• Stephan Rudzki.
• Canberra Sports Medicine, Deakin, Australian Capital Territory 2600, Australia.
• Mil Med. 2022 Apr 21.

IntroductionTreatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder.Materials And MethodsThe medical literature was reviewed over a 6-year period primarily using the medical database PUBMED.ResultsThe literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1β has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1β correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling.ConclusionIn order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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