In a rat model of schizophrenia (MAM-treated rats), ketamine reduced methamphetamine self-administration in control animals but not in MAM-treated animals. MAM rats showed a lack of habituation in locomotor activity but maintained stable methamphetamine intake similar to controls. Ketamine's effect may stem from increased glutamatergic signaling in the prefrontal cortex via NMDA receptor antagonism and disinhibition of GABA interneurons, a mechanism impaired in MAM rats. This suggests ketamine's anti-craving potential in clinical settings, though it may be ineffective in schizophrenia.
Rats exposed to the toxin methylazoxymethanol acetate (MAM) before birth or to THC shortly after birth showed adult behaviors resembling schizophrenia, such as social withdrawal and memory problems, along with increased expression of cannabinoid and dopamine receptor genes in the prefrontal cortex linked to DNA methylation changes. Giving THC during adolescence impaired social behavior in otherwise healthy rats but did not worsen the schizophrenia-like traits in rats already exposed to THC after birth. In rats exposed to MAM before birth, adolescent THC paradoxically reversed their memory deficit by altering dopamine receptor gene expression. The effects of adolescent THC exposure appear to depend on individual differences in dopamine signaling.
Adolescent cannabis use, especially of high-THC strains, is linked to long-term social and cognitive deficits in adulthood, as shown by both human and animal studies. Cannabis disrupts the endocannabinoid system, which normally regulates stress circuitry during brain development. Early intervention may prevent these adult deficits. Cannabidiol (CBD), the second most abundant compound in cannabis, is being studied as a potential treatment for neuropsychiatric disorders. This review examines evidence that adolescent THC exposure represents a critical window of vulnerability, possibly contributing to schizophrenia, and also considers adolescence as a window of opportunity for early CBD treatment to reduce risk of neurodevelopmental disorders. The review covers CBD's efficacy for positive, negative, and cognitive symptoms, its safety, and molecular targets.