As legal cannabis gains a foothold in many US states and Canada, more and more people have access to medicinal and recreational choices. Whilst many of us now enjoy the right to choose our bud carefully, we still know fairly little about the clinical benefits of cannabis (within an evidenced based framework).
Besides its famous applications, such as for inflammation and pain, cannabis may also influence metabolic health, independently of appetite. Although systematic reviews are lacking, there are some RCT’s, observational studies and plenty of animal studies to go by, which may help determine whether cannabis could influence weight and body composition.
Cannabinoids, Appetite & Body Composition
If you personally enjoy a good smoke or edible then you’ll certainly know about the munchies and the effect cannabis has on appetite. Intuitively, its made sense that consuming cannabis could increase our food intake and would therefore contribute to weight gain….Right?
Whilst some of us may be more prone to sinking a whole tub of ice cream than our sober counterparts, that might not be the case for everyone.
Due to the lack of clinical research to date, its hard to highlight the intricacies and nuances in the effects of cannabis from person to person. However, there is some indication as to how the effects of cannabis on appetite can vary based on dosing, and its frequency of use.
An ancient study (from 1986) held 9 participants in a laboratory for 25 days (*) . They found that smoking one joint had no effect on food intake, but 3 joints increased caloric intake (between meals) compared to control. However, there are limitations to this study, so interpret results with caution:
- Small sample size (may not be representative of true effect within actual population)
- Cannabis used was old school, only 1.84% THC! (not representative of strength of most weed today)
Whilst smoking 3 joints of old school schwag reportedly increased food intake compared to 1; what might the effect of a single or multiple more refined joints be?
In a more recent case-control study (2013)(*), the food intake and dietary quality of 30 cannabis smokers and 30 matched controls (non-smokers) was assessed. Interestingly, cannabis smokers did not consume a greater number of total calories, but derived a greater portion of calories from carbohydrates.
However, half of cannabis users also smoked tobacco, which may impact appetite and food intake. The average use duration amongst smokers was 9.5 years, and they smoked an average of 6 joints a day – they were chronic users.
Another ancient study (1976) studied heavy and casual cannabis users for 21 days in a ward. Caloric intake and weight gain increased significantly after the first 5 days in both heavy and casual groups compared to control. After 5 days of smoking, food intake plateaued whilst body weight continued to increase.
This indicates a desensitisation to cannabis overtime with regards to appetite, but also suggests a metabolic effect of cannabis use beyond just food intake. (*).
Whats interesting to note about this study, though, is that participants were all marijuana users before the study started (apart from control). It is only when confined to a ward and given free access to snacks that they actually gained weight. So their cannabis use didn’t change from typical real world use, just their surroundings and behaviours (and being sedentary). This trial may lack external validity – its applicability to real world conditions.
When we take a look at studies of populations, outside of laboratory conditions, we actually see conflicting results.
For example, a cohort study following 3,617 participants over 15 years found that heavy (20-25 days/month) and casual (10 days/month) cannabis use was associated with a higher caloric intake, but not a higher BMI. (*)
Carbs – white bars; Alcohol – black bars; Protein – crossed; Sat fat – light grey; Unsat fat – dark grey
However, BMI is not a great assessment of actual body composition, and (*) actually found that cannabis users, whilst having a similar BMI to controls, had a higher level of abdominal visceral fat (bad fat).
This may indeed be related to the fact that cannabis increases desire for highly palatable foods, and cannabis users in this study got more of their share of energy from carbohydrates (sugars), which drives visceral fat accumulation.
But, its hard to say with conviction whether cannabis is solely responsible for the outcomes measured in observational studies, given tobacco & drug use, as well as errors in dietary self reporting. Thats why we need more RCT’s to control for confounders, allowing us to point the finger directly at cannabis for outcomes we see.
Cannabis Use Is Associated with a Lower BMI and Better Blood Sugar Regulation
Cross sectional data was analysed on two different sample populations of 43,093 and 9,282, to establish the prevalence of obesity in relation to cannabis use. Those who smoked cannabis 3 days or more/week revealed 14.3% & 17.2% of the sample who were obese vs 22% & 25.3% for non smokers, with obesity being defined as BMI > 30. The use of cannabis (tobacco use adjusted for) was associated with lower BMI in both samples. (*).
Other epidemiological data suggests that the prevalence of obesity and insulin resistance is lower in cannabis users. Cannabis use was associated with lower fasting insulin, HOMA-IR and waist circumference (*).
So far, we have seen that short term (old school) cannabis use under laboratory conditions appears to increase appetite and caloric intake. In contrast, we have seen that in samples of various populations that cannabis use is associated with both higher and indifferent caloric intake, a lower BMI, and a higher amount of visceral fat.
Without a good supply of clinical evidence to draw on for any causal relationships, looking at the mechanisms can help bridge the gap of cause and effect.
Endocannabinoid Activity In obesity
Endocannabinoids are key regulators of appetite and body composition, operating via a network of specific receptors throughout the body. CB1 and CB2 are the main cannabinoid receptors which are expressed on various tissues, cells and organ systems.
CB1 tends to be expressed on cells which constitute organ systems (liver), neurones and the brain. The majority of CB2 are on immune cells, although there is a small crossover between them (*).
2-AG & AEA, as shown above, are the two main endocannabinoids.
Stress, sleep, diet, environmental, genetic and lifestyle factors all affect Endocannabinoid system (ECS) activity.
That activity basically boils down to a few variables of ECS function which could ultimately influence appetite and body composition:
- Rate of endocannabinoid synthesis (ECS specific enzyme activity)
- Rate of endocannabinoid degradation (ECS specific enzyme activity)
- Expression of CB receptors centrally and peripherally (up or down regulated)
- Dietary status (Omega-3:6 consumption)
- Influence from plant cannabinoids (THC, CBD) or others (Yangonin from Kava Kava)
For example, in obesity common findings are that the EC system is overactive:
- High 2-AG correlates positively with visceral obesity, BMI, Triglycerides, Insulin and waist circumference, and negatively with adiponectin and HDL. (*). Basically suggesting BMI etc increase with higher EC levels, and HDL (good cholesterol) decreases.
- Plasma 2-AG levels fall after lifestyle modification and weight loss (*). Further suggesting role of high EC levels in pushing weight gain.
- Low activity of FAAH, the enzyme that deactivates endocannabinoids in visceral obesity (*). Less FAAH activity = more Endocannabinods to drive weight gain.
- Downregulation of CB1 receptors on fat cells in association with high plasma 2-AG (bodies attempt to reduce impact of high levels of endicannabinoids) (*).
The increased tone of the EC system has downstream effects, and hijacks two key mechanisms involved in energy balance, both centrally and peripherally.
Effects of Cannabinoids on Appetite (Central Mechanism)
In the case of appetite regulation, we’ll focus particularly on the CB1 receptors found on neurones within the hypothalamus.
The hypothalamus is a regulator of feeding behaviour in the brain, and signals hunger and satiety through orexigenic and anorexigenic neurones.
Orexigenic = feed
Anorexigenic = full
Together, these neurones control appetite and satiety via their respective neuropeptide messengers:
POMC – Increases satiety and reduces appetite
NPY – Increases food intake and promotes storage of energy as fat
AgRP – Increases appetite and decreases energy expenditure and metabolism
CB1 receptors are found on both sets of neurones within the hypothalamus. This allows endocannabinoids (and cannabinoids) to influence appetite through interacting with CB1 on these neurones.
As we’ve seen, a high ECS tone isn’t great news, and can potentially interfere with the signalling of these neurones.
This can be seen in mice who under express the CNR1 gene, which reduces CB1 receptors available for activation. These mice were lean, had reduced caloric intake and body weight compared to mice without CNR1 gene variant.
Fewer CB1 receptors = less binding opportunity for endocannabinoids
Neuropeptides which regulate appetite were also active in the mice, in conjunction with CB1 activity, suggesting a role for endocannabinods in driving feeding behaviour (*).
There’s also a direct relationship between activity at the CB1 receptor and the appetite stimulating hormone, ghrelin. Mice who had genetic depletion of CB1, and mice who were given a CB1 blocker Rimonabant had less response to the appetite stimulating effects of ghrelin (*).
This makes sense, as endocannabinoids activating CB1 increase ghrelin, and appetite: (*)
This is the same mechanism by which THC induces appetite, by activating CB1. Rats given CB1 agonists (that activate the CB1 receptor) stimulates ghrelin release from the stomach (*). Additionally, HIV patients using smoked cannabis had increased ghrelin, leptin and reduced Peptide YY afterwards (*).
Peptide YY is a satiety hormone released in the gut after feeding, and can offset the stimulatory effects of ghrelin.
Leptin is hormone which communicates the bodies available resources from fat cells to the hypothalamus, and in doing so controls energy balance via feeding cues. Leptin signalling is commonly disrupted in obesity and weight issues, and is associated with increased endocannabinoids in the hypothalamus of obese mice (*).
Therefore, the number of CB1 receptors as well as the levels of circulating endocannabinoids affect system tone, hormonal and neuropeptide signalling, which influences appetite.
Now, pharmacologically it makes sense to intervene at the CB1 receptor, which is exactly where a lot of attention has been directed.
CBD also acts as a partial antagonist at the CB1 receptor (blocks it). Although, it typically has a fairly weak binding affinity. Some indication of CBD for use as a weight loss tool – https://www.projectcbd.org/condition/38/Obesity
THCV also has an appetite reducing effect as it blocks CB1 (antagonist), but is typically found in low concentrations in most well known cannabis strains (≤ 5%) (*). That being said, THCV tends to be more abundant in Sativas than Indicas, which would explain the tendency for a heavy Indica to bring about the munchies.
The synthetic cannabinoid Rimonabant was designed to block CB1 receptors after the discovery of the ECS role in obesity. Initially, it showed to be pretty effective.
Part of the efficacy for rimonabant is a result of the reduction in food intake, as evidenced by the mechanism by which endocannabinoids interact with hypothalamic feeding messengers.
However, a study in mice taking Rimonabant found that after initial reductions in food intake, it began to return to normal, but body weight maintained its new lower level. (*)
This suggests that the effects of endocannabinoids are not just limited to their effects on appetite, and could extend to regulate metabolism.
Contrary to rimomibant, THC is a CB1 agonist. It activates the CB1 receptor in a way that increases appetite acutely (hence the munchies). Notwithstanding, animal studies on THC and appetite don’t fully reflect this: (*)
Additionally, the method of administration may have an impact on appetite and food intake, as energy intake was significantly higher in suppositories than in oral capsules relative to smoking (*).
We all know anecdotally that THC increases appetite, which is evidenced in the early clinical trials looking at short to mid term cannabis use. However, observational studies suggest that:
- Increased appetite may not necessarily impact body composition, potentially as a result of another mechanism, and;
- Energy intake is not significantly different to non-smokers, possibly due to desensitisation to appetite stimulating effects from chronic use.
One theory behind decreased food intake in response to THC is an appetite suppressing effect, given the sedative effects at high doses seen in animal studies.
Another theory is a peripheral mechanism by which endocannabinoids influence body composition independently of appetite, which could help shed some light on the situation.
Effects of Cannabinoids on Fat Cells (Peripheral Mechanism)
Endocannabinoids aren’t just limited to central effects. There are receptors for them all over the place. CB1 are also expressed on adipocyctes (fat cells), which allow endocanabinoids to instruct changes in their activity, independently of central regulation.
The CB1 receptor regulates metabolic activity within the fat cells they are found on. Specifically, changes in CB1 activity regulate fat oxidation, and Krebs cycle enzymes, altering the cells metabolic activity (*).
These are pathways by which fat is metabolised in the cell and converted into ATP for use as an energy currency for the body. Therefore, binding or blockade of the CB1 receptor may actually influence cellular metabolism, lipogenesis/lipolysis, glucose metabolism and body composition as a result of net cellular activity (*)
The default setting of the ECS encourages fat accumulation and reduction in energy expenditure, which is why a high EC system tone/activity results in metabolic problems.
In support of this, cannabinoid agonists stimulate gene expression involved in fatty acid synthesis – SREBP-1c – a fat storing transcription factor. SREBP-1c acts on enzymes acetyl-CoA carboxylase-1 and fatty acid synthase in liver cells, promoting fat accumulation in the liver (*).
Further supporting this notion are the famous Rimomibant trials. Rimomibant is a synthetic CB1 receptor blocker (antagonist), which initially demonstrated powerful effects on blood lipids, metabolic health and body composition in humans (*). However, the drug was withdrawn due to psychiatric side effects.
So this is evidence that there is a powerful effect from pharmacologically blocking the CB1 receptor. The metabolic effects of CB1 blockage are also evident from using an actual cannabinoid, THCV.
THCV is similar to THC but with different pharmacologic effects, acting mainly as an antagonist (Blocking CB1).
THCV alone (2 x 5mg daily) significantly increased adiponectin, and significantly reduced fasting blood glucose but had no effect on body weight. Additionally, CBD/THCV combos failed to demonstrate an effect, as well as CBD alone.
Jadoon et al. 2016. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study.
Although there were no significant decreases in weight, THCV may prove beneficial in offsetting one of the driving forces behind the progression of obesity – poor glycemic control, insulin sensitivity and adiponectin signalling. Adiponectin is a hormone which regulates both glucose metabolism and fat oxidation, and is found to decease as BMI increases (*).
THCV may indeed be a key player in the overall effects of cannabis, as it has the ability to modify the effects of THC (*). However, typical cannabis strains tend to be quite low in THCV, and are dominated by high THC concentrations. (*)
There are specific landrace, and specially bred strains of cannabis which have higher THCV values ~ ≥ 5% (*). But, since breeding up until very recently has focused on THC, we could assume that most studies used contemporary cannabis that more or less reflected that breeding preference.
Adaptive Mechanisms Which Could Support Healthier Metabolism
THC on its own may not actually be all that bad after all. In fact it might hold the key to understanding some of the surprising findings in observational studies.
Lets look back at the early clinical evidence that cannabis (THC) increases appetite and body weight. These early findings are consistent with the use of THC in the short term in rats, that THC increases the desire to eat (*).
Conversely, chronic administration of THC over both 13 weeks and 2 years in rats produced body weights that were significantly lower than controls (*).
This gives some grounding to the observational evidence we’ve covered earlier, and suggests differential effects of short vs long term use.
A few key mechanisms may be able to explain this :
THC as a Functional Antagonist
Basically, in cases of obesity where endocannabinoid activity is high (2-AG), THC may actually block the CB1 receptor as opposed to activating it. This prevents high levels of 2-AG from activating the receptor and further driving metabolic complications.
Chronic Exposure to THC
If a high level of THC is being consumed on a regular basis, gradually CB1 receptors fall in number and become desensitised to the effects of THC as a result. Because THC and endocannabinoids are alike, this may in fact reduce the overactivation of CB1 by 2-AG, which drives weight gain.
Central vs Peripheral Influences
The effects on appetite and body composition could be somewhat independent of one another, separated by central and peripheral effects. Increased metabolic activity of cells may partly offset the increased food intake from appetite stimulation.
These mechanisms may account for the discrepancy in findings between studies, and explain why acute administration of THC could induce increased energy intake and weight gain, but not in the long term.
In fact, long term use seems to be associated with better body composition and markers of metabolic health compared to non-smokers. This may indeed suggest adaptive mechanisms to THC (and possibly other cannabinoids).
The role of the EC system in energy metabolism, appetite and therefore body composition is a leading one. This also leads us to believe that higher circulating endocannabinoids not only increase appetite, but also affect energy metabolism in a way that alters body composition.
Therefore, cannabis could be acting as an adaptogen, working to addresses unique imbalances in our own ECS function to achieve balance.
This, you could argue, is reflected in the differing outcomes cannabis has on body composition in different population groups.
For example, in HIV patients who are underweight, cannabis acutely increases appetite and BMI, whereas normal or overweight cannabis users tend to have lower BMI’s than non smokers.
As cannabinoids are akin to endocannabinoids, they can interact with the ECS and potentially correct the imbalances in its function, which could be driving metabolic issues.
There are also a couple gene polymorphisms which are associated with cannabinoid system tone and body mass:
Influences receptor density, and binding activity of AEA & 2-AG (*)
- rs1049353 polymorphism of the CNR1 gene is associated with hypoadiponectinemia
- rs806381, rs1049353 SNP’s are associated with body fat distribution
- rs1049353 SNP is associated with BMI, waist circumference and Triglycerides
Encodes Fatty Acid Amide hydroxylase, and enzyme which deactivates AEA *
- rs324420 polymorphism is associated with class III obesity in a french population of 5,109 (*)
- rs324420 was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol in a sample population of 1.644 individuals (*).
- rs324420C>A is associated with obesity, and carriers of CC genotype had a better weight loss, fat mass and waist circumference response to a hyocaloric diet than A carriers (*)
Encodes monoacylglycerol lipase, an enzyme which deactivates 2-AG
Five single nucleotide variants in MGLL gene were associated with extreme obesity and endocannabinoid metabolite level (*).
Encodes diacylglycerol lipase, an enzyme which increases 2-AG synthesis
Chow or high fat diet-fed DAGLA KO mice were leaner than their normal siblings, and had 47% lower body fat (*).