Humans have known and used the cannabis plant for as long as 10,000 years. During this time it has been utilized to such different things as to make ropes and clothes, to induce mental states in religious rituals and to treat diseases. Once considered a sacred plant, possession and use of cannabis is illegal in most countries, although a debate on its use with medicinal purposes has sparked in the last years resulting in changes in its legal status in many places.
Most of the effects of the cannabis plant are due to the action of a group of chemical compounds called cannabinoids. Strange as it may seem, cannabinoid research is a very active field, especially in the area of neuroscience. There are two receptors to which cannabinoids bind, CB1R and CB2R, with CB1R being mainly expressed in the central nervous system and CB2R in the immunological system. In physiological conditions these receptors are activated by a group of molecules that are produced by the body and hence called endocannabinoids. When marihuana is consumed, cannabinoids in the plant (including the famous Δ-9-tetrahydrocannabinol or THC) can also activate these receptors. Prolonged stimulation has a plethora of well-established effects, such as uncontrolled laughter, relaxation and analgesia, difficulty to perform motor activities, mouth dryness and a long etcetera. Although marihuana use can have some prejudicial side effects (mainly paranoia, anxiety and depression) there is compelling interest in understanding the mechanism of action of cannabinoids, as they can be potentially used in the clinic to treat nausea and vomiting in patients subjected to chemotherapy, chronic pain associated to neurodegenerative diseases and other pathological conditions.
One of the most notorious effects of cannabis is the stimulation of appetite, a phenomenon so well established that even has an specific term for it – the munchies. Although some research has been made into how cannabinoids regulate food homeostasis, the molecular mechanisms are still unclear. In a paper recently published in Nature, researchers from the University of Yale have increased our understanding on which cells and molecules are involved in the induction of appetite by the activation of one of the cannabinoid receptors,CB1R 1.
When mice are injected with ACEA, a synthetic activator of CB1R, they eat even if they are sated. Appetite in the brain is controlled in the hypothalamus by two groups of neurons, which are called orexigenic and anorexigenic. When the orexigenic neurons are stimulated, the animals feel hunger, whereas activation of the anorexigenic neurons induces satiety. At least that’s what theory says. So the first question that the researchers wanted to ask was if the activation of CB1R repressed the anorexigenic neurons, which would inhibit the feeling of satiety and trigger hunger. To their surprise they found the opposite: although cannabinoids stimulate appetite in animals that have already eaten they do so by activating the neurons that induce satiety. And this activation is actually necessary to induce the munchies.
This apparent paradox was resolved by taking a deeper look into these‘satiety neurons’, which showed that actually we shouldn’t call them that way. These cells do produce a molecule that induces satiety, called α-MSH, but they also produce another molecule called β-endorphin, which is a natural opioid that has analgesic effects and, importantly, increases appetite. The researchers observed that when the ‘satiety neurons’ were stimulated by ACEA, the concentration of β-endorphin (but no α-MSH) increased, and that if the effect of β-endorphin was blocked the animals did not show enhanced appetite.I think these results are interesting because they show the inherent intricacy of biology and how nature challenges rigid definitions: the idea that there are populations of neurons with well-defined tasks might be helpful to tackle certain problems but the real situation is always more complex.
The authors also found other changes in these neurons related to their mitochondria, the part of the cell where most of the energy is produced. When CB1R is activated, mitochondria consume more oxygen and are found at a higher proportion next to the endoplasmic reticulum, a location in the cell that could improve their activity. These effects (along with the stimulation of appetite) do not take place if UCP2, a mitochondrial protein, is not present, which makes the authors suggest an important role for it, although little is said about what this role would be.
Unravelling the mechanisms by which cannabis induces hunger is important both to deepen our understanding on the appetite circuits in the hypothalamus and to develop drugs that can be used to treat eating disorders. And as this work has proven, marihuana can also help us to look at reality from a different perspective.
- Koch et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature (2015) doi:10.1038/nature14260 ↩