A novel CB1 antagonist (TM38837) designed to stay mostly outside the brain produced significantly less fear than rimonabant while maintaining anti-obesity effects in previous studies.
Obesity researchers, pharmaceutical developers, and psychiatrists interested in CB1-related drug safety.
10x less potent for fear
What the researchers found
Oral TM38837 required 10x higher doses than rimonabant to produce comparable fear-promoting effects (100 mg/kg vs 10 mg/kg). When injected directly into the brain, TM38837 was still less potent at promoting fear. Previous studies showed equivalent weight-loss efficacy between the two drugs, suggesting a therapeutic window for TM38837.
Why it matters
Rimonabant was pulled from the market due to psychiatric side effects (anxiety, depression, suicidality). If a peripherally restricted CB1 blocker can reduce weight without penetrating the brain enough to cause these effects, it could resurrect an entire drug class.
The numbers in context
TM38837 oral: only 100 mg/kg (but not 10 or 30 mg/kg) increased fear. Rimonabant oral: 10 mg/kg significantly increased fear. Intracerebral: TM38837 10-30 ug/mouse caused less fear response than rimonabant 1-10 ug/mouse.
How the study worked
Fear conditioning paradigm in mice (C57BL/6N) comparing oral and intracerebral TM38837 vs rimonabant at multiple doses, measuring freezing behavior during tone re-exposure.
What this study cannot tell us
Mouse study; human psychiatric side effects may not be predicted by mouse fear conditioning. The therapeutic window between metabolic efficacy and fear promotion has not been validated in humans. Long-term safety unknown.
How to read the evidence
Preliminary: mouse behavioral study, though with strong translational rationale.
When this study was published
Published in 2019.
The bigger picture
The failure of rimonabant demonstrated that CB1 receptors in the brain are crucial for emotional regulation. TM38837 represents a second-generation approach: keep the metabolic benefits of CB1 blockade while avoiding the brain to minimize psychiatric harm.
Questions still open
- Can the therapeutic window identified in mice be maintained in human dosing? Would long-term peripheral CB1 blockade produce any compensatory central effects?
Common questions
Why was rimonabant pulled from the market?
How is TM38837 different?
Read the original research
The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.
Frontiers in pharmacology, 10, 207
Citation
Micale, Vincenzo; Drago, Filippo; Noerregaard, Pia K; Elling, Christian E; Wotjak, Carsten T. (2019). The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.. Frontiers in pharmacology, 10, 207. https://doi.org/10.3389/fphar.2019.00207
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