Ketamine for Treatment of Posttraumatic Stress Disorder: State of the Field

Abstract

Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition. Although several psychotherapeutic and pharmacological treatments are recommended for PTSD, many individuals do not respond to treatment or respond only partially, highlighting a critical need for additional treatments. Ketamine has the potential to address this therapeutic need. This review discusses how ketamine emerged as a rapid-acting antidepressant and has become a potential treatment for PTSD. A single dose of intravenous (IV) ketamine has been shown to facilitate rapid reduction of PTSD symptoms. Repeated IV ketamine administration significantly improved PTSD symptoms, compared with midazolam, in a predominantly civilian sample of individuals with PTSD. However, in a veteran and military population, repeated IV ketamine did not significantly reduce PTSD symptoms. Further study of ketamine as a treatment for PTSD is necessary, including which populations benefit most from this therapy and the potential benefits of combining psychotherapy and ketamine.

Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition characterized by exposure to a traumatic event resulting in distress and impaired functioning. PTSD was first formally recognized in the 1980s, following activism by Vietnam War veterans to improve recognition of war-related mental illness in the late 1970s. Since then, the condition has been expanded to include nonmilitary personnel experiencing symptoms after traumatic events (1). Symptoms necessary to diagnose PTSD include recurrent intrusions (e.g., trauma memories, nightmares), avoidance of trauma reminders, negative alterations in mood and cognitions, and enhanced arousal and reactivity (2). PTSD symptoms are often intense, debilitating, and can expand far beyond those formalized by the DSM-5 diagnostic criteria (3). Although PTSD symptoms are often diverse, the criterion all these patients have in common is exposure to a traumatic event—the first prerequisite for developing PTSD. Most U.S. adults will experience a traumatic event at some point, but not every individual will develop PTSD (4). In the United States, the lifetime prevalence of PTSD is thought to be between 6% and 9% in the general population (5), and there is evidence that the risk for developing PTSD is influenced by trauma severity, history of prior trauma, childhood adversity, family history of psychopathology, and other factors (6, 7).

Psychotherapeutic Treatments for PTSD

The American Psychiatric Association (APA) clinical practice guideline recommends several psychological treatments to reduce symptoms of PTSD. These treatments include cognitive-behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), and prolonged exposure (PE) therapy (8). These same guidelines also recommend eye movement desensitization and reprocessing (EMDR) therapy and narrative exposure therapy (NET) (8). PE aims to alter a person’s representation and meaning of fearful stimuli so that they are no longer markedly distressing. PE originates from emotional processing theory, which posits that emotions related to a traumatic event have not been fully processed. The therapy is completed in 8–15 sessions and includes psychoeducation about common reactions to a traumatic event, in vivo exposure, imaginal exposure, and breathing retraining. CPT aims to alter a person’s beliefs surrounding the trauma, and their role in it, in order to take in new learning and new beliefs. CPT typically incorporates exposure therapy and CT components. It involves 12 weekly sessions in which individuals learn to challenge their cognitions and restructure their beliefs (9). Similar to CPT, CBT also involves a component of exposure therapy. CBT includes exposure and behavioral techniques aimed at restructuring negative thought patterns and removing the behaviors associated with those patterns. The effectiveness of these treatments has varied widely across studies, with a wide range of participants who no longer meet diagnostic criteria for PTSD (9). Although these psychological treatments are the current first-line recommendation for treating PTSD, these psychotherapies are limited by their significant dropout rates. In a meta-analysis by Imel et al. (10), there was substantial variability in dropout rates across studies; whereas the average dropout rate across all treatments was 18%, the dropout rate for trauma-specific therapies was 36%. Furthermore, evidence has shown that dropout from PTSD therapies, especially ones that are trauma focused, may be substantially higher in real-world conditions (11).

Pharmacological Treatments for PTSD

Despite questions of efficacy, pharmacological interventions are commonly recommended for the treatment of PTSD (12). The U.S. Department of Veterans Affairs and the Department of Defense recommend selective serotonin reuptake inhibitors (SSRIs) as the first-line pharmacological treatment (8). The APA guideline for PTSD treatment supports the use of SSRIs sertraline, fluoxetine, and paroxetine, and of the serotonin-norepinephrine reuptake inhibitor venlafaxine, although only sertraline and paroxetine are approved by the U.S. Food and Drug Administration for the treatment of PTSD (8). A review and meta-analysis (12) of 51 randomized controlled trials (RCTs) showed that SSRIs proved superior to placebo in reducing PTSD symptoms. That same review found evidence supporting the efficacy of venlafaxine. However, effect sizes of these pharmacological treatments were small (12). Other medications prescribed for PTSD in the community include an adrenoreceptor antagonist (prazosin) and benzodiazepines, yet results from clinical trials have been equivocal and there is mounting evidence that benzodiazepine use may be detrimental to PTSD patients (13). Given significant rates of nonresponse or partial response to medications among patients with PTSD, polypharmacy can be common.

Animal Models Implicate Glutamatergic N-Methyl-D-Aspartate (NMDA) Receptor Activity in Fear and Depression

Not long after PTSD was recognized as a distinct psychiatric disorder, animal researchers posited that fear conditioning (FC) in animals might represent a tractable animal model of emotional memory, perhaps involving circuits relevant for PTSD (1). In the classical fear conditioning paradigm, a neutral stimulus is paired with an aversive cue—such that presentation of the neutral stimulus becomes sufficient to elicit defensive fear behavior (now a conditioned cue). In fear extinction, repeated presentations of the conditioned cue then result in gradual reduction of defensive behavior. A mechanistic link between FC and PTSD was first theorized in 1982 by Kolb and Mutalipassi (14); subsequently, there has been an explosion of interest in understanding the neurotransmitters and circuits that may be important in PTSD through the study of animal models, many of which integrate FC in some way (15).

Fear Acquisition and Extinction in Animals Linked to Glutamatergic NMDA Receptor Activity

Multiple studies of FC in animals have demonstrated the importance of glutamatergic NMDA receptor activation in FC, and in extinction of conditioned fear, which is now viewed as an active process itself (16). An early study of FC suggested that administration of an NMDA receptor antagonist into the amygdala (an area of the brain thought to be critical to FC) during fear acquisition blocked fear conditioning (17, 18). Later studies suggested NMDA receptors in the prefrontal cortex (PFC) were critically involved in the process of fear extinction as well (19). These findings are perhaps not surprising, because both FC and extinction are thought to be learning processes, many of which have been shown to involve NMDA receptors (20).

Ketamine Emerges as a Treatment for Depression and Possibly for PTSD

Systemic Administration of NMDA Antagonists, Including Ketamine, Improves Depressive- and PTSD-Like Symptoms in Rodents

In the 1990s, studies emerged suggesting that systemic administration of NMDA antagonists could alleviate depressive-like symptoms in rats (21) and mice (22). Ketamine, a noncompetitive NMDA receptor antagonist that is thought to enhance synaptic plasticity, was also shown to alleviate depressive- (23) and PTSD-like symptoms (24) in rodents. Although it may appear contradictory that ketamine, as an NMDA receptor antagonist, improves depressive- and PTSD-like symptoms, researchers have shown that systemic administration of ketamine results in transiently increased excitatory activity in the PFC, possibly because ketamine may preferentially inhibit GABAergic inhibitory neurons in rodents and humans (25). Thus, systemic ketamine administration may facilitate an NMDA receptor–dependent process in the PFC that is crucial for fear extinction.

Ketamine Emerges as a Rapid-Acting Antidepressant and Novel Treatment for Depression

Although ketamine had been approved by the FDA since 1970 as an anesthetic agent, a placebo-controlled double-blind study of ketamine as a treatment for depression was not performed until 2000 (26). In this small study, seven participants with major depression were randomly allocated, under double-blind conditions, to receive a single intravenous (IV) infusion of ketamine (0.5 mg/kg, a subanesthetic dose) or of saline, administered over 40 minutes, with each infusion separated by at least 1 week. IV ketamine was associated with robust and rapid reduction in depressive symptoms, as assessed using the Hamilton Depression Rating Scale (HDRS) (26). In 2006, results from a randomized, double-blind crossover study performed at the NIH were published; in this study, 18 patients with treatment-resistant depression received two IV infusions, one of ketamine (0.5 mg/kg) and the other of saline, with each infusion separated by 1 week. Ketamine, compared with placebo, was associated with significant improvement in depressive symptoms (as assessed by the HDRS within 110 minutes after the infusion), with the improvement persisting for a week after the infusion (27). The drug effect size was large (d=1.46 after 24 hours and d=0.68 after 1 week). The rapid antidepressant effect of a single subanesthetic dose of IV ketamine among patients with treatment-resistant depression was subsequently confirmed in a large, two-site RCT of ketamine versus midazolam, which served as a psychoactive placebo (28). Additional research showed that antidepressant effects could persist for 2 to 4 weeks following a course of six repeated ketamine infusions (29), and that improvement could be maintained further by subsequent weekly infusions (30).

Studies Examining Effects of Peritraumatic Ketamine Administration on Development of PTSD

Initial studies of ketamine for PTSD explored whether ketamine administration during the peritraumatic period might be associated with higher or lower risk of developing PTSD. Two studies by Schönenberg et al., a retrospective cohort study published in 2005 (31) and a prospective naturalistic study published in 2008 (32), evaluated whether racemic ketamine or esketamine treatment, administered in the ambulance during the peritraumatic period, was associated with development of acute stress disorder symptoms or PTSD among moderately injured, predominately male accident victims. The earlier study (31) (N=56 patients) found higher levels of retrospectively assessed acute stress disorder symptoms and current PTSD symptoms among patients who received enantiomer esketamine, compared with those who received racemic ketamine or opioids; the racemic ketamine group also showed mildly elevated acute stress disorder symptoms compared with the opioid group. The later study (32) (N=50 patients) found a significant association between racemic ketamine administration and higher acute stress disorder symptom levels when assessed within 3 days of hospitalization, compared with symptom levels among those treated with opioids or nonopioid analgesics.

Conversely, the McGhee et al. (33) retrospective study (2008) of medical records from U.S. service members treated for burns found that ketamine administration, during surgery in the peritraumatic phase, was associated with lower rates of developing PTSD. The same group later published another retrospective study (34) of a larger sample of 289 service members treated for burns, in which no significant difference in PTSD prevalence was found between those who did and did not receive ketamine intraoperatively, but the ketamine group was more severely burned and had undergone more surgeries than those who did not receive intraoperative ketamine. In more recent retrospective studies, including a study of 274 wounded soldiers who received ketamine in the battlefield and/or in the field hospital (35) and a large matched cohort study of 1,158 combat-injured U.S. service members who were administered ketamine for analgesia during hospitalization (36), ketamine was not found to be associated with differential PTSD prevalence. Overall, the evidence to date about ketamine administration shortly after trauma does not clearly suggest it can mitigate development of PTSD, and some concern persists about its potential to increase PTSD risk in this setting.

An emerging research direction aims to evaluate whether ketamine administered prior to trauma exposure might mitigate against the development of PTSD, following findings from animal studies showing prophylactic effects of ketamine when administered 1 week prior to stress exposure (37, 38). In a recent double-blind randomized pilot study of 24 healthy human adults (39), a single ketamine infusion (0.5 mg/kg), compared with a single infusion of midazolam (0.045 mg/kg), was associated (although without reaching significance, p=0.06), with a moderate-to-large reduction in anxiety on completion of the Trier Social Stress Test, when the infusion was administered 1 week before this stressor.

Ketamine as a Treatment for Chronic PTSD

Positive findings from initial studies of ketamine for patients with treatment-resistant depression, coupled with research suggesting glutamatergic system dysfunction in PTSD, raised the possibility that ketamine might be beneficial in treating chronic PTSD. In the early 2000s, there was concern that administering ketamine to patients with chronic PTSD might exacerbate PTSD symptoms, given ketamine’s acute dissociative effects. In 2013, Zeng et al. (40), in secondary analyses of a subset of patients with history of trauma or comorbid PTSD who had participated in one of three clinical trials of a single ketamine infusion for treatment-resistant depression or bipolar disorder, found no evidence of worsening psychotic, anxiety, or dissociative symptoms. That same year, two separate case reports (41, 42) of two young veterans with comorbid treatment-resistant depression and PTSD described rapid and remarkable improvement in depressive and PTSD symptoms lasting for 2 weeks following a single subanesthetic dose of IV ketamine combined with other agents.

First RCTs of Repeated Ketamine for Chronic PTSD

In 2014, results from the first RCT (43) of ketamine for chronic PTSD were published. In this crossover study, 41 participants (mostly civilians) with a primary diagnosis of chronic PTSD and moderate-to-severe symptoms were assigned to receive two IV infusions—a single infusion of ketamine (0.5 mg/kg) and a single infusion of midazolam (0.045 mg/kg)—administered 2 weeks apart in randomized counterbalanced order, with each infusion lasting 40 minutes. In this study, ketamine, compared with the psychoactive placebo midazolam, was associated with rapid reduction in PTSD symptom severity, as assessed 24 hours postinfusion with the Impact of Event Scale–Revised (IES-R) (43). Notably, in the crossover, ketamine was associated with improvement in all domains of the IES-R, including intrusion, avoidance, and hyperarousal (43). Whereas ketamine was also associated with reduction in comorbid depressive symptoms, improvement in PTSD symptoms remained even after the analyses were adjusted for depressive symptom severity at baseline and 24 hours postinfusion, suggesting an effect of ketamine on core PTSD symptoms beyond its effect on depressive symptoms. Additionally, seven patients who received ketamine during their first infusion remained significantly improved 2 weeks after the infusion, compared with only one patient who received midazolam first. This study also found ketamine to be safe and generally well tolerated among patients with chronic PTSD. Any dissociative symptoms emerging during ketamine infusion were short-lived, and ketamine was not observed to induce or worsen sustained dissociation.

The same group of investigators subsequently conducted another RCT (44), to evaluate the efficacy and tolerability of a course of repeated IV ketamine infusions on PTSD symptoms among patients with chronic PTSD, and to examine whether repeated infusions could maintain symptom improvement for a longer period of time. In this new RCT, 30 individuals with chronic moderate-to-severe PTSD were randomly assigned to receive a course of six infusions (three infusions per week over the course of 2 weeks) of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg), administered over 40 minutes. The primary outcome of this study was change in PTSD symptom severity between baseline and 2 weeks after the first infusion, as assessed via the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Findings from this study (44), published in 2021, showed that repeated ketamine infusions were associated with rapid and significantly greater improvement in PTSD and comorbid depressive symptoms, compared with a course of midazolam infusions. In the ketamine group, 67% of patients achieved treatment response, defined as at least a 30% reduction in PTSD symptom severity on the CAPS-5 from baseline to 2 weeks, compared with only 20% in the midazolam group. Significantly greater symptom improvement among those receiving ketamine compared with those receiving midazolam was observed across three of the four DSM-5 PTSD symptom clusters: intrusion, avoidance, and negative mood and cognitions. Patients who responded to ketamine remained improved a median of 4 weeks after completing the six infusions. In this study (44), a course of ketamine infusions was also found to be generally well tolerated among patients with chronic PTSD, again with only transient dissociative symptoms, which resolved shortly after infusion end.

Larger RCT of Repeated Ketamine for Antidepressant-Resistant PTSD of Veterans and Active-Duty Service Members

Results from another RCT (45) of repeated IV ketamine infusions, among a large sample of veterans and active duty service members with chronic moderate-to-severe PTSD refractory to treatment with at least one FDA-approved antidepressant, were recently published by Abdallah et al. In this three-arm study, 158 participants were randomly allocated to receive a total of eight repeated IV infusions, administered twice weekly for 4 weeks, of either a standard subanesthetic dose of ketamine (0.5 mg/kg) (N=51), low-dose ketamine (0.2 mg/kg) (N=53), or saline (N=54), over 40 minutes. Saline was used for the placebo arm because prior studies had suggested that benzodiazepines might worsen PTSD outcomes (46). The primary outcome of the study was PTSD symptom severity, as assessed via the self-report PTSD Checklist for DSM-5 (PCL-5) across the 4 weeks of treatment. Although there was a significant effect of time, with PCL-5 scores improving over time for all treatment groups, there was no significant effect of treatment and no significant treatment-by-time interaction. Secondary analyses with the CAPS-5 similarly yielded a significant effect of time but not of treatment, and no significant treatment-by-time interaction (45). There was a higher proportion of treatment responders (≥25% improvement in PCL-5 scores) in the two active treatment groups than in the placebo group 24 hours after the first infusion, but this difference was not statistically significant (45). In additional secondary analyses, ketamine at the standard dose was associated with a significant effect on depressive symptoms 24 hours after the first infusion, and a significant treatment-by-time interaction across the 4 weeks of treatment, as assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), suggesting the potential utility of ketamine for the treatment of depressive symptoms commonly occurring with chronic PTSD (45). In this study, repeated ketamine infusions were also found to be safe and well tolerated in PTSD, with only transient emergence of dissociative symptoms.

Although findings from the Abdallah et al. study (45) were counter to those of Feder et al. (44), a number of factors might explain the differences in study results. First, the Abdallah et al. study (45) was conducted in a military population, and at least one meta-analysis (47) has suggested that veterans with PTSD may have lower treatment response. The Abdallah et al. study also required treatment resistance to at least one antidepressant medication (43, 44). Additionally, the military sample was predominantly male, whereas the majority of participants in the Feder et al. RCT (44) were female. There were also differences in the frequency of ketamine administration and in the total number of infusions, as well as other methodological differences, including in the primary outcomes and their assessment. Further study is needed to examine a range of factors that may be associated with response to ketamine treatment for PTSD, including demographic characteristics, nature of primary trauma, degree of prior treatment resistance, and dosing of ketamine. For example, more frequent ketamine infusions (at least 3 times per week) may be necessary for treatment of PTSD.

Ketamine Studies Among Individuals With Comorbid PTSD

Prior to completion of the first RCT of repeated ketamine for PTSD, findings were published from two preliminary studies of repeated ketamine treatment among patients with treatment-resistant depression comorbid with PTSD. The first one, a retrospective study published in 2018 (48), examined hospital records from 37 individuals with comorbid treatment-resistant depression and PTSD, who had received adjunctive treatment with long-term oral ketamine and had failed to respond to at least two medications for depression; in 15 of these patients, PTSD was the primary diagnosis. Treatment with oral ketamine was associated with a 65% reduction in psychiatric hospital admissions and a 70% reduction in inpatient hospital days, with no long-term adverse effects (48). Results from the second study, an open-label trial of repeated ketamine infusions for 15 individuals with comorbid PTSD and treatment-resistant depression, were also published in 2018 (49). In this study, after six IV infusions of ketamine (0.5 mg/kg) administered three times per week across 2 weeks, the PTSD remission rate was 80% (as assessed via the PCL-5, with improvement seen in all subdomains), and the treatment-resistant depression response rate was 93.3% (as assessed via the MADRS), with no worsening of PTSD symptoms.

Given prior evidence on the use of ketamine for treatment of chronic pain, and the high comorbidity of chronic pain and PTSD, Dadabayev et al. (50) conducted an RCT comparing the effects of a single IV ketamine infusion (0.5 mg/kg over 40 minutes) and the active placebo ketorolac, a nonsteroidal anti-inflammatory agent, among a sample of U.S. veterans with chronic pain, with and without PTSD. In this study, both IV ketamine and ketorolac were associated with improvement in PTSD symptoms and chronic pain 24 hours postinfusion, persisting for 1 week. Patients who had both conditions showed fewer dissociative side effects than those with only chronic pain (50).

Additionally, following FDA approval of intranasal esketamine as an adjunctive treatment for patients with treatment-resistant depression, a recent retrospective case series analysis evaluated the effect of repeated intranasal esketamine among 35 veterans referred for evaluation and treatment of treatment-resistant depression comorbid with PTSD. Esketamine treatment was associated with improvement in depressive and PTSD symptoms, although some patients exhibited improvement in PTSD symptoms without clear improvement in depressive symptoms (51). This study (51) also explored subdomains of PTSD via the PCL-5 and found esketamine treatment resulted in improvements in all domains.

Framework for Understanding How Ketamine May Improve PTSD

Although the exact nature by which ketamine may improve PTSD symptoms is unclear, studies from animal models and humans have suggested that ketamine treatment facilitates neuroplasticity and can enhance activity in the PFC. A recent functional MRI study (52) of a subsample of the Feder et al. participants (44) examined functional connectivity before and after repeated ketamine infusions, compared with repeated midazolam infusions, for chronic PTSD. The study (52) found that increased functional connectivity between the amygdala and ventromedial PFC (vmPFC) when viewing emotional faces was associated with PTSD symptom improvement with treatment, and that this association was stronger in the ketamine group. Interestingly, there was substantial overlap in the circuits identified as important to ketamine response in individuals with PTSD and in the circuits that have been implicated in fear extinction in animal studies (52). Indeed, structural and functional imaging studies of humans and animals have suggested that normal fear extinction involves the vmPFC across species (53). Recent brain stimulation studies (54, 55) have also provided some evidence that stimulation protocols devised to activate the vmPFC may improve fear extinction in humans. A recent study (24) in rodents also has suggested that ketamine administration may change glutamatergic release in the PFC to facilitate fear extinction. Furthermore, studies of individuals with PTSD have suggested that decreased vmPFC functional activation to trauma-related cues is associated with greater PTSD symptoms and, in some studies, successful treatment of PTSD has appeared to be associated with increased vmPFC activation and increased functional connectivity of vmPFC and subcortical areas, irrespective of the intervention used (53). A summary of RCTs that have examined the efficacy of ketamine for PTSD is presented in Table 1.

TABLE 1.

Randomized controlled trials that examined the efficacy of ketamine for the treatment of PTSD

Publication	Diagnosis	Population	Sex, female (%)	N	Ketamine intervention	Effect on PTSD symptoms
Feder et al., 2014 (43)	Chronic PTSD	Community	46	41	Single intravenous (IV) infusion of ketamine hydrochloride (.5 mg/kg) vs. single IV infusion of midazolam (.045 mg/kg)	Ketamine superior to midazolam
Feder et al., 2021 (44)	Chronic PTSD	Community	77	30	Repeated IV infusions of ketamine hydrochloride (.5 mg/kg) vs. midazolam (.045 mg/kg), 3 times a week for 2 weeks (total six infusions)	Ketamine superior to midazolam
Abdallah et al., 2022 (45)	Treatment-resistant chronic PTSD	Veterans and active-duty service members	23	158	Repeated IV infusions of standard-dose ketamine (.5 mg/kg) vs. low-dose ketamine (.2 mg/kg) vs. placebo (saline), twice weekly for 4 weeks (total eight infusions)	No significant between-group differences

Next Steps: Combining Ketamine and Psychotherapy for Chronic PTSD

Mechanistic studies in animal models and in humans with chronic PTSD suggest that ketamine may improve PTSD symptoms by enhancing the process of fear extinction, a form of learning. Indeed, some studies have suggested that individuals with PTSD have altered fear processing and extinction, with alterations in the same circuits (PFC-amygdala) thought to be affected by ketamine treatment (56). Interestingly, recent mechanistic studies of some psychotherapies for PTSD have suggested involvement of the same circuits. For example, one RCT (57) of EMDR versus a waitlist control condition for PTSD found that patients who received EMDR therapy had improved fear extinction learning after treatment and functional modifications between multiple brain areas, including in the amygdala and subregions of the PFC. Indeed, multiple studies (58, 59) have suggested that fear extinction learning is impaired in individuals with PTSD and can be corrected with EMDR therapy. Rodent studies also support the utility of combining ketamine with extinction learning for PTSD symptoms (60). These findings bring up the interesting possibility that certain psychotherapies may work synergistically with ketamine, engaging similar circuits to alleviate symptoms of PTSD. Indeed, early studies have begun to evaluate whether combining ketamine with certain psychotherapies might result in long-lasting improvement of PTSD symptoms (61–65), including whether repeated ketamine infusions can augment PE therapy, a gold-standard PTSD psychotherapy treatment (66, 67). A summary of pilot studies that have examined the efficacy of ketamine combined with psychotherapy for PTSD is presented in Table 2. Currently, there are a number of ongoing studies exploring whether ketamine may be useful in augmenting several types of psychotherapy for PTSD; if successful, this approach could dramatically change the way we treat PTSD (68, 69).

TABLE 2.

Pilot studies that evaluated the combination of ketamine and psychotherapy for the treatment of PTSD^a

Publication	Diagnosis	Population	Sex, female (%)	N	Ketamine intervention	Therapy intervention	Study design	Effect on PTSD symptoms
Shiroma et al., 2020 (67)	Chronic PTSD	Veterans	30	10	Repeated IV infusions of ketamine (.5 mg/kg) once a week for 3 weeks	PE weekly for up to 10 weeks	Open label clinical trial	Improved symptoms
Pradhan et al., 2018 (64)	Treatment-resistant chronic PTSD	Community	60	20	Single IV infusion of ketamine (.5 mg/kg) vs. single IV infusion of normal saline	TIMBER psychotherapy, 12 sessions	Pilot randomized clinical trial	No significant between-group difference at 24 hours. Longer duration of improvement in the ketamine group
Keizer et al., 2020 (63)	Chronic pain and PTSD	Veterans	27	11	Continuous IV infusion of ketamine starting at 2 μg/kg/min, increased to a final dose of 11–15 μg/kg/min, lasting approximately 96 h at this final dose	Bedside psychotherapy for 90 minutes	Case series, patients receiving ketamine infusion for chronic pain	Improved symptoms

^a IV, intravenous; PE, prolonged exposure; TIMBER, Trauma Interventions using Mindfulness Based Extinction and Reconsolidation for trauma memory.

Insights From Studies Exploring the Role of Ketamine in PTSD

A number of recent meta-analyses (70–72) have examined whether available evidence supports the use of ketamine for PTSD. Overall, there appears to be evidence suggesting that ketamine treatment results in rapid improvement of PTSD symptoms among certain individuals with PTSD. Importantly, in all of the studies that have been completed thus far, there have been no reports of serious adverse events, and the treatment has been relatively safe and well tolerated (43–45). Still, there are important practical considerations when considering the translation of these studies to the community. For example, both the Feder et al. studies and the Abdallah et al. study excluded individuals with significant substance use disorders or psychotic symptoms. Therefore, how ketamine treatment may affect individuals with PTSD and these comorbid conditions remains unknown. This is a practical concern, because it is thought that 19%–52% of individuals with PTSD have a comorbid substance use disorder (73) and in certain populations, such as veterans, this number may be even higher (74). Future studies exploring the role of substance abuse in responsiveness to ketamine for PTSD would be useful but likely difficult to perform. In addition, future studies should address the role of specific trauma-exposed populations and explore whether ketamine may be helpful for nonfear-related symptomatology, such as reward processing deficits that have been reported in PTSD (75). Notably, there is some evidence from a naturalistic study of patients with treatment-resistant depression (76) suggesting that individuals with childhood maltreatment and trauma have an enhanced response to ketamine treatment. Still, there are reasons to be hopeful that ketamine treatment could represent a major step forward in the treatment of PTSD. Specifically, there is active research examining whether the combination of ketamine with certain psychotherapies may work synergistically to improve PTSD symptoms, which could represent the future of PTSD treatment if found to be successful (clinicaltrials.gov, NCT04560660, NCT04889664, NCT05737693). Mechanistic studies among humans and in animal models suggest the potential for synergy between these interventions, given the shared action of both interventions on the connectivity between the amygdala and the PFC. A better understanding of the mechanisms behind the effect of ketamine in PTSD would also benefit the field.

Conclusions

Ketamine has been shown to be a rapid-acting antidepressant, capable of improving depressive symptoms among patients with some of the most difficult-to-treat conditions. Whether ketamine holds the same promise for individuals with PTSD remains unclear, but there is compelling evidence that certain individuals with PTSD, and especially individuals with PTSD and comorbid depression, would likely benefit from ketamine treatment. Further investigations are necessary to better understand which individuals with PTSD would benefit most from this intervention.