.

“The redundancy of the system definitely plays a major role” in the failure of previous pharmacotherapy approaches for weight loss, says Tamas Horvath, a Yale neurobiologist. “It’s a very plastic system both in the brain and the periphery, so if you try to push it one way it will find a way to counter-act your actions.”

Horvath is adamant that modifying cannabinoid levels is not the ideal way to attack obesity, but he believes there is probably a subpopulation of people who might benefit from a drug such as the one recently deemed “approvable” for weight loss by the U.S. Food and Drug Administration. The drug, called rimonabant, blocks a class of cannabinoid receptors in the brain and periphery (cannabinoid-1 or CB-1 receptors). It transiently suppresses appetite and food intake while also more stably producing direct beneficial effects on cells in the liver and fat tissue.

Rimonabant has now been studied in about 3,000 people worldwide, and study participants taking the higher dose of the drug (20 mg) reduced their body weight by an average of 4.5 per-cent. In addition, people taking rimonabant had favorable changes in blood fats, cholesterol, and glucose tolerance, all of which are risk factors for cardio-vascular disease.

Still, the clinical trials raised some notes of caution, including a high dropout rate among participants, and Food and Drug Administration (FDA) approval of the drug seems to have hit a speed bump that is slowing its launch (see “Speed Bump for Rimonabant?”). Even with the questions outstanding, experts and pharmaceutical analysts are confident rimonabant will be the first cannabinoid regulator to hit the market, probably within a year.

"I was amazed by the very large number of often unrelated physiological systems and diseases in which there is published evidence that endocannabinoids are involved, and in which the possibility exists that modifying ECB action has therapeutic potential."

Beyond Obesity: Ramping Up ECBs

Weight loss may represent only the tip of the iceberg for this emerging class of endocannabinoid drugs, or ECBs.

Rimonabant itself also has been studied in nicotine addiction (an indication the FDA rejected), and George Kunos, a senior investigator at the National Institute on Alcohol Abuse and Alco-holism has begun a study to test its usefulness in reducing alcohol cravings among heavy drinkers. And that may be just the beginning of the potential applications for cannabinoid modulators.

“I was amazed by the very large number of often unrelated physiological systems and diseases in which there is published evidence that endocannabinoids are involved, and in which the possibility exists that modifying ECB action has therapeutic potential,” Kunos says.

Many other cannabinoid modulators are at various stages of preclinical and clinical development. Some, like rimonabant, also block the CB-1 receptor. Others seek to stimulate this same path-way, turning up, rather than shutting down, endocannabinoid signaling. This aim has been a bit trickier to accomplish because drug developers want a medicine that is therapeutically active but does not induce the psychotropic effects and controversies connected with the medical use of marijuana.

Daniele Piomelli, a pharmacologist at the University of California, Irvine, says researchers have used two primary strategies to accomplish this goal. The first seeks to selectively activate the subclass of cannabinoid receptors found mostly outside of the brain (dubbed CB-2 receptors). Under review are agents that either do not couple with the slightly different molecular structure of receptors in the brain or do not cross the blood-brain barrier, the tight layer of tissue in brain blood vessels that seals off the brain to protect ultrasensitive neurons.

This approach may be particularly suitable for treating pain conditions, Piomelli says, because CB-2 receptors are located in areas of the peripheral nervous system that are key relay stations for the processing of pain and inflammation.

“Many animal studies have demonstrated very clearly that if you activate those receptors, you virtually shut off the pain signal before it ever gets to the spinal cord and into the brain,” he says.

Companies pursuing this approach are developing CB-2 agonists “that work like a charm in animal studies” but do not cross the blood-brain barrier, he adds.

As of April 2005, more than a dozen cannabinoid modulators were under development for pain, according to a report in Drug Discovery Today, including cancer pain, general pain, and post-herpetic pain (from shingles).

The other strategy for ramping up endogenous cannabinoid levels is to decrease the enzymes that degrade them. “If we clog the drain that empties endogenous cannabinoid signals, the signals increase—but only in specific areas of the brain,” Piomelli says. The net result, he says, is to produce very select antianxiety, antidepressant, and analgesic actions, without the undesirable psychotropic effects.

Drug candidates that act through this mechanism are under development, Kunos says: “Some are very likely to emerge within a year or two.”