DISCOVER CANNABIS

The Science Behind the “Munchies”

If you're familiar with cannabis, you probably know what it means to have a case of the "munchies." But why does cannabis make you run for the snacks?

“The munchies” are a well-known side-effect of consuming cannabis. The term is used to describe the way cannabis can overwhelmingly stimulate the appetite. But why? The answer is mostly because of THC.  

Early experiments in humans showed that THC not only makes us eat more, but it specifically makes us eat more sweets, such as chocolate milkshakes and marshmallows1 2.  Since those studies, researchers discovered that THC increases our appetite through the body’s endocannabinoid system (ECS), a system that carries out essential functions, including controlling our appetite.

The major components of the ECS are receptors and the molecules they bind with. There are two types of ECS receptors, called CB1 and CB2. The molecules they bind with are called cannabinoids. Our bodies make two cannabinoids (called endocannabinoids): AEA and AGA. Cannabis plants contain hundreds of cannabinoids (phytocannabinoids), including THC and CBD. All of these cannabinoids interact with the ECS receptors in the body.

Role of the ECS in Appetite

The ECS controls hunger and eating in a few ways. In the hypothalamus, a part of the brain that is associated with appetite, researchers think ECS receptors interact with the pathways for motivation and craving. This might be why cannabis makes us want to find and eat rewarding foods, like sweets and fats3. In one study, scientists explored the ECS receptors in the brain by activating them after depriving subjects of food for a short time. They found this affected the enzymes (chemical signalers produced in our bodies) that stimulate or reduce appetite4.

In animal models, the ECS also appears to play an essential role in controlling how much young rodents eat5, as well as how their fetuses develop. Endocannabinoids are found in the developing fetal brain and in maternal milk. They have a vital role in nursing. When researchers inhibit the CB1 receptor in the brains of newborn mice, it makes them suckle less and drink less milk6.

Outside of the brain, the CB1 receptor is also present in fat tissue and appears to be involved in fat accumulation. Here, activating the CB1 receptor increases the activity of key enzymes that control fat metabolism.

The CB1 receptor is also present in skeletal muscle, the muscles that move our body. Here, CB1 seems to regulate how much glucose gets absorbed from our blood. In the gastrointestinal tract, CB1 receptors control the signals that determine how “full” a person feels. In the liver, stimulating CB1 receptors seems to increase fatty acid synthesis, which leads to an increase in body fat and weight7.

 

Therapeutic Cannabis to Modulate the ECS and Control Weight

Will consuming cannabis make you fat? Not exactly.

Large studies in the general population consistently find that cannabis users have a lower body mass index compared with non-users8. The exact reasons for this are not clear. However, the link between cannabinoids and weight control has been well-established, and several cannabis-based therapies have been approved to treat weight-related disorders and conditions.

Dronabinol, (brand name Marinol), is a synthetic form of THC that has been approved since 1986 to treat chemotherapy-induced nausea and vomiting9, as well to increase appetite in patients with HIV/AIDS10 11. In clinical trials with HIV patients, Dronabinol substantially increased appetite12 and stabilize weight13. It can also improve appetite and increases body weight in Alzheimer’s patients suffering from excess weight loss14, and in cancer patients suffering cachexia (wasting syndrome)15.

Anorexia nervosa is a debilitating mental illness that can make people see their bodies in a distorted way, become obsessed with weight loss, and feel intense anxiety about eating. It’s defined by excessive weight loss, and it can cause serious problems with heart function and fertility. One study, where women with chronic anorexia nervosa were either given Dronabinol or a placebo, showed that Dronabinol caused a small but important weight gain16. Prior to this, another study showed that THC produced a small to moderate weight gain in anorexia nervosa patients17.

In recent years, researchers have also been exploring what happens when they inhibit the CB1 receptor, hoping it would reduce eating to stimulate weight loss and treat obesity-related disorders. In animal studies, a drug called rimonabant (Acomplia®), which inhibits CB1, reliably decreased eating18 19 20 21. It also reduced craving for regular22 and highly rewarding food23, and reduced weight gain. It worked in animals that had fasted (been temporarily food-deprived) and ones who had not fasted24.

Rimonabant was able to reduce body weight and fat composition in mice that were intentionally fed too much, even though it only reduced their feeding for a short time25 26. These results showed that CB1 inhibition not only affects eating but changes the way bodies metabolize glucose and fats.

In human trials, Rimonabant significantly reduced weight in overweight and obese patients compared with placebo27 28 29 30. Based on results such as these, Rimonabant was approved in 2006 as a weight loss medication in the EU. Shortly after, however, Rimonabant was removed from the market because it was causing significant psychiatric side-effects31. Similarly, other CB1 receptor inhibitors, such as Taranabant, caused significant weight-loss while also producing psychiatric side-effects32.

To eliminate these psychiatric side-effects, research has shifted back to animal models and refocused on developing inhibitors that target the CB1 receptor outside the brain, and these trials have had promising results33 34. In addition, recent studies have found that a less common and non-psychoactive cannabinoid, cannabigerol (CBG), can increase appetite in animal models35, but further investigation and research is still needed.

Summary

The appetite-stimulating effects of cannabis come mostly from THC, which switches on the body’s normal appetite control system, the ECS. This discovery led to a treatment for vomiting and nausea called Dronabinol, which is a synthetic compound similar to THC. It helps patients gain weight in several disorders and conditions. Research has also focused on other parts of the ECS, such as inhibitors for the CB1 receptor, to treat obesity-related disorders, although this area needs a lot more research.

 

References

[1] Hollister LE. Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. 1971;12(1):44-49.

[2] Abel EL. Effects of marihuana on the solution of anagrams, memory and appetite. Nature (London). 1971;231(5300):260-261.

[3] Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neuroscience. 2005;8(5):585-589.

[4] Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neuroscience. 2005;8(5):585-589.

[5] Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. Journal of Clinical Investigation. 2003;112(3):423-431.

[6] Fride E. The endocannabinoid-CB1 receptor system in pre- and postnatal life. European Journal of Pharmacology. 2004;500(1):289-297.

[7] Tibiriça E. The multiple functions of the endocannabinoid system: a focus on the regulation of food intake. Diabetology and metabolic syndrome. 2010;2(1).

[8] Sansone RA, Sansone LA. Marijuana and Body Weight. Innovations in Clinical Neuroscience. 2014;11(7-8):50-54.

[9] Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manage. 1997;14(5):311-314.

[10] Balog DL, Epstein ME, Amodio-Groton MI. HIV wasting syndrome. Annals of pharmacotherapy. 1998;32(4):446-458.

[11] Badowski ME, Yanful PK. Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer. Therapeutics and clinical risk management. 2018;14:643-651.

[12] Beal JE, Olson R, Lefkowitz L, et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. Journal of Pain and Symptom Management. 1997;14(1):7-14.

[13] Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. Journal of Pain and Symptom Management. 1995;10(2):89-97. 

[14] Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of Dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. 1997;12(9):913-919.

[15] Badowski ME, Yanful PK. Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer. Therapeutics and clinical risk management. 2018;14:643-651.

[16] Andries A, Frystyk J, Flyvbjerg A, Stoving RK. Dronabinol in severe, enduring anorexia nervosa: a randomized controlled trial. The International journal of eating disorders. 2014;47(1):18-23. 

[17] Gross H, Ebert MH, Faden VB, Goldberg SC, Kaye WH. A Double-Blind Trial of Delta-9-Tetrahydrocannabinolin Primaryanorexia-Nervosa. Journal of Clinical Psychopharmacology.
 1983;3(3):165-171.

[18] Wiley JL, Burston JJ, Leggett DC, et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. 2005;145(3):293-300.

[19] Arnone M, Maruani J, Chaperon F, et al. Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. 1997;132(1):104-106.

[20] Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sciences. 1998;63(8):PL113-PL117.

[21] DiPatrizio NV, Astarita G, Schwartz G, Li X, Piomelli D. Endocannabinoid signal in the gut controls dietary fat intake. 2011;108(31):12904-12908.

[22] Freedland CS, Poston JS, Porrino LJ. Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding. Pharmacology Biochemistry and Behavior. 2000;67(2):265-270.

[23] Ward S, Dykstra L. The role of CB1 receptors in sweet versus fat reinformcement: Effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940). Behavioural Pharamacology. 2005;16:381.

[24] Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. 2009;156(7):1154-1166.

[25] Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sciences. 1998;63(8):PL113-PL117.

[26] Freedland CS, Poston JS, Porrino LJ. Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding. Pharmacology Biochemistry and Behavior. 2000;67(2):265-270.

[27] Despres JP, Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study G. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353(20):2121-2134.

[28] Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, Group RI-ES. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389-1397.

[29] Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, Group RI-NAS. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295(7):761-775.

[30] Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, Group RI-DS. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368(9548):1660-1672.

[31] Moreira FA, Crippa JAS. The psychiatric side-effects of rimonabant J Revista Brasileira de Psiquiatria 2009;31:145-153.

[32] Martin-Garcia E, Burokas A, Martin M, et al. Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant. J Neurochem. 2010;112(5):1338-13351.

[33] Ma H, Zhang G, Mou C, Fu X, Chen Y. Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice. Frontiers in Pharmacology. 2018;9:156.

[34] Chen W, Shui F, Liu C, et al. Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice. Frontiers in Pharmacology. 2017;8:707

[35] Brierley DI, Samuels J, Duncan M, Whalley BJ, Williams CM. Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats. Psychopharmacology (Berlin, Germany). 2016;233(19-20):3603-3613.