Peripherally restricted CB1 blocker caused far less anxiety than rimonabant in mice
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
Fear conditioning paradigm in mice (C57BL/6N) comparing oral and intracerebral TM38837 vs rimonabant at multiple doses, measuring freezing behavior during tone re-exposure.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?Can the therapeutic window identified in mice be maintained in human dosing?
- ?Would long-term peripheral CB1 blockade produce any compensatory central effects?
Trust & Context
- Key Stat:
- 10x less potent for fear
- Evidence Grade:
- Preliminary: mouse behavioral study, though with strong translational rationale.
- Study Age:
- Published in 2019.
- Original Title:
- The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.
- Published In:
- Frontiers in pharmacology, 10, 207 (2019)
- Authors:
- Micale, Vincenzo(5), Drago, Filippo(5), Noerregaard, Pia K, Elling, Christian E, Wotjak, Carsten T
- Database ID:
- RTHC-02177
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Why was rimonabant pulled from the market?
Rimonabant, a CB1 receptor blocker approved for obesity in Europe, caused psychiatric side effects including anxiety, depression, and suicidality because it blocked CB1 receptors in the brain.
How is TM38837 different?
TM38837 is designed to largely stay outside the brain, blocking CB1 receptors primarily in peripheral tissues to achieve weight-loss effects with reduced psychiatric risk.
Read More on RethinkTHC
- THC-amygdala-anxiety-brain
- anandamide-weed-withdrawal
- cannabinoid-receptors-recovery-time
- cannabis-developing-brain-teenagers
- cant-enjoy-anything-without-weed
- dopamine-recovery-after-quitting-weed
- endocannabinoid-system-explained-simply
- endocannabinoid-system-withdrawal
- nervous-system-weed-withdrawal-fight-flight
- teen-weed-use-under-18-effects-brain
- thc-brain-withdrawal
- thc-prefrontal-cortex-brain-effects
- weed-cortisol-stress-hormones
- weed-memory-loss-recovery
- weed-motivation-amotivational-syndrome
- weed-nervous-system-effects
- weed-reward-system-brain
Cite This Study
https://rethinkthc.com/research/RTHC-02177APA
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
MLA
Micale, Vincenzo, et al. "The Cannabinoid CB1 Antagonist TM38837 With Limited Penetrance to the Brain Shows Reduced Fear-Promoting Effects in Mice.." Frontiers in pharmacology, 2019. https://doi.org/10.3389/fphar.2019.00207
RethinkTHC
RethinkTHC Research Database. "The Cannabinoid CB1 Antagonist TM38837 With Limited Penetran..." RTHC-02177. Retrieved from https://rethinkthc.com/research/micale-2019-the-cannabinoid-cb1-antagonist
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.