A phoenix rising from its ashes: the renaissance of CB1 as a therapeutic target against metabolic disease

Sections:

1. Obesity and current pharmacological therapies
2. Is CB1 receptor a good anti-obesity target?
3. Peripheral-CB1 antagonists and novel ways to target the CB1 receptor
4. The Future: New combinatorial therapies

Obesity is a major global health challenge, and scientists are constantly seeking better and more effective ways to treat it. Medications like Ozempic and Wegovy, which mimic a hormone called glucagon-like peptide-1 (GLP-1), have recently revolutionized the treatment of obesity and type 2 diabetes (T2D). These drugs contain the long-acting GLP1 agonist semaglutide that helps regulating appetite and blood-sugar levels. However, these medications are costly, require weekly injections, cause unpleasant side effects and can lead to weight regain, when their use is stopped. Therefore, researchers are focusing on developing new drugs and novel combinatorial therapies that target multiple pathways in the body at once. One promising strategy is to target the cannabinoids type 1 receptor (CB1), as the inhibition of the activity of this receptor can improve metabolic responses and certain conditions associated with obesity, like glucose imbalance, non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), and kidney injury, possibly opening new treatment venues against metabolic disorders associated with obesity.

1. Obesity and current pharmacological therapies

Obesity is characterized by excessive fat accumulation in the body, leading to cardiovascular, kidney, liver, pancreatic and mental health-related disorders. For decades, the main treatments for obesity were lifestyle changes, like low-calorie diets and more exercise, and bariatric surgery. Healthy diets and regular exercise are always recommended but in people with obesity, weight loss rarely exceeds 10% and can be hard to maintain over time (Wadden et al., 2020). Bariatric surgery can reduce body weight by 30% or more but it is an invasive treatment with potential important side effects.

Scientists have been trying to find safe, effective, and non-invasive pharmacological treatments to help people lose weight permanently (Prillaman, 2023). In 2017, the U.S. Food and Drug Administration (FDA) approved semaglutide (named Ozempic), a GLP-1 receptor agonist, for the treatment of T2D. This drug acts like the hormone GLP-1, helping to control blood sugar and appetite. Interestingly, patients taking semaglutide also lost weight. Four years later, a drug based on the same principle named Wegovy, was approved, resulting in 15% of weight loss in obese patients.

Very recently, new drugs have been developed combining different mechanism of action to increase the benefits and reduce side effects. One such drug is tirzepatide (sold as Zepbound and Mounjaro), which targets both GLP-1 and gastric inhibitory polypeptide (GIP) receptors, and it is approved for T2D and obesity with a 21% decrease in weight (Dolgin, 2025).

Although these medications are successful in inducing weight loss, they also have limitations. They require weekly injections and often cause unpleasant side effects like nausea, vomiting and diarrhea. Long-term issues include potential loss of muscle mass, weight regain after stopping treatment and a risk of developing arthritis and pancreatitis (Xie et al., 2025). In addition, 10 to 30% of people who take these drugs don't respond to them.

2. Is CB1 receptor a good anti-obesity target?

It has been known for centuries that cannabis use can stimulates appetite. In the 1960s, researchers isolated the Δ9-tetrahyrocannabinol (THC), the main psychoactive component of Cannabis Sativa (Gaoni & Mechoulam, 1964)). Twenty years later, they discovered that THC acted through a receptor in the brain called CB1 receptor (Devane et al., 1988). That was the mechanism by which cannabis consumption often led to increased appetite, or "the munchies".

Further research led to the discovery of other cannabinoid receptors (like CB2), the identification of endogenous ligands called endocannabinoids (natural cannabinoids produced by the body), and the enzymes that synthetize and break down these substances in the body. Together with the cannabinoid receptors, these components form the endocannabinoid system (ECS). This system orchestrates millions of cells in various organs towards one goal: promoting food consumption and fat accumulation (Mazier 2015). In today's world, with sedentary lifestyles with 24/7 access to high-calorie foods, the ECS promotes obesity (Piazza et al., 2017).

Therefore, tuning down the ECS emerged as a promising strategy for obesity treatment. In 1994, rimonabant, a CB1 receptor inverse agonist, was developed and used for smoking cessation but it also showed promise in reducing body weight and food intake (Rinaldi-Carmona et al., 1994). After initial clinical trials in 2006, the European Medicines Agency (EMA) approved it as an anti-obesity agent. However, two years later, it was withdrawn from the European market due to serious neuropsychiatric side effects (anxiety, depression, and suicidal thoughts) in some patients. This setback significantly impacted efforts to develop CB1 receptor-targeting drugs and halted all similar clinical trials.

Why did rimonabant cause these side effects? Rimonabant is a drug that penetrates the brain, meaning that it affects CB1 receptors in the brain as well as in the rest of the body. The effects of CB1 on metabolic functions depend by its expression in the brain as well as in peripheral organs like the adipose tissue, the kidney, the liver, the muscle, and the intestine (Cota et al., 2003). Over the last decades, peripheral CB1 receptors activation been found to promote fat accumulation, reduce fat burning, lead to leptin insensitivity and insulin resistance, promote fatty liver disease, impair pancreatic functions, drive fibrosis and diabetic kidney disease, and induce obesity-related inflammation.

These findings have led to a new strategy: developing selective drugs that block only peripheral CB1 receptors or that block CB1 only under pathological conditions (neutral CB1 antagonist and signaling-specific inhibitors). This offers the metabolic benefits of inhibiting CB1 without the neuropsychiatric side effects. So far, a few CB1 receptors blockers have been developed and have shown promising effects in treating obesity and metabolic diseases.

3. Promising CB1 receptors-targeting drugs

Preclinical phase:

• JD5037: A peripheral restricted CB1 receptors inverse agonist that reduces body weight and greatly improves metabolic alterations in preclinical animal models. It has been approved for human clinical trials (Quarta & Cota, 2020).
• MRI-1867: A multi-targeting drug that blocks peripheral CB1 receptors and an enzyme involved in insulin signaling and tissue inflammation. It improves the consequences of obesity on kidneys and liver function (Quarta & Cota, 2020).
• JM-00266: A CB1 peripherally restricted antagonist used to improve obesity-related metabolic disorders (Muller et al., 2022).
• NESS0327: A neutral antagonist of CB1 receptor (not restricted to periphery) that reduces weight gain and food intake without the negative effects caused by rimonabant (Meye et al., 2013).

Clinical phase:

• Monlunabant: A peripheral restricted CB1 inverse agonist developed by Novo Nordisk. It reached phase2a trial for obesity and obesity-related complications, such as diabetic kidney disease and fibrotic disorders (Jacquot et al., 2023).
• AEF0217 and AEF0117: New signaling-specific inhibitors (SSi) of CB1. These drugs selectively inhibit the receptor in pathological conditions while preserving its normal functions. These drugs are in phase2 trial for cognitive impairments and cannabis use disorder. However, their potential effect in obesity-related disorders has not been addressed yet (Haney et al., 2023).

4. The Future: New combinatorial therapies

Obesity is a complex disease that requires drug approaches targeting multiple mechanisms of action. In the next three years, several weight-loss medications based on a combination of GLP-1 receptor agonist with other drugs are expected to be approved in the US (Dolgin, 2025). Interestingly, a recent study from our lab has demonstrated that combinatorial therapy with GLP-1 receptor agonists and peripheral CB1 receptor antagonists may potentiate metabolic benefit in obesity (Zizzari et al., 2021).

While the results obtained from new CB1 blockers are promising, researchers must carefully explore all potential side effects to avoid past mistakes. First, it is crucial to develop drugs specific for different types of obesity, depending on the fat accumulation location and which metabolic complications are associated with it. Each type of obesity may need a different anti-obesity strategy. Second, it is crucial to assess how the body processes and responds to the medications over time. Factors such as dose, duration of treatment as well as the sex and age of a patient can change the behavior of the drug. Finally, since obesity requires long-term treatments, chronic administration of these compounds needs to be assessed for potential cardiovascular, gastrointestinal (nausea, vomiting, and diarrhea were common dose-related complications of Rimonabant), mental (anxiety) and other side effects.

In conclusion, new CB1 drugs in preclinical and clinical stage represent potentially safe alternatives for treating obesity and related metabolic complications and are promising compounds to be combined with existing anti-obesity drugs.

Table of definitions and abbreviations:

Definitions:

• Agonist: it binds to a receptor and activates it, triggering a biological response.
• Inverse agonist: is a compound that binds to and prevents constitutive receptor activity in the absence of an agonist, leading to a biological effect opposite to that of an agonist.
• Antagonist: it blocks or dampens a biological response by binding to and blocking the receptor.
• Neutral antagonist: it has no activity in the absence of an agonist or inverse agonist but can block the activity of either.
• Signaling-specific inhibitor: it selectively blocks certain signaling pathways activated by a receptor while leaving others unaffected.
• Leptin: is a hormone primarily produced by adipocytes that signals when the body has enough energy stored in fat and reduces appetite. In obesity, there is an over production of leptin that leads to resistance to the biological actions of the hormone, overeating and difficulty losing weight.
• Insulin: is a hormone produced by beta-cells in the pancreas that helps to regulate blood sugar levels. Insulin resistance appears in obesity and type 2 diabetes when cells become less responsive to insulin effects.
• Glucagon: is a hormone produced by alpha cells in the pancreas and it works as the counterpart of insulin by raising blood sugar levels when they are too low.

Abbreviations:

• ECS: endocannabinoid system
• CB1/2: cannabinoid type 1 and 2 receptor
• THC: Δ9-tetrahyrocannabinol
• GLP-1: glucagon-like peptide 1
• GIP: gastric inhibitory polypeptide
• T2D: type 2 diabetes
• NAFL: non-alcoholic fatty liver disease
• NASH: non-alcoholic steatohepatitis
• EMA: European medicines agency
• FDA: US food and drug administration

Conflict of interest: D. Cota is stakeholder and consultant for the company Aelis Farma.

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