<p>Chronic methamphetamine (Meth) abuse represents a significant global public health crisis, characterized by profound and often persistent cognitive deficits, particularly in hippocampal-dependent memory and learning. This narrative review synthesizes current evidence on the molecular mechanisms through which chronic Meth exposure disrupts hippocampal synaptic plasticity, ultimately driving cognitive impairment. We establish that the initiating event involves Meth-induced dysregulation of dopaminergic signaling, primarily through dopamine transporter (DAT) inhibition, leading to sustained extracellular dopamine surges. This dopamine excess triggers a pathogenic cascade dominated by three interconnected processes: (1) pronounced oxidative stress via dopamine auto-oxidation and mitochondrial dysfunction, generating reactive oxygen species (ROS) that damage synaptic components; (2) mitochondrial apoptotic activation through p53-Bax signaling, cytochrome <i>c</i> release, and caspase-3-mediated cleavage of synaptic scaffolding proteins (e.g., PSD-95, ARC); and (3) suppression of neurotrophic support via BDNF-TrkB-PI3K/Akt pathway impairment, compounded by glutamate receptor dysregulation (NMDAR internalization, AMPAR trafficking defects). These mechanisms converge to induce structural synaptic pathology—including dendritic spine loss (notably mature mushroom spines in dentate gyrus), presynaptic vesicle depletion, and postsynaptic density disintegration—and functional deficits in LTP and LTD. Critically, these processes are amplified by neuroinflammation (microglial TNF-α/IL-1β release) and epigenetic dysregulation (HDAC2 upregulation, BDNF promoter methylation), creating a self-sustaining cycle of synaptic injury. Preclinical and clinical evidence consistently links these molecular disruptions to measurable cognitive decline, including impaired spatial navigation, pattern separation, and declarative memory. Therapeutic strategies targeting key nodes of this cascade show significant promise: dopamine stabilizers (e.g., aripiprazole) normalize D1/D2 receptor imbalance; anti-apoptotics (e.g., minocycline, resveratrol) inhibit caspase-3 and p53; neurotrophic agents (TrkB agonists, BDNF mimetics) restore synaptic protein synthesis; and antioxidants (e.g., N-acetylcysteine) counteract ROS. Future research must address critical gaps in understanding sex-specific vulnerabilities, circuit-selective susceptibility (e.g., hippocampal-VTA loops), and the role of stable epigenetic modifications in sustaining cognitive deficits. Advancing multi-target therapeutic approaches aligned with the temporal progression of Meth neurotoxicity offers the best hope for reversing synaptic dysfunction and mitigating the enduring cognitive burden of Meth addiction.</p> Graphical Abstract <p></p> <p>Chronic methamphetamine exposure initiates hippocampal synaptic disruption through dopamine transporter dysfunction, causing sustained extracellular dopamine elevation that triggers oxidative stress, mitochondrial apoptosis (p53/Bax/caspase-3), and neuroinflammation (microglial TNF-α/IL-1β). These convergent mechanisms dismantle synaptic integrity via PSD-95 cleavage, AMPAR internalization, and BDNF suppression, leading to dendritic spine loss and impaired LTP. The resulting hippocampal damage manifests as declarative memory deficits and spatial navigation impairment. Therapeutic strategies targeting dopamine stabilization (aripiprazole), neurotrophic restoration (7,8-DHF), and oxidative stress (N-acetylcysteine) show promise for reversing synaptic injury and mitigating cognitive decline.</p>