Neurochemical, Neurocircuitry, and Psychopathological Mechanisms of PTSD: Emerging Pharmacotherapies and Clinical Perspectives.
Santosh Kumar Prajapati, Shreyasi Majumdar, Snehapriya Murari, Kirti MachhindraVadak, Sairam Krishnamurthy
ACS Chemical Neuroscience June 10, 2025 DOI: 10.1021/acschemneuro.5c00335 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | MDMA PTSD Serotonin |
| Keywords | Glutamatergic system Hypothalamic–pituitary–adrenal-axis Neurocircuitry Neuroscience brain chemistry Neural pathways Psychopharmacology MDMA |
| Citations | 14 |
| Key findings | PTSD involves complex neurobiological anomalies across the HPA axis, monoamines, glutamate, GABA, and orexinergic systems, with emerging pharmacological targets including MDMA, ketamine, suvorexant, and cannabinoid modulators. |
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by exposure to traumatic events, with complex neurobiological anomalies that remain incompletely understood. This review aims to comprehensively explore the neurocircuitry, neurochemical dysregulation, and emerging pharmacological targets associated with PTSD, offering a consolidated framework for developing more effective treatments. Particular emphasis is employed on the role of the hypothalamic-pituitary-adrenal (HPA) axis, monoamines, glutamate, GABAergic, and the orexinergic system, as well as emerging therapeutic agents such as 3,4-methylenedioxymethamphetamine (MDMA), ketamine, suvorexant, and cannabinoid modulators. Psychotherapeutic approaches including cognitive-behavioral therapy (CBT) and prolonged exposure therapy are also discussed in the context of their neurobiological effects. Articles were identified through a structured search in PubMed, Scopus, and Google Scholar, focusing on English-language publications from 1950 to 2025. Inclusion criteria encompassed original research, clinical trials, and reviews relevant to PTSD mechanisms and treatment. By integrating recent findings, this review advances the understanding of PTSD pathophysiology and highlights potential avenues for targeted, personalized therapies, thereby contributing to clinical and translational research in neuropsychiatry.
Comparable studies
Other narrative reviews on MDMA for PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. | 2016 | Review | |
| MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? | 2018 | Review | |
| Clinical applications of hallucinogens: A review. | 2016 | Review | |
| MDMA‐Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta‐Analysis | 2021 | Review | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |