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.
Read this if you take antipsychotic medication and are concerned about weight gain side effects.
CB1 blockade reversed weight gain without interfering with antipsychotic efficacy
What the researchers 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.
Why it 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 numbers in context
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 the study worked
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.
What this study cannot 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.
How to read the evidence
Animal study with comprehensive metabolic and behavioral assessment. Preliminary because the approach has not been tested in humans.
When this study was published
Published in 2017.
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.
Questions still open
- 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?
Common questions
Can the endocannabinoid system explain antipsychotic weight gain?
Could a cannabinoid blocker prevent medication weight gain?
Read the original research
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
Citation
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
Explore the wider topic
- How THC Affects Your Amygdala: The Brain's Threat Detector and Cannabis
- The Anandamide Connection: Your Body's Natural Bliss Molecule
- How Long for Cannabinoid Receptors to Return to Normal
- Cannabis and the Developing Brain: What Every Teenager (and Parent) Should Know
- Why Can't I Enjoy Anything Without Weed? The Science Behind It
- Dopamine Recovery After Quitting Weed: What the Science Says
- The Endocannabinoid System Explained Simply: What It Does and Why It Matters
- Your Endocannabinoid System Explained: Why Withdrawal Happens
- Your Nervous System After Quitting Weed: Fight or Flight
- Using Weed Under 18: What It Does to Your Developing Brain
- What THC Does to Your Brain: Why Withdrawal Happens
- THC and Your Prefrontal Cortex: What Cannabis Does to Your Decision-Making Brain
- Weed, Cortisol, and Stress: What Cannabis Does to Your Stress Hormones
- Weed and Memory: What the Science Says About THC and Your Hippocampus
- Weed and Motivation: Is Amotivational Syndrome Real?
- Weed and Your Nervous System: What THC Actually Does to Your Brain and Body
- How Weed Rewires Your Reward System (And How to Reset It)