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 |
Citations in the library
Cited by 2
- Toward dimensional body consciousness impairments in post-traumatic stress disorder and its dissociative subtype: A predictive processing approach. Neuroscience & Biobehavioral Reviews March 1, 2026
- A retrospective analysis of ketamine intravenous therapy for post-traumatic stress disorder in real-world care settings. Psychiatry Research August 20, 2025
Cites 13
- Reviewing the Potential of Psychedelics for the Treatment of PTSD The International Journal of Neuropsychopharmacology March 12, 2020
- The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity Biological Psychiatry January 10, 2014
- Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology August 1, 2020
- Psilocybin and MDMA for the treatment of trauma-related psychopathology International Review of Psychiatry April 3, 2021
- Diverse therapeutic developments for post-traumatic stress disorder (PTSD) indicate common mechanisms of memory modulation. Pharmacology & Therapeutics November 1, 2022
and 8 more in the library