This is a systematic review of the evidence for hyperbaric oxygen therapy (HBOT) treatment of post-traumatic stress disorder (PTSD) symptoms.

Until recently, PTSD was implicitly a psychiatric disorder that ensues from a trauma that is sufficiently disturbing to leave a person with residual emotional and behavioral sequelae. The essential feature of PTSD, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) of the American Psychiatric Association (1), is the development of characteristic symptoms following exposure to one or more traumatic events in which the individual is exposed to actual or threatened death, serious injury, or actual violence. Intrusive symptoms (nightmares and flashbacks) are the hallmark of PTSD, while avoidance, hypervigilance, cognitive and mood changes are seen in most cases. The symptoms, severity, and persistence vary widely for unknown reasons (2).

Epidemiological studies report that over half of the general population are exposed to a serious traumatic event in their lifetime, but only about 7 percent of those are likely to develop PTSD (3). However, among military personnel who have been involved in combat, the prevalence of PTSD is much higher and is often comorbid in 37% of servicemembers with mild traumatic brain injury (mTBI) (4).

Treatment of PTSD is problematic, especially for the persistent, disabling, or more severe forms. When PTSD becomes chronic nearly half of patients become treatment resistant (5, 6). Meta-analyses (7, 8) show that psychological interventions can significantly reduce PTSD symptoms when compared to control subjects; however, the effect sizes are often small or not reported. Pharmacological interventions were shown to be less effective than trauma-based psychological treatments for reducing PTSD symptoms or improving sleep with less than 60 percent reporting a meaningful clinical response and only 20 to 30 percent reporting remission (9, 10).

Improved brain imaging technology and research on U.S. war veterans from the Iraq and Afghanistan conflicts have revealed PTSD-associated changes in brain structure and function. This suggests that PTSD can no longer be considered a strictly psychiatric disease. Fear-conditioned learning was always identified as one of the main causative factors in PTSD. The growing literature, however, shows that PTSD is associated with specific neuroanatomical abnormalities or changes in fear neural pathways including the thalamus, amygdala, hippocampus, and medial prefrontal cortex (11–13). Veterans with severe PTSD show an indentation in the centromedial amygdala (14). A meta-analysis (15) reported a significant gray matter volume reduction of the left parahippocampal gyrus. Multiple studies demonstrate reductions in grey matter volumes in the amygdala, hippocampus, and prefrontal cortex, and the white matter volumes in the tracts connecting these three regions, including the cingulum bundle, uncinate fasciculus, and fornix/stria terminalis (16). Studies also reveal that PTSD is associated with a smaller hippocampus (17, 18). People with PTSD have been shown to have decreased activity in the prefrontal cortex which helps regulate the emotional responses triggered by the amygdala. It is not clear whether some neural circuit PTSD-associated abnormalities are present before a trauma or if the abnormalities develop after. Nonetheless, exposure to traumatic events has been shown to cause long-term changes in brain activity and in microstructure (19–21). The PTSD-related brain changes identified in these studies suggest wounding and inflammatory processes (19) that could be responsive to treatments for wounds and inflammation (22).

Hyperbaric oxygen therapy (HBOT) has been historically defined as intermittent treatment with 100% oxygen at a minimum arbitrary pressure of 1.4 atmospheres absolute (ATA) and more recently 1.0 ATA for a narrow list of acute and chronic wound conditions (22, 23). The U.S. Food and Drug Administration (FDA) corrected the confusion and misunderstanding in this definition by re-categorizing HBOT as a prescription medical drug (oxygen) and device consisting of increased barometric pressure and hyperoxia (24). Scientifically, it has been defined as “a medical treatment that uses increased atmospheric pressure and increased oxygen as drugs by fully enclosing a person or animal in a pressure vessel and then adjusting the dose of the drugs to treat pathophysiologic processes of the diseases” (25, 26). The exposure to increased atmospheric pressure and hyperoxia must be intermittent to achieve the therapeutic benefit, but the length and depth of exposure, use, frequency, and number of air breaks, frequency and total number of treatments, total oxygen and pressure dose, i.e., all variables of dosing, have not been well-defined. Based on this scientific definition, HBOT can be appreciated as a treatment for common acute and chronic wound pathophysiology (23, 25, 27, 28) found in acute and chronic wound conditions (23, 25, 27–30) and inflammatory conditions (28–33).

PTSD responsiveness to HBOT was first suggested as a serendipitous finding in the treatment of a U.S. war veteran with mTBI Persistent Postconcussion Syndrome (PPCS) (34). This positive response was replicated in a case series of 30 mTBI PPCS veterans (87% with PTSD) (35, 36), and a series of U.S. Department of Defense (DoD) sponsored civilian (37) and military-conducted studies (38–41). Due to misinterpretation of the DoD studies’ data based on design flaws and the confused definition of HBOT (22, 23), the efficacy of HBOT in mTBI PPCS as well as PTSD has been unclear. A recent systematic review and dosage analysis of these studies clarified the confusion (42). By analyzing both the combined and separate effects of increased barometric pressure and hyperoxia, according to the scientific and FDA’s understanding of HBOT, efficacy for HBOT in mTBI PPCS was demonstrated in a narrow pressure and wide oxygen dose range. Using the same analysis, this is a systematic review of the effectiveness of HBOT in the treatment of both military individuals and civilians with PTSD symptoms or PTSD.

This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (43). The PRISMA abstract and manuscript checklists are attached as Supplementary Files S1, S2.

Literature search yielded 115 articles [PRISMA flow chart (43), (Figure 1)]. Eight studies met inclusion criteria, were included in the final analysis, and are listed chronologically in Table 1. Four of the studies in Table 1, (38–41), were U.S. Department of Defense (DoD) sponsored. The subjects were active duty military or veterans from the Middle East conflicts with comorbid mTBI. Some percentage of all four studies’ subjects had comorbid diagnoses of PTSD. All four studies were designed to compare the effects of hyperbaric oxygen therapy on mTBI. PTSD was a secondary measure using the PCL-M or PCL-C administered before and after treatment. All four studies also attempted to control the placebo effect of the hyperbaric exposure with purported sham exposures. These sham exposure groups were based on the historical misdefinition of HBOT (22, 23) that defined HBOT as the use of 100% oxygen at ≥1.4 ATA. The bioactive components of HBOT are increased barometric pressure and hyperoxia (25, 26, 42). A sham treatment must omit both of these to control for the independent effects of pressure and hyperoxia. By design none of the sham groups in the 4 DoD studies could do this. The sham exposures are pseudo-sham/pseudo-control groups that used lower doses of hyperbaric oxygen therapy as a treatment. Thus, they are analyzed as comparative dosing studies. The only DoD study with an acceptable control group (40) used a no-HBOT treatment control group, similar to the civilian studies (37, 44, 45).

Wolf et al. (38), the first of the DoD studies, is a comparative dosing study that randomized 50 active-duty military, to treatment and “control” groups for thirty 90-min exposures to 2.4 ATA 100% oxygen (2.4 ATA oxygen, 6,900 AMs oxygen) or 1.3 ATA 21% oxygen, room air (0.27 ATA oxygen, 1.002 AMs oxygen). Within-group change in PCL-M symptoms was a statistically significant 8.4-point RC decrease in PTSD symptoms for the 2.4 ATA group (50–41.6, p < 0.05) and a near identical significant RC decrease of 8.3 points (48.9–40.6, p < 0.05) for the 1.3 ATA 21% oxygen group. No statistical analysis of change scores between the two groups was performed. No conclusions were drawn about the efficacy of HBOT for PTSD.

Cifu et al. (39) was a similar comparative dosing study of three different doses of oxygen at a constant pressure. The study randomized sixty-one male military subjects to forty 60-min exposures to 2.0 ATA 100% oxygen (2.0 ATA oxygen, 4,860 AMs oxygen), 2.0 ATA 75% oxygen (1.5 ATA oxygen, 3,720 AMs), or 2.0 ATA 10.5% oxygen (0.21 ATA oxygen, 76 AMs). There were no differences in PCL-M scores between-groups before treatment or between groups after treatment, but no change score differences between-groups were analyzed. Within group analyses showed a statistically significant RC score PCL-M improvement of 6.8 points (49.4 to 42.6, p < 0.05) for the 2.0 ATA 100% oxygen dose group and non-significant change scores of 1.4 points (44.7 to 43.3) for the 1.5 ATA oxygen group and 1.2 points (45.1 to 43.9) for the 0.21 ATA oxygen group. No conclusions were drawn about the efficacy of HBOT for PTSD.

Miller et al. (40) is the only controlled DoD study. It randomized 72 subjects to forty 60-min exposures to 1.5 ATA 100% oxygen (1.5 ATA oxygen, 3,120 AMs), 1.2 ATA 21% oxygen, room air (0.25 ATA oxygen, 600 AMs), or a true control group of Routine Care without hyperbaric treatment. Within-group treatment effects showed a CMC 11.4 point PCL-C decrease (53.5–42.1) in the 1.2 ATA group, a 5.0 point RC decrease in the 1.5 ATA group (48.5–43.5), and a 2.1 point decrease (51.8–49.7) in the Routine Care group which was neither aCMC nor an RC. There were no between group, within group, or treatment vs. true control group statistical analyses performed. The study noted improvement in PTSD symptoms “after the interventions, favoring the “sham” group… over the HBO group…,” but no conclusions were drawn about the efficacy of HBOT for PTSD.

The fourth DoD study, Weaver et al. (41) randomized 71 mostly active duty military members with mTBI PPCS to the same HBOT treatment schedule as Miller et al. (40), but did not include a true no-treatment control group. Subjects received forty 60 min exposures to 1.5 ATA 100% oxygen (1.5 ATA oxygen, 3,120 AMs) or 1.2 ATA 21% oxygen, room air (0.25 ATA oxygen, 600 AMs). Between-group analysis demonstrated a statistically significant change score difference between groups (improvement in favor of the 1.5 ATA oxygen group) of 7.3 points (−13.5, −1.0; p = 0.02), despite a significant disease severity bias against the 1.5 oxygen group. The 1.5 ATA oxygen group was older, had more combat deployments, worse anger control, and higher mean pre-treatment PCL-C scores than the 1.2 ATA group. When those subjects diagnosed with PTSD by the Structured Clinical Intervidew for DSM-IV PTSD module (the PTSD subgroups) were analyzed the 1.5 ATA oxygen HBOT benefit was even greater: a 12.3 point statistically significant (−21.4, −3.1; p = 0.01) difference between groups. This was composed of a 9.3 point RC improvement for the 1.5 ATA oxygen group and a 3.0 point worsening of the 1.2 ATA (0.25 ATA oxygen) group.

Summarizing the above four studies, RC improvements in PTSD symptoms have been demonstrated at 2.4 ATA oxygen and 1.3 ATA air (0.27 ATA oxygen) (38), 2.0 ATA oxygen (39), 1.5 ATA oxygen (40, 41), and CMC at 1.2 ATA air (0.25 ATA oxygen) (40). The Wolf et al. (38) and Cifu et al. (39) dose group improvements were statistically significant within-group changes and the Weaver et al. (41) study showed a statistically significant between group improvement in favor of the 1.5 ATA oxygen group compared to the 1.2 ATA air group. In the only study with a true control group, Miller et al. (40), the CMCs and RCs within-groups occurred only in the two treatment groups while none occurred in the No Treatment control group. The remainder of the within group changes (40), between group changes (38, 39), and changes compared to true control group (40) were not statistically analyed in the studies.

The remaining 4 studies consisted of a case series with imaging controls and three studies with true treatment controls. The U.S. DoD-administrated case series of Harch et al. (36) prospectively treated 30 active duty and retired military members with mTBI PPCS, 23 of whom met the PCL-M threshold for PTSD diagnosis. The subjects received forty 60-min exposures to 1.5 ATA 100% oxygen (1.5 ATA oxygen, 3,420 AMs oxygen). The subjects had the greatest pre-treatment PTSD scores (mean of 63.4) of all the studies with military subjects, which was 32% higher than subjects in the four DoD studies. These subjects experienced the greatest reduction in the PCL, 16.6 points. This was statistically significant (−22.6, −10.6; p < 0.001) and a CMC. The controlled neuroimaging component of the study demonstrated significant SPECT brain blood flow improvements in right posterior hemispheric gray and white matter regions in the HBOT-treated veterans compared to controls.

Two of the three remaining studies, Hadanny et al. (44) and Harch et al. (37), used a randomized crossover design where all subjects received HBOT and the randomly assigned control group crossed over to receive HBOT after the control period. Hadanny et al. (44) is the only study that was exclusively non-military subjects, all women (with sexual trauma in childhood), and had no comorbid TBI. Thirty women received sixty 90-min exposures to 2.0 ATA 100% oxygen (2.0 ATA oxygen, 11,400 AMs). The treatment group experienced a statistically significant 8.2 point (28.9–20.7, p = 0.006) decrease in the PSS-I compared to 1.5 points in the control group (29.9–28.4, p = 0.22). After the control period the control group crossed-over and was treated with the same 2.0 ATA 100% oxygen, 11,400 AMs. Following treatment, the crossed-over control group experienced a significant 6.6 point (28.4 to 21.8, p = 0.005) decrease in PTSD symptoms. No statistical analysis of change scores between groups was performed. The raw point reductions would be reliable changes on a PCL questionnaire. Considering the condensed PSS-I scale vs. the PCLs (51 points vs. 85 points) if re-scaled to a PCL questionnaire the scores for CMC and RC would be 14.5 and 11.0 points, respectively. SPECT brian blood flow imaging analysis revealed significant increases in blood flow in 7 Brodmann areas compared to the control group. Correlation analysis of perfusion changes and questionnaire scores were significant between 7 Brodmann areas and multiple questionnaire components. MRI DTI results demonstrated significant increases in fractional anisotropy (FA) in anterior thalamic radiation, left insula, right thalamus, and superior thalamic radiation (p < 0.001) in HBOT subjects compared to controls. When all HBOT-treated subjects (HBOT group and crossover Control Group) were compared to Controls pre-HBOT three of the four significant findings persisted; superior thalamic radiation was no longer significant.

The second crossover study, Harch et al. (37), was a study on mTBI PPCS that excluded subjects with CAPS scores high enough to be diagnosed as PTSD. Sixty-three subjects, 83% civilian and 17% military, were randomized to forty 60-min exposures to 1.5 ATA 100% oxygen (1.5 ATA oxygen, 3,420 AMs) or a true control group without hyperbaric treatment. The Control group then crossed over to receive the same 1.5 ATA oxygen HBOT treatment at the end of the control period. Between-group analysis of PCL change scores demonstrated a statistically significant change score difference (improvement in favor of the 1.5 ATA oxygen group) of 9.7 points (−17.7, −8.6; p = 0.0001). Within-group analyses showed a statistically and CMC score improvement of 11.9 points (37.9–26.0, p < 0.0001) for the 1.5 ATA oxygen dose group and non-significant change scores of 2.2 points (39.7–37.5, p = n.s.) for the no treatment control group. After the Controls crossed over and received HBOT treatment they achieved a similar statistically significant and CMC decrease in PCL-C of 10.5 points (37.5–27.0, p < 0.0001).

The final study by Doenyas-Barak et al. (45) was similar to Hadanny et al. (44). Both studied treatment-resistant PTSD without comorbid TBI using identical doses of HBOT, but Doenyas-Barak et al. (45) studied military members in a treatment vs. true control no-treatment design, while Hadanny et al. (44) studied civilians in a crossover true control design. Doenyas-Barak et al. (45) randomized 28 veterans to sixty 90-min exposures to 2.0 ATA 100% oxygen (2.0 ATA oxygen, 11,400 AMs) or a control group without HBOT treatment who received their ongoing psychotherapy. Within-group analyses demonstrated a statistically and clinically significant decrease (improvement) in CAPS-5 score of 18.1 points in the HBOT group (46.6–28.5, C.I: −25.4, −10.8, p < 0.0001) compared to a 2.0 point increase (worsening) in the control group (49.5–51.5, p = 0.211). Cohen’s net effect size was 1.643. Translating the CAPS to a PCL score indicates that this is a 25.9 point decrease in the PCL, a very large change score. Brain imaging MRI DTI demonstrated significant increases in fractional anisotropy in the left anterior and posterior limbs of the internal capsule and right parietal white matter in HBOT-treated subjects compared to controls. Functional MRI showed within-group increases in fMRI BOLD signal for the HBOT-treated subjects in the left dorso-lateral prefrontal, middle temporal and temporal gyri, both thalami, left hippocampus, and left insula. No significant within group changes were found for the control group. Statistically significant correlations were found between mean percent BOLD signal changes in peak significantly activated regions and percent change in total CAPS score (r = 0.42–0.67, p < 0.05).

In summary, six of the eight studies were conducted on military subjects and two on civilians. Two studies were designed to investigate PTSD without TBI. One of these studies was on military subjects with treatment resistant PTSD who did not have a TBI and the other involved women who were sexually abused as children with long-term PTSD. There are four studies with five pseudo-sham control groups that received lower doses of hyperbaric oxygen therapy. Two of the five pseudo-sham groups showed significant improvement in PTSD, one at 1.3 ATA and the other at 1.2 ATA. The other 3 pseudo-sham treatments only showed −1 point (improvement) to +3 points (deterioration).

In this systematic review of HBOT treatment of PTSD symptoms eight studies (7 randomized trials) were analyzed for symptom outcomes according to composite doses of hyperbaric oxygen therapy and component doses of barometric pressure and hyperoxia. Overall, the studies’ data demonstrate that HBOT caused statistically significant, reliable change, or clinically meaningful change/improvements in PTSD symptoms and/or PTSD compared to true control groups and within nearly all treatment groups. In two of the studies with the greatest improvement symptom relief was obtained for treatment-resistant PTSD that was over a decade long. The improvements in three of the studies were supported by functional and anatomic imaging changes in PTSD-associated brain structures. These results were achieved despite heterogeneity of study design, statistical analysis, and subject populations. Treatment effects were non-specific to cause of PTSD, occurring in male and female subjects, both military and civilian, with childhood sexual trauma and fibromyalgia.

The symptom improvements were achieved with multiple different doses of HBOT and occurred at composite doses of oxygen and pressure at 1.3, 1.5, 2.0, and 2.4 atmospheres. The pressure threshold for improvement appeared to be 1.2–1.3 ATA and the total oxygen threshold of 1,002 atmosphere minutes. There was increasing benefit with increasing total doses of oxygen from 1,002 to 11,400 AMs. These total doses of oxygen are summative from 30 to 60 repetitive intermittent exposures to hyperoxia and pressure. The average greatest symptom improvement occurred with the highest total oxygen dose in two studies (44, 45), but the dominant contributing component(s) to this dose (FiO2, absolute pressure, length of each treatment, absence/presence/number of air breaks, treatment frequency, and total number of treatments) could not be identified. It may have been the presence of all of these variables in the regimen of these two studies that is responsible for the large symptom improvement, however a near equivalent percent symptom improvement occurred in Harch et al. (36) in similar subjects (44) with the same FiO2, half the increase in barometric pressure, half the treatment length, no air breaks, twice the frequency, two-thirds the number of treatments, and with a lesser incidence of emotional flooding/side effects. Due to the small number of studies and large number of variables it is impossible to draw further conclusions beyond increasing symptom improvement with increasing total oxygen dose. There is no evidence, however, that the HBOT-induced effects on PTSD could occur from a continuous total exposure to oxygen of 1,002–11,400 AMs.

All seven randomized trials were judged to be of moderate to high quality by the PEDro scoring system. The rigor of all seven studies was excellent, but due to limitations of blinding inherent to hyperbaric oxygen treatment their PEDro bias ratings were compromised by at least one point and in four of the seven by two points. PEDro criteria require blinding of subjects and all “therapists.” To blind subjects to both pressure and oxygen they must not go in a hyperbaric chamber. A no-chamber experience group unblinds the control subjects [one point PEDro scale loss each for four of the studies (37, 40, 44, 45)]. To blind all therapists, which includes chamber operators/gas composition allocators, the operators/allocators cannot know the pressures or gas compositions. Using the most sophisticated chamber designs and equipment, this is nearly impossible to achieve and was not achieved in the DoD studies (38–41): one-point PEDro scale loss each.

The inability to blind subjects and operator therapists to treatment group should predispose to placebo effects that lower the rigor and increase the bias of a study. It appears that these PEDro scale losses did not compromise the rigor of the studies because the placebo effect in these studies was negated by the pressure and oxygen dose analyses. The analyses showed that there are minimum thresholds necessary for treatment effects. If placebo was involved the treatment effect should occur regardless of oxygen or pressure dose. That did not occur. In addition, different effects were seen with different doses which is contrary to a placebo contribution. The placebo contribution is also negated by the Cifu et al. study (39) in which all subjects had the identical chamber experience yet only one group showed a significant outcome. If the ritual of the chamber experience had a placebo effect all of Cifu et al.’s (39) groups should demonstrate the same placebo outcome. They did not. Essentially, the PEDro scale overestimated the bias in the studies.

The most common side effect seen in HBOT, middle ear barotrauma, occurred in 5.5–43% of subjects. The higher range of this side effect in some of the studies was due to intensity of schedule in one study (37) and chamber operations in another study (41). In two other studies with the highest rates (44, 45) this was not explained. Other side effects were minor and/or rare. An unusual side effect that was documented in several studies was a significant, but reversible, revisiting of the old traumatic memories at the highest oxygen doses in 30–39% of subjects (44, 45). The surfacing of old traumatic memories is also considered to be part of the emotional healing process of PTSD, particularly when psychotherapy is provided at the same time. The investigators in these two studies suggest revisiting these memories is due to HBOT-induced metabolic and circuitry changes in brain areas associated with emotional and pain processing (44) and induced neuroplasticity effects in the hippocampus (45). Alternatively, this phenomenon may partly reflect increasing oxidative stress. The resurfacing of old memories was minor in the lower oxygen dose studies (36, 37), but more intense with the highest doses of oxygen, suggesting accumulating oxidative stress/toxicity from the intermittent exposure (42), despite air breaks. In the military study of Doenyas-Barak et al. (45) it occurred gradually with increasing number of treatments >25–35 HBOTs (2.0/90): 2 × 90 × 35 = 6,300 AMs, which is the similar point at which reversal of improvement in PTSD and mTBI PPCS symptoms occurred in the military study of Wolf et al. (38): 30 HBOTs at 2.4/90: 2.4 × 90 × 30 = 6,480 AMs. The Wolf et al. (38) effect at 2.4 ATA of oxygen has been identified as an oxidative stress/toxicity phenomenon (42). Regardless of the intensity, these side effects resolved during the completion of the therapeutic process.

PTSD is a mental health condition triggered by a terrifying event that causes flashbacks, nightmares, and severe anxiety. Once considered primarily a psychiatric disorder, PTSD is now understood to be accompanied by significant changes in the brain (11–21). These neuroanatomical changes help explain the behavioral changes and symptoms as the brain controls our behavior. However, more than explaining the behavioral changes of a person suffering from moderate to severe PTSD symptoms, the brain changes may also help us understand why almost 50% of PTSD sufferers fail traditional treatments and their PTSD becomes chronic and resistant to treatment. Many studies have demonstrated the brain changes in PTSD subjects (11–21); however, this is the first review of studies that measured pre-and-post HBOT brain changes.

Three of the studies in this systematic review (35, 36, 44, 45) included neuroimaging to measure brain changes in chronic and/or treatment resistant subjects as a function of the HBOT treatment. Harch et al. (36) demonstrated significantly increased SPECT brain blood flow in the right posterior hemispheric gray and white matter areas in the HBOT treated veterans compared to controls. Hadanny et al. (44) also included SPECT imaging and the brain blood flow imaging analysis shows significant increases in blood flow in 7 Brodmann areas compared to the control group before cross-over. Hadanny et al. (44) reported MRI DTI results of significant increases in FA in anterior thalamic radiation, left insula, and right thalamus compared to the control subjects pre-cross-over. The significant increases in FA persisted after all control subjects were treated. It is relevant that these women had chronic PTSD that went back to their childhood abuse, but none of the subjects had a history of brain trauma, such as mTBI.

The third study, Doenyas-Barak et al. (45), also studied treatment-resistant PTSD in military veterans with no history of TBI. The study included MRI DTI and demonstrated statistically significant increases in FA in the left anterior and posterior limbs of the internal capsule and right parietal white matter in subjects who received HBOT treatment versus the control subjects. Subjects also showed within-group increases in the fMRI BOLD, which signals an over-oxygenation (actively actuated increase in blood flow and volume) (53) for the HBOT subjects in the left dorso-lateral prefrontal, middle temporal, and temporal gyri, both thalami, left hippocampus and left insula. The increases in fMRI BOLD are usually regarded as increased/improved activity due to flow-metabolism coupling. No within group changes were found for the No Treatment Control subjects.

Hyperbaric oxygen therapy is a dual-component drug therapy consisting of intermittent increased barometric pressure and hyperoxia (25, 26) that has wide-ranging beneficial effects on acute and chronic wound pathophysiology (23, 25, 27, 28) found in acute and chronic wound conditions (23, 25, 27–30) and inflammatory conditions (28–33). HBOT has been demonstrated to have wide-ranging effects on inflammation and a dysregulated immune system (54–59) that may be due to its broad effects on expression and suppression of immune-active genes (60–62). The anatomic and functional imaging findings (11–21) and immune dysregulation in PTSD (19, 63) imply that the experience of a terrifying traumatic event triggers wounding and inflammatory changes in the brain. The structural and functional imaging changes documented in the reviewed studies (35, 36, 44, 45) suggest that the HBOT-generated improvement in PTSD symptoms are the result of HBOT’s well-documented effects on wound pathophysiology and wound-healing. This is apparent in the improvements in connectivity and blood flow in the hippocampus documented by Harch et al. (35) and Doenyas-Barak (45). Given the known immune system-activity of HBOT it is also likely that the symptomatic improvements are in part due to HBOT’s beneficial impact on the immune system dysregulation in PTSD. These imaging and immune system findings coupled with HBOT’s effects on inflammation and wounds suggests that PTSD can no longer be considered strictly a psychiatric condition.

Multiple high quality low bias randomized controlled trials and randomized trials of HBOT in the treatment of PTSD symptoms or PTSD demonstrated statistically significant, clinically significant, and/or reliable change improvements in symptoms that occurred across a wide range of oxygen and pressure doses with a dose–response relationship for symptom relief and total oxygen dose. Side effects were minor except for a transient period of significant emotional symptoms at the highest oxygen doses.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

SA: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. PH: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.