Investigational drugs in PTSD.
Ted Obi, Kerry J. Ressler
Neuropsychopharmacology June 1, 2026 DOI: 10.1038/s41386-026-02371-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Adults with PTSD |
| Topics | PTSD |
| Key findings | Rapid-acting interventions like ketamine and MDMA-assisted psychotherapy represent major advances in PTSD therapeutics, but many mechanistically plausible candidates have failed in late-stage trials due to high placebo responses, patient heterogeneity, and translational gaps. |
Abstract
Post-traumatic stress disorder (PTSD) remains one of psychiatry's most challenging disorders, common, disabling, and biologically complex. Despite decades of research, only sertraline and paroxetine are FDA-approved, both with modest efficacy. Even first-line trauma-focused psychotherapies leave up to half of patients with persistent symptoms. However, advances in neurobiology are reframing PTSD as a disorder of maladaptive stress circuitry, neuroplasticity, and memory reconsolidation, opening new therapeutic possibilities. This comprehensive review examines current PTSD pharmacotherapy, emerging neurobiological targets, and investigational treatments, highlighting 45 actively enrolling clinical trials. Emerging approaches target the hypothalamic-pituitary-adrenal (HPA) axis, adrenergic signaling, glutamatergic/GABAergic systems, endocannabinoids, neuropeptides, and serotonergic-based psychedelics. Rapid-acting interventions represent a major advance in PTSD therapeutics. Ketamine produces symptom reductions within hours, MDMA-assisted psychotherapy has demonstrated Phase 3 efficacy, and neurosteroids offer novel approaches to targeting hyperarousal. However, questions remain regarding durability, optimal dosing, patient selection, precision approaches, and long-term safety. Several early-stage assets also show preliminary promise but require rigorous evaluation. At the same time, the development pipeline remains unforgiving: many mechanistically plausible candidates, from NK-1 antagonists to AMPA modulators, have failed in late-stage trials, often due to high placebo responses, patient heterogeneity despite subtype-specific medication targets, and translational gaps. Brexpiprazole's recent FDA rejection, despite supportive early data, underscores persistent regulatory hurdles. While traditional approaches remain standard of care, breakthrough therapies represent paradigm shifts toward disease modification. Future progress depends on biomarker-guided precision medicine, novel trial designs to mitigate placebo effects, and integration of pharmacologic innovations with evidence-based psychotherapies.
Comparable studies
Other narrative reviews on PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic Psychiatry's Brave New World. | 2020 | Review | |
| Reviewing the Potential of Psychedelics for the Treatment of PTSD | 2020 | Review | |
| 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 |
Citations in the library
Cites 23
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- Global Street Food: la cocina de la calle Diseño interior 2009
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study EClinicalMedicine September 24, 2020
- A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry January 5, 2021
and 18 more in the library