Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

“…Preclinical animal work demonstrated significant reductions in abused drug–induced phasic dopamine release (Cheer et al 2007), drug-seeking behavior (Cippitelli et al 2005, Cohen et al 2004, De Vries et al 2001, Fattore et al 2005, Justinova et al 2008), and feeding behavior (Di Marzo & Matias 2005, Rinaldi-Carmona et al 2004) due to functional antagonism of the CB1 receptor by the inverse agonist rimonabant. Owing to its effects on appetite and reward seeking, rimonabant was approved and marketed for the treatment of metabolic syndrome in obese patients (Christensen et al 2007, Ward & Raffa 2011) and went to advanced clinical trials for smoking cessation (Cohen et al 2004, Gelfand & Cannon 2006). However, even with psychiatric exclusions, clinical trials revealed adverse side effects of high doses, including anxiety, depression, and suicidal ideations (Christensen et al 2007).…”

“…However, even with psychiatric exclusions, clinical trials revealed adverse side effects of high doses, including anxiety, depression, and suicidal ideations (Christensen et al 2007). Part of the failure of rimonabant is thought to be due to its action as an inverse agonist of the CB1 receptor, producing an effect intrinsically opposite to that of the classical agonist (Ward & Raffa 2011). Currently, neutral antagonists for the CB1 receptor are under investigation for their effects on food intake and reward seeking (see sidebar, Δ9-Tetrahydrocannabivarin) (Riedel et al 2009, Tudge et al 2015, Ward & Raffa 2011).…”

“…Part of the failure of rimonabant is thought to be due to its action as an inverse agonist of the CB1 receptor, producing an effect intrinsically opposite to that of the classical agonist (Ward & Raffa 2011). Currently, neutral antagonists for the CB1 receptor are under investigation for their effects on food intake and reward seeking (see sidebar, Δ9-Tetrahydrocannabivarin) (Riedel et al 2009, Tudge et al 2015, Ward & Raffa 2011). Nevertheless, these results emphasize the critical involvement of the CB1 receptor in motivation for reward and highlight the need for alternative receptor targets for the treatment of motivational disorders.…”

Cannabinoids and value-based decision making: Implications for neurodegenerative disorders

“…Interestingly, despite the cannabinoid CB1 receptor antagonist Rimonabant being withdrawn from the market, there is large therapeutic potential of cannabinoid mechanisms in several metabolic, psychiatric and neurodegenerative disorders [22,23]. …”

Harveian Oration 2016: Some observations on the causes and consequences of obesity

“…This was the problem that caused the withdrawal of rimonabant, an anti-cannabinoid drug that powerfully suppressed appetite and promoted weight loss, but which unfortunately had anti-hedonic properties that promoted suicidal behaviour in some recipients. 67 Should we give up? I don't think so.…”