A study led by Yale researchers has uncovered a novel contribution of a subset of neurons in driving marijuana induced feeding, otherwise known as “the munchies.”

Using mouse models, a group led by Yale researchers found that a subset of neurons which had been thought to promote fullness were actually integral in inducing hunger in the presence of cannabinoids, the active ingredient in marijuana. These neurons, located in the hypothalamus — the part of the brain that links the nervous system to the endocrine system — normally produce a satiety hormone but switch their function and produce a hunger-driving hormone when their cannabinoid receptor is activated. The findings were published in the journal Nature on Feb. 18.

“We ran these experiments as a control study to see whether these neurons would be turned off at a time when you are hungry or exposed to cannabinoids,” said professor of comparative medicine and neurobiology Tamas Horvath, who was the study’s senior author. “And we found that they are not only not turned off, but they are actually more turned on than before, which is the exact opposite of what has been shown by the previous 20 years of work.”

Marco Koch, the study’s lead author, who is currently in the department of anatomy at the University of Leipzig and a previous research associate in Yale’s Horvath Lab, said the research spanned three years. When they first saw the findings, they thought there might be something wrong with their protocol.

“We followed up our finding by many control experiments, and they all confirmed this contrary, surprising initial finding,” Koch said.

After understanding that cannabinoids flip a hormonal switch in those neurons, the group sought to identify the cellular mechanism by which the switch is flipped. They found the process was linked to mitochondrial protein modification in those neurons. When they blocked that mitochondrial adaptation, cannabinoid induced feeding was blocked and the mice ate less, Horvath explained.

Professor of psychiatry, neuroscience and pharmacology at Mount Sinai Hospital Yasmin Hurd, who was not involved in the study, praised its simplicity and apt use of model organisms.

“I thought it was a beautiful, mechanistic study. You cannot achieve this kind of mechanistic understanding in humans, so I do think these animal models were quite appropriate for the questions they were asking,” she said, adding that studies of this quality are rare in the field of marijuana research.

Horvath, reflecting on the study, said that although he was initially surprised by the results, it is logical that these neurons would have the ability to switch their function and promote hunger even when the body should feel full. It is evolutionarily grounded in humans’ past as hunter-gatherers, when it would have been advantageous to eat as much as possible when food was available.

“We used to spend our time in the scarcity of food,” he said.

Hurd said this research may help researchers understand the underlying mechanisms behind appetite, which could in turn help them create drugs that could target this appetite-regulating pathway. Horvath agreed, saying that these medicines could potentially selectively flip on hunger in people who often do not feel it, such as cancer or AIDS patients.

Koch said the group in Leipzig plans to follow up on this research by developing therapeutics that will selectively modify appetite as a way to treat obesity and eating disorders in which appetite has been distorted. Horvath’s group is pursuing the possible mechanistic links between the “munchies” and the high associated with marijuana use, after finding that these hypothalamic neurons produce endorphins — hormones associated with pleasure — when exposed to canniboids. He hopes to further uncover cellular mechanisms that bring about the switch in these neurons in the hopes of developing pharmacological compounds that could make that switch for patients.

Funding for this research was provided by the National Institue of Health, the American Diabetes Association, the Klarmann Family Foundation, the Helmholtz Society and the Deutsche Forschungsgemeinschaft SFB.