Interventional Psychiatry and Emerging Treatments for Posttraumatic Stress Disorder (PTSD): A Systematic Review

Reinhard Janssen-Aguilar; Shakila Meshkat; Huda F Al-Shamali; Argyrios Perivolaris; Jennifer Swainson; Yanbo Zhang; Andrew Greenshaw; Lisa Burback; Olga Winkler; Jennifer L Phillips; Murray W Enns; Jitender Sareen; Andrew Nicholson; Eric Vermetten; Rakesh Jetly; Ruth Lanius; Venkat Bhat

doi:10.5152/pcp.2025.241027

. 2025 Aug 11;35(Suppl1):S57–S89. doi: 10.5152/pcp.2025.241027

Interventional Psychiatry and Emerging Treatments for Posttraumatic Stress Disorder (PTSD): A Systematic Review

Reinhard Janssen-Aguilar ^1,², Shakila Meshkat ^1,², Huda F Al-Shamali ^1,², Argyrios Perivolaris ^1,², Jennifer Swainson ^3,⁴, Yanbo Zhang ^3,⁴, Andrew Greenshaw ^3,⁴, Lisa Burback ^3,⁴, Olga Winkler ^3,⁴, Jennifer L Phillips ⁵, Murray W Enns ⁶, Jitender Sareen ⁶, Andrew Nicholson ^5,¹², Eric Vermetten ⁷, Rakesh Jetly ⁵, Ruth Lanius ^8,^9,¹⁰, Venkat Bhat ^1,^2,^11,^✉

PMCID: PMC12410247 PMID: 40879152

Abstract

Background:

Posttraumatic stress disorder (PTSD) is a severe, often difficult-to-treat condition, highlighting the need for innovative therapies. Interventional treatments, including neuromodulation, rapid-acting pharmacotherapies such as intravenous ketamine (IV-KET) and esketamine (ESK), and emerging psychedelic-assisted psychotherapies, offer promising solutions. This systematic review evaluates the efficacy, safety, and future research priorities of these treatments for PTSD.

Methods:

A search strategy was implemented across 3 electronic databases. Peer-reviewed articles written in English that focused on interventional psychiatry treatments for adult patients with PTSD were included.

Results:

The systematic review encompassed 94 studies, including 39 on transcranial magnetic stimulation (TMS), 8 on IV-KET, 3 on intranasal esketamine (IN-ESK), 4 on intravenous ketamine (IV-KET) assisted therapy (KET-AT), 1 on esketamine (ESK) assisted therapy (ESK-AT), and 14 on 3,4-methylenedioxymethamphetamine assisted therapy (MDMA-AT). Randomized controlled trials demonstrated response rates of 12.5%-80% for TMS, 17%-67% for IV-KET, and 50%-87% for MDMA. Additional treatments reviewed included Electroconvulsive Therapy, transcranial direct current stimulation, and other pharmacological and neurostimulation treatments. Most treatments were well tolerated, with only mild, transient adverse effects.

Conclusions:

This review highlights the heterogeneity in efficacy, safety, and tolerability across neuromodulation and pharmacologic treatments for PTSD. Variability in response rates reflects differences in patient populations, protocols, and comorbidities. While repetitive TMS, IV-KET, ESK, KET-AT, and MDMA-AT show symptom improvement, sustained efficacy varies, underscoring the need for maintenance strategies. Although direct evidence on stage-specific approaches is limited, these methods, guided by neuroscience-based nomenclature, may improve therapeutic precision, especially in complex cases.

Introduction

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that can arise following a traumatic event (e.g., interpersonal violence, childhood maltreatment, combat, natural disasters),¹-³ and is characterized by significant emotional distress, impaired functioning, and psychological and physical symptoms (Figure 1).⁴ The general population has a PTSD past year prevalence of approximately 3.9%. However, this rate is significantly higher among psychiatric populations, reaching upwards of 30%-50% in certain groups.⁵^,⁶ Posttraumatic stress disorder staging typically includes classifications such as acute (symptoms lasting less than 3 months post-trauma), chronic (symptoms persisting for over 3 months), and difficult-to-treat PTSD (persistent symptoms despite adequate treatment).⁵^,⁶ Despite the availability of evidence-based treatments, approximately half of PTSD sufferers face ongoing or recurrent symptoms,⁷ highlighting the urgent need for innovative therapeutic approaches.

Figure 1. — Circuits, brain structures, and symptoms involved in PTSD. Abbreviations: ACC, anterior cingulate cortex; BLA, basolateral amygdala; CNA, central nucleus of the amygdala; DFM networks, default mode networks; HPA, hypothalamic-pituitary-adrenal axis; PFC, prefrontal cortex; PTSD, posttraumatic stress disorder. Adapted from Shalev A, Cho D, Marmar CR. Neurobiology and treatment of posttraumatic stress disorder. Am J Psychiatry. 2024;181(8):705-719. doi:10.1176/appi.ajp.20240536.

Interventional psychiatry has emerged as a promising field, developing and testing advanced treatments with the aim of modulating dysfunctional neuronal circuits specifically implicated in psychiatric conditions, especially in difficult-to-treat cases.⁸ Procedural interventional psychiatry treatments encompass neuromodulation techniques such as Repetitive Transcranial Magnetic Stimulation (rTMS), Electroconvulsive Therapy (ECT), Deep Brain Stimulation (DBS), Vagus Nerve Stimulation (VNS), and Transcranial Direct Current Stimulation (tDCS), as well as pharmacological approaches like ketamine treatment (KET). These interventions impact brain networks involved in trauma processing, emotional regulation, and memory reconsolidation, with effects varying by treatment, placement, and individual response (Figure 1).⁹^-¹² For instance, rTMS and tDCS influence cortical excitability and connectivity, offering non-invasive methods to alter brain function,¹³^,¹⁴ while DBS and VNS target subcortical regions involved in mood and stress responses.¹⁵ Non-procedural novel treatments include psychedelic-assisted psychotherapies (P-AT) and KET-assisted psychotherapy (KET-AT). These approaches utilize substances such as MDMA, psilocybin, and KET to enhance the effects of psychotherapy. KET, KET-AT, and P-AT stand out due to their rapid action, potentially offering relief by facilitating neuroplasticity and emotional insight.¹¹^,¹² These approaches may be particularly promising in individuals with difficult-to-treat PTSD by leveraging distinct therapeutic mechanisms.

Interventional psychiatry, grounded in neurophysiology and procedural expertise, uses specialized training to treat symptoms, identify biomarkers, and develop new therapies, enhancing psychiatric care.⁸ Despite growing interest and evidence supporting these approaches, notable gaps remain in understanding how these various interventional modalities compare and which patient populations may benefit the most. Existing reviews have predominantly focused on specific treatments such as rTMS or KET for PTSD, often without comprehensive consideration of other modalities or their comparative effectiveness. The current literature’s heterogeneity in protocols, patient characteristics, and study designs complicates conclusions on efficacy, optimal dosing, frequency, and long-term effects of treatments. Limited comparative data, particularly head-to-head trials, adds to the uncertainty about the best interventions for PTSD symptoms or comorbidities. To address these limitations, this systematic review makes a unique contribution by synthesizing and integrating evidence across a broader spectrum of interventional psychiatry treatments for PTSD. It not only assesses efficacy, safety, and mechanisms but also highlights research gaps, providing a comprehensive framework to guide future studies and inform clinical practice. This inclusive approach aims to generate novel insights into how various modalities compare and to identify the patient populations most likely to benefit from these treatments.

Material and Methods

The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.¹⁶ A protocol for this review was registered in PROSPERO (CRD42024602536).

Information Sources and Search Strategy

On Oct 1, 2024, a search was conducted in MEDLINE (Ovid Interface 1946-2024), APA PsycINFO (Ovid Interface 1974-2024), and Embase (Ovid Interface 1974-2024) using keywords and subject headings on 2 concepts: PTSD and interventional psychiatry treatments. The full search strategy can be found in Supplementary Material 1. To identify ongoing clinical trials that have not yet been published, registered clinical trial data were obtained from ClinicalTrials.gov.

Eligibility Criteria

Articles were eligible if they included participants aged 18 or older undergoing an interventional psychiatry intervention for clinically diagnosed PTSD, with the diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases, or equivalent diagnostic criteria. Additionally, the studies were required to include PTSD as an outcome, measured using standardized PTSD scales (e.g., Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), PTSD Checklist for DSM-5 (PCL-5)). Only peer-reviewed, English-language quantitative studies were included.

Data Screening and Extraction

All identified articles were uploaded into Covidence (https://www.covidence.org), where duplicates were automatically removed. Screening was conducted by 2 independent reviewers in 2 phases: title and abstract screening, followed by full-text screening. Conflicts were resolved by a third reviewer or through discussion and consensus. The following data were extracted by 1 reviewer and verified by a second: authors, year, country, study design, participant information, intervention description, adjuvant treatments, primary and secondary outcomes, adverse events, and main findings.

Registered clinical trials were similarly extracted with the addition of the principal investigator, actual/estimated completion year, completion status, and actual/projected intention-to-treat sample sizes.

Risk of Bias Assessment

Risk of bias assessment was completed using the Joanna Briggs Institute (JBI) appraisal tools,¹⁷ selecting the appropriate tool for each study type: randomized controlled trials (RCT), analytical cross-sectional study, case report, case series, qualitative study, or cohort study. All questions were rated as “yes,” “no,” “unclear,” or “not applicable.” The JBI tools do not provide a summative quality score; instead, inclusion decisions were based on the assessor’s judgment of each study’s value in offering meaningful insights into interventional treatments for PTSD. Two independent assessors conducted the risk of bias assessment, and any discrepancies between their evaluations were resolved through discussion. Each reviewer also had an opportunity to review and confirm the results.

Result Synthesis

A narrative analysis following the SWiM (Synthesis Without Meta-analysis) methodology¹⁸ was conducted, focusing on aggregate data, particularly regarding PTSD symptom reduction, safety, and study quality. Studies were grouped, standardized outcome measures analyzed, and heterogeneity explored. Extracted and aggregate data are presented in evidence tables, with synthesis limitations addressed in the discussion.

Results

The complete database search identified 7264 articles, and after duplicate removal, 5121 proceeded to screening, of which 94 were included for analysis (Figure 2). A reference list of the included articles can be found in Supplementary Material 2.

Risk of Bias Results

Included articles were evaluated using the JBI appraisal tools. In total, 60 articles were assessed using the appraisal tool for RCTs, 11 with the analytical cross-sectional study tool, 10 with the case report tool, 10 with the case series tool, and 3 with the qualitative study tool. All trial types, whether randomized or open-label, were evaluated using the randomized controlled trial tool to provide insights on the reliability of the methods and follow-up. Studies where it was not applicable were not evaluated on blinding or randomization processes. All included studies were deemed of sufficient quality to be included in this review. The results of the quality assessment are presented in Supplementary Material 3.

Study and Sample Characteristics

A total of 8552 individuals participated in the included studies, and among those who reported their sex, 24% were female. Most of the included articles were conducted in the United States of America (n = 66; 70%) and were RCTs (n = 41; 44%). Fifty-five of the studies enrolled civilians (59%), while 52 studies enrolled veterans or military members, and all participants had a PTSD diagnosis based on the DSM or a DSM-based scale. Posttraumatic stress disorder symptoms were most often measured using the PCL (n = 55; 59%) (Figure 3).

Figure 3. — General sample characteristics. A: Years of publication of the included studies. B: Countries of publication of the included studies. C: Instruments used to measure PTSD. D: Interventions included in the study. Results in each panel are presented as frequency values. Abbreviations: BPRS, Brief Psychiatric Rating Scale; CAPS, Clinician-Administered PTSD Scale; CGI, clinical global impressions; DTS, Davidson Trauma Scale; ECT, electroconvulsive therapy; IES, Impact of Event Scale; ITQ, International Trauma Questionnaire; KET, ketamine; LDS, Life Distress Scale; MDMA, 3,4-methylenedioxymethamphetamine; MPPSD, Mississippi PTSD Scale; PCL, PTSD checklist; PDS, Posttraumatic Diagnostic Scale; PSS, PTSD Symptom Scale; PTGI, posttraumatic growth inventory; TABS, Trauma Appraisal and Beliefs Scale; tDCS, Transcranial Direct Current stimulation; TMS, transcranial magnetic stimulation.

The systematic review examines 12 distinct interventions within the domains of neurostimulation and novel pharmacotherapies. The neurostimulation interventions include 39 studies on TMS, 5 studies on tDCS, 2 studies on DBS, 2 studies on stellate ganglion neuromodulation (SGNM), and single studies on infrared LED treatment, trigeminal nerve stimulation (TNS), and VNS (Table 1). In the pharmacological domain, the review includes 8 studies on intravenous KET (IV KET), 3 studies on intranasal esketamine (ESK), 5 studies on KET-AT (1 IV KET, 1 IN KET, 1 ESK, and 2 with other routes of administration), 14 studies on MDMA-assisted therapy (MDMA-AT), 2 studies on cannabis, and single studies on Ibogaine, 5-MeO-DMT, and Ayahuasca (Table 2).

Table 1.

Neuromodulation Interventions

Author and Year	Study Design	Sample Size (n)	Participants	PTSD Diagnosis	Intervention Description	Drop Outs	Adverse Events	Main Findings
Repetitive Transcranial Magnetic Stimulation
Randomised Controlled Trials
Ahmadizadeh et al, 2018	RCT	Bilateral = 22 Unilateral = 21 Sham = 22	Military 100% Male	PCL-M, SCID	High-frequency rTMS (20 Hz; 100% MT) applied to DLPFC bilaterally or the right DLPFC, with 3 sessions per week for 2 weeks, then reduced to twice weekly for the next 2 weeks.	Bilateral = 6 Unilateral = 4 Sham = 6	Bilateral = headaches (n = 2), discomfort (n = 1) Unilateral = Warmth (n = 1)	After 10 sessions, the bilateral and unilateral groups showed greater PTSD symptom reductions than the sham group, with no significant difference between bilateral and unilateral at endpoint. Response definition: PCL score improved by 2+ SDs compared to baseline.Response rates: Bilateral: 62.5% (n = 10) Unilateral right: 41.2% (n = 6) Sham group: 0%
Bogdanova et al, 2015³⁸	RCT	n = 42 (subset of n = 12 received TMS)	Military Sex/gender NR	PCL-M	High-frequency rTMS (20 Hz) applied to the right DLPFC was administered daily for 1 week.	NR	NR	The active rTMS group showed significant improvements in PTSD symptoms (PCL-M) and sleep compared to the sham group. Response definition/ rates: NR
Boggio et al, 2010	RCT	Right rTMS = 10 Left rTMS = 10 Sham = 10	Civilian 70% Female PTSD duration: mean 3.9± 4.3 years	SCID	High-frequency rTMS (20 Hz, 80% MT) applied to either the left or right DLPFC was administered for 10 sessions over 2 weeks.	Right rTMS = 1 Left rTMS = 1 Sham = 2 All dropouts were due to travel difficulties.	NR	Both right and left rTMS treatments significantly reduced PTSD symptoms after 5 and 10 days, while the sham treatment showed no effect. Right rTMS showed a marginally more significant improvement in symptoms compared to left rTMS. Response definition/rates:NR
Bozzay et al, 2021²¹	RCT	iTBS = 25 Sham = 25	Military 16% Female Comorbid AUD PTSD began at least 6 weeks prior to treatment	DSM-5	iTBS (50 Hz bursts at 5 Hz, 80% MT) applied to the right DLPFC for 10 sessions.	NR	AE: Treatment site discomfort SAE: Active = suicidal ideation (n = 1) Sham = Homicidal Ideation (n = 1)	PTSD symptoms showed significant improvement from baseline to the 1-month follow-up, with the most progress in Veterans who completed the full iTBS dose. Participants with AUD reported more adverse events (35% vs. 11%) than those without AUD, regardless of treatment. Response definition/rates:NR
Cohen et al, 2004²⁵	RCT	1 Hz rTMS = 8 10 Hz rTMS = 10 Sham = 6	Military and Civilian. 29% Female	DSM-IV (SCID)	Low-frequency rTMS (1 Hz, 5-second trains, 80% MT) or high-frequency rTMS (10 Hz, 2-second trains, 80% MT) over 10 daily sessions across 2 weeks.	1 Hz rTMS = 2 10 Hz rTMS = 1 Sham = 2	AE: Headache, neck pain, muscular contraction, dizziness, rage, ear discomfort. SAE: A manic episode occurred in 1 participant from each active treatment group	High-frequency rTMS significantly reduced PTSD symptoms compared to both low-frequency rTMS and the sham group. Response definition/rates:NR
Fryml et al, 2019	RCT	rTMS = 5 Sham = 3	Military 13% Female	CAPS	High-frequency rTMS (10 Hz, 120% MT) was applied to either the right or left DLPFC once a week for 8 weeks. Participants in all groups also received prolonged exposure therapy before rTMS sessions.	Four of 12 participants dropped out after consenting but before treatment, leaving 8 participants who were randomized and completed the study.	NR	At session 5, the active rTMS group showed a 55% reduction in CAPS scores, compared to a 40% reduction in the sham group. Response definition/rate: NR
Isserles et al, 2013²⁴	RCT	DTMS+BE-TE = 10 DTMS+BE-NTE = 10 Sham+BE-TE = 10	Military and Civilian 20% Female TR-PTSD	CAPS	Participants received deep high-frequency TMS (20 Hz, 120% MT) to the mPFC with brief exposure therapy to either a traumatic (BE-TE) or non-traumatic event (BE-NTE), while the sham group received BE-TE. Treatment was administered 3 times per week for 4 weeks.	Twenty-six received at least 8 sessions. One participant could not tolerate the stimulation intensity and was removed from the analysis.	AE: DTMS+BE-TE = headache, discomfort, anxiety Sham+BE-TE = discomfort SAE: DTMS+BE-TE = tonic-clonic generalized seizure during the 8th session	A 50% or greater improvement from baseline CAPS scores was achieved in 44% of patients in the DTMS+BE-TE group, 12.5% in the DTMS+BE-NTE group, and none in the Sham+BE-TE group. Response definition: 50% or greater CAPS score improvement. Response rates: DTMS + TE: 44% (n = 4), DTMS + NTE: 12.5% (n = 1) Sham DTMS + TE: 0%
Isserles et al, 2021¹⁹	RCT	dTMS = 60 Sham = 65	Civilian 30% Female Outpatients	CAPS-5	High-frequency deep TMS (18 Hz, 100% MT) was applied bilaterally to the mPFC and anterior cingulate cortex, 3 times a week for 4 weeks. All participants received script-driven imagery therapy.	Sixteen participants excluded from analysis.	AE: Headache, anxiety (both groups) SAE: 2 participants in the dTMS group developed suicidal ideation.	Both groups showed significant CAPS-5 score improvements at 5 weeks, with less improvement in the dTMS group compared to sham; response rates at 5 and 9 weeks were 42.5% and 53.8% for dTMS and 54.9% and 68% for sham (P > .055), with low remission rates in both groups. Response definition: 50% or greater CAPS score improvement. Response rates: dTMS: 42.5% (n = 25) Sham: 54.9% (n = 36)
Jiang et al, 2023	RCT	rTMS+BE = 20 rTMS = 20 Sham = 20	Civilian 35% Female Post-stroke PTSD	CAPS-5	Low-Frequency rTMS (1 Hz, 90% MT) was applied to the right DLPFC over 10 sessions across 2 weeks.	Five participants withdrew due to discomfort, 3 due to stroke progression, and 2 were lost to follow-up.	Transient headache, nausea, and discomfort.	The TMS + BE and TMS groups showed significant reductions in PTSD symptoms (IES-R) compared to sham at T3, with TMS + BE improving faster by T2; 3-month follow-up showed lower PTSD rates in TMS + BE and TMS than in sham. Response definition: No longer meet PTSD criteria (CAP-5) Response rates: TMS + BE: 38.89%. TMS: 25.00%. Sham: 68.75%.
Kozel et al, 2018	RCT	rTMs+CPT = 54 Sham+CPT = 49	Military Predominantly Male	CAPS	Low-frequency rTMS (1 Hz, 110% MT) was applied to the right DLPFC once a week for 12 sessions, with each session followed by a 60-minute CPT session.	Seventy participants (68%) completed assessments at session 5, 61 (59%) at session 9, and 59 completed the 6-month follow-up assessment.	NR	Both groups showed significant reduction in PTSD symptoms, as measured by CAPS, with the rTMS+CPT group showing greater improvement than the sham+CPT group. Response definition/rates: NR
Kozel et al, 2019	RCT	1Hz rTMS = 17 10 Hz rTMS = 18	Military 29% Female	CAPS-5, PCL-5	Participants received either low-frequency (1 Hz, 110% MT) or high-frequency (10 Hz, 110% MT) rTMS to the right DLPFC over 5 sessions across 6 weeks, followed by a taper of 3 sessions in week 1, 2 in week 2, and 1 in the final week.	1 Hz rTMS = 2 (work), 1 (lost to follow-up) 10 Hz rTMS = 2 (could not tolerate), 1 (parking), 1 (lost to follow-up), 1 (headache from a medical condition).	No treatment related AEs were reported; 2 SAEs occurred but were unrelated to the treatment.	Both the 1 Hz and 10 Hz groups showed significant improvements in PTSD and depression scores, measured by the PCL-5 and MADRS, by the end of treatment, with the 10 Hz group also showing functional gains, though neither frequency had a significant advantage over the other. Response definition:50% (QIDS-SR, MADRS) or 30% (PCL-5 and CAPS-5) reduction in score. Response rates: 1 Hz: 29% (n = 4) 10 Hz: 31% (n = 4)
Leong et al, 2020²²	RCT	1Hz rTMS = 11 10 Hz rTMS = 10 Sham rTMS = 10	Civilian 77% Female Outpatients	DSM-IV (MINI)	Participants received either low-frequency (1 Hz, 120% MT) or high-frequency (10 Hz, 120% MT) rTMS to the right DLPFC over 10 sessions across 2 weeks.	1Hz rTMS = 1 (suicidal ideation) 10 Hz rTMS = 1 (did not receive treatment) Sham rTMS = 1 (did not receive treatment), 2 (lost to follow-up	SAE: 1 case of suicidal ideation after 1 session (1 Hz group).	The 1 Hz rTMS group showed significant improvement in PTSD symptoms (CAPS) compared to sham, an effect not observed in the 10 Hz rTMS group. Response definition/rates:NR
Nam et al, 2013	RCT	rTMS = 7 Sham = 9	Civilian 63% Female Inpatients	DSM-IV-TR	Low-frequency rTMS (1 Hz, 100% MT) was applied to the right PFC, 5 sessions per week for 3 weeks.	Eighteen participants were randomised; 2 withdrew before treatment began, and all remaining 16 completed the study.	AE: rTMS = Headache, dizziness Sham = headache, dizziness, difficulty concentrating	Significant improvements in PTSD symptoms, as measured by the CAPS, compared to the sham group. Response definition/rates: NR
Oathes et al, 2022	RCT	n = 45	Civilian Sex/gender NR	PCL	Received iTBS applied to the subgenual anterior cingulate or the DLPFC (no additional details were provided).	NR	NR	MADRS and PCL scores improved, showing a 3-way interaction between site, task, and trauma. For low-trauma patients, fMRI-guided TMS with working memory had the greatest effect, while 6cm targets with working memory had the least. For high-trauma patients, fMRI-guided with relaxation was most effective, with fMRI-guided with working memory being least effective. The same pattern held for PTSD symptoms. Response definition/rates: NR
Osuch et al, 2009	RCT	n = 9	Civilian 89% Female Chronic PTSD PTSD duration: mean 22.3± 13 years	CAPS	Participants received sham or low-frequency rTMS (1 Hz, 100% MT) applied to the right DLPFC with exposure therapy for 3-5 sessions weekly for a total of 20 sessions.	NR	NR	Active rTMS showed greater improvement for hyperarousal symptoms, with increases in 24-hour urinary norepinephrine and serum T4, and a decrease in serum prolactin, suggesting both symptomatic and physiological effects. Response definition/rates:NR
Petrosino et al, 2020	RCT	n = 46	Military 15% Female	DSM-5 (SCID)	One year follow-up of Philip et al, 2019 iTBS vs. sham study (see next row for details).	NR	See Philip et al, 2019	After 1 year, 22 patients (47.8%) experienced clinical relapse, with the 4-week treatment group showing significantly lower relapse rates (33.3%) and longer time to relapse compared to the 2-week group (63.6%). Response definition/rate:NR
Philip et al, 2019	RCT	iTBS = 25 Sham = 25	Military 16% Female 90% had comorbid depression, and over half had SUD	DSM-5 (SCID)	iTBS (50 Hz bursts at 5 Hz, 80% MT) was applied to the right DLPFC for 10 days over 2 weeks. All participants could opt for an additional 10 sessions, totaling 4 weeks of treatment.	iTBS = 1 (headache), 2 (lost to follow-up) Sham = 1 (homicidal ideation), 1 (withdrew consent), 1 (lost to follow-up)	AE: Headache, treatment site discomfort. SAE: 1 participant could not tolerate the MRI, homicidal ideation (sham)	Participants in the active iTBS group experienced significant reduction in PTSD symptoms, as measured by the CAPS and PCL, compared to the sham group. Response definition/rate: NR
Rosenberg et al, 2002	RCT	1 Hz rTMS = 6 5 Hz rTMS = 6	Military 100% Female	DSM-IV (SCID)	Participants received either high-frequency (5 Hz, 90% MT) or low-frequency (1 Hz, 90% MT) rTMS applied to the left DLPFC for 10 consecutive days.	One participant dropped out due to tension headaches.	AE: Headache No SEA occurred.	rTMS resulted in a small but significant 6% reduction in core combat PTSD symptoms as measured by the MISS, with no difference between high-frequency and low-frequency rTMS protocols; significant improvement in depression was also observed. Response definition:50% or greater decrease in Ham-D scores. Response rates: 1 Hz = 67% (n = 4) 5 Hz = 83% (n = 5)
Thierrée et al, 2022²⁰	RCT	HF-rTMS = 18 LF-rTMS = 20	Civilian 66% Female	DSM-IV (MINI), PCL-5	Participants received either high-frequency (10 Hz, 110%) or low-frequency (1 Hz, 70%) rTMS applied to the right DLPFC for 8 daily sessions. Both groups also received trauma script exposure.	HF- rTMS = 1 participant lost to follow-up LF-rTMS = 1 due to SAE, 1 no reason provided	AE: Headache (n = 2 in HF-rTMS), diarrhea, nausea, vomiting, increase in suicidal thoughts SAE: psychogenic nonepileptic seizure (n = 1 in LF-rTMS), anxiety attack (n = 1 in LF-rTMS)	From baseline to 3 months, the HF-rTMS group showed greater reductions in CAPS, PCL-5, and HAM-D scores compared to the LF-rTMS group, with a 42.1% decrease in PCL-5 scores for HF versus 30.7% for LF, although the difference was not statistically significant (P = .32). Response definition: 30% or greater reduction in CAPS score Remission definition: no longer meets PTSD criteria (CAPS) Remission rates: HF-rTMS: 53.8% (n = 7) LF-rTMS: 25.0% (n = 4)
van Rooij et al, 2024	RCT (Ongoing)	n = 27	Civilian 85% Female	PCL-5	Participants received sham TMS or Low-frequency (1 Hz) TMS applied to the right DLPFC (amygdala) twice a day for 10 days.	NR	NR	Participants showed significant improvement in PTSD symptoms, as measured by the PCL-5, with 52% in the LF-TMS group achieving a clinically significant response. Response definition: >30% improvement in PCL-5. Response rates: 52% of participants responded
Watts et al, 2012	RCT	rTMS = 10 Sham = 10	Military and Civilian 10% Female	CAPS, SCID	Low-frequency (1 Hz, 90%) rTMS was applied to the right DLPFC for 10 sessions over 2 weeks.	NR	NR	There was a significant reduction in PTSD and anxiety symptoms measured by CAPS and PCL, with no change in cognitive function (BNCE) in the rTMS group compared to sham. While improvements persisted for 2 months post-treatment, subtle signs of waning effects appeared. Anxiety improvements with rTMS were not statistically significant compared to sham, and cognition showed minimal change. Response definition/rates: NR
Yuan et al, 2023	RCT	iTBS = 25 rTMS = 25 Sham = 25	Civilian 100% Women	PCL-C	Participants received either high-frequency rTMS (10 Hz, 80% ) or iTBS (50 Hz bursts at 5 Hz, 80%) applied to the right DLPFC for 5 days a week for 3 weeks.	iTBS = 3 rTMS = 5 Sham = 4	Side effects were tolerable and similar to what has previously been reported (no additional information provided)	PTSD symptoms, as measured by the PCL-C, significantly decreased in the iTBS and rTMS groups compared to sham. Response definition/rates: NR
Other Study Designs
Berlow et al, 2023	Chart Review	n = 500	Military Sex/gender NR	CAPS	Received 20 or more TMS sessions (no additional details were provided)	NR	NR	49% of participants no longer met PTSD criteria, and 37% saw a 50% reduction in symptoms.
Berlow et al, 2022	Pre-post test design	n = 75	Military Sex/gender NR	PCL-5	Left-sided high frequency TMS. assessed after every 5 sessions.	NR	NR	PTSD symptoms, as measured by the PCL-5, declined significantly following treatment.
Carpenter et al, 2018²³	Pre-post test design	n = 35	Civilian 40% Female Comorbid MDD	DSM-IV	High-frequency rTMS (5 Hz, 120% MT) applied to the left PFC was administered in a treatment course allowing up to 40 sessions (mean ± SD) = 32.9 ± 9.3; range 5-40), with the first 35 delivered daily over 7 weeks, followed by a tapering schedule for the final 5 sessions over 3 weeks.	5 drop outs due to AE or withdrawal of consent/lost to follow-up	3 participants experienced worsening symptoms with suicidal ideation, and 1 also had suicidality with substance abuse.	PTSD symptoms, as measured by the PCL-5, declined significantly following treatment with a mean score reduction of 35.5%.
Cassidy et al, 2021	Chart Review	n = 35	Civilian 43% Female	PCL-5	Bilateral rTMS was administered to the right side (1 Hz) and left side (10 Hz) across 30 sessions, followed by 22 maintenance sessions.	1 drop out	NR	PTSD symptoms, measured by the PCL-5, declined significantly after treatment, with the number of sessions positively correlating with the extent of improvement.
Chang et al, 2023	Case Report	n = 1	Civilian 100% Female Comorbid MDD	DSM-5	Bilateral TBS (50 Hz bursts at 5 Hz, 80% MT) targeted the DLPFC, starting with cTBS to the right DLPFC, followed by 2 rounds of iTBS to the left DLPFC with a 20-minute break between rounds.	N/A.	Transient headache and dizziness	PTSD and MDD symptoms, measured by the DTS and BDI, improved post-treatment, with greater improvement observed in depression symptoms.
Grisaru et al, 1998²⁶	Pre-post test design	n = 10	Military and Civilian 30% Female	DSM-IV	One session of bilateral low-frequency rTMS (0.3 Hz, 100% MT) was applied to the motor cortex.	NR	One participant reported a headache, and another experienced an increase in intrusive thoughts.	Significant improvements in PTSD symptoms, anxiety, and somatization, as measured by the IES and SCL-90, were observed 24 hours post-TMS, with some effects diminishing by 28 days.
Makale et al, 2023	Pre-post test design	n = 195	Military 50% Female	PCL-5	EEG-guided personalized high-frequency rTMS (8-13 Hz, 25-60% MT) was delivered over 28 sessions across 6 weeks.	The dropout rate reached 31% (60 patients) by treatment 27 and rose to 92% (180 patients) by week 22, leaving 1 patient at week 80.	Occasional mild and transient AE (e.g., discomfort) were experienced.	Over half of participants (n = 96) were below the PTSD diagnostic threshold (PCL-5) following treatment.
Nursey et al, 2020	Case Series	n = 8	Military 13% Female	PCL	Bilateral TBS (50 Hz bursts at 5 Hz, 120% MT) was applied to the DLPFC, 5 sessions per week for 4 weeks.	NR	AE = headache, site pain	A significant reduction in PTSD symptoms, as measured by the CAPS, was maintained at the 3-month follow-up.
Oznur et al, 2014	Chart Review	n = 20	Military 100% male PTSD duration: mean 7.3± 3.1 years	DSM-IV (SCID)	Low-frequency rTMS (1 Hz, 80% MT) was applied to the right DLPFC, 5 sessions per week for 4 weeks.	NR	AE: Headache	Significant reduction in hyperarousal scores, measured by the IES, following treatment.
Parks et al, 2021	Chart Review	n = 299	Civilians Sex/gender NR	PCL-5	Received personalised rTMS 5 days a week for up to 60 sessions (no additional details were provided).	NR	NR	Eighty-four percent of participants responded to treatment.
Philip et al, 2022	Chart Review	iTBS = 10 5Hz TMS = 10	Military and Civilian 15% Female 50% with comorbid MDD	DSM-IV/ DSM-5	Participants received either high-frequency rTMS (5 Hz) or iTBS (50 Hz bursts at 5 Hz) targeting the left DLPFC, administered 5 days per week over 6 weeks.	NR	Side effects aligned with the known TMS AE, with no seizures reported.	Both protocols effectively reduced PTSD and MDD symptoms, but 5 Hz rTMS showed greater effectiveness, particularly for PTSD.
Philip et al, 2016	Case Series	n = 10	Military 20% Female Comorbid MDD	Clinical Interview with Psychiatrist	High-frequency rTMS (5 Hz, 120% MT) was administered to the left DLPFC for 30 sessions, followed by a taper of 6 additional sessions over 3 weeks.	The average number of rTMS sessions was 30.8 ± 7.11, with 60% (6 patients) completing all 36 sessions.	NR	Significant improvements in PTSD and MDD were observed. Half had at least a 50% improvement in depression, and 40% in PTSD. One patient’s depression worsened (QIDS increased from 25 to 30), with minimal PCL change (74 to 75).
Shenasa et al, 2023	Case Series	iTBS = 51 rTMS = 47	Military 21% Female Comorbid TRD	PCL-5	Participants received either high-frequency rTMS (10 Hz, 120% MT) or iTBS (50 Hz bursts, 120%) applied to the left DLPFC for 5 sessions per week for 6 weeks.	NR	No treatment related AE	Both iTBS and 10-Hz rTMS effectively decreased depression and PTSD symptoms, but neither method showed a significant advantage over the other. Although iTBS demonstrated a greater reduction in PTSD scores, this difference was not statistically significant.
Sisko et al, 2018	Case Series	n = 14	Civilians Sex/gender NR	PCL	High-frequency deep rTMS (18 Hz, 100% MT) was applied to the DMPFC 3-5 times per week, with participants exposed to a personalized traumatic event script before each session.	NR	NR	All patients improved significantly per CGI-S and PCL/MPSS, with those receiving over 20 treatments showing the greatest improvement.
Steele et al, 2021	Case Report	n = 1	Military 100% Male Persistent PTSD	PCL-5	Low-frequency rTMS (1 Hz) was applied to the right DLPFC for 5 sessions per week over 6 weeks, with a taper phase involving 13 additional sessions over 15 weeks.	NR	NR	After 30 TMS sessions and a 15-week taper, the patient’s dystonic symptoms improved significantly, though they slightly rebounded, while depression remitted (MADRS <7); however, PTSD symptoms remained clinically significant (PCL-5 >33).
Vaithianathan et al, 2022	Chart Review	n = 8	Military 100% Male Comorbid TRD	CAPS	Bilateral sequential TBS (40-50 Hz bursts, 120% MT) was applied to the DLPFC for 19-30 sessions over 4-6 weeks.	NR	AE: Discomfort, scalp irritation, muscle contraction, change in systolic blood pressure.	PTSD symptoms, as measured by the PCL-5, improved by 37.6%.
Woodside et al, 2017	Case Series	n = 14	Civilian 100% Female	DSM-IV	Participants received either high-frequency rTMs (10 Hz, 1 received 20 Hz, 120%) or iTBS (50 Hz bursts at 5 Hz, 120%) applied to the DMPFC for 20-30 sessions.	NR	No AE besides transient headache.	PCL-C scores improved significantly (mean reduction 51.99%; P < .001), with 57% of participants achieving >50% reduction. Responders saw a 72.3% mean improvement. No worsening of PTSD symptoms was reported.
Electroconvulsive Therapy
Randomised Controlled Trial
Araujo et al, 2023²⁷	RCT	ECT-TR = 8 ECT-NR = 6	Civilian 86% Female Severe TR-PTSD	DSM-IV	All participants received bitemporal ECT following memory retrieval, with 8 participants recalling a traumatic memory (ECT-TR) and 6 recalling a neutral memory. Most underwent 6 ECT sessions, although 1 participant received 12 sessions.	NR	None mentioned	ECT reduced PTSD symptoms as measured by the DTS, with greater improvement observed in the group that underwent traumatic memory retrieval. Response definition/rates: NR
Tang et al, 2021²⁸	RCT	ECT-TR = 14 ECT-NR = 11	Civilian 100% Female Longstanding TR-PTSD (up to 20 years)	DSM-IV (MINI)	Participants initially underwent right unilateral ECT, with non-responders switching to bilateral ECT. They were assigned to either traumatic or neutral memory retrieval and received an average of 10.8 to 14.3 ECT sessions.	ECT-TR = 3 ECT-NR = 3	AE: Some cognitive impairment, measured by the CGI. No SAE reported	PTSD symptoms significantly decreased on the MPSS-SR and CAPS-5, with reductions of 35.6% and 36.5% post-ECT and similar reductions at 3 months, though no significant difference was found between the traumatic and neutral memory groups. Response definition/rates: NR
Youssef et al, 2020²⁹	RCT	LAP-ST = 3 ECT = 4	Civilian 29% Female Comorbid MDD	PCL	Participants received either Low Amplitude Seizure Therapy (LAP-ST) or right unilateral (RUL) ECT. Sessions were provided 3 times per week for an average of 6 sessions.	2 participants discontinued due to administrative reasons, and 1 due to a clinical need for nonrandomized standard-of-care ECT.	Did not report	Both groups showed rapid PTSD symptom improvement. In the LAP-ST group, the mean PCL score dropped from 42.5 to 31, while in the standard RUL ECT group, it decreased from 64.7 to 41. Response definition/rates: NR
Other Study Designs
Margoob et al, 2010	Pre-post design	n = 20	Civilians 50% Female PTSD duration: mean of 35.9 months	DSM-IV	Participants received 6 sessions of bitemporal ECT, administered twice weekly. Psychotropic medications were tapered and discontinued before starting ECT; immediately after completing the course, patients were prescribed sertraline (100-150 mg/day) or mirtazapine (15-30 mg/day).	Three drop outs	Did not record AEs	PTSD and MDD symptoms decreased by 34.4% and 51.1% on the CAPS and MADRS, respectively, though no patients achieved remission (CAPS ≤ 20).
Ahmadi et al, 2016	Case-control	ECT = 92 Control = 3393	Civilian 14 % Female Comorbid MDD	DSM-IV	Participants received bifrontal ECT 3 times a week for an average of 6 sessions.	N/A.	In 8 years, the ECT group had a 9.7% death rate (2% suicide), compared to 18% (5.9% suicide) in the non-ECT group. Cardiovascular and all-cause mortality were 204% and 153% higher in PTSD and MDD patients without ECT.	ECT significantly reduced PTSD and MDD symptoms. Additionally, ECT was linked to a lower risk of cardiovascular and all-cause mortality, as well as suicidality in PTSD and MDD patients, unlike those untreated with ECT.
Watts et al, 2007	Chart Review	n = 26	Military 15% Female PTSD duration: 22 years	DSM-IV	Participants received right unilateral ECT, switching to bitemporal ECT after 8 sessions if unresponsive. On average, patients underwent 9.65 unilateral treatments, with 5 receiving an additional 4.6 bitemporal sessions.	NR	Did not report	PTSD symptoms decreased, with 35% of participants reaching responder status (≥20% reduction on the PCL), and 42% achieving remission from MDD.
Ozdemir et al, 2013	Case Series	n = 2	Military 100% Male	DSM-IV-TR	Bilateral ECT was administered 3 times weekly for 8-10 sessions. Participants also received risperidone (4 mg/day) and venlafaxine (225 mg/day).	NR	Did not report	PTSD symptoms decreased, with a 37.3% reduction in Participant 1 and a 37.2% reduction in Participant 2 on the CAPS scale, and both maintained progress on a reduced risperidone dose (1 mg/day) post-ECT.
Kuc et al, 2024	Case Report	n = 1	Civilian 100% Female Comorbid MDD and Anorexia Nervosa	PCL-5	The participant received bitemporal ECT for 3 sessions, followed by unilateral ECT for 9 sessions, with sessions held twice weekly.	N/A.	Mild cognitive side effects, which improved after switching to unilateral treatment.	Depression and PTSD improved by 21 and 8 points respectively, as measured by the BDI-II and PCL-5. While PTSD symptoms persisted, the participant reported “having more strength to deal with them.” BMI increased from 14.7 to 17.6 kg/m².
Transcranial Direct Current Stimulation (tDCS)
Randomised Controlled Trial
van ‘t Wout-Frank et al, 2024³¹	RCT	tDCS = 26 Sham = 28	Military 6% Chronic PTSD	CAPS-5	tDCS stimulation (2-mA anodal) was applied to the VMPFC over 6 sessions, conducted during warzone VR exposure.	NR	Mild AE consistent with literature. No treatment related SAE.	Active tDCS combined with VR exposure significantly reduced self-reported PTSD symptoms, as measured by CAPS-5, at 1 month and improved psychophysiological habituation to VR events. Response definition:A clinically meaningful reduction of 10 or more points on the PCL-5. Response rates: tDCS + VR Group: 61.5% (n = 26), Sham tDCS + VR Group: 35.7% (n = 10)
van ‘t Wout-Frank et al, 2019	RCT	n = 12	Military 100% Male	PCL-5	tDCS stimulation (2-mA anodal) was applied to the VMPFC over 6 sessions, conducted during warzone VR exposure.	NR	AE: tingling, itching	Both groups experienced reductions in PTSD symptoms (PCL-5), with the active group decreasing from 41.83 to 32.5 and the sham group from 44.33 to 35.8, though differences were not statistically significant (P > .1). Response definition/rates: NR
Other Study Designs
Marcolin et al, 2023	Pre-post design	n = 8	Civilian 87.5% Female	PCL-C	tDCS stimulation (2-mA) was applied with the cathode over the right DLPFC and the anode over the contralateral deltoid muscle, administered over 10 daily sessions.	NR	AE: mild and temporary headache (n = 1), discomfort (n = 2), local hyperemia (n = 1).	PTSD symptoms improved, as indicated by a 20% reduction in the PCL-C.
Hampstead et al, 2020	Case Series	n = 5	Primarily Civilians 40% Female	CAPS	Received high-definition tDCS (2-mA) targeting the right lateral cortex, administered over 10 daily sessions over 2 weeks.	One drop out due to tinnitus (unrelated to intervention)	AE: tingling, itching	Four of the 5 participants experienced a reduction in PTSD symptoms, with CAPS total scores improving by 7% to 57%.
van ‘t Wout-Frank et al, 2017	Case Series	n = 9	Military Sex/gender NR	PCL	tDCS stimulation (2-mA anodal) was applied to the VMPFC over 6 sessions, conducted during warzone VR exposure.	NR	AE: headache (n = 1), scalp discomfort (n = 4), mood change (n = 2)	PTSD symptoms significantly decreased, as measured by the PCL, with scores dropping from 46.5 to 32.67 post-treatment and 29.33 at 1-month follow-up.
Deep Brain Stimulation (DBS)
Hamani et al, 2022³³	Pre-post design	n = 4	Civilians 100% female Mean PTSD duration: 13.0 ± 1.4 years	CAPS-5	DBS targeting the subgenual cingulate gyrus (SCG) and uncinate fasciculus (UF) guided by tractography with >100 Hz stimulation, weekly programming for 3 months, then biweekly as needed over 6 months.	None	Transient paresthesia at incision site (1 patient); discomfort at connector site (1 patient, managed with analgesics)	Average 56.2% reduction in CAPS-5 scores after 6 months (P < .05); 2 responders (87.3% reduction), 1 partial responder (35.1%), 1 non-responder. DBS targeting SCG and UF was safe and effective for treatment-resistant PTSD. Further studies with larger sample sizes recommended.
Koek et al, 2024³²	Case series	n = 2	Military 100% male; Treatment-resistant combat PTSD PTSD duration: 9 and 5.5 years	CAPS-IV	Bilateral basolateral amygdala (BLA) deep brain stimulation (DBS) with quadripolar electrodes, adjusted based on PTSD symptoms, monitored over 4 years with PET scans and EEG	None	None	CAPS-IV reduction: 55% improvement in participant 1 (from 119 to 53), 44% improvement in participant 2 (from 68 to 38) after 4 years. DBS of the amygdala was safe and associated with significant long-term symptom reduction.
Stellate Ganglion Neurostimulation
Alkire et al, 2014³⁷	Clinical study	n = 12	Military Sex/gender NR PTSD duration not specified	CAPS	Single right-sided stellate ganglion block (SGB) administered with 2% lidocaine and 0.25% bupivacaine under fluoroscopic guidance	None	None reported	CAPS scores decreased by 38% from baseline (81 ± 14) to 50 ± 23 at 1 week (P < .001) and by 45% at 1 month (44 ± 27, P < .01). Effects faded by 3 months (59 ± 24, P = .07) and returned to near baseline at 6 months (67 ± 29, P = .19). 75% of participants met responder criteria with a 59% CAPS reduction at 1 month.
Punekar & Siefferman, 2022³⁶	Case series	n = 3	Military Sex/gender NR PTSD duration not specified	PCL-5	Stellate Ganglion Peripheral Neuromodulation (SPRINT PNS): Temporary implantation of a peripheral nerve stimulator over the Stellate Ganglion for up to 60 days; implantation side based on response to prior SGB	One patient had explantation due to superficial infection	One case of superficial lead site infection (1/3 patients)	Significant improvement in PTSD symptoms, global functioning, and pain observed, with symptom worsening during treatment interruptions (”off phases”) and post-explantation.
Infrared LED treatment
Bogdanova et al, 2015³⁸	Case series	n = 3	Civilians 2 female, 1 male PTSD duration not specified	PCL-M	Noninvasive red/near-infrared (NIR) light-emitting diode (LED) therapy for enhancing cellular function in brain regions affected by chronic TBI. 2 participants received transcranial LED therapy applied to the scalp, and 1 received intranasal LED therapy through nasal passages. Each participant underwent 18 sessions (3 per week for 6 weeks).	None	NR	One participant showed a 12-point reduction in PTSD symptoms at 1 week and 19 points at 2-3 months on the PCL-M scale.
Trigeminal Nerve Stimulation (TNS)
Cook et al, 2016³⁵	Open outpatient trial	Total = 12; Age range = 18-75	Civilians 8 women, 4 men. PTSD duration of at least 6 weeks.	MINI	eTNS applied to the supraorbital and supratrochlear nerves for 8 hours each night (for 8 weeks) as an adjunct to pharmacotherapy. Parameters: 120 Hz frequency, 250 µsec pulse width, 30 seconds on/30 seconds off duty cycle. Participants adjusted the current to a setting between 2 and 4 (approximately 4-6 mA peak current) based on initial in-office assessment. Subjects maintained a daily diary to track nightly stimulation hours.	None	One participant died by suicide at week 7, but it was not determined to be treatment-related.	PCL scores significantly decreased from 63.3 (7.8) to 43.0 (18.3) (P = .003). E-TNS treatment led to significant improvements in PTSD symptoms, with effect sizes of 1.5 for PCL. E-TNS was generally well tolerated with minimal adverse events.
Vagus Nerve Stimulation (VNS)
Bremner et al, 2021³⁴	RCT	20 participants (9 in active tcVNS, 11 in sham)	Military and civilians tcVNS Group: 6 females Sham Group: 7 females PTSD duration not reported	CAPS-5 PCL	Active transcutaneous cervical Vagal Nerve Stimulation (tcVNS), administered twice daily for 3 months targeting the vagus nerve (5 kHz, 25 Hz, 2-minute sessions), followed by an additional 3-month open-label tcVNS phase.	4 participants (3 sham, 1 active tcVNS)	No significant AE reported	PTSD Symptoms (PCL): Active tcVNS group had a 31% reduction in PTSD symptoms vs. sham (P = .013). Hyperarousal Symptoms: 21% reduction in hyperarousal symptoms (P = .008) in the active tcVNS group. tcVNS shows promise for reducing PTSD symptoms, especially hyperarousal and anxiety, and modulating inflammatory response to stress. Response definition/rates: NR

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AE, adverse events; AUD, alcohol use disorder; BDI, Beck’s Depression Inventory; BLA, Bilateral basolateral amygdala; BMI, Body Mass Index; BNCE, Brief Neuropsychological Cognitive Examination; CAPS, Clinician-Administered PTSD Scale; CAPS-5, Clinician-Administered PTSD Scale for DSM-5; CGI-S, Clinical Global Impression Scale; CPT, cognitive processing therapy; cTBS, continuous theta burst stimulation; DBS, deep brain stimulation; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DSM-5, Diagnostic and Statistical Manual of Mental Illnesses fifth edition; DSM-IV, Diagnostic and Statistical Manual of Mental Illnesses fourth edition; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Illnesses fourth edition text revision; dTMS, deep repetitive transcranial magnetic stimulation; DTMS+BE-NTE, deep repetitive transcranial magnetic stimulation with brief exposure therapy to a non-traumatic event; DTMS+BE-TE, deep repetitive transcranial magnetic stimulation with brief exposure therapy to a traumatic event; DTS, Davidson Trauma Scale; ECT, electroconvulsive therapy; ECT-NR, electroconvulsive therapy with neutral memory retrieval; ECT-TR, electroconvulsive therapy with traumatic memory retrieval; EEG, electroencephalogram; eTNS, external trigeminal nerve stimulation; FMRI, Functional magnetic resonance imaging; HF-rTMS, high frequency repetitive transcranial magnetic stimulation; Hz, hertz; IES, Impact of Events Scale; IES-R, Impact of Events Scale revised; iTBS, intermittent theta busrt stimulation; LAP-ST, Low Amplitude Seizure Therapy; LED, light-emitting diode; LF-rTMS, low field repetitive transcranial magnetic stimulation; mA, milliampere; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder; MINI, Mini International Neuropsychiatric Interview; MISS, Mississippi Scale for Combat-Related PTSD; MPSS, Modified PTSD Symptom Scale; MT, Motor threshold; N, sample size; N/A., Not applicable; NIR, Noninvasive red/near infrared; NR, not reported; PCL-C, PTSD Checklist for DSM-5 Civilians version; PCL-M, PTSD Checklist for DSM-5 Military version; PTSD, posttraumatic stress disorder; QIDS, Quick Inventory of depressive symptomology; RCT, randomized controlled trial; rTMS, repetitive transcranial magnetic stimulation; rTMS+BE, repetitive transcranial magnetic stimulation with brief exposure therapy; RUL, right unilateral; SAE, serious adverse events; SCG, subgenual cingulate gyrus; SCID, Structured Clinical Interview for DSM; SCL-90, Symptom Checklist 90; SGB, stellate ganglion block; Sham+BE-TE, sham deep repetitive transcranial magnetic stimulation with brief exposure therapy to a traumatic event; TBI, traumatic brain injury; tcVNS, transcutaneous cervical Vagal Nerve Stimulation; tDCS, transcranial direct current stimulation; TNS, trigeminal nerve stimulation; TRD, treatment resistant depression; TR-PTSD, treatment resistant posttraumatic stress disorder; UF, uncinate fasciculus; VMPFC, ventromedial prefrontal cortex; VR, virtual reality.

Table 2.

Pharmacological Interventions

Author & Year	Study Design	Sample Size	Participants	PTSD Diagnosis	Intervention Description	Drop Outs	Adverse Events	Main Findings
Ketamine (IV KET, ESK and KAP)
Randomised Controlled Trials
Abdallah et al, 2022⁴³	RCT KET	N = 158 (Placebo: 54, Low dose KET: 53, Standard dose: 51)	Military 23% Female PTSD duration not specified	CAPS-5, PCL-5	Low (0.2 mg/kg) and standard doses (0.5 mg/kg) of IV KET biweekly for 4 weeks; placebo group received normal saline.	Placebo group: 19% dropped, Low dose: 15%, Standard dose: 16%; specific reasons not provided;	87% of participants reported adverse events (e.g., agitation, anxiety, headache, nausea).	No significant treatment-by-time effect on PTSD symptoms (PCL-5). Response definition: A ≥25% reduction in CAPS-5 scores from baseline. Response rates: IV KET 0.2 mg/kg: 47.00% (n = 25) IV KET 0.5 mg/kg: 47.00% (n = 24) MDZ 0.045 mg/kg: 33% (n = 18)
Dadabayev et al, 2020⁴²	RCT KET	N = 41, divided into 4 groups: CP + PTSD with KET: 11; CP+PTSD with ketorolac: 10; CP with KET: 10; CP with ketorolac: 10	Age range: 29-65 years; CP+PTSD (KET): 4 female, CP+PTSD (ketorolac): 4 female; CP (KET): 1 female; CP (ketorolac): 1 Female.	CAPS-5	IV KET (0.5 mg/kg over 40 minutes) or IV ketorolac (15 mg over 40 minutes).	2 participants (1 from CP+PTSD receiving KET due to unrelated medical emergency; 1 from CP+PTSD receiving ketorolac who was lost to follow-up)	Minimal side effects; dissociative symptoms reported in CP group for both KET and ketorolac, fewer dissociative symptoms in CP+PTSD group.	Both KET and ketorolac significantly reduced PTSD and CP symptoms, lasting up to 7 days post-infusion. Significant PTSD symptom reduction (IES-R) from baseline to Day 1 (P < .05) and Day 7 (P < .01); greater pain reduction in CP+PTSD than CP alone by Day 7 (P < .001). Response definition/rates:NR
Feder et al, 2023⁴⁰	RCT KET	n = 30 (KET: 15, MDZ: 15)	Military and Civilian 86.7% Female (KET) 66.7% Female (MDZ) PTSD duration: mean 15.1 years	CAPS-5, (score ≥30 for inclusion)	IV KET infusion (0.5 mg/kg, administered 6 times over 2 weeks, 40-minute infusions, 3x/week); MDZ (0.045 mg/kg IV) as active placebo with the same schedule	1 participant withdrew from the KET group after 2 infusions due to worsening symptoms	Side effects in the KET group: blurred vision (53%), dizziness (33%), fatigue (33%), headache (27%), nausea (20%)	CAPS-5 showed significant improvement (mean difference of 11.88 points, P = .004); 67% response rate in the KET group vs. 20% in placebo. Response definition: ≥30% reduction in CAPS-5scores from baseline Response rates: IV KET 0.5 mg/kg: 67.00% (n = 10) MDZ 0.045 mg/kg: 20% (n = 3)
Feder et al, 2014⁴¹	RCT KET	n = 41 total; KET group: 22 participants (received KET first), MDZ group: 19 participants (received MDZ first)	Civilian; 59.1% Female (KET), 31.6% Female (MDZ); PTSD duration: Not specified	CAPS SCID-I–Patient Version	Participants received a single IV infusion of KET (0.5 mg/kg) or MDZ (0.045 mg/kg) over 40 minutes, with a 2-week washout period before crossing over to the alternate treatment.	0 dropouts reported	Common adverse events for KET included transient dissociative symptoms (69%), blurred vision (36%), dry mouth (21%), restlessness (23%), and nausea/vomiting (21%). Blood pressure elevation requiring β-blockers occurred in 3 participants.	KET group showed a significant reduction in PTSD symptoms 24 hours post-infusion compared to MDZ (mean difference in IES-R score = 12.7, P = .02). Response definition: CAPS score <50 at 2 weeks post-infusion Response rates: IV KET 0.5 mg/kg: 31.80% (n = 7) MDZ 0.045 mg/kg: 5.30% (n = 1)
Other Study Designs
IV KET
Albott et al, 2018⁴⁴	Pre-post test IV KET	n = 15	Military Comorbid PTSD and TRD 5 Female PTSD duration: mean 26.1 ± 18.4 years	CAPS-5	6 infusions of IV KET (0.5 mg/kg) over 12 days	1 participant withdrew for personal reasons; 1 excluded due to protocol changes; 2 withdrew before starting treatment	3 participants treated for blood pressure elevation; transient dissociative symptoms resolved post-infusion	Significant reductions in PTSD symptoms (CAPS-5 score reduction of 33.3 points, P < .0005) .
Highland et al, 2020⁴⁵	Matched Cohort IV KET	n = 1158 total (KET group: 107; Full-sample non-KET group: 1,051; 1:1 matched non-KET group: 107; 1:4 matched non-KET group: 428)	Military 100% male PTSD duration not specified	PTSD Checklist (PCL) with score ≥44	KET administered perioperatively as part of inpatient medical care for combat-related injuries; specific dose, frequency, and duration not detailed	NR	No significant adverse events associated with KET administration reported	No significant differences in PTSD screening risk or symptom levels between KET-exposed and non-KET groups.
Ross et al, 2019⁴⁷	Case Series IV KET	n = 30	Military Sex distribution not specified Duration of PTSD not specified.	PCL-5	Six 1-hour high-dose KET infusions over 2-3 weeks; starting dose 1 mg/kg (maximum of 60 mg), individualized to achieve psychotropic therapeutic response.	NR	Minor adverse events like nausea; no significant adverse events or vital sign abnormalities observed.	PCL-5 scores reduced by 44% (from 56.2 to 31.3; Cohen’s d = 1.42, P < .001).
Lipov et al, 2023⁴⁴	Case Report IV KET	n = 1	Military Male PTSD duration >10 years (since combat deployments, 2004-2014)	PCL-5	IV KET: 5 subanesthetic infusions starting at 0.5 mg/kg, escalating daily; CSB on both sides with bupivacaine.	Not applicable	No adverse events reported	Significant reductions in PTSD (73.8% reduction in PCL-5).
Esketamine
Artin et al, 2022⁴⁸	Retrospective case series ESK	n = 35	Military comorbid TRD and PTSD 10 Female Mean PTSD duration 15.5 ± 7.9 years	PCL-5 (score >33)	IN ESK, 56-84 mg, administered biweekly for 4 weeks (8 treatments), followed by weekly or less frequent doses	NR	No serious adverse events; side effects not specified in detail	Significant reduction in PTSD symptoms (PCL-5 mean reduction of 15.5 points, P = 2e-7); 46% achieved a clinically meaningful reduction in PTSD symptoms.
Bentley et al, 2022⁴⁹	Retrospective chart review ESK/ IV KET	n = 15	Military Comorbid TRD and PTSD 7 Female, PTSD duration not specified	PCL-5	IN ESK (56-84 mg) for 3 sessions; switched to IV (R,S)-KET (0.5 mg/kg to 1 mg/kg) for poor responders	1 participant (excluded due to incomplete PHQ-9 data after 1 IV-KET session)	No systematic review of side effects; adverse events were not systematically tracked	Significant decrease in PTSD symptoms (PCL-5, reduction of 11.8 points, P = .03).
Nokes et al, 2023⁵⁰	Retrospective Analysis ESK	n = 24	Military with treatment-refractory PTSD; 20.8% female; all had PTSD unresponsive to 2 medications in the past 2 years.	PCL-5	IN ESK, twice weekly for 4 weeks, then weekly (mean total doses = 8.3).	NR	Not reported	Significant PTSD symptom reduction with each ESK dose (β = −0.95; P < .001).
KET-AT
Rothamel et al, 2022	Pre-post test ESK-AT	n = 11	Civilian; 9 females Chronic PTSD with comorbid TRD	CAPS-5	IN ESK (56 or 84 mg) was given twice weekly for a month, then weekly to biweekly over 6 months, with optional CBT or EMDR for some patients to assess effects on depression and PTSD.	3 (27%) - reasons included remission, travel issues, and lack of efficacy.	Dissociation (7), somnolence (4), nausea (4), sedation (3), dizziness (3), anxiety (2), increased blood pressure (1); no serious adverse events reported.	PTSD symptoms improved for those in trauma-focused therapy, with a mean PCL-5 reduction of 45.3%.
Shiroma et al, 2020⁵⁹	Pre-post test IV KET-AT	n = 12 (10 completed treatment)	Military Sex distribution not specified Chronic PTSD (>6 months)	CAPS-5 PCL-5	Veterans received 0.5 mg/kg IV KET 24 hours before weekly PE therapy for 3 weeks, followed by up to 7 additional PE sessions over 10 weeks.	2 participants (reasons not specified)	None reported	Significant reduction in PTSD symptoms (CAPS-5 and PCL-5).
Robison et al, 2024⁶²	Case Series KET-AT (SL, IM)	n = 10	Civilians Comorbid burnout 50% female PTSD duration not specified.	PCL-5	Six group therapy sessions over 3 weeks: 1 preparation session, 3 KET dosing sessions (2 SL, 1 IM), and 2 integration sessions.	NR	No significant adverse events reported; KET well tolerated.	Significant reduction in PTSD (PCL-5: 59%). At post-treatment, 100% screened negative for PTSD.
Rohde et al, 2024⁶¹	Case Series IN KET-AT	n = 3	Civilian all female chronic PTSD (>6 months)	CAPS-5	Eight-week program combining weekly nasal (R,S)-KET (0.5 mg/kg) followed by trauma-focused psychotherapy 24 hours later, including cognitive restructuring and exposure.	NR	Mild side effects: tension, anxiety, body sensation, headaches; no severe adverse events.	Significant reduction in PTSD symptoms (CAPS-5 mean reduction: −18.00 at post-assessment, −25.33 at follow-up). Well-tolerated, suggesting potential for combined KET and psychotherapy.
Dames et al, 2021⁶⁰	Cohort KET-AT (PO, IM)	n = 94 (across 3 cohorts)	Civilians Sex distribution and PTSD duration not specified	PCL-5	KET-AT within a 12-week CoP model, including 3 sessions (PO lozenge and IM), weekly CoP sessions. This program curriculum is designed to enhance resilience and personal growth by fostering authentic self-expression and connection among participants. It emphasizes healing through secure attachments and emotional regulation within a supportive environment.	NR	Not reported	79% improved in depression, 86% transitioned from positive to negative PTSD screening.
3,4-methylenedioxymethamphetamine (MDMA)
MDMA-AT
Randomised Controlled Trials
Bouso et al, 2008⁵⁷	RCT	n = 6 (Low dose MDMA: 3, Placebo: 3)	All female, ages 29-49; Civilian population, chronic PTSD secondary to sexual assault	SCID-IV	MDMA-assisted psychotherapy with a single session (50 mg or 75 mg MDMA) and 3 preparatory and 3 integration sessions.	NR	Mild side effects, including concentration difficulties, asthenia, and palpitations in 2 participants.	MDMA was safe and showed potential in reducing PTSD symptoms. The 75 mg dose showed the most symptom improvement; all participants experienced some symptom reduction. Further studies needed. Response definition/rates:NR
Gorman et al, 2020⁵³	RCT	n = 60 (45 active MDMA dose, 15 placebo)	Civilian 29 women Active MDMA group PTSD duration 234.5 months Control 145.9 months	CAPS-IV	MDMA-assisted therapy with 75-125 mg MDMA in 2 sessions, scheduled 3-5 weeks apart, with an optional supplemental dose (half the initial dose).	NR	No serious adverse events or substance misuse reported.	Significant improvements in PTSD symptoms in the MDMA group; 67.3% no longer met PTSD criteria at 12-month follow-up (P < .001). Response definition/rates:NR
Mitchell et al, 2023⁵¹	RCT	n = 104 (MDMA-AT = 53, placebo with therapy = 51)	Military and civilians 71.2% female. PTSD duration: Mean = 16.2 years (SD = 13.3)	CAPS-5	MDMA-AT: Three 8-hour therapy sessions with MDMA, each followed by 3 90-minute integration therapy sessions. MDMA given in split doses: initial dose of 80 mg with 40 mg supplemental dose in the first session, 120 mg with 60 mg supplemental in later sessions.	9 participants (MDMA-AT: 1, placebo: 8)	MDMA-AT group: Muscle tightness, nausea, hyperhidrosis; 5 severe treatment-emergent adverse events. Placebo group: 2 severe adverse events, 3.9% incidence.	Significant PTSD symptom reduction in MDMA-AT group (CAPS-5 score reduction: MDMA-AT mean = −23.7; placebo mean = −14.8, P < .001). 71.2% of MDMA-AT group no longer met PTSD criteria at study end. Response definition: ≥10-point reduction from baseline in CAPS-5 score. Response rate: MDMA-AT group: 86.5% (n = 45) Placebo: 69.0% (n = 29)
Mitchell et al, 2023⁵¹	RCT	n = 89	Not specified	CAPS-5, score ≥ 25	MDMA was administered 3 times at monthly intervals in conjunction with integrative therapy; the placebo group received a placebo plus therapy with an identical structure.	NR	Not specified, though MDMA indicated improved patient safety.	MDMA-therapy significantly reduced CAPS-5 scores compared to placebo (P < .0001, d = 0.91). Participants with dissociative PTSD showed reductions similar to non-dissociative PTSD participants. Response definition/rates:NR
Mitchell et al, 2023⁵¹	RCT	n = 90 (MDMA group = 46, placebo group = 44)	Military and civilians MDMA group: 27 female; Placebo group: 32 female. Duration of PTSD: MDMA group: Mean = 14.8 years (s.d. 11.6) 11.6); Placebo group: Mean = 13.2 years (s.d. 11.4)	CAPS-5	MDMA-assisted therapy: Three 8-hour therapy sessions with MDMA; 3 preparatory sessions and 9 integrative therapy sessions. Placebo group received identical therapy sessions but with placebo instead of MDMA.	NR	MDMA group: Transient and mild/moderate muscle tightness, nausea, hyperhidrosis, feeling cold. Placebo group: 2 serious adverse events (suicidal ideation and suicidal behavior).	MDMA significantly reduced PTSD symptom severity (mean CAPS-5 reduction: MDMA group = −24.4, placebo group = −13.9, P < .0001). Response definition/rates:NR
Mitchell et al, 2019	RCT	n = 36	Civilian with treatment-resistant PTSD; 17 female Duration of PTSD not specified	CAPS with a score >34	Participants received 3 doses of MDMA (80 or 120 mg, with an optional half-dose after 1.5-2 hours) during 8-hour psychotherapy sessions at monthly intervals. Three preparatory psychotherapy sessions were held before the MDMA doses, and psychiatric medications were discontinued before the first experimental session.	NR	NR	Significant reduction in CAPS scores from baseline (45.67) to post-treatment (16.03) after the third MDMA dose (P < .0001). MDMA-assisted psychotherapy led to significant reductions in PTSD symptoms, with no notable difference in response based on early life trauma or sex. Response definition/rates:NR
Mithoeferet et al, 2018	RCT	n = 26 (30 mg: 7, 75 mg: 7, 125 mg: 12)	Military Sex distribution not reported PTSD duration not specified	CAPS-IV	Two MDMA-assisted sessions (30 mg, 75 mg, or 125 mg), 3-5 weeks apart, with half-dose supplemental. 3 integration sessions followed each MDMA session.	2 (8%): adverse event, felt further MDMA unnecessary	85 adverse events in total: anxiety, headache, muscle tension; no serious drug-related adverse events.	Significant reduction in PTSD symptoms in 75 mg and 125 mg groups (P = .0005 for 75 mg group); MDMA effective and well-tolerated for veterans and first responders. Response definition: ≥30% decrease in CAPS-IV total score. Response rate: 30 mg MDMA group: 29% (n = 2) 75 mg MDMA group: 100% (n = 7) 125 mg MDMA group: 67% (n = 8)
Mithoeferet al, 2011	RCT	n = 20 (12 MDMA, 8 placebo)	Civilian with chronic PTSD 85% female; PTSDPTSD 85% female; PTSD duration >19 years	CAPS	MDMA-assisted psychotherapy with 2 MDMA sessions (125 mg initial, with 62.5 mg supplemental dose); sessions followed supportive therapy protocol.	2 (relapse of depression, travel issues)	Tight jaw (79% MDMA), nausea (50% MDMA), insomnia, fatigue, low mood.	MDMA group had significant PTSD symptom reduction compared to placebo (P = .015); well-tolerated with no serious adverse effects. Response definition: >30% reduction from baseline in CAPS total severity score. Response rate: MDMA group: 83.3% (n = 10) Placebo group: 25% (n = 2)
Oehen et al, 2013⁵⁵	RCT	n = 12 (Full-dose group: 8, Active placebo group: 4)	Civilian 83% Female Mean duration of PTSD of 18.3 years (SD 12)	CAPS-IV	Each participant in the full-dose group received 125 mg of MDMA followed by a 62.5 mg supplemental dose 2.5 hours later during 3 experimental psychotherapy sessions. 2 preparatory psychotherapy sessions were conducted before the first MDMA session, followed by 12 non-drug integration sessions. Participants in the active placebo group received 25 mg of MDMA followed by a 12.5 mg supplemental dose as an active placebo.	2 participants (16.6%) dropped out after the first session due to stress and cultural adjustment issues.	Common reactions included insomnia (43% in the MDMA group), anxiety (27%), and loss of appetite (41%). No serious drug-related adverse events were reported.	CAPS score reduction in the full-dose group was 23.5% (15.6 points) but was not statistically significant (P = .066). Three MDMA sessions were more effective than 2 (P = Response definition: ≥30% reduction in CAPS scores Response rate: 125 mg: 50% (n = 4) 25 mg: 0%
Ot’alora et al, 2018⁵⁴	RCT	n = 28 (40 mg: 6, 100 mg: 9, 125 mg: 13)	Civilian 68% female PTSD duration: Mean 29.4 years	CAPS-IV	MDMA-assisted therapy (40 mg, 100 mg, or 125 mg), with optional half-dose supplemental, 3 integration sessions after each MDMA session.	1 (large response excluded from PP analysis)	Mild/moderate events: anxiety (60.7%), jaw clenching (64.3%), fatigue (39.3%), dizziness (42.9%), headache (46.4%); no serious events.	Significant PTSD symptom reduction in 125 mg group compared to 40 mg (P = .01); CAPS-IV scores improved significantly at 12-month follow-up. Response definition:A ≥30% reduction in CAPS-IV total score Response rate: 40 mg group: 16.7% (n = 1), 100 mg group: 55.6% (n = 5), 125 mg group: 50.0% (n = 6)
Ponte et al, 2021⁵²	RCT	n = 63 (Active MDMA: 47, Placebo/Low Dose: 16)	Military and civilians Chronic PTSD with treatment resistance 54% male Mean PTSD duration 225.3 months	CAPS-IV	MDMA-assisted psychotherapy (75-125 mg) with 2-3 sessions, optional half-dose. Integration therapy sessions followed each MDMA session.	NR	Insomnia during sessions: 47% MDMA, 36% control.	Significant CAPS-IV reduction (P = .003) and PSQI improvement in MDMA group vs control; improvements in sleep quality sustained at 12-month follow-up. Response definition/rates:NR
Other Study Designs
Jardim et al, 2021	Pre-Post test	n = 3	Civilian 2 female PTSD duration at least 6 months	CAPS-IV	MDMA-assisted psychotherapy with 3 MDMA sessions (75-125 mg, with optional supplemental dose), 3 integration sessions after each MDMA session.	NR	Somatic pain, anxiety, fatigue common; 54 events during preparatory, 20 during MDMA, 73 during integration sessions.	Significant reductions in CAPS-IV scores (29-64 points)
Monson et al, 2020	Pre-Post test	n = 6 couples (12 participants in total)	Civilians Patients: 4 male, Partners: 2 male; Minimum of 6 months PTSD duration	CAPS-5	15 sessions of Cognitive-Behavioral Conjoint Therapy (CBCT) for PTSD delivered over 7 weeks. 2 sessions included MDMA administration (75 mg in the first session, 100 mg in the second session, with optional supplemental doses after 1.5 hours). Sessions were conducted in-person and via video calls, with MDMA sessions facilitated by expert therapists in both MDMA and CBCT.	NR	Common adverse events included diminished appetite, anxiety, headache, and jaw tightness. No serious adverse events reported.	Significant improvements in PTSD symptoms for patients (d = 2.10-3.59) and partners (d = 1.85-2.72). MDMA-facilitated CBCT for PTSD demonstrated benefits in PTSD and related symptoms for both patients and partners.
Mithoeferet al, 2013	Longitudinal	n = 19	Civilians 16 women Treatment resistant PTSD Mean PTSD duration before treatment: over 19 years	CAPS	MDMA-assisted psychotherapy (2 to 3 sessions of MDMA plus supportive psychotherapy); MDMA dose: 125 mg with a supplemental 62.5 mg dose 2-3 hours later during each session. Therapy sessions lasted 8 hours in a supportive, non-directive environment. Weekly non-drug psychotherapy sessions were provided between MDMA sessions. Follow-up sessions and long-term monitoring continued after treatment, with some participants receiving ongoing psychotherapy or medication for support.	3 did not complete all follow-up measures but provided LTFU data	No drug-related serious adverse events; no substance abuse or drug dependency reported.	At long-term follow-up (17-74 months post-treatment, mean = 45.4 months), PTSD symptom reduction was durable, with no significant differences between CAPS scores at study exit and long-term follow-up. 13% relapsed with moderate-to-severe PTSD symptoms; most participants maintained symptom reduction, reporting improved well-being, reduced avoidance, better sleep, and enhanced relationships.
Cannabis
Bonn-Miller et al, 2022	longitudinal	n = 150 (Cannabis users: n = 75, Controls: n = 75)	Military 73% male PTSD duration not specified	CAPS-5	Cannabis users accessed dispensary-obtained cannabis, primarily THC-dominant strains, with varying usage frequency over 1 year. Control group had no cannabis use for the last 6 months.	33% attrition (more males and veterans in the control group)	NR	Cannabis users showed a greater reduction in PTSD symptoms over time (P = .02) and were 2.57 times more likely to no longer meet PTSD criteria (P = .03).
Greer et al, 2014	Retrospective chart review	n = 80	All adults above 18 years; civilian population; PTSD duration not specified	CAPS-IV	Participants used medical cannabis. CAPS scores were analyzed retrospectively during periods of cannabis use vs. no-cannabis use. Usage frequency was self-reported but not specified.	NR	NR	Significant reduction in total CAPS scores with cannabis use vs. no-cannabis use (F(1,79) = 1119.55, P < .0001).
Ibogaine, 5-MeO-DMT, and Ayahuasca
Davis et al, 2020	Pre-post test	n = 51	Military 96% male PTSD duration not specified	PCL-5	Psychedelic-assisted therapy with ibogaine and 5-MeO-DMT over 3 days. Day 1: ibogaine 10 mg/kg orally; Day 3: 5-MeO-DMT, inhaled, total 50 mg with incremental doses; integration sessions followed each treatment	NR	NR	Significant reductions in PTSD (d = −3.6).
Ragnhildstveit et al, 2023	Case report	n = 1	Civilian Female chronic PTSD resistant to first- and second-line treatments; symptoms present for several years	SCID-5 PCL-5	Single dose of vaporized bufotoxin (10-15 mg of 5-MeO-DMT) administered in a home setting with a facilitator; follow-up at 24 hours, 1 month, 3 months, 6 months, and 12 months	NR	Mild nausea, onset of night terrors at 3 months	Clinically significant improvements in PTSD, hopelessness, and suicide risk sustained at all follow-ups. Strong mystical experience reported. Night terrors onset at 3 months but remained below clinical thresholds. months.
Weiss et al, 2023	case series	n = 8	Military 100% male Duration of PTSD not reported	PCL-5	3-day ayahuasca retreat in Costa Rica with 3 ceremonies (130 ml of ayahuasca per ceremony) held on consecutive evenings in a Shipibo-style maloca, guided by shamans with icaro prayers.	1 participant (12.5%) did not attend 2 ceremonies	57% experienced mystical states; 50% experienced distress; 1 participant reported an extreme negative experience without lasting effects	71.4% of participants showed reliable reductions in PTSD symptoms post-treatment, with benefits sustained at the 3-month follow-up. Significant reductions in PTSD, negative affect, and positive affect were reported in daily life.

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5-MeO-DMT, 5-methoxy-N,N-dimethyltryptamine; CAPS-IV/CAPS-5, Clinician-Administered PTSD Scale for DSM-IV/DSM-5; CoP, community of practice; CP, chronic pain; CSB, cervical sympathetic blockade; ESK, esketamine; ESK-AT, esketamine-assisted therapy; IM, intramuscular; IN, intranasal; IV, intravenous; KET, ketamine; KET-AT, KET-assisted therapy; LTFU, long-term follow-up; MDMA, 3,4-methylenedioxymethamphetamine; MDMA-AT, MDMA-assisted therapy; MDZ, midazolam; NR, not reported; PCL-5, PTSD checklist for DSM-5; PE, Prolonged exposure therapy; PHQ-9, PHQ-9 (Patient Health Questionnaire-9); PO, oral; PTSD, posttraumatic stress disorder (R,S)-KET, racemic ketamine; RCT, randomized controlled trial; SCID-IV, structured clinical interview for DSM-IV; SL, sublingual; THC, tetrahydrocannabinol; TRD, treatment-resistant depression; TR-PTSD, treatment-resistant PTSD.

Registered Clinical Trials

A total of 128 registered clinical trial protocols were identified, of which 47 focused on TMS, 32 on intravenous IV-KET, 35 on MDMA, 10 on TDCS, 2 on ECT, and 2 on Ketamine. Other interventions included ESK and ECT with 2 trials each, and tDCS with 10 trials. The trials primarily included both male and female participants (n = 120, 94%). In terms of study status, there were 8 active trials, 54 completed studies, 28 recruiting, and 2 currently enrolling participants. Furthermore, 12 trials were not yet recruiting, 7 were terminated, 5 withdrawn, 1 no longer available, and 11 had an unknown status. The research was geographically diverse, with the United States leading with 89 trials (Figure 4).

Figure 4. — Countries and trial status presented by most frequent intervention. Panel A) Countries. Panel B) Trial status. Results in each panel are presented as frequency values. Abbreviations: ECT, electroconvulsive therapy; IV KET, intravenous ketamine; MDMA, 3,4-methylenedioxymethamphetamine; RGCT, registered clinical trial; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.

Neuromodulation

Transcranial Magnetic Stimulation:

Thirty-nine articles examined TMS as a treatment for PTSD, of which 22 were RCTs. The studies investigated 3 main TMS protocols: high-frequency repetitive TMS (HF-rTMS; n = 21), low-frequency rTMS (LF-rTMS; n = 15), and theta burst stimulation (TBS; n = 10). 3 articles did not specify the TMS protocol used.

High frequency repetitive transcranial magnetic stimulation protocols utilized frequencies ranging from 5-20 Hz, delivered over 5-60 sessions across 1-12 weeks. Of these studies, 8 targeted the left dorsolateral prefrontal cortex (L-DLPFC), 7 targeted the right DLPFC (R-DLPFC), 2 stimulated bilaterally (DLPFC or medial PFC), and 2 targeted the dorsomedial PFC. One of the studies compared stimulation of the left and right DLPFC, and another compared bilateral stimulation to right-sided DLPFC stimulation. RCT response rates ranged from 12.5% to 80%, while sham group responses varied from 0% to 55% (Figure 5).

Figure 5. — Response rates reported in TMS, IV KET, and MDMA randomized controlled trials that included response rate data. Abbreviations: BE, brief exposure; BL, bilateral; DTMS, deep transcranial magnetic stimulation; HF-TMS (RU), high-frequency repetitive transcranial magnetic stimulation (right unilateral); IV KET, intravenous ketamine; LF-TMS (RU), low-frequency repetitive transcranial magnetic stimulation (right unilateral); MDMA, 3,4-methylenedioxymethamphetamine; MDZ, midazolam; mg/kg, milligrams per kilogram; TE: therapy; TMS, transcranial magnetic stimulation.

Low frequency repetitive transcranial magnetic stimulation primarily used a frequency of 1 Hz, with treatment sessions ranging from 1-30 over 1-12 weeks. Among these studies, 11 focused on the R-DLPFC, while single studies targeted the R-PFC, the L-DLPFC, and bilateral stimulation of the motor cortex. Randomized controlled trials response rates ranged from 25% to 39% (Figure 5).

Theta burst stimulation protocols utilized a 50 Hz burst repeated at a 5 Hz frequency. While all studies employed intermittent TBS (iTBS), 2 studies implemented a sequential approach, starting with continuous TBS (cTBS) followed by iTBS. Treatment durations ranged from 2-6 weeks with 10-30 sessions. Three studies targeted the R-DLPFC, 3 applied bilateral stimulation, 2 targeted the L-DLPFC, 1 stimulated the DMPFC, and 1 compared DLPFC to subgenual anterior cingulate cortex stimulation.

Of the 22 RCTs, 6 examined HF-rTMS, 6 focused on LF-rTMS, 4 investigated iTBS, 5 compared low- to high-frequency rTMS, and 1 compared HF-rTMS to iTBS. Overall, TMS significantly reduced PTSD symptoms, measured by scales like CAPS and PCL, compared to sham (response rates: 12.5-80%). Only 1 study reported that TMS was not more effective than sham. In this study, deep TMS combined with adjunct script-driven imagery was compared to a sham condition that also included script-driven imagery. Interestingly, the sham group showed a higher response rate (68% [n = 44/65]) compared to the deep TMS group (53.8% [n = 32/60]).¹⁹

Transcranial magnetic stimulation was generally well-tolerated across protocols. Seventeen studies reported no treatment-related adverse events, while others noted mostly mild, transient effects like headaches, dizziness, scalp discomfort, nausea, pain at the treatment site, and muscle contractions. Rarely reported adverse events included diarrhea, vomiting, neck pain, rage episodes, ear discomfort, changes in blood pressure, and warmth near the treatment site, typically in single studies.

Serious adverse events were reported in 8 articles, affecting a small fraction of participants, with suicidal ideation being a notable concern. Thierrée et al²⁰ conducted an RCT (n = 38) and reported suicidal thoughts in participants receiving both low- and high-frequency rTMS, although the exact number of affected individuals was not specified. Similarly, Isserles et al,¹⁹ in an RCT involving 125 participants (60 participants in the deep TMS group), found that participants undergoing deep HF-rTMS experienced serious events: 3 had moderate to severe anxiety, 1 developed suicidal ideation, and 1 attempted suicide while intoxicated with alcohol. Bozzay et al²¹, in an RCT with 50 participants (25 in each group), observed that 1 participant receiving iTBS treatment developed suicidal ideation; notably, this participant had comorbid alcohol use disorder (AUD), and patients with comorbid AUD exhibited a higher frequency of adverse events overall. Leong et al²² reported in their RCT (n = 31; 11 participants in the low-frequency group) that 1 participant receiving low-frequency rTMS experienced suicidal ideation. Additionally, Carpenter et al²³, using a pre-post test study design with 35 participants, noted worsening symptoms in 3 cases and suicidal ideation in 4 cases among participants receiving HF-rTMS.

Other serious adverse events included seizures and mood disturbances. For instance, in an RCT performed by Isserles et al²⁴, involving 30 participants (10 in each group), 1 patient undergoing deep HF-rTMS experienced a short tonic-clonic generalized seizure. Similarly, Thierrée et al²⁰ reported 1 case of psychogenic nonepileptic seizure in the LF-rTMS group (1 Hz, motor threshold = 70%). Mood disturbances were also observed in a study by Cohen et al²⁵, where in a sample of 24 participants, 1 patient in the HF-rTMS group and another in the LF-rTMS group experienced manic episodes. Furthermore, Grisaru et al²⁶, in a pre-post design study with 10 participants, reported that a patient receiving LF-rTMS developed intrusive thoughts.

Electroconvulsive Therapy:

Electroconvulsive Therapy was evaluated in 8 articles, including 3 RCTs. The initial treatment course generally involved 6 sessions (range: 6-12). Bitemporal ECT was used in 3 studies, right unilateral ECT in 2, bifrontal ECT in 1, bilateral ECT in 1, and 1 study began with right unilateral ECT before switching to bitemporal.

The 3 RCTs found that ECT was able to reduce PTSD symptoms. Two studies examined the impact of memory activation prior to ECT, with 1 finding that traumatic memory activation led to greater PTSD symptom reduction,²⁷ while the other observed no additional benefit from this approach.²⁸ The third RCT compared ECT with low-amplitude seizure therapy (LAPST) and found both treatments effective in reducing PTSD symptoms, with a PCL score reduction of 8.5 in the LAPST group and 23.7 in the ECT group.²⁹

Regarding ECT tolerability, 2 studies reported temporary mild cognitive impairment post-treatment, with no long-term adverse effects observed. An 8-year follow-up study found significantly lower suicide rates (2% [n = 2/92] vs. 5.9% [n = 201/2634]) and overall mortality (9.7% [n = 9/92] vs. 18% [n = 612/3393]) among participants who received ECT, suggesting a protective effect beyond symptom reduction.³⁰ However, as 5 studies did not report adverse events, conclusions on ECT’s safety for PTSD remain cautious.

Transcranial Direct Current Stimulation:

Five studies evaluated the effectiveness and safety of tDCS for PTSD treatment, 2 of which were RCTs, all using a stimulation amplitude of 2 mA and providing between 6 and 10 treatment sessions. Each study found tDCS to be effective in reducing PTSD symptoms, with CAPS or PCL scores showing reductions ranging from 7% to 57%. Three of these studies combined tDCS with exposure-based therapy using virtual reality (VR) to present war-related visuals, and all reported that this combined intervention reduced PTSD symptoms as measured by the PCL or CAPS.

Across the studies, tDCS was well tolerated, with most side effects being mild and transient, including local hyperemia, discomfort, scalp itching, tingling, headaches, and occasional mood changes. No serious adverse events were directly associated with tDCS. However, 1 participant in the sham group, who received VR exposure-based therapy combined with sham tDCS, reported experiencing suicidal ideation.³¹

Other Neuromodulation Treatments

Seven studies explored various neuromodulation treatments for PTSD, including DBS, VNS, TNS, SGNM, and infrared light therapy, generally reporting significant PTSD symptom reductions. In DBS studies, Koek et al³² and Hamani et al³³ showed symptom reductions of up to 49.5% and 56.2%, respectively, with minimal side effects. VNS, studied by Bremner et al³⁴, significantly reduced PTSD symptoms with no adverse effects. TNS, used by Cook et al³⁵ alongside pharmacotherapy, also showed substantial PTSD and depression symptom improvements without serious side effects. SGNM studies revealed mixed outcomes: Punekar and Siefferman³⁶ noted significant improvements but required device removal due to infection, while Alkire et al³⁵ observed sustained symptom reduction from a single stellate ganglion block. Lastly, Bogdanova et al³⁸ found that LED therapy improved sleep, cognition, and PTSD symptoms without adverse effects.

Novel Pharmacotherapies

Ketamine:

This review encompasses 14 studies investigating the efficacy of KET for PTSD, including both IV (n = 8) and intranasal (IN, n = 3) forms for their pharmacologic effects. Although non-parenteral forms of KET, including oral (PO, n = 1), sublingual (SL, n = 1), and intramuscular (IM, n = 2), are sometimes prescribed for home use and may not always be considered traditional interventions,³⁹ they were included for comprehensiveness (Table 2).

Intravenous Ketamine:

Four RCTs primarily used IV-KET at subanesthetic doses, typically 0.5 mg/kg (range: 0.2-0.5 mg/kg), administered over 40 minutes. Four studies used a placebo: 2 used midazolam (MDZ),⁴⁰^,41 1 used ketorolac⁴², and 1 used an inactive placebo (saline).⁴³ Three of the RCTs found positive outcomes (response rates: IV-KET = 17%-67%, control = 2.4%-20%) and 1 observed negative outcomes (response rate: IV-KET = 47%, control = 33%) (Figure 5).

Studies demonstrating positive outcomes include Feder et al,⁴¹ which included 41 participants (IV-KET = 22, MDZ = 19), primarily civilians. This study involved a single IV infusion of (R,S)-KET at 0.5 mg/kg, while the control group received MDZ at 0.045 mg/kg. The results showed a significant 12.7-point reduction on the IES-R 24 hours post-infusion (P = .02). Dadabayev et al⁴² involved 41 participants divided into 4 groups (Chronic pain (CP) + PTSD with IV-KET = 11, CP+PTSD with ketorolac = 10, CP with IV-KET = 10, and CP with ketorolac = 10), all from a military population. The CP+PTSD group received 40 minutes of either IV-KET (0.5 mg/kg IV) or ketorolac (15 mg IV), reporting significant reductions in PTSD symptoms (IES-R) from baseline to Day 1 (P = .03) and Day 7 (P < .01). Feder et al⁴⁰ studied 30 participants (IV-KET = 15, MDZ = 15) from military and civilian populations. Over 2 weeks, participants received 6 IV infusions of (R,S)-KET (0.5 mg/kg, 40 minutes, 3 times weekly) or MDZ (0.045 mg/kg). The IV-KET group showed significant PTSD symptom improvement, with a mean CAPS-5 reduction of 11.88 points (P = .004) and a 67% response rate versus 20% in the MDZ group.

In contrast, Abdallah et al⁴³ included 158 participants, with 54 in the placebo group, 53 receiving low-dose IV-KET (0.2 mg/kg), and 51 receiving standard-dose IV-KET (0.5 mg/kg), primarily from a military population. Participants received IV infusions of low-dose or standard-dose IV-KET, or normal saline, twice weekly for 4 weeks. The study reported no significant treatment effect for either IV-KET dose compared to placebo (P = .08), despite noting overall PTSD symptom improvement across all groups.

As part of this review, 1 pre-post study,⁴⁴ 1 cohort study,⁴⁵ and 2 case reports/case series⁴⁶^,⁴⁷ were included (Table 2).

Across studies, adverse events were mild and transient, with no severe effects reported. Common transient side effects included dissociation (not specified), dizziness, nausea, and mild blood pressure increases. In studies using MDZ as a comparator, adverse events were more common in the IV-KET groups, but remained manageable. No studies reported adverse psychological experiences or an exacerbation of PTSD symptoms following the IV-KET dissociation.

Esketamine:

Three retrospective studies explored IN-ESK for PTSD.⁴⁸^,⁴⁹^,⁵⁰ Details can be found in Table 2. Adverse events were mostly mild and included dissociation (not specified), dizziness, and nausea.

Other Novel Pharmacotherapies

Novel pharmacotherapies for PTSD include medical cannabis and other psychedelics, such as ayahuasca, ibogaine, and 5-MeO-DMT. Two studies on cannabis found significant PTSD symptom reduction, with 1 study showing that those using THC-dominant strains were more than twice as likely to no longer meet PTSD criteria. Detailed information about the studies on ibogaine, 5-MeO-DMT, and ayahuasca can be found in Table 2.

Psychedelic Assisted Therapy (P-AT)

3,4-Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT):

Fourteen studies were included (Table 2), with MDMA administration protocols varying in doses from 40-180 mg, typically administered across 2 to 3 8-hour therapy sessions. Thirteen studies incorporated macrodosing protocols, although 1 did not specify the dose. Treatment response rates for MDMA ranged from 50% to 87%, active placebo from 0% to 52%, and inactive placebo from 25% to 69% (figure 5).

Eleven RCTs demonstrated promising outcomes for MDMA-AT in PTSD treatment. For instance, Mitchell et al⁵¹ reported significant reductions in CAPS-5 scores after 3 MDMA sessions (80 mg/40 mg and 120 mg/60 mg), with 71% (n = 37/52) of participants no longer meeting PTSD criteria compared to a placebo group. Similarly, Ponte et al⁵² found sustained improvements in PTSD symptoms and sleep quality 12 months post-treatment after 2-3 MDMA sessions (75-125 mg), with a low-dose control group receiving 0-40 mg as an active placebo. Other studies also documented significant symptom reductions, with 67.3% (n = 37/55) achieving remission and notable improvements in PTSD, depression, and dissociation symptoms.⁵³^,⁵⁴ Earlier research confirmed significant symptom relief with lower doses,⁵⁵^,⁵⁶ while 2 studies⁵¹^,⁷ showed improved outcomes with various MDMA dosing strategies.

Ketamine Assisted Therapy (KET-AT):

Five studies explored KET-AT for PTSD (Table 2): 1 study investigated IV-KET-AT, 1 study examined IN-KET-AT, 1 study focused on ESK-AT, and 2 studies reviewed KET-AT with other routes of administration (PO, SL, and IM). Rotharmel et al⁵⁸ conducted a pre-post study using ESK-AT twice weekly for 1 month, then weekly for up to 6 months, alongside trauma-focused therapy. The PCL-5 scores decreased by 45.3% on average, with 63.6% (n = 7/11) classified as responders after 6 months. Shiroma⁵⁹ reported significant PTSD symptom reductions in military patients who received IV-KET-AT over 3 weeks. Dames et al⁶⁰ studied a civilian cohort in a 12-week KET-AT (PO, IM) program, showing that 86% (n = 80/94) transitioned from positive to negative PTSD screening. Rohde et al⁶¹ reported significant CAPS-5 reductions in a case series using weekly IV-KET-AT. Lastly, Robison et al⁶² found a 59% reduction in PTSD symptoms, with 100% (n = 10) screening negative for PTSD post-treatment following a 3-week program of KET-AT (SL, IM).

Registered Clinical Trials

The registered clinical trials using TMS for PTSD highlight diverse protocols including HF-TMS (n = 4), LF-TMS (n = 3), cTBS (n = 2), and iTBS (n = 3). Specific target regions include the L-DLPFC (n = 3), R-DLPFC (n = 5), and general DLPFC (n = 2). Other unique targeting approaches include the L-DLPFC combined with dmPFC (n = 1), and 1 trial each targeting the R-FC, primary motor cortex (M1), left area 8Av, sensory cortex, vmPFC, and left hippocampus (Table 3).

Table 3.

Registered Clinical trials of Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder (recruiting, not yet recruiting, and active but not recruiting)

NCT Number	Study Status	Sex	Target Population	Country	Target	Protocol	Intervention Description
NCT04563078	Recruiting	Male and female	All	USA	Not specified	Not specified	10-day treatment (2 per day with a 10-minute break, 20 sessions in total) of active Transcranial Magnetic Stimulation (TMS). TMS is a noninvasive treatment that uses magnetic fields to induce a small electric current in specific brain regions.
NCT06111976	Recruiting	Male and female	All	FRANCE	Not specified	Not specified	rTMS with simultaneous reactivation of traumatic memory will be performed 3 to 4 times a week for 3 to 4 weeks through 12 sessions.
NCT06587659	Not yet recruiting	Male and female	Military	Not specified	R-DLPFC	ITBS	IR-TMS will be delivered to the right DLPFC using connectivity-based, image-guided aiming with the IR-TMS coil positioned using a robotic arm.
NCT05149534	Recruiting	Male and female	Veterans	USA	DLPFC	Not specified	Active repetitive transcranial magnetic stimulation completed prior to written exposure therapy.
NCT06294106	Recruiting	Male and female	Veterans	USA	Not specified	Not specified	EEG is utilized to determine a personalized frequency to then apply TMS to the frontal lobe.
NCT05512143	Recruiting	FEMALE	All	USA	L-DLPFC	HF-TMS	Participants will receive 30 sessions (5 days/week, 6 consecutive weeks) of active TMS to the left dorsolateral prefrontal cortex (DLPFC).
NCT06434766	Recruiting	Male and female	All	CHINA	M1	iTBS	An active coil is used to deliver iTBS. The stimulation dose is 20 sessions (1800 pulses per session; 2 sessions a day, at least 1 hour apart) over the course of 2 weeks.
NCT06639061	Recruiting	Male and female	All	ISRAEL	Left hippocampal	HF-TMS	Brain stimulation using rTMS will be given after a deliberate memory re-activation, using repetitive pulses at 1Hz frequency for 15 minutes, once a week over 5 weeks.
NCT05544110	Recruiting	Male and female	All	CHINA	Not specified	Not specified	Participants receive active transcranial magnetic stimulation.
NCT03932773	Recruiting	Male and female	Veterans	USA	rDLPFC	LF-TMS	A Magstim Rapid2 Stimulator repetitive transcranial magnetic stimulation (rTMS) device will be used to deliver 1 hertz (Hz) stimulation to the right dorsolateral prefrontal cortex (rDLPFC) at 110% of a participant’s rTMS motor threshold.
NCT06544408	Not yet recruiting	Male and female	Military	USA	Arm 1 = left dl-PFC; Arm 2 = dm-PFC	Not specified	Participants will undergo a standard course of TMS treatment (30 sessions/6 weeks).
NCT04207346	Active, not recruiting	Male and female	Veterans	USA	rDLPFC	Not specified	The coil parallel to the scalp is placed on the target for real and effective stimulation.
NCT05646732	Recruiting	Male and female	Veterans	USA	Left area 8Av	Not specified	Participants will receive active TMS in combination with CPT.
NCT02990793	Recruiting	Male and female	All	USA	Not specified	Not specified	Participants will undergo simultaneous TMS-fMRI as part of this study.
NCT06449326	Recruiting	Male and female	Veterans	USA	rDLPFC	Not specified	Participants will undergo a battery of physiological and behavioral tests, and data will be collected before and after the application of eTMS.
NCT05560113	Recruiting	Male and female	Veterans	USA	DLPFC	ITBS	Participants will engage in a 4-week treatment protocol (20 treatments).
NCT05916417	Recruiting	Male and female	Veterans	USA	Dorsolateral Prefrontal Cortex (dl-PFC)	ITBS	Participants in this arm will undergo 50 sessions of active accelerated (10x/day, 5 days) image-guided iTBS.
NCT04568369	Active not recruiting	Male and female	Veterans	USA	Left DLPFC	Not specified	cTBS, a patterned form of TMS, will be applied over the targeted sensory cortical region using real-time neuronavigation.
NCT03995173	Active not recruiting	Male and female	Veterans	CANADA	vmPFC	10 HZ	TMS-fNIRS dl-PFC data will be acquired with participants being randomized to active or sham stimulation of the dl-PFC.
NCT05512143	Recruiting	FEMALE	All	USA	L-DLPFC	HF-TMS	Participants will receive 30 sessions (5 days/week, 6 consecutive weeks) of active TMS to the left dorsolateral prefrontal cortex (DLPFC).

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CPT, cognitive processing therapy; cTBS, continuous theta burst stimulation; DLPFC, dorsolateral prefrontal cortex; EEG, electroencephalogram; eTMS, electroencephalogram personalized transcranial magnetic stimulation; fMRI, functional magnetic resonance imaging; HF-TMS, high-frequency transcranial magnetic stimulation; IR-TMS, image-guided robot-navigated transcranial magnetic stimulation; ITBS, intermittent theta burst stimulation; L-DLPFC, left dorsolateral prefrontal cortex; LF-TMS, low-frequency transcranial magnetic stimulation; M1, primary motor cortex; NCT, national clinical trial; PTSD, posttraumatic stress disorder; R-DLPFC, right dorsolateral prefrontal cortex; rTMS, repetitive transcranial magnetic stimulation; TMS, transcranial magnetic stimulation; vmPFC, ventromedial prefrontal cortex.

In parallel, registered clinical trials evaluating the efficacy of IV-KET for PTSD are in progress. These studies typically involve the administration of IV-KET at various dosages (range: 0.2-2 mg/kg), often comparing its effects against control substances like MDZ (Table 4).

Table 4.

Registered Clinical trials of Ketamine for Posttraumatic Stress Disorder (recruiting, not yet recruiting, active but not recruiting, enrolling).

NCT Number	Study Status	Sex	Target Population	Country	Formulation	Dose	Intervention Description
NCT05737693	Recruiting	Male and female	Civilian	USA	IV KET	Arm 1: 0.2mg/kg, Arm 2: 0.5mg/kg	Participants receive either 0.2 mg/kg or 0.5 mg/kg KET infusions on days 2 and 4 of therapy, with monitoring. The control group receives MDZ (0.045 mg/kg) under similar conditions.
NCT04560660	Recruiting	Male and female	Military	USA	IV KET	0.5 mg/kg	Participants receive 0.5 mg/kg of KET or placebo (MDZ 0.045 mg/kg) 24-72 hours before therapy sessions at weeks 1, 2, and 3, followed by 7 additional therapy sessions.
NCT06228391	Not yet recruiting	Male and female	Military	USA	IV KET	0.5 mg/kg	Participants will receive KET (0.5 mg/kg) or MDZ (placebo) twice a week for 3 weeks, assessing symptom reduction for both PTSD and depression.
NCT04032301	Active, not recruiting	Male and female	Military	USA	IV KET	0.5 mg/kg	Participants receive 6 infusions of KET (0.5 mg/kg) over 3 weeks. The control group receives saline infusions, with evaluations of PTSD and MDD symptoms.
NCT06378528	Not yet recruiting	Male and female	All	USA	IV KET	0.5 mg/kg	Participants will receive 3 intravenous administrations of KET (0.5 mg/kg) prior to psychotherapy sessions, followed by integration sessions.
NCT06179485	Recruiting	Male and female	Civilian	USA	IV KET	2 mg/kg	Participants receive intravenous KET (2 mg/kg) as a sedative during emergency tracheal intubation to assess subsequent PTSD symptoms.
NCT06498700	Enrolling by invitation	Male and female	Civilian	EGYPT	IV KET	0.5 mg/kg	Participants will receive either a continuous infusion of KET (0.5 mg/kg/h) or dexmedetomidine (0.1 µg/kg/h) during and after surgery to evaluate the prevention of PTSD symptoms.
NCT05855876	Recruiting	Male and female	Military	USA	IV KET	Not specified	Subjects will receive subanesthetic KET infusions in combination with bilateral cervical sympathetic blocks to evaluate their effects on PTSD symptoms.
NCT06608277	Not yet recruiting	Male and female	Military	USA	IV KET	up to 0.3 mg/kg	Participants will be assigned to receive either SGB with bupivacaine plus placebo KET, sham SGB plus KET, or SGB with KET, to assess pain relief and PTSD symptoms.
NCT02734602	Recruiting	Male and female	Civilian	USA	IV KET	Not specified	Participants undergo multiple PET scans, some with KET administered after the baseline scan to observe changes in synaptic density related to MDD and PTSD.

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IV KET, intravenous ketamine; MDD, major depressive disorder; NCT, National Clinical Trial; PET, positron emission tomography; PTSD, posttraumatic stress disorder; SGB, stellate ganglion block; TBI, traumatic brain injury.

Discussion

In this systematic review, studies that assessed the effect of interventional psychiatry modalities for the treatment of PTSD were identified and evaluated. Included studies mostly focused on brain stimulation treatments, with fewer records assessing pharmacological agents. The results of included studies mostly indicated a significant reduction in PTSD symptoms following treatment administration.

Brain stimulation, particularly TMS and ECT, has emerged as a promising PTSD treatment, with RCTs supporting TMS’s efficacy. High-frequency, low-frequency rTMS, and TBS have shown significant symptom reductions, with some studies indicating comparable effects between high- and low-frequency protocols. Mechanistically, TMS is thought to work by modulating neural circuits involved in fear processing, emotional regulation, and memory, primarily targeting regions such as the prefrontal cortex and amygdala.⁶³ This modulation may be particularly beneficial for patients with single-incident trauma, where fear circuits play a central role.⁶⁴ However, in cases of chronic developmental trauma or complex PTSD, where the neural circuitry extends beyond the fear response to involve more extensive, long-term adaptations, TMS’s efficacy may be limited by the shortcomings of the fronto-limbic model of PTSD.⁶⁵ This model does not fully account for the complex interplay of systems affected in chronic forms of trauma, potentially impacting the effectiveness of TMS. Furthermore, ECT also demonstrated efficacy, particularly in individuals with comorbid PTSD and MDD, likely due to its impact on enhancing neuroplasticity, increasing connectivity between critical brain regions, and boosting neurotransmitter levels, such as serotonin and dopamine.³⁰ Given that approximately two-thirds of PTSD patients continue to meet full diagnostic criteria despite pharmacological and psychotherapeutic interventions, brain stimulation may represent a viable alternative or adjunctive approach in the treatment landscape.

Intravenous ketamine and ESK have emerged as promising pharmacological interventions for PTSD in the included studies, with IV-KET administration being the most common route, followed by ESK, then SL, PO, and IM-KET delivery. Results of this review are consistent with previous systematic reviews and meta-analyses, which have reported KET’s efficacy in reducing PTSD symptoms.¹¹^,66^,67 Most studies to date have focused on ESK and IV-KET, both of which must be administered in healthcare settings, limiting their accessibility. Future research on non-parenteral forms of KET, such as SL-KET, could expand access and provide viable options for home use, as has been explored in depression treatments.³⁹ Another important consideration is the role of psychotherapy. Ketamine and ESK have shown effectiveness both with and without concurrent therapy, suggesting that KET treatment without therapy could be a more scalable, resource-efficient intervention. However, the necessity and impact of psychotherapy with KET remain unclear, and further research is needed to determine its role in optimizing treatment outcomes. Although no reports of distressing psychological experiences or PTSD exacerbation following dissociation with KET could be found, this remains a potential risk, particularly in the absence of therapeutic support. This combination of more predictable dosing and faster onset likely contributes to the greater efficacy of IV-KET compared to the IN form in treating PTSD. Future studies should focus on comparing the long-term efficacy and safety of different routes of KET administration, including IV, IN, and PO, in patients with PTSD. Additionally, research should explore the optimization of dosing regimens and treatment protocols to enhance therapeutic outcomes. Expanding research on PO-KET, which remains understudied, could provide valuable insights into its feasibility and efficacy as a treatment option.

Psychedelic-assisted psychotherapies has emerged as a novel approach in PTSD treatment, with MDMA being the most commonly assessed psychedelic in RCTs. These studies have consistently demonstrated significant therapeutic effects of MDMA on PTSD symptoms. Meta-analyses have shown that MDMA-assisted therapy has a larger effect size compared to prolonged exposure therapy (Hedges’ g = 1.17 vs. g = 1.08).⁶⁸ This efficacy includes reducing depressive symptoms linked to PTSD, suggesting broader benefits.69 While MDMA’s standalone therapeutic potential without psychotherapy remains unstudied, future research could explore this through safety-only observation protocols, akin to those for IV-KET administration. Future research should investigate combining psychedelics with psychotherapy, as clinical observations suggest that without therapeutic support, the intense psychological experiences they induce may be challenging to process and potentially harmful. Documenting and studying the interaction between these pharmacologic agents and psychotherapy will be essential to establish protocols that optimize safety and therapeutic outcomes.

Advancing PTSD treatment research requires acknowledging its heterogeneity and adopting a staged model for interventional psychiatry to refine treatment strategies and enhance clinical utility.70 Integrating the RDoC (Research Domain Criteria) framework and stratifying populations beyond military and civilian categories can help tailor treatments to disorder constructs like threat and arousal, while network analyses may clarify individual treatment responses.71 These approaches, combined with a focus on non-responders, could optimize personalized care and improve outcomes for difficult-to-treat PTSD cases.

To the authors’ knowledge, this is the first systematic review evaluating interventional psychiatry treatment for PTSD. However, it has some limitations. Restricting the inclusion criteria to English-language studies might introduce language bias by excluding potentially relevant research published in other languages. The review faced challenges from the small number of studies and limited samples for some treatments, and high heterogeneity in treatments and protocols made meta-analysis unfeasible. Lastly, although the JBI tools were used for the risk of bias assessment, these tools do not provide an overall quality score for each study, which may hinder the ability to quantitatively assess study quality across diverse designs.

This study reviewed evidence for the efficacy and safety of various interventional psychiatry treatments for PTSD, including neurostimulation and novel pharmacotherapies. While some treatments demonstrated potential for reducing PTSD symptoms, the evidence is limited by small sample sizes, variability in study designs, and inconsistent protocols across studies. It is important to recognize the need for further refinement in study design, particularly in considering factors such as treatment stage orientation and population stratification. Stratifying research populations by disease stage and considering allostatic load in PTSD could improve the accuracy of effect ratings and prevent null findings due to heterogeneous responses. The allostatic load effect highlights PTSD as a chronic condition that exerts cumulative wear and tear on systems biology, supporting an RDoC approach to understanding treatment impacts across stages. Future research should also prioritize head-to-head comparisons and the sequential application of treatments to determine optimal approaches, such as assessing whether TMS should precede IV-KET and at what stage each treatment might be most beneficial. Incorporating these considerations into high-quality, large-scale studies would help establish clearer guidance on the safest and most effective interventional treatments for PTSD, thereby advancing the field with an understanding of therapeutic efficacy across patient subgroups and disease stages.

Supplementary Materials

Supplementary Material

supplementary_material.pdf^{(182.2KB, pdf)}

Funding Statement

The authors declared that this study has received no financial support.

Footnotes

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – V.B., R.J.A.; Design – S.M., H.F.A.; Supervision – V.B.; Resources – V.B., R.J.; Materials – V.B.; Data Collection and/or Processing – R.J.A., H.F.A., S.M., A.P.; Analysis and/or Interpretation – R.J.A., H.F.A.; Literature Search – H.F.A., S.M., A.P., R.J.A.; Writing – H.F.A., R.J.A.; Critical Review – J.S., Y.Z., A.G., L.B., O.W., J.P., M.E., J.S., A.N., E.V., R.J., R.L., V.B.

Declaration of Interests: Eric Vermetten and Andrew Greenshaw are Associate Editors at Psychiatry and Clinical Psychopharmacology, however, their involvement in the peer-review process was solely as authors. Reinhard Janssen, Shakila Meshkat, Huda F. Al-Shamali, Argyrios Perivolaris, Yanbo Zhang, Andrew Greenshaw, Lisa Burback, Jitendar Sareen, Olga Winkler, Ruth Lanius, Jennifer Phillips, Eric Veremetten, Andrew Nicholson and Murray W. Enns have no disclosures. Jennifer Swainson has received honoraria for speaking or advisory roles from Abbvie, Bausch Health, Biron, Eisai, Idorsia, Janssen, Lundbeck, Novo Nordisk, and Otsuka. Rakesh Jetly is the CMO of Mydecine Innovation Group. Venkat Bhat is supported by an Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research funding from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai.

Data Availability Statement:

The data that supports the findings of this study are available on request from the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material

supplementary_material.pdf^{(182.2KB, pdf)}

Data Availability Statement

The data that supports the findings of this study are available on request from the corresponding author.

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PERMALINK

Interventional Psychiatry and Emerging Treatments for Posttraumatic Stress Disorder (PTSD): A Systematic Review

Reinhard Janssen-Aguilar

Shakila Meshkat

Huda F Al-Shamali

Argyrios Perivolaris

Jennifer Swainson

Yanbo Zhang

Andrew Greenshaw

Lisa Burback

Olga Winkler

Jennifer L Phillips

Murray W Enns

Jitender Sareen

Andrew Nicholson

Eric Vermetten

Rakesh Jetly

Ruth Lanius

Venkat Bhat

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Figure 1.

Material and Methods

Information Sources and Search Strategy

Eligibility Criteria

Data Screening and Extraction

Risk of Bias Assessment

Result Synthesis

Results

Figure 2.

Risk of Bias Results

Study and Sample Characteristics

Figure 3.

Table 1.

Table 2.

Registered Clinical Trials

Figure 4.

Neuromodulation

Transcranial Magnetic Stimulation:

Figure 5.

Electroconvulsive Therapy:

Transcranial Direct Current Stimulation:

Other Neuromodulation Treatments

Novel Pharmacotherapies

Ketamine:

Intravenous Ketamine:

Esketamine:

Other Novel Pharmacotherapies

Psychedelic Assisted Therapy (P-AT)

3,4-Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT):

Ketamine Assisted Therapy (KET-AT):

Registered Clinical Trials

Table 3.

Table 4.

Discussion

Supplementary Materials

Funding Statement

Footnotes

Data Availability Statement:

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases