The Anti-Munchies

Marijuana is well-known for its ability to stimulate food intake, so it’s not entirely surprising that cannabinoid receptors are emerging as major targets for weight-contol drugs. European authorities approved sales of the CB1 receptor antagonist rimonabant (Sanofi-Aventis) back in 2006. Now Merck is announcing the development of another CB1 antagonist called taranabant, which reportedly decreases caloric intake. The research appears in the journal Cell Metabolism, but I can’t seem to access the article despite my fancy academic licenses.

Scientific American has a nice summary of the findings:

Heymsfield and his team found that obese people given low doses of taranabant consumed fewer calories, expended more energy and shed pounds. The scientists initially tested the drug on animals, which lost weight on doses that inhibited just 30 percent of their cannabinoid receptors. Armed with this knowledge, the researchers used positron emission tomography (PET) imaging to determine the amount (four to six milligrams) of taranabant that would achieve a similar goal in humans.

They found that obese patients lost significant weight during the 12-week trial at surprisingly low doses ranging from 0.5 to six milligrams; those who took a 12-milligram dose consumed 27 percent fewer calories than subjects given a placebo. The researchers reported that plump participants on the drug also expended more energy while at rest and appeared to burn more fat.

Blocking cannabinoid receptors does not come without a cost:

The medical team said higher doses had some potential negative side effects, most notably nausea, vomiting and moodiness. This was not entirely unexpected, Heymsfield said, given that it has the opposite effect of marijuana, which has been known to quell nausea associated with cancer treatments and, also, to calm rather than irritate people.

Perhaps subsequent pharmaceuticals will specifically target hunger and satiety systems without affecting other aspects of cognition. This is a challenging goal considering how little we know about the mechanism of action for drugs like rimonabant and taranabant. A 2005 Nature Neuroscience review argued that the body’s natural ligands for cannabinoid receptors (endocannabinoids such as anandamide and 2-AG) may operate at two levels. First, basal levels of endocannabinoids act on mesolimbic pathways to facilitate the motivation to eat and the subsequent rewards.  Second, the hypothalamus uses endocannabinoids to recruit other hunger hormones after periods of transient food deprivation.

The hypothesis of a dual action in mesolimbic and hypothalamic regions was substantiated by the finding that injection of endocannabinoids into these brain areas stimulates food intake in rats24, 25. Furthermore, endocannabinoid levels vary in both the hypothalamus and the limbic forebrain (but not in the cerebellum, which is not involved in appetite regulation) during the four phases of feeding behavior in rats. These levels are highest during food deprivation and lowest during food consumption, as expected from endogenous orexigenic mediators25. In the hypothalamus, these changes in endocannabinoid levels seemed to be inversely correlated with the changes that are known to occur in blood levels of the neurohormone leptin, which is pivotal in regulating the hypothalamic orexigenic and anoretic signals. Indeed, leptin decreases endocannabinoid levels in the hypothalamus, much as it does for other orexigenic mediators, and obese rodents with defective leptin signaling show significantly higher hypothalamic endocannabinoid concentrations23. It has been suggested that an enhanced endocannabinoid tone is also linked to enhanced ghrelin levels in the bloodstream after food deprivation and may underlie some of the orexigenic effects of this peptide when injected into the rat hypothalamus—effects that are in fact blocked by antagonism at CB1 receptors with rimonabant26.

Despite the multitude of questions that remain to be answered, the development of new drugs like taranabant could help millions of people who struggle with obesity issues. Now that cannabinoid research has established clinical relevance (not to mention profit potential), you can expect to see a lot more of it.

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