Synthetic Cannabinoid Nabilone Was Poorly Tolerated for Obesity Treatment but May Affect Gut Bacteria | Research

The takeaway

A pilot RCT of nabilone for obesity was terminated early due to poor tolerability at higher doses, though low-dose nabilone showed preliminary effects on body weight and gut microbiome composition.

Obesity researchers and anyone interested in the endocannabinoid system as a weight management target.

All high-dose participants withdrew due to adverse events

What the researchers found

The trial was terminated early because all four high-dose participants (6 mg/day) withdrew due to adverse events. Among the 8 completers (4 low-dose, 4 placebo), there was a significant treatment effect on body weight, with low-dose nabilone (2 mg/day) reducing weight. The low-dose group also showed greater changes in fecal microbiome composition than placebo.

Why it matters

Epidemiological data shows cannabis users have lower obesity rates, and the endocannabinoid system is a known obesity target. However, this trial shows that directly activating CB1 receptors with nabilone is poorly tolerated, especially at higher doses. The microbiome finding opens an unexpected new avenue.

The numbers in context

18 randomized, 15 received drug, 8 completed. All 4 high-dose withdrew due to adverse events. Low-dose (n=4) vs placebo (n=4): significant treatment effect on body weight. Greater fecal microbiome change in low-dose arm (Bray-Curtis dissimilarity, p significant).

How the study worked

Randomized, double-blind, placebo-controlled pilot trial with 18 adults (25-45, BMI indicating obesity) assigned 1:1:1 to high-dose nabilone (6 mg/day), low-dose (2 mg/day), or placebo for 12 weeks. Outcomes included body weight, BMI, waist circumference, gut microbiome, blood biomarkers, and mood.

What this study cannot tell us

Extremely small sample (8 completers). Early termination due to poor tolerability. Participants had not used cannabinoids for 6 months, which may have contributed to adverse events. The weight and microbiome findings are from only 4 participants per group.

How to read the evidence

Pilot RCT with extremely small completion numbers (n=8). Provides feasibility data rather than efficacy evidence.

When this study was published

Published in 2025.

The bigger picture

Previous attempts to target the endocannabinoid system for obesity (like the CB1 blocker rimonabant) failed due to psychiatric side effects. This study shows that the opposite approach (CB1 activation) also has tolerability problems. The microbiome finding suggests the endocannabinoid-gut connection deserves further exploration.

Questions still open

Would very low doses of nabilone be tolerable and still effective? Could other cannabinoids with different receptor profiles be better tolerated? Is the microbiome effect driving the weight change or is it coincidental?

Common questions

Does cannabis help with weight loss?

Epidemiological data suggests cannabis users tend to have lower BMI, but this trial shows that the synthetic cannabinoid nabilone was poorly tolerated for weight management. The mechanism linking cannabis use to lower weight remains unclear.

Why was the high dose so poorly tolerated?

Participants had not used any cannabinoids for at least 6 months. Starting at 6 mg/day of nabilone (a potent CB1 agonist) in cannabinoid-naive individuals likely caused intolerable psychoactive and somatic side effects.

Read the original research

Feasibility and Tolerability of Nabilone for the Treatment of Obesity: A Randomized Controlled Pilot Trial.

Cannabis and cannabinoid research, 10(5), 640-651

View on PubMed ↗Publisher’s paper ↗

Citation

Matheson, Justin; Tertigas, Dominique; Malik, Saima; Taylor, Valerie; Chavez, Sofia; Sharkey, Keith A; Silvestri, Cristoforo; Surette, Michael; Le Foll, Bernard. (2025). Feasibility and Tolerability of Nabilone for the Treatment of Obesity: A Randomized Controlled Pilot Trial.. Cannabis and cannabinoid research, 10(5), 640-651. https://doi.org/10.1089/can.2025.0034