Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity

Mol Psychiatry. 2013 Dec;18(12):1294-301. doi: 10.1038/mp.2012.145. Epub 2012 Oct 16.


Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Animals
  • Anxiety / drug therapy
  • Anxiety / physiopathology
  • Dopaminergic Neurons / drug effects
  • Eating / drug effects
  • GABAergic Neurons / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / physiopathology
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / physiology
  • Rimonabant
  • Ventral Tegmental Area / drug effects
  • Weight Gain / drug effects


  • CNR1 protein, human
  • N-piperidinyl-(8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo(6,7)cyclohepta(1,2-c)pyrazole-3-carboxamide)
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Rimonabant