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Rationale <p>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.</p> Objectives <p>This narrative review aims to elucidate the molecular mechanisms underlying memory impairment associated with chronic, high-dose Δ9-tetrahydrocannabinol (Δ9-THC) and cannabis exposure, and to distinguish these effects from the beneficial outcomes observed at lower doses.</p> Methods <p>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.</p> Results <p>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 Δ9-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.</p> Conclusions <p>Chronic exposure to highdose Δ9-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.</p> Graphical Abstract <p>This graphical abstract synthesizes the core molecular and cellular mechanisms through which chronic, high-dose Δ9-tetrahydrocannabinol (THC) exposure leads to memory impairment. Sustained overstimulation of the endocannabinoid system, particularly via presynaptic cannabinoid type 1 (CB1) receptors, initiates a cascade of adverse events in the hippocampus and related memory circuits. The illustrated pathways include:</p> <p>1. Neuroinflammation: Microglial activation and release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6).</p> <p>2. Oxidative Stress &amp; Mitochondrial Dysfunction: Increased reactive oxygen species (ROS) production, lipid peroxidation, and disruption of cellular antioxidant defenses.</p> <p>3. Apoptotic Signaling: Induction of endoplasmic reticulum stress, mitochondrial outer membrane permeabilization (MOMP), and activation of caspase-dependent neuronal death pathways.</p> <p>4. Neurotransmitter Dysregulation: Disruption of the critical balance between glutamate and GABA, impairing synaptic plasticity essential for learning and memory.</p> <p>5. Impaired Neuroplasticity: Suppression of hippocampal neurogenesis, reduced synaptogenesis, dendritic remodeling, and spine loss.</p> <p>6. Disruption of Neurotrophic Support: Altered brain-derived neurotrophic factor (BDNF) signaling, compromising neuronal health and synaptic integrity.</p> <p>These interconnected mechanisms converge to disrupt long-term potentiation (LTP), degrade the structural integrity of hippocampal networks, and ultimately manifest as deficits in memory formation, consolidation, and retrieval.</p> <p></p>

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Memory impairment and chronic high-dose Δ9-THC/cannabis exposure: a narrative review of molecular mechanisms underlying neurotoxic effects

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Habibeh Mashayekhi-Sardoo,
  • Ali Ahmad Azadbakht,
  • Mahdiyeh Hedayati-Moghadam,
  • Ahmad Golkar,
  • Yousef Baghcheghi

摘要

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 Δ9-tetrahydrocannabinol (Δ9-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 Δ9-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 Δ9-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.

Graphical Abstract

This graphical abstract synthesizes the core molecular and cellular mechanisms through which chronic, high-dose Δ9-tetrahydrocannabinol (THC) exposure leads to memory impairment. Sustained overstimulation of the endocannabinoid system, particularly via presynaptic cannabinoid type 1 (CB1) receptors, initiates a cascade of adverse events in the hippocampus and related memory circuits. The illustrated pathways include:

1. Neuroinflammation: Microglial activation and release of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6).

2. Oxidative Stress & Mitochondrial Dysfunction: Increased reactive oxygen species (ROS) production, lipid peroxidation, and disruption of cellular antioxidant defenses.

3. Apoptotic Signaling: Induction of endoplasmic reticulum stress, mitochondrial outer membrane permeabilization (MOMP), and activation of caspase-dependent neuronal death pathways.

4. Neurotransmitter Dysregulation: Disruption of the critical balance between glutamate and GABA, impairing synaptic plasticity essential for learning and memory.

5. Impaired Neuroplasticity: Suppression of hippocampal neurogenesis, reduced synaptogenesis, dendritic remodeling, and spine loss.

6. Disruption of Neurotrophic Support: Altered brain-derived neurotrophic factor (BDNF) signaling, compromising neuronal health and synaptic integrity.

These interconnected mechanisms converge to disrupt long-term potentiation (LTP), degrade the structural integrity of hippocampal networks, and ultimately manifest as deficits in memory formation, consolidation, and retrieval.