Cannabis for Wasting Syndrome
Cachexia, or wasting syndrome, is defined by weight loss, muscle atrophy, fatigue, weakness, and loss of appetite in a person who is not actively trying to lose weight. Wasting syndrome is associated with a variety of conditions including but not limited to cancer, HIV/AIDS, Alzheimer’s, and the degeneration of the body associated with aging. Treatments for some conditions, such as cancer and HIV/AIDS, make eating and weight management difficult on top of the effects of the disease itself.
The Endocannabinoid System (ECS), Appetite, and Weight Gain
Cannabis has been known to enhance appetite for centuries, however it is only recently that we have begun to understand how cannabinoids modulate appetite and weight gain. While we now understand some of the mechanisms of appetite and satiety (feelings of fullness) that the endocannabinoid system is involved in, the physiological controls of eating, energy use, and weight gain or loss remain complex with many unknowns.
The ECS works in the brain as well as in the periphery of the body to stimulate appetite. CB1 receptors located in different regions of the brain as well as in the GI tract, liver, and fatty tissue all play a role in stimulating appetite. Levels of the body’s own endocannabinoids, anandamide and 2-AG rise and fall to stimulate or suppress hunger depending on a variety of factors including availability of food, diet, and levels of appetite-related hormones such as leptin (the hormone that regulates energy balance by inhibiting hunger). [1, 2] Phytocannabinoids (e.g. THC) may act similarly to endocannabinoids, activating CB1 receptors and shifting the balance of the ECS towards increased appetite.
ECS/CB1-Modulated Mechanisms of Appetite and Body Weight
Central nervous system
Limbic System: Governs food palatability and evaluation of pleasure. Has a significant concentration of CB1 receptors. Generates emotional and behavioral response towards rewarding stimuli including food. ECS may work with opioid pathways in making eating pleasurable and food taste good. 
Peripheral of the body
Fatty Tissue: Stimulation of CB1 receptors on fat cells underneath the skin triggers the metabolic formation of more fat.  CB1 receptors also modulate fat production in the liver.  Fat production may contribute to cannabinoids’ effect on body weight independent of their effects on food intake. 
Intestines: Stimulation of CB1 receptors in the gut may influence central processes. Anandamide as well as interactions between the ECS and peptides may serve as “hunger signals” originating in the periphery—signals that stimulate central appetite modulation pathways. 
Despite being associated with increased appetite, caloric intake, and the formation of fat, cannabis use is also associated with lower body mass index (BMI) as well as lowered rates of obesity and diabetes.  While these correlations have been observed, the mechanisms explaining this paradox have yet to be discovered.
Nausea and Vomiting
Nausea and vomiting do not necessarily accompany wasting syndrome. Many patients, however, may experience these symptoms that make eating and maintaining weight even more difficult. Specifically, a significant number of HIV/AIDS and cancer patients experience nausea and vomiting as they are common side effects of conventional treatments.
Cannabis as a Treatment
Most of the information we have regarding cannabinoids and appetite is focused on THC. As an agonist of the CB1 receptor and the most commonly occurring cannabinoid, it appears that THC is the main active compound responsible for appetite stimulation. 
Cannabis is used to treat both nausea and wasting syndrome in cancer patients. Approximately 50% of cancer patients experience wasting syndrome, early satiety, and/or weight loss at diagnosis, with the majority of patients experiencing these symptoms later in the disease. [3, 6] A study done with 54 advanced cancer patients showed that THC produced significant weight gain, an increase in body fat, and improved mood compared to placebo.  Another study comparing cannabis to megestrol (Megace), a pharmaceutical drug used as an appetite stimulant, showed that cannabis did increase appetite and weight, however not as much as megestrol.  It should be noted that megestrol has significant side effects, none of which improve the patient’s mood.
Cannabis has also been shown to reduce nausea and vomiting in cancer and HIV/AIDS patients while also increasing appetite. In a survey of 252 patients with HIV/AIDS, 53% reported improved appetite with smoking cannabis. A correlation between nausea and cannabis use was also found in the survey, suggesting that patients were using cannabis to address nausea.  Another study with AIDS patients showed that a dose of 2.5 mg of THC twice daily stabilized body weight for at least 7 months. 
In 2006 a CB1 receptor blocker, rimonabant (Acomplia), was released by pharmaceutical companies as a treatment for obesity. The expectation was that by blocking the CB1 receptors, cannabinoids would no longer be able to stimulate appetite, thus allowing for weight loss. However, the complexity of the endocannabinoid system was under-appreciated, and rimonabant was withdrawn from the market in 2009 because risks outweighed the benefits, most notably an increase in serious psychiatric problems including suicides among patients using the drug. Apparently we can activate the CB1 receptors to increase appetite, but so far we cannot safely block them.
THC’s appetite stimulating effects appear to be dose dependent. Low doses of THC tend to be more effective at stimulating appetite, while high doses may actually suppress appetite.  THC may also have undesirable psychoactive effects, which can be counteracted at least in part by using a formulation or strain of cannabis that also has CBD. In general, inhalation appears to be more effective than oral delivery for increasing appetite, but inhalation does carry the additional risk of lung and throat irritation.  Vaporization is less irritating than smoking. Studies have also shown that a social setting (e.g. eating with other people) may enhance cannabis’ effects on appetite, as well as the availability of palatable/appealing foods rather than bland/unappealing food. 
- Monteleone P, et al. Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa. Neuropsychopharmacology (2005) 30, 1216–1221. www.neuropsychopharmacology.org
- Fride I, Bregman T, et al. Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood. Exp Biol Med 230:225–234, 2005
- Cota D, et al. Endogenous Cannabinoid System as a Modulator of Food Intake. International Journal of Obesity (2003) 27, 289–301. www.nature.com/ijo
- Lictman AH and Cravatt BF. Food for Thought: Endocannabinoid Modulation of Lipogenesis. The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 5 May 2005
- Penner EA, Buettner H, Mittleman MA. The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance Among US Adults. American Journal of Medicine (2013). http://dx.doi.org/10.1016/j.amjmed.2013.03.002
- Abrams DI. Cannabis in Cancer Care Presentation.
- Prentiss D, et al. Patterns of Marijuana Use Among Patients with HIV/AIDS Followed in a Public Health Care Setting. J Acquir Immune Defic Syndr. Volume 35, Number 1, January 1 2004.
- Abrams DI, et al. Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection. Ann Intern Med. 2003;139:258-266.