Blocking CB1 Receptors Reversed Antipsychotic-Induced Weight Gain Without Reducing Drug Efficacy
CB1 receptor antagonists reversed olanzapine-induced weight gain, metabolic disruption, and liver enzyme changes in female rats without interfering with the antipsychotic's behavioral benefits.
Quick Facts
What This Study Found
Weight gain is a major side effect of the antipsychotic olanzapine, and this study tested whether blocking CB1 cannabinoid receptors could counteract the metabolic problems without reducing the drug's psychiatric benefits.
Female rats treated with olanzapine for 15 days gained weight and developed alterations in blood markers related to energy balance and glucose metabolism. In the brain, olanzapine changed cannabinoid markers in the nucleus accumbens and shifted hunger-related signaling in the hypothalamus toward increased appetite.
Co-treatment with either rimonabant (a CB1 inverse agonist) or the novel compound NESS06SM (a CB1 neutral antagonist) reversed these effects: food intake decreased, weight gain was reduced, blood parameters returned to normal, and liver and fat tissue enzymes were restored.
Critically, neither CB1 antagonist interfered with olanzapine's positive behavioral effects, meaning the antipsychotic still worked as intended while its metabolic side effects were neutralized.
Key Numbers
15-day olanzapine treatment. Novel CB1 neutral antagonist NESS06SM was compared to rimonabant. Both compounds decreased food intake, weight gain, and restored blood parameters and tissue enzymes.
How They Did This
Female rats received 15-day treatment with olanzapine alone or in combination with CB1 receptor antagonists (rimonabant or NESS06SM). Outcomes included body weight, food intake, blood metabolic parameters, brain cannabinoid and hunger markers (nucleus accumbens, hypothalamus), behavioral effects, and liver/fat tissue enzyme expression.
Why This Research Matters
Antipsychotic-induced weight gain is a leading cause of treatment discontinuation and contributes to cardiovascular disease in psychiatric patients. Demonstrating that CB1 blockade can neutralize these side effects without reducing therapeutic efficacy opens a potential clinical pathway.
The Bigger Picture
This study connects two important pharmacological systems: the endocannabinoid system and antipsychotic metabolism. The use of a neutral CB1 antagonist (rather than an inverse agonist like rimonabant, which was withdrawn due to psychiatric side effects) represents an approach that could avoid the safety problems that ended rimonabant's clinical use.
What This Study Doesn't Tell Us
Animal study using female rats only, limiting generalizability across sexes. The 15-day treatment period is short relative to long-term antipsychotic use in humans. Rimonabant was withdrawn from human use due to psychiatric side effects, and the novel compound NESS06SM has not been tested in humans.
Questions This Raises
- ?Would peripheral-only CB1 antagonists (that don't enter the brain) achieve the same metabolic benefits without psychiatric side effect risk?
- ?Does this approach work for other weight-promoting antipsychotics besides olanzapine?
- ?Could this translate to a clinical co-treatment strategy?
Trust & Context
- Key Stat:
- CB1 blockade reversed weight gain without interfering with antipsychotic efficacy
- Evidence Grade:
- Animal study with comprehensive metabolic and behavioral assessment. Preliminary because the approach has not been tested in humans.
- Study Age:
- Published in 2017.
- Original Title:
- Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.
- Published In:
- European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 27(7), 667-678 (2017)
- Authors:
- Lazzari, P, Serra, V, Marcello, S, Pira, M, Mastinu, A
- Database ID:
- RTHC-01430
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Can the endocannabinoid system explain antipsychotic weight gain?
This study found that olanzapine altered cannabinoid markers in the brain's reward center and shifted hunger signaling in the hypothalamus, suggesting the endocannabinoid system mediates antipsychotic-induced weight gain. Blocking CB1 receptors reversed these changes.
Could a cannabinoid blocker prevent medication weight gain?
In this rat study, co-treating with a CB1 receptor blocker prevented olanzapine weight gain without reducing its antipsychotic effect. However, the first CB1 blocker tried in humans (rimonabant) was withdrawn due to psychiatric side effects, so newer, safer compounds are needed.
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Cite This Study
https://rethinkthc.com/research/RTHC-01430APA
Lazzari, P; Serra, V; Marcello, S; Pira, M; Mastinu, A. (2017). Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 27(7), 667-678. https://doi.org/10.1016/j.euroneuro.2017.03.010
MLA
Lazzari, P, et al. "Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.." European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2017. https://doi.org/10.1016/j.euroneuro.2017.03.010
RethinkTHC
RethinkTHC Research Database. "Metabolic side effects induced by olanzapine treatment are n..." RTHC-01430. Retrieved from https://rethinkthc.com/research/lazzari-2017-metabolic-side-effects-induced
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.