Cannabis and Appetite: More Than the Munchies

Before cannabis became widely known in the Western world for its medicinal properties, its recreational use was often linked to the munchies. The marriage of marijuana and late-night snacking became a sort of pop culture trope, but the image deserves another look. Across studies, cannabis users have a lower body mass index than that of nonusers.1 The phenomenon counters preconceived notions about cannabis and highlights a growing consensus regarding the complexity of the plant. Concerning appetite, weight, and metabolic health, cannabis may play a chameleonlike role.

Cannabis and Hunger: New Perspectives on an Ancient Plant
Cannabis is already used to induce appetite; FDA-approved cannabis-based treatments include drugs like Dronabinol, which is used to increase appetite in patients with cancer and AIDS.2 More recently, researchers, stakeholders, and marketers are questioning whether cannabis can be used to decrease appetite. The answers lie in the complexity of the plant, which has more than 500 different chemical compounds, including cannabinoids, terpenoids, flavonoids, and omega fatty acids.3 Many of the effects of cannabis come from the synergies between the cannabinoids and the terpenes,” says Janice Newell Bissex, MS, RDN, FAND, a holistic cannabis practitioner and program director of cannabinoid medical sciences at John Patrick University School of Integrative and Functional Medicine. Specific to appetite, THC has been shown to stimulate hunger, whereas tetrahydrocannabivarin (THCV) may suppress it. The terpene humulene (also found in hops, sage, ginger, and ginseng) can abate hunger as well. CBD may decrease or increase appetite, depending on several factors, including the person consuming it.

Clinically, the compounds of cannabis are often studied in isolation, which may explain seemingly contradictory results. Similar to foods, the whole cannabis plant will have a different impact than that of its various components; it works a bit like nutrition. For example, calcium is important to vitamin D absorption, and both can be found in whole foods, such as leafy greens and eggs. However, most of the calcium in an egg is found in the yolk—eating only the egg white will could limit vitamin D absorption.4 Terpenes and cannabinoids work similarly.

Cannabis and Its Compounds: Can It Control Appetite?
Specific cultivars of cannabis vary in their ratio of compounds, causing different effects on appetite. Compounds such as THC, THCV, CBD and various terpenes may act via direct interaction with receptors or by influencing the reuptake of exogenous cannabinoids, causing a person’s naturally occurring cannabinoids to have a more intense or longer-lasting influence. Cannabinoids may also act through other means—such as influencing transient receptor potential vanilloid subtype 1 (TRPV1) and G protein-coupled receptor 55 (GPR55) channels.

There are two primary receptors in the endocannabinoid system: CB1 receptors, which are found mostly in the central and peripheral nervous system, and CB2 receptors, which are abundant in the immune system. Researchers believe that acute THC intake stimulates appetite by binding to CB1 receptors found in regions of the brain related to hunger and reward. THCV may decrease appetite by acting as a neutral CB1 antagonist, quelling its effects.

CBD could increase or decrease appetite depending on its function. It may increase appetite by improving digestion via its interaction with the immune system and gut health. It could also decrease appetite by improving mood and reducing anxiety. Now, add in terpenes. A cannabis cultivar high in THC could bring on the munchies, but if that same cultivar is high in humulene, the effect could be blunted.

In other words, cannabis is a complex plant, and its influence on appetite will depend on many factors. A person’s response to any particular cultivar will also depend on the interaction with their individual biology. “Factors such as a person’s age, gender, history of substance use, method of intake, and medications could all impact their response to cannabis,” says Eloise Theisen, MSN, RN, AGPCNP-BC, a board-certified adult-geriatric nurse practitioner, past president of the American Cannabis Nurses Association, and CEO of Radicle Health.

Exogenous Cannabinoids and Receptors
The CB1 receptor is a primary target of drugs aimed at influencing appetite and weight. Whereas THC’s affinity for CB1 receptors makes it an ideal candidate for inducing appetite, drugs that deactivate CB1 could suppress appetite. The endocannabinoid THCV is a neutral CB1 antagonist and sometimes is considered a counterpart to THC, curbing many of its psychoactive effects. In obese mice, THCV suppressed appetite and promoted weight loss.

Focus on CB1 deactivation led to the development of the CB1 inverse agonist, rimonabant, a synthetic drug similar to THCV. The drug worked by selectively blocking CB1 activation and was approved in Europe in 2006 for the treatment of anorectic obesity. While rimonabant successfully decreased appetite, it also increased rates of depression, anxiety, and suicidal ideation. The drug was discontinued in 2008.5

Whereas rimonabant induced severe psychological side effects, THCV and CBD don’t appear to have the same downside. On the contrary, in certain studies, they have correlated with improved mood and feelings of well-being. In a small clinical trial with 20 participants, THCV was studied for its role in food aversion and reward.6 The researchers found that THCV successfully increased food aversion and decreased reward signaling without any of the negative psychological effects produced by rimonabant. “The different effects of isolated synthetics vs THCV speaks to the entourage effect—the role of the whole plant,” Theisen says.

The case of rimonabant led many pharmacology companies to abandon the development of inverse CB1 receptor agonist drugs; more research has focused on the naturally occurring THCV as a weight loss therapy.

The overexpression or overactivation of CB1 receptors likely does play a role in obesity. In one study, researchers found an increased expression of CB1 receptors in the abdominal fat of obese participants.7 The localization of this overexpression points to the metabolic role of endocannabinoids. However, it’s unclear whether CB1 receptors are the sole target or if they work in conjunction with other receptors and pathways. “It appears that the other cannabinoids or terpenes function alongside THCV to influence different receptors as well, which may prevent THCV from having an overly dominant effect on a single receptor,” Theisen says.

CB2 receptors and their immune function may also affect appetite, weight, and metabolic health. One rodent study examined the role of CB2 receptors in glucose tolerance. Researchers found that acute administration of CB2 receptor agonists improved glucose tolerance in nonobese mice.8 The study also showed that a 10 mg/kg dose of CB2 agonist significantly decreased food intake. Next, the researchers gave the mice a 5 mg/kg dose of a CB2 antagonist, which reversed the effects and confirmed the importance of CB2 receptors in glucose tolerance.

Finally, the researchers examined the effects of chronic CB2 receptor activation. The mice were given a 10 mg/kg CB2 agonist for 21 days. Food intake was significantly decreased for the first six days, and body weight continued to be decreased for the full 21-day period.

While CB2 receptors may show promise for weight loss therapy, the evidence is inconclusive. Previous studies that fed a high-fat diet to CB2 receptor knockout mice showed reduced inflammation, less weight gain, and improved insulin sensitivity.9 While one study suggests that activating CB2 receptors promotes weight loss, another suggests that deactivating CB2 receptors leads to weight loss. This could be due to many factors, including but not limited to dosage.

“We need more research,” says Bissex, who adds, “The preliminary research is compelling, but we need robust clinical trials to determine the best dosage and the best route of administration.”

Beyond Cannabinoid Receptors
The endocannabinoid system is complex and includes more than CB1 and CB2 receptors. Consider the previously mentioned study on CB2 receptors and weight loss in mice. Researchers believed the protein kinase A (PKA) channel, which was activated in white adipose tissue, played a major role in the results. In addition to their presence in the immune system, CB2 receptors are localized on metabolically active tissues, such as the liver, skeletal muscles, and pancreatic islet cells. As well as exhibiting improved glucose tolerance, mice in the CB2 study showed a significant reduction in plasma glucose levels and improved glucose clearance. There was also a significant decrease in proinflammatory TNF-α and a significant increase in anti-inflammatory IL-10, highlighting the important role of the immune system in metabolic health and weight—likely a reciprocal relationship.

In addition to the cannabinoid receptors CB1 and CB2, specific channels and receptors are involved in appetite modulation. “We think that THCV may be modulated by other noncannabinoid receptors; serotonin, the transient receptor potential channels, and GPR55,” Theisen says.

The exact effects of TRPV1 on appetite are unknown, but it’s clear that in obesity, the channel becomes dysregulated.9 The close interaction between TRPV1 channels and the endocannabinoid system—the endogenous cannabinoid anandamide (AEA) is an agonist for TRPV1—may explain some of the metabolic effects of cannabis. CB1 receptors can enhance or inhibit TRPV1 activity, depending on other channels involved—an interaction that seems to be dose dependent. Moderate to high doses of AEA appear to activate TRPV1 channels, whereas low doses appear to inhibit TRPV1 activity, possibly through inhibition of the AC-PKA pathways. Peripheral CB1 antagonists, such as THCV, may interact with these channels to suppress appetite and reduce body weight.

GPR55 is considered a nonclassical cannabinoid receptor and may regulate energy metabolism and endocrine function. GPR55 knockout mice exhibit insulin resistance and increased adiposity, indicating that the receptor plays a crucial role in metabolic health. The exact mechanisms that modulate GPR55 are unknown.10

With so many unknowns, unraveling the interaction between cannabis and appetite seems untenable. However, a few things seem certain: the many compounds in cannabis work differently in isolation than in entourage, various pathways are involved, effects are dose dependent, and more high-quality research is needed.

THCV and CBD: The Answers to the Obesity Epidemic?
Is cannabis the answer to the obesity epidemic? Most likely not, but the endocannabinoid system certainly affects metabolism—a finding that should be considered when recommending medicinal cannabis. Practitioners could also consider how lifestyle factors, such as diet, sleep, and toxins can affect and potentially dysregulate the endocannabinoid system.

A randomized, double-blind, placebo-controlled, parallel-group pilot study focused on THCV in people with type 2 diabetes. In addition to decreased plasma glucose levels, the THCV group showed improved scores on the Homeostasis Model Assessment of pancreatic beta-cell function. In contrast to the synthetic rimonabant, the plant-derived THCV did not elicit adverse psychological events.5 THCV seems to competitively inhibit one or more endogenously produced cannabinoids through CB1 receptor activity; THCV may also interact with GPR55 and TRPV1 to affect metabolic functioning. “THCV is like CBD in that it’s a little bit of a promiscuous cannabinoid. I think it’s inconclusive because in some situations THCV acts as an antagonist and in some situations, it acts as an inverse agonist—most likely dose dependent,” says Theisen, who further explains that THCV may counteract some of the effects of THC, “sort of like an antidote to THC, which is how CBD is often portrayed.”

CBD is sometimes touted as an appetite suppressant, although there are few studies to support its use for this specific purpose. “I’m not sure that CBD is a strong appetite suppressant,” Bissex says. “It has a neuro-calming effect and may decrease emotional eating. It also helps with inflammation, which could help with weight loss,” she adds. CBD may also work by its modulation of the aforementioned channels—TRPV1 and GPR55.

Another possibility is that CBD modulates appetite by rebalancing the endocannabinoid system. The endocannabinoid system plays an important role in energy homeostasis and metabolic health. For example, endocannabinoid levels in white adipose tissue are negatively regulated by insulin resistance11 and leptin.12 During insulin or leptin resistance, endocannabinoids could become dysregulated, leading to increased fat accumulation. CBD may help to rebalance a dysregulated endocannabinoid system by attuning levels of endogenous cannabinoids.

A growing area of research seeks to understand the connection between the endocannabinoid system, the gut microbiome, and metabolic health. Nominally, a Western diet is higher in omega-6 fatty acids than in omega-3 fatty acids, which can lead to an inflammatory state and disrupt the crosstalk between the endocannabinoid system and the gut microbiome.13 Research in mice models showed that an increase in dietary linoleic acid (which has dramatically increased in Western diets during the 20th century) led to an increase in liver levels of endogenous cannabinoids—AEA and 2-AG. The mice also presented with elevated plasma leptin, larger adipocytes, and more macrophage infiltration in adipose tissue. The results were maintained, even when the mice were fed a low-fat diet.14

Many diseases, including metabolic syndrome, have been related to an imbalanced endocannabinoid system. Recall that despite THC’s appetite-stimulating effects, chronic cannabis users have a lower BMI than that of the average population. Some researchers believe that intaking exogenous cannabinoids, such as THC, can rebalance the endocannabinoid system by downregulating CB1 receptors. CBD and THCV may also improve metabolic health by modulating the expression of CB1 as well as by acting as TRPV1 agonists. Of course, the question remains, how do we rebalance a disrupted endocannabinoid system? It’s not as simple as prescribing a certain dose and strain of cannabis; each person will respond differently. As it stands, diagnosing an imbalanced endocannabinoid system is clinical—based on a series of symptoms, such as fatigue, weight gain, and inflammation. While studies suggest that the three conditions, fibromyalgia, migraine, and irritable bowel syndrome are common comorbidities to an imbalanced endocannabinoid system, evidence is inconclusive.15 Moreso, treating a disrupted endocannabinoid system is an imprecise science. To begin, a provider who specializes in cannabis would work with the patient, starting with small doses based on thorough patient history. None of this means that providers should abandon the diagnosis or treatment of endocannabinoid deficiency; on the contrary, it may spotlight the need to approach medicine more holistically.

The endocannabinoid system is known to play a role in appetite, energy homeostasis, and metabolic functioning. There isn’t enough research to recommend cannabis as a primary weight loss tool, and it’s not possible to predict how individual people will react to individual cultivars.

“We need to look at cannabis as more homeopathic than pharmaceutical,” Theisen says. It’s a difficult concept in a pharmacological-dependent culture, but it could also change the way we approach therapies. It’s also important to consider cannabis’ effect on metabolism and appetite when recommending it for other uses, such as for pain or anxiety.

Cannabis, Appetite, Weight, and Metabolism: Practical Applications
While the literature regarding its role as an acute appetite suppressant is sparse, CBD may be used to blunt THC-induced increases in appetite and cravings. Theisen explains how understanding the different components of cannabis can help practitioners recommend a product that more precisely serves their patients’ needs. “For example, with pain patients who are concerned about weight gain, I’d start with a cultivar higher in CBD,” says Theisen, who would recommend a high-CBD strain before THCV, primarily based on cost and accessibility. Theisen also cautions people against unsubstantiated claims. “There are a couple companies out there that are making THCV through hemp varieties that you can purchase online in the United States. One of the companies based its formulation on a Nitro V study, which a New York Times journalist showed to be fabricated.” That product, Wanafit, is still on the market, and like other unsubstantiated products, can be attractive in an unregulated market that lacks solid research studies. Theisen recommends that practitioners always look for third-party testing and acquire as much knowledge about a product as possible. The available information depends on each state and its labeling policies; for example, Nevada requires terpenes to be included on the labels, whereas California does not.

“If someone is already using cannabis, we might steer them toward the cultivars that are higher in humulene and THCV,” Bissex says. Cannabis may not be a weight loss drug, but practitioners can be aware of how different products will affect appetite and weight.

Perhaps the best application of cannabis to appetite, weight, and metabolism is a holistic approach—considering both the plant and the patient.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

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