The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats.
Hanna J Szkudlarek, Rajkamalpreet Singh Mann, Krystyna Wieczerzak, Mohammed Halit Sarikahya, Taygun C Uzuneser, Marta De Felice, Mar Rodríguez-ruiz, Juan Pablo Galindo, Mathusha Pusparajah, Shawn N Whitehead, Walter J Rushlow, Daniel B Hardy, Susanne Schmid, Ken K-c Yeung, Steven R Laviolette
Translational psychiatry October 6, 2025 Peer reviewed DOI: 10.1038/s41398-025-03580-4 via PubMed
Summary
Adolescent exposure to THC, the psychoactive component of cannabis, increases later risk of neuropsychiatric symptoms by raising oxidative stress in the medial prefrontal cortex. In a rodent model, the antioxidant N-acetylcysteine (NAC) prevented cognitive, synaptic, neuronal, and neurochemical deficits caused by chronic adolescent THC exposure. NAC normalizes glutamate and GABA activity. The findings identify oxidative stress as a key mechanism and suggest NAC as a potential preventive treatment.
Study at a glance
| Design | preclinical study |
|---|---|
| Population | rodent model of adolescent brain development |
| Key finding | NAC treatment prevents cognitive, synaptic, neuronal, and neurochemical deficits induced by adolescent THC exposure. |
Abstract
Clinical and pre-clinical evidence demonstrates that adolescent Δ-9-tetrahydrocannabinol (THC) exposure, the primary psychoactive component of cannabis, increases the risk of developing neuropsychiatric symptoms in later life. The medial prefrontal cortex (mPFC) serves as a pathophysiological nexus point underlying many cannabis-related pathophysiological outcomes. Nevertheless, the molecular mechanisms underlying these risk factors are poorly understood. THC increases oxidative stress, which is a well-established causal factor for increased neuropsychiatric risk, including schizophrenia. N-acetylcysteine (NAC) is an antioxidant glutathione precursor that normalizes glutamate and GABA activity in neuropathological states. We examined if NAC may prevent the pathophysiological impacts of THC using a rodent model of adolescent brain development and chronic THC exposure. We report that NAC treatment prevents cognitive, synaptic, neuronal and neurochemical deficits induced by adolescent THC. These findings highlight the critical role of THC-induced oxidative stress as a contributing factor to cannabinoid-mediated neuropsychiatric risk and identifies a novel antioxidant treatment candidate for the prevention and/or reversal of these pathophysiological outcomes.