High-dose ketamine infusion for the treatment of posttraumatic stress disorder in combat veterans.

Combat veterans face a high burden of posttraumatic stress disorder (PTSD) together with frequent comorbid mental health and substance use problems, and many do not receive adequate care. Earlier research has shown ketamine’s rapid antidepressant effects and emerging signals of benefit in PTSD, but there is limited evidence specifically addressing combat-related PTSD in veteran populations and little investigation of higher-dose, experiential ('psychedelic') ketamine regimens. Ross and colleagues designed the present study to characterise outcomes after a high-dose ketamine induction series in US military veterans with clinician-diagnosed combat-related PTSD. The primary aim was to describe changes in self-reported PTSD and depressive symptoms following an induction of six 1-hour ketamine infusions targeted to produce a transpersonal dissociative experience, and to report safety and substance-use-related measures in this cohort.

This observational case series enrolled 30 US military veterans who had served in designated combat zones and had clinician-diagnosed combat-related PTSD. Eligible participants were aged 18–75, passed medical screening, were not taking lamotrigine or monoamine oxidase inhibitors, and did not have psychosis. Institutional Review Board approval and written informed consent were obtained. Each participant received an induction series of six 1-hour intravenous ketamine infusions delivered over 2 to 3 weeks. The first infusion started at 1 mg/kg (maximum 60 mg) with no bolus; subsequent doses were individually titrated up or down to achieve what the investigators termed the psychotropic therapeutic response (PTR), defined as the dose producing the participant’s optimum transpersonal and transformative experience. Patients were monitored continuously with pulse oximetry and 3-lead cardiac monitoring, and blood pressure was recorded at intervals. Infusions occurred in private, relaxed rooms with one staff member present; many patients viewed nature videos or listened to music. The authors describe this use as ketamine for non‑anaesthetic indications (KNAI). Outcome assessment relied on self-report instruments administered prior to the first infusion and prior to the sixth infusion (thus reflecting effects after five infusions). The PTSD Checklist for DSM-5 (PCL-5; 20 items) tracked PTSD symptoms and the Patient Health Questionnaire (PHQ-9) assessed depressive symptoms. Substance use screening included the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Abuse Screen Test (DAST-10); participants were also asked about current marijuana use, prior recreational ketamine use, and their subjective dissociative/psychomimetic experiences. The extracted text does not describe a formal statistical analysis plan beyond pre–post comparisons of these measures.

All 30 participants completed the induction series as reported. The ketamine doses used were generally higher than those in many prior studies, yet participants remained responsive to verbal stimuli during infusions. Aside from occasional nausea, no significant adverse events or major vital-sign abnormalities were reported. The extraction includes references to tables of dose calculations and individual scores, but those tables are not clearly reproduced in the provided text. On the PHQ-9 (depression), mean scores decreased from 18.9 before treatment to 9.5 after the fifth infusion, a 50% reduction; this change was statistically significant (F = 90.0, P < .001) with a reported Cohen's d effect size of 1.38. On the PCL-5 (PTSD), mean scores fell from 56.2 to 31.3, a 44% reduction; this change was statistically significant (F = 55.6, P < .001) with a reported Cohen's d of 1.42. Regarding individual responses, no participants reported increased PHQ-9 scores and 2 participants (7%) reported no change on the PHQ-9. On the PCL-5, 3 participants (10%) endorsed increased symptoms post-treatment. Substance-use measures were incompletely reported: 6 participants had missing DAST-10 data and 7 had missing AUDIT data. Self-reported levels of alcohol and drug use did not show a statistically significant decline over the induction period, although the authors note a downward trend and anecdotal reports from some participants of reduced desire to drink alcohol. The extracted text does not report longer-term follow-up or time-to-relapse outcomes.

Ross and colleagues interpret their findings as supportive of ketamine infusion therapy as a potentially valuable treatment for combat-related PTSD, noting large pre–post reductions in both depressive and PTSD symptom scores after a high-dose, experience-focused induction. They place their results alongside prior case reports and clinical series suggesting benefit of ketamine in veteran samples, and reference a recent study that used twice-weekly 0.5 mg/kg infusions which also reported symptom decreases and short-term remissions. The investigators discuss possible mechanisms, mentioning ketamine’s effects at the N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and they emphasise the potential therapeutic importance of the experiential or 'psychedelic' component (the PTR) rather than treating dissociation as a mere adverse effect. Treatment context was highlighted as important; the authors report proactive staff support and a carefully managed 'set and setting' and contrast their approach with more conventional infusion-centre models. The authors acknowledge several limitations: the observational design without a placebo control, administration of the post-treatment questionnaires before the sixth infusion (so the reported change corresponds to five completed infusions), incomplete AUDIT and DAST-10 data, reliance on self-report, and lack of long-term outcome data. They note that 3 participants showed increased PTSD symptoms and that it is unclear why this occurred; the authors suggest that timing relative to the traumatic event and the treatment context may explain differences from studies that reported symptom worsening when ketamine was given soon after injury. Finally, they state that, based on clinical experience, booster infusions may be required to maintain benefit, and they call for controlled studies to clarify safety, durability, mechanism, and the role of the experiential component.

The study provides preliminary evidence that a titrated, higher-dose ketamine induction aiming to produce a transpersonal dissociative experience was associated with substantial reductions in self-reported depressive and PTSD symptoms in a small sample of combat veterans. The authors conclude that the experiential or 'psychedelic' effects of ketamine may be an important therapeutic element and recommend further research to clarify mechanisms, safety, and long-term outcomes. The paper discloses that Dr Bonnett is the medical director and owner of the ketamine infusion centre where the study was conducted; outcome measures and statistical analyses were verified by Cassie Ross, PsyD, who had no financial relationship with the centre. Additional authors disclosed various professional relationships as reported in the extracted text.