The Link Between Cannabinoid System & Weight Gain (CNR1)

Everyone’s heard of cannabis, but we still have a lot to learn about the cannabinoid system—a common name for complex pathways in our bodies, activated by internal and external cannabinoids.

The CNR1 gene encodes the type-1 cannabinoid receptor (CB1), one of the primary receptors responsible for stimulating the cannabinoid system, especially in the brain [R, R].

It’s deeply involved in a myriad of processes, including [R, R, R, R, R]:

• Mood control 
• Wakefulness
• Stress response
• Cognition/synaptic plasticity
• Metabolism
• Inflammation

Given its complex roles in the mind & body, impairments in the CB1 receptor function can contribute to fatigue, mood & mental health issues, “brain fog,” metabolic disorders, and more [R, R, R].

To date, genetic research of the cannabinoid system has mostly focused on cognition and mental health. However, emerging evidence points to the roles in weight control and glucose metabolism [R, R].

The CNR1 gene encodes the type-1 cannabinoid receptor (CB1). It’s a critical part of the cannabinoid system, involved in cognition, mental health, metabolism, inflammation, and more.

CB1 Receptor in Obesity & Metabolism

Cannabinoids control food intake and metabolism via the CB1 receptors in the brain, but also the liver, fat tissue, and pancreas [R, R]. Their activation in the brain enhances appetite and the rewarding effects of food [R, R].

Mice lacking the CB1 receptor are lean, even on a high-fat diet. They are not prone to overeating and have enhanced fat-burning potential [R]. Inhibition of the CB1 receptor causes weight loss and improves insulin sensitivity in humans and animals [R, R].

On the other hand, overactive cannabinoid system can result in [R, R, R]:

• Excess fat storage
• Overeating
• Impaired glucose & fat metabolism

This makes sense given that most people have increased appetite from smoking marijuana, popularly called “the munchies”. Some marijuana users experience weight gain, but, surprisingly, large studies have observed the opposite effect in a general population [R, R].

The cannabinoid system controls food intake and metabolism via the CB1 receptor. The excess activity can increase appetite, slow down metabolism, and contribute to weight gain. 

Rs1049353 (1359G/A)

The most studied SNP in this gene is rs1049353 or 1359G/A. Plenty of studies have examined its link with weight and obesity, but they yielded mixed results.

According to a large meta-analysis, the “T” allele is associated with a lower body mass index (BMI), while it doesn’t seem to impact energy or macronutrient intake [R].

The same allele correlates with gut inflammation and IBD severity, which indicates a potential link with lectin sensitivity. This SNP might also impact:

• Psychological stress [R]
• Response to antidepressants [R]
• Addictive and eating disorders [R, R, R]

People with the ‘T’ variant may be protected against obesity, but they are more prone to anxiety and digestive issues.

Note: “1359G/A” marks the alleles on a negative (-) DNA strand. We always report on a positive strand, where “G/A” becomes “C/T.”

The “T” allele at rs1049353 is associated with a lower BMI. This SNP may also be involved in gut inflammation, stress response, and mental disorders.

Other Variants

A group of authors analyzed the link between CNR1 variants and obesity in three groups of total 5,750 European subjects. According to their results [R]:

• The “G” allele at rs6454674 correlates with 52% higher odds of obesity in children.
• The “T” allele at rs2023239 correlates with 40% higher odds of obesity in adults.

In a study of 1,452 Japanese subjects, men with the “CC” genotype at rs806368 had 70% higher obesity rates [R]. This variant was associated with a higher waist-hip ratio among 756 Brazilian adults [R].

Three less-known SNPs in the CNR1 gene may correlate with obesity in different populations.

How It Works

The primary SNP, rs1049353, doesn’t change the CB1 receptor structure, but it may impair gene expression and receptor activity [R, R].

As discussed, lower activity of the cannabinoid system can prevent weight gain and speed up metabolism. On the other hand, it can have detrimental effects on mental health and inflammation [R, R, R, R].

Food Intake

Cannabinoids increase appetite and the rewarding effects of food. Discussed variants showed a correlation with impulsive behavior and eating disorders, so they likely influence food intake and appetite [R, R].

In one trial, people with rs1049353-T ate significantly less saturated fat and cholesterol [R]. However, other studies found no difference in energy and nutrient intake [R].

Fat Metabolism

Animal and clinical studies suggest that cannabinoids (via CB1) impair fat burning and reduce adiponectin levels [R, R]. In a 305 subjects trial, those with rs1049353-T had higher adiponectin, compared with the “C” allele carriers [R].

Adiponectin is a fat-derived hormone that enhances fat burning and insulin sensitivity and prevents weight gain [R].

CNR1 variants may change CB1 receptors’ activity and thus impact appetite, food preference, and fat metabolism.

Limitations

For rs1049353, some studies observed the opposite effect: increased weight gain and obesity rates among the “T” allele carriers [R, R]. According to one review, 90% of all studies failed to establish any correlation between this SNP and obesity [R].

Some papers found no significant effects of CNR1 SNPs on weight, altogether [R, R, R].

Drug Research

The pharmaceutical industry has been trying to leverage the effects of the cannabinoid system on weight loss. In early clinical trials, CB1 inhibitor, rimonabant, showed beneficial effects on weight, waist circumference, blood lipids, and glucose metabolism [R, R].

Rimonabant was approved for obesity treatment in Europe (2006) and Brazil (2007). However, health authorities withdrew it in 2008 due to severe psychiatric adverse effects, including suicide [R, R].

SNP Summary

Primary SNPs:

CNR1 rs1049353

• ‘C’ = not associated with weight or obesity
• ‘T’ = associated with a lower BMI

Population Frequency: Around 45% of European descendants carry the “T” allele. It’s less common in other populations, ranging from 31% in South Asians to 6% in Africans.

CNR1 rs6454674

• ‘T’ = not associated with obesity 
• ‘G’ = associated with higher obesity rates, especially in children

Population Frequency: Around 40-42% of people carry one copy and 8-14% carry both copies of the “G” allele across all populations.

CNR1 rs2023239

• ‘C’ = not associated with obesity 
• ‘T’ = associated with higher obesity rates

Population Frequency: Around 71% of Europeans, 42% of Africans, and 95% of East Asians carry both copies of the “T” allele.

Other Important SNPs:

CNR1 rs806368

• ‘T’ = not associated with obesity
• ‘C’ = associated with higher obesity rates in Japanese men

Population Frequency: Around 4% of Europeans carry the obesity-associated “CC” genotype. It’s much more common in East Asians (26%) and nearly non-existent in Africans.