Temporal Immune Effects of Oral Ketamine on PTSD: Transcriptomic Evidence of Short-Term Inflammation Suppression and Long-Term Immune Remodelling
Nathan J Wellington, Bonnie L. Quigley, Ana P. Bouças, Megan Dutton, Adem T. Can, Jim Lagopoulos, Anna V. Kuballa
medRxiv Preprint Server May 26, 2025 preprint DOI: 10.1101/2025.05.26.25328370 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Sample size | 23 |
| Population | PTSD participants (9 males, 14 females) |
| Intervention | Oral ketamine |
| Duration | 6-week intervention; PBMCs collected at baseline, one week, and four weeks post oral ketamine |
| Topics | Esketamine Ketamine PTSD |
| Keywords | Ketamine therapy PTSD Treatment Mental health treatment Ketamine For PTSD Immunology Immune system Immune regulation Inflammation Anti-inflammatory Gene expression Gene activity Gene regulation Genomics Molecular mechanisms Personalized medicine Precision mental health Individualized therapy Tailored care |
| Key findings | Ketamine induces a transition from short-term inflammation suppression and antimicrobial activity to long-term sustained immune regulation, inflammation remodulation, and tissue repair in PTSD patients. |
Abstract
Ketamine’s rapid acting symptom relief make it a promising intervention for PTSD. However, the mechanisms driving its long-term efficacy over weeks and months remain poorly understood. This study investigated the short-and long-term impacts on gene expression of a six-week subanesthetic oral ketamine trial in 23 PTSD participants (9 males, 14 females). Peripheral Blood Mononuclear Cells (PBMCs) were collected at baseline, one week (short-term), and four weeks (long-term) post oral ketamine for RNA sequencing and transcriptome analysis. Differential expression analysis identified substantial and persistent transcriptomic changes over time, with 533 genes upregulated and 621 downregulated across timepoints. Notably, there was a 37% increase in differential gene expression between the short-and long-term responses, accompanied by a 6.5-fold rise in expression magnitude and an 8.8-fold enhancement in pathway activity. Pathway analysis emphasised critical immune and inflammatory pathways that appear to be modulated by ketamine, including interferon alpha/beta signalling (z = 4), IL-17 signalling pathway (z = 3.36), and cytokine storm signalling (z = 4.26), neutrophil degranulation (z = 6.0) and antimicrobial peptide signalling (z = 1.63) which differed across timepoints. The findings suggest a transition from short-term inflammation suppression and antimicrobial activity to long-term sustained immune regulation, inflammation remodulation and tissue repair. Key cytokines, chemokines, interferons and antimicrobial peptides included, IL-6, IL-1β, IFI27, IL-10 signalling, CXCL8, SOCS1/3 and CAMP which represent central regulators of immune and inflammatory pathways. These molecular changes offer novel insights into the short-and long-term therapeutic potential of ketamine for PTSD and highlight avenues for precision psychiatry and individualised maintenance therapy to prevent relapse.
Comparable studies
Other observational and cohort studies on ketamine for PTSD, most cited first.