Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD.
Psychopharmacology – June 01, 2025
Source: PubMed
Summary
Groundbreaking research reveals how ketamine rewires trauma-affected brains. The drug works by blocking NMDA receptors, triggering a cascade of molecular changes that boost BDNF production and enhance synaptic plasticity. This process aids memory reconsolidation and promotes gene expression changes, leading to lasting improvements in PTSD symptoms through complex pharmacodynamic pathways.
Abstract
Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine's acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions. This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects. A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874). We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC). These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.