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The “munchies” may be triggered not only by marijuana hitting the brain, but also by its effects on the gut, according to new research that suggests intriguing possibilities for the development of new drugs to fight obesity.

It turns out that, biologically, the effect of marijuana on the gut mirrors that of eating fatty foods. Studying the digestive tract of rats, researchers led by Daniele Piomelli, professor of pharmacology at the University of California, Irvine, teased out why that first bite of fatty food spurs increased craving.

The taste of fatty food hitting the tongue sets off a cascade of cellular effects. Initially, it sends a message to the brain. The brain then sends a message to the gut, where intestinal receptors are stimulated to produce endocannabinoids. In turn, these chemicals affect hunger and satiety and ramp up your appetite for even more fat-laden foods. That’s why you can’t eat just one French fry.

The intestinal receptors, known as CB1 receptors, are the same type of receptors that interact in the brain with THC, the main active ingredient in cannabis. That helps explain why marijuana notoriously triggers the “munchies:” a desire to eat high-fat or sweet foods. But, until now, scientists had thought all the action was in the brain.

Piomelli’s group designed a clever experiment in rats to study where the munchies arose. The rats were given various liquid diets: a health shake, a sugar solution, a protein-heavy liquid and high-fat drink made with corn oil. The food was surgically prevented from staying in the rats’ stomachs; it was drained through a tube before it could reach the intestines. That allowed the researchers to figure out whether the signal to keep eating came from the brain based on the taste of fatty foods on the tongue, or whether the gut was somehow involved.

Since the food never reached the gut, the researchers expected to find that the signal occurred only in the brain. “We were looking everywhere and we were sure that somewhere in the brain CB1 would be activated,” says Piomelli. “Very much to our surprise, we saw nothing of the sort.”

Fortunately, after the feeding experiment, researchers had saved frozen organ tissues from the rats. By going back and examining them, they discovered that fatty food activated CB1 receptors in part of the upper intestine, the jejunum. Further investigation revealed that this occurs because tasting fat triggers the brain to want more — and this signals the gut to increase activity at CB1 receptors, making craving stronger.

The intestinal area affected was not a surprise. “The gut’s got a brain of own and that’s one of the very important regions,” says Piomelli. Indeed, the gut has more nerves than any other area of the body outside the brain (and even more of the mood-associated neurotransmitter serotonin than the brain does).

Piomelli notes that evolutionarily speaking, it would make sense for animals to gorge on as much fat as possible. You never know whether famine is around the corner. But the researchers were also surprised to find that it was only fat — not the sugar- or protein-laden liquids — that activated gut CB1 receptors. “Sugar and protein had no effect,” Piomelli says, noting that there must be other mechanisms aside from CB1 involved in the appetite pathway, because smoking marijuana can also produce sugar cravings.

The researchers found that when they blocked CB1 receptors with a drug, rats lost interest in eating additional fat (but not other types of food). If a drug could be developed to mimic that effect — to reduce the cravings spurred by having a single potato chip — it could be enormously helpful in fighting obesity and binge eating.

In fact, one such drug, rimonabant (Acomplia), which blocks CB1 receptors in both the brain and body, made it to market in Europe as an effective obesity fighter. But it was not approved by the U.S. Food and Drug Administration. Ultimately, due to safety concerns over increased risk of anxiety, depression and even suicide, it was pulled in Europe.

“Rimonabant … induced bad side effects like suicidal thoughts due to its activity [in the brain],” says Jonathan Farrimond, a researcher at the University of Reading who studies cannabinoids and feeding and was not associated with the study. So to avoid side effects, a new drug would have to block gut receptors without affecting the brain.

In Piomelli’s study, the researchers used just such an experimental drug, which blocks CB1 but does not cross the blood-brain barrier. Unfortunately, this chemical has toxic metabolites that prevents it from being used in humans. Still, the research supports the idea that a safer CB1-blocking compound is possible.

“Our research suggests that one can target binge eating with a peripheral CB1 antagonist,” says Piomelli. He says people might one day avoid or reduce obesity with a “pill to take when one has the urge to splurge on high-fat foods like French fries, potato chips or ice cream.”

Since Piomelli’s research was done only on rats and looked only at short-term feeding, rather than weight gain over time, much more work is required before a new drug could be developed. The study was published in the Proceedings of the National Academy of Sciences.