Monlunabant induces clinically meaningful weight loss, raises questions over tolerability

medwireNews: Individuals with obesity and metabolic syndrome experience significantly greater weight loss with monlunabant, a second-generation cannabinoid receptor 1 (CB1R) inverse agonist, than with placebo but higher doses are not well tolerated, phase 2a study findings indicate.

Filip Knop (Novo Nordisk, Sørborg, Denmark) and co-authors report in The Lancet Diabetes & Endocrinology that weight loss with monlunabant “increased only slightly with higher doses but did not appear to reach a plateau […] and was accompanied by dose-dependent psychiatric and gastrointestinal adverse events [AEs], resulting in high rates of withdrawal.”

They add: “The implications of this trial, combined with existing evidence, suggest that monlunabant has potential as a novel treatment option for people with obesity and metabolic syndrome, if a safe and effective therapeutic window can be established.”

The trial included 242 adults (mean age 54 years, 69% women) with obesity and metabolic syndrome from 25 outpatient research centers in Canada. At baseline, participants had a mean BMI of 39.7 kg/m², bodyweight of 110.1 kg, waist circumference of 119.9 cm, and a mean glycated hemoglobin (HbA1c) level of 5.9% (41 mmol/mol). People with an investigator-assessed active diagnosis or history of a significant psychiatric disorder were excluded from participation.

The researchers report that after 16 weeks of once-daily oral treatment with monlunabant mean weight loss was 7.1 kg among the 61 individuals randomly assigned to receive a dose of 10 mg/day, 7.7 kg among the 60 participants given 20 mg/day, and 8.0 kg in the 60 people given 50 mg/day.

By comparison, mean weight loss was significantly lower, at 0.7 kg, among the 61 participants randomly assigned to receive placebo.

Compared with placebo, participants in all three monlunabant groups also experienced significantly greater reductions in the estimated mean percentage decrease in bodyweight (estimated treatment difference [ETD] 5.9–7.4%), estimated mean waist circumference (ETD 3.8–5.4 cm), and HbA1c (ETD 0.16–0.17 percentage points).

Conversely, there were no significant improvements with monlunabant versus placebo in most lipid measurements, insulin dose, or C-peptide levels.

AEs of any grade occurred in 69%, 78%, and 92% of participants given monlunabant 10 mg, 20 mg, and 50 mg, respectively, and in 69% of those given placebo.

Knop et al note that although the “majority of adverse events were non-serious and not severe,” there was a high rate of early treatment withdrawal due to AEs, which seemed to be dose dependent.

Indeed, withdrawals due to AEs occurred at rates of 13%, 27%, and 42% of individuals in the monlunabant 10 mg, 20 mg, and 50 mg groups, respectively, and in none of the participants in the placebo group. Gastrointestinal events and psychiatric disorders accounted for most of the AEs leading to early withdrawal from the trial, particularly nausea, anxiety, diarrhea, irritability, and sleep disturbance. Two participants (given monlunabant 10 mg and 50 mg) reported low-risk suicidal ideation, but no cases of severe suicidal ideation or behavior were recorded.

Knop and team conclude that “the dose-dependent adverse events highlight the need for careful dose optimisation and monitoring.”

They say: “Further investigation of monlunabant at lower doses and with a close monitoring of adverse events is needed to establish if a safe, effective, and clinically relevant dose range of monlunabant exist.”

In an accompanying comment, Kishore Gadde and colleagues, from the University of California Irvine School of Medicine in the USA, reflect on the psychiatric AEs recorded during the trial.

They point out that “[m]onlunabant is the first peripherally restricted CB1 inverse agonist to reach phase 2 clinical development” but note that “psychiatric adverse events were similar to those seen with centrally acting CB1 antagonists whose development was terminated.”

Gadde et al therefore suggest: “In a therapeutic landscape now dominated by incretin-based drugs, which have revolutionized obesity treatment despite their own limitations, future cannabinoid-based approaches should prioritise more reliable peripheral restriction and a nuanced understanding of CB1 signalling mechanisms to minimise adverse effects and improve efficacy.”

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Lancet Diabetes Endocrinol 2025; doi:10.1016/S2213-8587(25)00216-5
Lancet Diabetes Endocrinol 2025; doi: 10.1016/S2213-8587(25)00255-4