Rimonabant
The first selective CB1 cannabinoid receptor antagonist/inverse agonist, marketed in Europe as Acomplia from 2006 for obesity. It produced real weight loss and metabolic improvement but was withdrawn in 2008-2009 after it roughly doubled the risk of depression, anxiety and suicidality. It was never approved in the US.
01 Overview
Rimonabant blocks the CB1 receptor, part of the endocannabinoid system that stimulates appetite (the mechanism behind cannabis-induced hunger). In the RIO trial programme it delivered about 5 kg of placebo-subtracted weight loss with improvements in HbA1c, HDL and triglycerides.
Those benefits were outweighed by psychiatric harm: meta-analysis showed a significant increase in depression and anxiety and reports of suicidality. The FDA declined approval in 2007 and the EMA suspended it in 2008; the manufacturer withdrew it. It stands as the key example of a CNS-targeted anti-obesity drug undone by neuropsychiatric side effects.
02 Mechanism
Selective CB1 cannabinoid receptor antagonist/inverse agonist, reducing appetite and improving peripheral metabolism by blocking endocannabinoid signalling.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Former therapeutic dose | 20 mg/day | Oral | 20 mg once daily; withdrawn from market. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Weight lossMeaningful weight and waist-circumference reduction in the RIO trials. | ~5 kg vs placebo/year | Clinical | |
| Improved metabolic markersFavourable changes partly independent of weight loss. | improved HbA1c, HDL, triglycerides | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Depression, anxiety and suicidalityIncreased mood disorders, anxiety and suicidal ideation, the reason for non-approval and withdrawal. | Severe | ~2x placebo | Clinical | |
| Nausea and gastrointestinal upsetNausea, diarrhoea and dizziness early in treatment. | Mild | Common | Clinical |