Low-dose FAAH inhibition improved memory deficits in a mouse schizophrenia model, but higher doses of both FAAH and MAGL inhibitors worsened symptoms.
Neuropharmacology researchers and psychiatrists exploring endocannabinoid-based treatments for schizophrenia.
Biphasic dose response
What the researchers found
URB 597 (FAAH inhibitor) at 0.3 mg/kg attenuated MK-801-induced memory impairment, but at 1 mg/kg it worsened it. JZL 184 (MAGL inhibitor) at 20-40 mg/kg intensified memory impairment and at 1 mg/kg potentiated hyperlocomotion caused by MK-801.
Why it matters
The endocannabinoid system is a potential therapeutic target for schizophrenia, but this study shows the relationship is not straightforward. Dose matters enormously, with low and high doses producing opposite effects.
The numbers in context
URB 597 at 0.3 mg/kg improved memory; at 1 mg/kg it worsened memory. JZL 184 at 20-40 mg/kg worsened memory. JZL 184 at 1 mg/kg increased hyperlocomotion induced by MK-801 at both 0.3 and 0.6 mg/kg.
How the study worked
Mice received MK-801 (NMDA antagonist) to model schizophrenia symptoms, then FAAH inhibitor URB 597 or MAGL inhibitor JZL 184 at various doses. Locomotor activity and passive avoidance memory were measured.
What this study cannot tell us
Mouse model using pharmacological induction of schizophrenia-like symptoms, which may not fully represent human schizophrenia. Only acute (single dose) administration tested. No chronic exposure data.
How to read the evidence
Preliminary: single acute-dose mouse study.
When this study was published
Published in 2019.
The bigger picture
The biphasic (low dose helps, high dose hurts) pattern seen here mirrors what is often observed with direct cannabinoid agonists. This suggests that fine-tuning endocannabinoid levels, rather than broadly boosting them, may be key to therapeutic benefit.
Questions still open
- What is the optimal dose window for FAAH inhibition to improve cognitive symptoms? Would chronic low-dose FAAH inhibition maintain its beneficial effects or lead to tolerance?
Common questions
What are FAAH and MAGL inhibitors?
Why did low and high doses have opposite effects?
Read the original research
Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice.
Molecular neurobiology, 56(11), 7251-7266
Citation
Kruk-Slomka, Marta; Banaszkiewicz, Izabela; Slomka, Tomasz; Biala, Grazyna. (2019). Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice.. Molecular neurobiology, 56(11), 7251-7266. https://doi.org/10.1007/s12035-019-1596-0
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