CB1 inverse agonists like rimonabant produced impulsivity in rats only when serotonin signaling was already disrupted, suggesting people with pre-existing serotonin deficits may be vulnerable to suicidal side effects.
Read this if you are interested in why the weight-loss drug rimonabant was pulled from the market and what safer alternatives might look like.
CB1 inverse agonists caused impulsivity only when serotonin signaling was already disrupted
What the researchers found
CB1 receptor inverse agonists like rimonabant showed promise as appetite suppressants but were withdrawn because they produced suicidal behavior in a small subpopulation during clinical trials. This study investigated why only some individuals were affected.
The researchers found that the CB1 inverse agonist AM 251 produced impulsivity in rats only when the serotonin 5HT1A receptor was simultaneously blocked. Without serotonin disruption, the CB1 blocker alone did not cause impulsive behavior.
Importantly, a neutral CB1 antagonist (AM 6527, which blocks without inverse agonism) did not produce impulsivity even with serotonin disruption. A peripherally restricted CB1 antagonist (AM 6545, which does not enter the brain) also had no effect.
These findings suggest that the suicidal side effects of rimonabant may have occurred specifically in people who already had compromised serotonin signaling, and that neutral CB1 antagonists (rather than inverse agonists) may be safer alternatives.
Why it matters
Rimonabant's withdrawal was a major setback for cannabinoid-based obesity medicine. Understanding that the dangerous side effects required pre-existing serotonin vulnerability opens a path forward: either screening patients for serotonin risk or using neutral antagonists instead of inverse agonists.
The numbers in context
AM 251 (inverse agonist) + WAY (5HT1A antagonist) produced impulsivity on both tasks. AM 6527 (neutral antagonist) + WAY showed mild effects on one task only. AM 6545 (peripheral) had no effects.
How the study worked
Male Sprague Dawley rats were tested on two behavioral tasks measuring impulsivity (paced fixed consecutive number task and a novel variable consecutive number task) after receiving CB1 inverse agonist, antagonist, or peripherally restricted antagonist, with or without the serotonin 5HT1A antagonist WAY 100,635.
What this study cannot tell us
Animal model of impulsivity may not fully capture human suicidal ideation. The serotonin blockade was pharmacologically induced rather than representing natural variation. Only male rats were tested.
How to read the evidence
Controlled animal pharmacology study. Preliminary but provides an important mechanistic explanation for a known clinical problem.
When this study was published
Published in 2017.
The bigger picture
This study provides a mechanistic explanation for the rimonabant crisis and demonstrates that the endocannabinoid and serotonin systems interact in clinically dangerous ways. It also shows that not all CB1 blockers are equal: neutral antagonists may avoid the serotonin interaction.
Questions still open
- Could serotonin function be screened before prescribing CB1-targeting medications? Would people on SSRIs (which affect serotonin) be protected from or vulnerable to these effects? Are neutral CB1 antagonists effective enough as appetite suppressants to be clinically useful?
Common questions
Why was rimonabant dangerous?
Could CB1 blockers still be used for weight loss?
Read the original research
Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor.
Psychopharmacology, 234(6), 1029-1043
Citation
McLaughlin, Peter J; Jagielo-Miller, Julia E; Plyler, Emily S; Schutte, Kerry K; Vemuri, V Kiran; Makriyannis, Alexandros. (2017). Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor.. Psychopharmacology, 234(6), 1029-1043. https://doi.org/10.1007/s00213-017-4548-2
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