Only the lowest THC dose helped schizophrenia-like symptoms in rats, while higher doses made them worse

In PCP-treated rats (schizophrenia model), only the lowest THC dose (0.1 mg/kg) reversed social interaction deficits and normalized elevated anandamide in the nucleus accumbens. Higher THC doses (0.3, 1.0 mg/kg) did not help. In control rats, THC dose-dependently produced social deficits and aberrant VTA dopamine neuron activity resembling schizophrenia. THC activated the Akt/GSK3β pathway dose-dependently in both groups.

Sub-chronic PCP rat model with THC at 0.1, 0.3, and 1.0 mg/kg. Assessed social interaction, amphetamine-induced motor activity, VTA dopamine neuron population activity, endocannabinoid levels, and Akt/GSK3β signaling.

This provides the clearest preclinical demonstration of why cannabis has seemingly contradictory effects on schizophrenia: extremely low doses may be therapeutic while typical recreational doses are harmful. The dose-response curve is not linear but inverted U-shaped.

The self-medication hypothesis for cannabis use in schizophrenia has been controversial. This study suggests it may be partially correct: patients might experience benefit from very low cannabinoid exposure, but typical cannabis use delivers doses that worsen the condition.

Animal model of schizophrenia (PCP model has limitations); narrow dose range tested; acute THC (does not model chronic use); rat-to-human dose translation uncertain; cannot confirm same inverted U-curve applies to humans.