The neutral CB1 receptor antagonist AM4113 reduced heroin self-administration in rats without the depression-like aversive effects seen with the withdrawn drug rimonabant, suggesting a safer approach to treating opioid addiction.
People interested in opioid addiction treatment, cannabinoid pharmacology, and the rimonabant story.
AM4113 blocked heroin self-administration without rimonabant's depression-like side effects
What the researchers found
AM4113 dose-dependently inhibited heroin self-administration but not cocaine or methamphetamine self-administration. Unlike rimonabant, AM4113 did not increase brain stimulation reward thresholds (a measure of depression/aversion). Rimonabant reduced heroin and methamphetamine self-administration but also produced aversive-like effects.
Why it matters
Rimonabant showed promise for addiction but was pulled due to depression and suicidality. The neutral antagonist AM4113 retains the anti-addictive effects for heroin while avoiding the mood-lowering properties, representing a potential breakthrough for opioid addiction treatment.
The numbers in context
AM4113 (3 and 10 mg/kg) reduced heroin but not cocaine or methamphetamine self-administration. SR141716A (3 and 10 mg/kg) reduced heroin and methamphetamine self-administration. AM4113 had no effect on brain stimulation reward; SR141716A increased thresholds (indicating aversive effects).
How the study worked
Rats were trained to self-administer heroin, cocaine, or methamphetamine and then treated with AM4113 or rimonabant. Brain stimulation reward thresholds were measured as an index of mood/aversion effects.
What this study cannot tell us
Rat model of self-administration may not fully predict human treatment response. AM4113 has not been tested in humans. Only acute effects studied. The specific selectivity for heroin over cocaine/methamphetamine requires mechanistic explanation.
How to read the evidence
Preliminary: well-designed rat study with appropriate controls and reward threshold measurements, but no human data.
When this study was published
Published in 2019.
The bigger picture
The opioid crisis has created urgent need for new treatments. The distinction between inverse agonists (rimonabant) and neutral antagonists (AM4113) at the CB1 receptor shows that pharmacological nuance matters enormously. Neutral antagonism blocks the receptor without inverting its baseline activity, avoiding the mood effects.
Questions still open
- Why does AM4113 affect heroin but not cocaine self-administration? Would AM4113 be effective in human opioid use disorder? Could combining AM4113 with existing opioid treatments improve outcomes?
Common questions
Could cannabinoid drugs treat opioid addiction?
What makes a "neutral" antagonist different?
Read the original research
Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.
Acta pharmacologica Sinica, 40(3), 365-373
Citation
He, Xiang-Hu; Jordan, Chloe J; Vemuri, Kiran; Bi, Guo-Hua; Zhan, Jia; Gardner, Eliot L; Makriyannis, Alexandros; Wang, Yan-Lin; Xi, Zheng-Xiong. (2019). Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.. Acta pharmacologica Sinica, 40(3), 365-373. https://doi.org/10.1038/s41401-018-0059-x
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