Activating Cannabinoid Receptors Improved Autism-Like Behaviors and Brain Lipid Balance in Rats

CB1R agonist (ACPA) and CB2R agonist (AM1241) both significantly alleviated ASD-like behaviors (marble burying, self-grooming, social deficits, hyperactivity) in VPA-exposed rats. Lipidomics revealed marked reductions in multiple hippocampal lipid classes in VPA rats, and both agonists restored these levels to near-normal, comparable to controls.

Male offspring from VPA-exposed dams (600 mg/kg, a validated ASD model) received CB1R agonist ACPA (0.1 mg/kg) or CB2R agonist AM1241 (3 mg/kg) from postnatal days 21–27. Behavioral testing (marble burying, self-grooming, social interaction, open field) and hippocampal lipidomics by UPLC-MS/MS were performed.

Autism spectrum disorder has no approved pharmacological treatments for core symptoms like social deficits and repetitive behaviors. The finding that cannabinoid receptor activation addresses both behavioral and metabolic aspects of ASD in an animal model opens a novel therapeutic avenue.

The dual behavioral-metabolic improvement suggests that lipid dysregulation may be an underlying mechanism of ASD symptoms, and that the endocannabinoid system's role in lipid homeostasis could be therapeutically relevant beyond just its neurotransmitter effects.

VPA rat model captures some but not all features of human ASD. Only male offspring studied. Short treatment window (7 days). Synthetic cannabinoid receptor agonists differ from plant-derived cannabinoids. Cannot directly extrapolate dosing to humans.