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Marijuana flips appetite switch in brain

Sudden attacks of ‘the munchies’ are triggered by a change in the hormone released by neurons.

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Understanding how pot sparks hunger has wider implications for the study of appetite control.

Smoking marijuana may stoke a yearning for crisps, but understanding how it affects hunger is relevant not just to those who indulge in it. The drug has yielded a ripe target for scientists who seek to stimulate or suppress appetite: the receptor CB1, found in cells throughout the body.

When activated by the anti-nausea drug dronabinol — which is also a component of marijuana (Cannabis sativa) — CB1 prompts the release of hunger-promoting hormones 1 . And suppressing its activity is thought to aid in weight loss 2 . But the mechanism by which the receptor kills or kindles appetite is not entirely understood.

Now neuroscientist Tamas Horvath, of Yale University in New Haven, and colleagues report in Nature that nerve cells called pro-opiomelanocortin (POMC) neurons play a key role in this process 3 . POMC had generally been thought to promote satiation, but Horvath’s team found that POMC neurons in the brain release not just a hunger-suppressing hormone, but also one that promotes appetite.

Which hormone is secreted is regulated by a protein in the cells’ mitochondria, structures that regulate energy levels. When the CB1 receptor is activated, this mitochondrial protein induces POMC to switch from secreting the substance that suppresses gorging to one that encourages it.

The finding is intriguing, says Uberto Pagotto, a neuroscientist at the University of Bologna who has studied cannabinoids for many years. “It gives us a different starting point to look at CB1 receptors and the mitochondria,” he says.

Change in attitudes

Research into manipulating the cannabinoid system to regulate appetite is once again gaining favour, having been starved of support for years. Marijuana use is becoming increasingly acceptable and that means that “people are coming to see studying [cannabinoids] and how they’re processed as a natural and beneficial thing to pursue”, says Horvath. The biggest hurdle was not the legal status, he adds, but the fact that drug firms have been cautious about funding such work after problems arose with weight-loss drugs that worked by targeting CB1.

In 2008, for example, Sanofi-Aventis was forced to withdraw rimonabant after studies showed that the weight-loss drug was linked to depression. As a result, pharmaceutical firms including Merck, Pfizer and AstraZeneca stopped their research on similar compounds. Some of these potential treatments were in late stages of development, and pulling them likely cost the industry several billion dollars, reckons Steven Heymsfield, an obesity researcher now at Pennington Biomedical Research Centre in Baton Rouge, who had worked on Merck’s CB1 drug, taranabant.

“Until recently, many people I’ve been speaking to have lamented that it has been incredibly hard to get funding to do this research,” says George Kunos, an expert on cannabinoids and appetite at the US National Institutes of Health in Bethesda, Maryland. But some companies have renewed their interest. One possible approach is to target only the receptors present in the peripheral nervous system, so as to avoid the psychiatric side effects of inhibiting CB1 in the brain.

But much remains unknown about how the body processes cannabinoids, Kunos says. For example, activating CB1 with a drug, as Horvath’s team did, may cause a different reaction from when it is stimulated with cannabinoids the body naturally produces.

“This was high-calibre work that fits well and adds to the research that has been going on,” says Pagotto, “but how it can be practically applied may still be some ways off.”

References

Kola, B. et al. J. Biol. Chem. 280 , 25196 – 25201 ( 2005 ).

Black, S. C. Curr. Opin. Investig. Drugs. 5 , 389 – 394 ( 2004 ).

Sudden attacks of ‘the munchies’ are triggered by a change in the hormone released by neurons.

Reefer research: cannabis ‘munchies’ explained by new study

Scientists have shown the urge to eat after smoking is caused by cannabinoids hijacking brain cells that normally suppress appetite

Research on the ‘munchies’ side-effect of smoking cannabis has helped scientists understand how the appetite centre of the brain responds to marijuana. Photograph: Alamy

Research on the ‘munchies’ side-effect of smoking cannabis has helped scientists understand how the appetite centre of the brain responds to marijuana. Photograph: Alamy

Last modified on Wed 29 Nov 2017 23.07 GMT

Besides making a bongo drum sound inexplicably magical and enhancing a person’s ability to talk nonsense for extended periods of time, generations of cannabis smokers will recognise the “munchies” as one of the drug’s most reliable side-effects.

Now scientists have shown that the insatiable urge to eat after smoking is caused by cannabinoids hijacking brain cells that normally suppress appetite. The study suggests that cannabis causes the brain to produce a different set of chemicals that transform the feeling of fullness into a hunger that is never quite satisfied.

Scientists believe the findings, which illuminate a previously unknown aspect of the brain’s feeding circuitry, could help design new drugs that would boost or suppress appetite at will.

Tamas Horvath, who led the work at Yale University, said: “By observing how the appetite centre of the brain responds to marijuana, we were able to see what drives the hunger brought about by cannabis and how that same mechanism that normally turns off feeding becomes a driver of eating. It’s like pressing a car’s brakes and accelerating instead.”

Scientists have previously shown that activating a cannabinoid receptor in the brain, called CB1R, tends to trigger an increased desire to eat. Until now, however, it was not known which bits of the brain’s appetite circuitry were involved. The latest study tested this in mice, by injecting cannabinoids into the brain and monitoring which neurons were activated in response.

The research, published in Nature, unexpectedly showed that activity was boosted in a group of nerve cells called POMC (pro-opiomelanocortin) neurons, which normally produce feelings of satiety.

“We were surprised to find that the neurons we thought were responsible for shutting down eating, were suddenly being activated and promoting hunger, even when you are full,” said Horvath. “It fools the brain’s central feeding system.”

Further investigation showed that the cannabis “subverted” these neurons, causing them to release hunger stimulating chemicals rather than appetite suppressing chemicals, explaining how the drug can produce a sudden urgent desire for a packet of Doritos or a bowl of Coco Pops.

The scientists speculate that cannabinoids “flips the switch” on the neurons by binding to tiny energy-generating organelles inside the cells, called mitochondria, in addition to receptors on the neurons’ surface.

Intriguingly, people who smoke cannabis regularly do not tend to gain weight – if anything they are less likely to be obese. It is not clear whether this is because the “munchies” effect wears off in people who smoke regularly, or whether habitual smokers eat less when not under the influence of the drug.

The scientists are now exploring whether the brain circuitry that produces the “munchies” is also central to the feeling of being “high”.

Previously, Japanese researchers have shown that cannabis appears to interact with taste receptors to enhance the sweet taste in foods, thus boosting certain cravings. Other work has shown that mice given THC (tetrahydrocannabinol), one of the active ingredients in cannabis, had an enhanced sense of smell and an overactive “reward” system, which provides hints to why some people find eating especially gratifying when under the influence.

Scientists have shown the urge to eat after smoking is caused by cannabinoids hijacking brain cells that normally suppress appetite