Memory impairment and chronic high-dose Delta9-THC/cannabis exposure: a narrative review of molecular mechanisms underlying neurotoxic effects

Abstract

RATIONALE: The increasing potency of cannabis and the growing prevalence of chronic, high-dose use have raised concerns about its potential neurotoxic effects on cognitive functions, particularly memory. While low-dose cannabinoids have demonstrated therapeutic benefits, the molecular basis of memory impairment under high-dose exposure remains insufficiently clarified. OBJECTIVES: This narrative review aims to elucidate the molecular mechanisms underlying memory impairment associated with chronic, high-dose Delta9-tetrahydrocannabinol (Delta9-THC) and cannabis exposure, and to distinguish these effects from the beneficial outcomes observed at lower doses. METHODS: A narrative review methodology was employed to synthesize evidence from both human studies and murine models, focusing on molecular, cellular, and neurobiological pathways involved in memory dysfunction. RESULTS: Chronic high-dose activation of the endocannabinoid system (ECS) induces acascade of adverse molecular events, including neuroinflammation, oxidative stress, and activation of apoptotic pathways. Significant dysregulation of key neurotransmitter systems was also observed. Importantly, high-dose Delta9-THC disrupts neuroplasticity by impairing hippocampal neurogenesis, synaptogenesis, and dendritic remodeling, thereby compromising mechanisms essential for memory formation and consolidation. Adolescents and elderly individuals were identified as particularly vulnerable populations. CONCLUSIONS: Chronic exposure to highdose Delta9-THC is strongly associated with memory impairment through interconnected molecular pathways. These findings provide a mechanistic framework linking cannabis exposure to cognitive deficits and highlight the need for longitudinal human studies and the development of targeted therapeutic interventions.