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

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.

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.

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.

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.

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.