A neutral CB1 blocker reduced heroin use in rats without causing depression-like side effects
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antagonist AM4113 reduced heroin self-administration in rats without the depression-like aversive effects seen with the withdrawn drug rimonabant, suggesting a safer approach to treating opioid addiction.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- AM4113 blocked heroin self-administration without rimonabant's depression-like side effects
- Evidence Grade:
- Preliminary: well-designed rat study with appropriate controls and reward threshold measurements, but no human data.
- Study Age:
- Published in 2019.
- Original Title:
- Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.
- Published In:
- Acta pharmacologica Sinica, 40(3), 365-373 (2019)
- Authors:
- He, Xiang-Hu, Jordan, Chloe J(2), Vemuri, Kiran(7), Bi, Guo-Hua, Zhan, Jia, Gardner, Eliot L, Makriyannis, Alexandros, Wang, Yan-Lin, Xi, Zheng-Xiong
- Database ID:
- RTHC-02068
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Could cannabinoid drugs treat opioid addiction?
This study suggests yes. AM4113, a neutral CB1 antagonist, reduced heroin self-administration in rats without the depression side effects that ended rimonabant's clinical development. It represents a potentially safer approach.
What makes a "neutral" antagonist different?
Rimonabant was an inverse agonist, meaning it actively suppressed CB1 receptor baseline activity, causing mood problems. AM4113 is a neutral antagonist that blocks activation without affecting baseline activity, potentially avoiding the aversive effects.
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Cite This Study
https://rethinkthc.com/research/RTHC-02068APA
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
MLA
He, Xiang-Hu, et al. "Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats.." Acta pharmacologica Sinica, 2019. https://doi.org/10.1038/s41401-018-0059-x
RethinkTHC
RethinkTHC Research Database. "Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits ..." RTHC-02068. Retrieved from https://rethinkthc.com/research/he-2019-cannabinoid-cb1-receptor-neutral
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.