By Ifunanya Onyima, MS, RD, LD
Abstract
Cannabinoids are naturally-occurring or synthetic compounds derived from the plant genus Cannabis (1, 22). Cannabinoids act on the endocannabinoid system (21) and include (−)-Δ9-trans-(6aR,10aR)-tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) (3). Cannabinoids have been shown to optimize health by attenuating emesis (6), altering weight status (34) and improving body composition (37). In December of 2018, the U.S. federal government legalized the use and sale of CBD recreationally via the Farm Bill (12). However, THC and several chemical derivatives are still federally illegal (12, 13). Several states have legalized the use and sale of all cannabis products recreationally, while six states have not permitted this use (13). Because obesity and dysregulated energy balance have been on the rise for the last 50 years, there is growing interest on treatment plans to manage weight, appetite and energy balance (19). This systematic review synthesized several experimental, primary research studies to understand the effects of cannabinoid use on appetite, weight and energy balance.
Multiple human and animal experiments have reported cannabinoids as an effective treatment tool for preventing or attenuating emesis (23-30) and improving food intake (6, 31-34, 38, 39), especially for those undergoing drug-therapy treatment that causes anorexia, nausea and vomiting. Additionally, participants often reported a preference for the cannabinoid treatment instead of the placebo (38, 39). Cannabinoids may also play a role in weight management. Alterations of the endocannabinoid system via the presence of agonists or antagonists have been associated with alterations in weight, body composition and lipid profiles (28, 35-37). Cannabinoids may be an effective treatment plan for those looking to manage their weight and food intake.
Key words: Cannabis; Cannabinoids; Appetite; Emesis; Weight Management
Background
Cannabis is used as an umbrella term to denote a set of chemical compounds derived from the plant genus Cannabis or Cannabis Sativa (1) and act on endocannabinoid receptors (21). Historians suggest that this plant has been cultivated and used by humans for at least 6,000 years (2). However, the majority of documented experiences regarding the effects of this plant on biological and biochemical processes has only taken place since the late 19th century. The cannabis plant is composed of over 400 known chemical constituents, including (−)-Δ9-trans-(6aR,10aR)-tetrahydrocannabinol (Δ9-THC), which is the most psychologically-active constituent within the plant, and Cannabidiol (CBD) (3), which has been shown to be an effective treatment tool for optimizing health outcomes in several ways, including attenuating epileptic seizures (4), protection of neurons via antioxidant activity (5) and attenuation of nausea and vomiting (emesis) (6). The endocannabinoid system is a set of ligands, enzymes and receptors that cannabinoid and cannabinoid-like constituents act upon (22). Research regarding this system is still relatively new (22). Cannabis can be consumed and utilized in a variety of ways, including smoking the dried cannabis flowers (currently the most popular method of ingesting the plant (7, 8), also known as marijuana (21)), incorporating the flower into food items (known as edibles (46)), extracting the chemical compounds and infusing them with lotion and other topical products (9) or utilizing the fibers within the plant (known as hemp) for the formulation of rope, clothing and paper (11).
“Oncology-related studies reported similar, positive effects on cancer treatment symptoms with cannabis use, including improved appetite, decreased nausea and decreased abdominal pain (38, 39)”
Currently, in the United States, cannabis and cannabis constituents (excluding CBD) are classified as a Schedule 1-A Controlled Substances, which means that, “the drug or substance has a high potential for abuse” and posses, “no currently accepted medical use in the United States” (10). It was not until the Farm Bill was signed into law in December of 2018 that the U.S. federal government legalized the production, marketing and sale of cannabis products so long as the products did not contain more than 0.3% THC based on dry weight (12). This decision was made based on the positive effects seen in patients experiencing seizures related to either Lennox-Gastaut syndrome or Dravet syndrome and anorexia-associated weight loss in patients diagnosed with AIDS (12). Today, 15 states and the District of Columbia allow recreational use (similar to alcohol and tobacco) of cannabis and cannabis products regardless of the THC content. In contrast, cannabis use and sale is completely illegal in six states, excluding the use that is permitted via the Farm Bill (13).
The amount of calories a person consumes each day is dependent on many factors, including food availability, social cues, stress levels, hormone fluctuation and genetic predispositions (14). Together, these factors formulate a person’s appetite – the sensation of hunger or the sensation of satiety (14). In humans, energy balance involves the up-regulation or down-regulation of appetite-related factors in order for the body to maintain an energy homeostasis where the amount of energy expended is equal to the amount of energy consumed (16). Appetite and energy balance are directly related to one another (e.g. a person who experiences sensations of hunger is likely to consume energy via food, while a person who is experiencing satiety is likely to halt their consumption of food until the sensations of hunger re-emerge) (15). However, the mechanisms behind the achievement of energy balance are quite complex due to the many factors that affect a person’s appetite. For example, despite the body’s ability to alter hormonal fluctuations that result in increased energy expenditure in response to increased intake or physical activity (17), living an obesigenic lifestyle (e.g. chronic over-consumption of calories) will eventually override these biochemical processes and lead to excess weight gain (18). In contrast, one 2019 study found that those who consumed more appetite-reducing nutrients (e.g. fiber) saw improved weight loss and weight management compared to the control group (20). Because of the significant increase in the prevalence of obesity in the last 50 years, there is an increased interest in the regulation of energy balance and weight management in humans (19).
Due to the increased interested in energy balance and weight management, recent cannabis legalizations (22) and because the consumption of cannabis products has been associated with several nutrition-related factors including alterations in appetite (6, 23, 31, 33, 34), promotion of anti-emesis (23, 24, 25, 26, 27, 28, 29, 30) and alterations in weight management, lipid profiles and fat oxidation (30, 32, 34, 35, 36, 37), understanding the effects of cannabis and cannabis-like substance consumption on energy balance is of growing importance, especially for dietitians. This systematic review aims to analyze and synthesize the body of in vivo, ex vivo and clinical research studies involving appetite, weight management and energy balance related to cannabis consumption and regulation of the endocannabinoid system.
Consumption of Cannabis Products, Appetite and Food Intake
Up-regulation and down-regulation of the receptors within the endocannabinoid system have been associated with subsequent alterations of appetite and food intake (31, 33, 34). A study involving eight children with various blood cancers and undergoing anti-cancer drug and chemotherapy found that, when participants were given 18mg of delta-8-THC two hours before and every six hours for twenty-four hours after anticancer treatment, seven participants reported that no emesis occurred during the dosing period or for two days afterwards, when compared to one participant who initially refused the THC intervention and experienced emesis for twenty-four hours after anti-neoplastic treatment. Upon initiating the THC intervention during the second treatment cycle, emesis was no longer reported from the participant who initially refused the treatment (6).
Other oncology-related studies reported similar, positive effects on cancer treatment symptoms with cannabis use, including improved appetite, decreased nausea and decreased abdominal pain (38, 39). Participants also reported a preference for the cannabinoid intervention when compared to the placebo or other appetite stimulant (38, 39). However, many of these studies are cross-sectional or have a short testing period. There is a lack of sufficient, long-term information regarding cannabis use and cancer/cancer treatment. It is also important to note the reported side-effects of cannabinoid consumption, which include tachycardia, drowsiness, hypotension and anxiety (23). Consumption of cannabinoids could be contraindicated in high-risk cancer patients with heart malfunctions.
Experiments unrelated to cancer or cancer-related treatments also reported alterations on subject’s appetite and food intake when consuming cannabis products or when endocannabinoid receptor activity was altered by using exogenous cannabinoids or cannabinoid receptor agonists/antagonists (31, 33, 34). An in-vivo study using Wistar rats analyzed their food intake after the endocannabinoid 2‐arachidonoylglycerol (2‐AG) was injected into their the nucleus accumbens shell (NAcS), which has been shown to be an activation site for the hypothalamus nuclei involved with appetite regulation. This area of the brain also expresses CB-1 receptors, which are endocannabinoid receptors (40). After analyzing the rat’s food intake after the first and fourth hour after 2-AG administration, researchers found that food intake was increased by about 100% when compared to the control group. In contrast, the hyperphagic effect was blocked after administering a CB-1 antagonist called AM25131. A 12-week weight loss study utilized an oral CB-1 inverse agonist, taranabant, to understand its affects on weight management in obese individuals. Body weight measurements from 368 participants reported significant weight loss and reduced waist circumference over the 12-week period. The same paper reported a significant decrease in food intake over 24 hours for obese individuals when compared to a placebo and the appetite suppressant sibutramine, even when participants were able to eat ad libitum during the testing period (34). A 2009 animal study suggests that the psychologically-active cannabinoid, THC, is a CB-1 antagonist and therefore suppresses hunger and appetite, while CBD may reverse the affect of THC and stimulate appetite (33).
Anti-Emetic Effects of Cannabis Products
The ability to manage weight and maintain energy balance depends greatly on being able to consume and properly digest food. The process of digestion is negatively affected when a person is experiencing emesis – food items cannot be fully or properly digested if they are regurgitated soon after consumption. Episodes of emesis can result in negative health outcomes including aspiration pneumonia, electrolyte imbalance and dehydration (41). Because nausea and emesis are side effects of several illnesses, medications and treatment plans (42), it is paramount to have several options available to attenuate its severity and duration.
Consumption of cannabinoids has been shown to reduce the frequency of emetic episodes and attenuate nausea especially amongst those undergoing cancer-related therapy and drug treatments (23, 24, 25, 26, 27, 28, 29, 30). A double-blind, crossover study published in 1983 studied the effects of nabilone (a synthetic cannabinoid that possesses a side-chain that prevents its conversion to delta-9-THC) on emetic episodes and chemotherapy side-effects when compared to the anti-emetic drug prochlorperazine. Those who were prescribed nabilone experienced decreased instances of nausea, retching, vomiting and during the three-day testing period when compared to the prochlorperazine group (25). A more-recent study found similar results amongst participants undergoing treatment for hepatitis C (HCV) (30). Interferon-ribavirin is a drug therapy used to combat HCV and has been shown to have adverse diet-related side-effects including nausea, loss of appetite, weight loss and anorexia (43). Researchers compared those using cannabinoid-containing medications to alleviate symptoms of interferon-ribavirin drug treatment to those who did not. Those who used cannabinoid-contaning medications were more likely to complete the drug therapy program and respond better to the treatment. Furthermore, over 60% of participants using the cannabinoid medication reported improvements with several interferon-ribavirin side-effects including nausea, anorexia and vomiting (30).
Animal models have been utilized to understand the mechanisms of action behind cannabinoids use and their affect on nausea and vomiting (27, 28, 29). One study suggests a dose of CBD between 1 and 5 mg/kg effectively alters endocannabinoid receptors, causing an anti-nausea response (28). An experiment conducted on ferrets and mice found a large portion of CB-1 receptors within the brain stem. When these receptors were flooded with CB-1 agonists, less emesis was reported in response to a dose of morphine. Conversely, when CB1-antagonist AM251 was administered, anti-emetic affects were attenuated (29), providing further evidence that manipulation of the endocannabinoid system is associated with changes in nausea and vomiting. A 2001 study also used a population of ferrets to study the effect of a synthetic cannabinoid agonist WIN 55,212-2, the naturally-occurring cannabinoid THC and an analog cannabinoid methandamide on episodes of retching and vomiting after a subcutaneous dose of morphine. THC was the only cannabinoid of the three which almost abolished the emetic effect of morphine when administered at 1mg/kg, but not at 0.5mg/kg, suggesting that naturally-occurring cannabinoids are superior for eliciting anti-emetic results when administered at an adequate dose (27).
In contrast to the anti-emetic affects of cannabinoids is the growing occurrence of cannabis hyperemesis (CH), which is defined as chronic vomiting amongst those who regularly ingest cannabis products (44). This condition affects both children and adults and was found to occur after at least three months of regular cannabis use in the pediatric population (44). CH may be due to the growing availability of high-potency, high-dose cannabis products and lack of effective regulation regarding these products (46). However, the mechanism of action and effective treatment of this condition is unclear (45).
Cannabis Consumption, Weight Management and Lipid Regulation
Cannabinoid consumption is associated with alterations in weight and lipid metabolism (30, 32, 34, 35, 36, 37). Rimonabant is a CB-1 antagonist, which means this compound may have the ability to down-regulate the activation of the endocannabinoid system (37). A 2009 study focused on 799 obese, dyslipidemic individuals who either consumed an oral dose of Rimonabant (20 mg/d) or a placebo for one year. Body weight, waist circumference, lipid profiles, blood glucose levels, adiponectin, high-sensitive C-reactive protein, abdominal, visceral and liver fat levels were assessed at baseline and after the 12-month period. Lipid profiles (including HDL-C, triglycerides, visceral fat, subcutaneous fat, visceral/subcutaneous fat ratio, adiponectin, total cholesterol/HDL-C ratio), waist circumference and body weight improved significantly when compared to the placebo (37). However, there was no participant instruction regarding exercise and food intake, so there may have been confounding factors contributing to these findings. Rimonabant was the cannabinoid of choice for a 2008 study and found significantly greater reductions in body weight and waist circumference and increased HDL levels in participants taking a 20mg dose of Rimonabant daily compared to those taking the placebo for one year (35).
Animal studies give support to the weight-management affects of cannabinoids (33, 36). Mice receiving Rimonabant at 50mg/kg/day for three months were found to have increased weight loss compared to the control mice even after controlling for food intake, suggesting that CB-1 antagonists can induce weight loss independent from energy restriction (36). Furthermore, the Rimonabant group displayed significantly decreased LDL , triglycerides, cholesterol and leptin levels when compared to the other experimental groups (36). However, it is important to note that several weight loss drugs, including Rimonabant and Sibutramine, have been pulled off of the market due to their negative effects on mental health and mood (47).
Study Limitations
There is a lack of formal research studies on cannabis use in long-term users (greater than a one-year testing period) which may be due to the controversy related to cannabis use, reported negative effects on mental health and the fact that its medicinal and recreational use and sale has only recently been permitted by U.S. state and federal legislation. Additionally, the literature currently lacks information about the effect of consuming cannabis products in various ways (e.g. smoking the dried cannabis flowers, utilizing tinctures or eating the flower via edibles) on appetite and weight management. This information is important because smoking or orally ingesting cannabis via edibles are common ways that people consume cannabis. Finally, the literature lacks experimental information on the effect of high doses or persistent use of cannabis on weight management or appetite. Many of the studies found used controlled doses of cannabis products, but it is unlikely that most people are consuming cannabis products in low, controlled doses (46).
Conclusions
Utilization of cannabis products may be an effective treatment plan for those looking to manage their weight, alter their appetite and achieve energy balance. Cannabis use may be contraindicated for those with heart problems or mental health disturbances because it has been associated adverse side-effects including tachycardia and anxiety. Long-term research studies are needed in order to understand the effects of habitual cannabis use on appetite and weight management, since many of the currently available studies have a testing period of one year or less. Further research is needed to understand the effect of high dose or high potency cannabis use, especially since this type of cannabis use is growing with the legalization and availability of medical and recreational cannabis and cannabis products. Finally, further research is needed to understand the mechanism of action behind the endocannabinoid system and its receptors, understand the action of various cannabinoids on these receptors and to identify effective and safe doses for the utilization of cannabinoids in weight management-related treatment plans.
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