Rapid and sustained reduction of treatment-resistant PTSD symptoms after intravenous ketamine in a real-world,psychedelic paradigm

Abstract

Background:

Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments—including preparatory, integration, sensory immersion, and psychotherapy sessions—could decrease PTSD symptoms meaningfully.

Methods:

A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials.

Results:

Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients’ final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms.

Conclusion:

Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine’s potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule’s cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.

Keywords

Ketamine PTSD psychedelic psychotherapy ketamine-assisted psychotherapy

Introduction

Post-traumatic stress disorder (PTSD) is a debilitating, chronic mental health condition that affects approximately one in four individuals exposed to trauma (Diamond et al., 2022). PTSD encompasses a range of symptoms such as recurrent intrusive thoughts, avoidance of trauma reminders, negative alterations in cognition and mood, and heightened physiological reactivity (American Psychiatric Association, 2013). The disorder not only affects individuals but also has far-reaching impacts on families, communities, and healthcare systems. With an estimated lifetime prevalence of approximately 9% among U.S. adults and higher rates in certain populations such as military veterans, PTSD represents a significant public health concern (Kilpatrick et al., 2013; National Center for PTSD, 2020).

While certain mental health conditions commonly resolve without treatment—such as 70% natural remission rates in alcohol addiction and 75% natural remission rates in borderline personality disorder (Biskin et al., 2012; Tucker et al., 2020)—a meta-analytic review of 42 studies revealed that only 44% of PTSD cases self-resolved after a mean of 40 months (Morina et al., 2014). The conventional treatments for PTSD primarily include cognitive-behavioral interventions and pharmacotherapy. These approaches present several challenges. Psychotherapies, while effective, can leave as many as 50% of clients essentially unimproved on PTSD measures, even with empirically supported approaches (Schottenbauer et al., 2008). Further, dropout rates average nearly one in five patients, can exceed 30% in veteran samples, and have reached as high as 78% (Imel et al., 2013; Goetter et al., 2015). High rates of nonresponse and dropout underscore an urgent need for PTSD interventions that are efficacious, tolerable, and relatively brief.

Pharmacotherapy, predominantly involving selective serotonin reuptake inhibitors (SSRIs), faces its own limitations. While SSRIs benefit some patients with PTSD, their efficacy is modest, not universal, and side effects are common. Additionally, their therapeutic effects often take weeks to manifest, a significant delay for those suffering from acute symptoms (Stein et al., 2006). Thus, rapid-acting, effective treatments for PTSD could benefit many, especially those with treatment-resistant forms of the disorder.

Growing evidence supports the potential for ketamine, an N-methyl-D-aspartate antagonist, to rapidly treat various mental health conditions. Ketamine was first developed as a “dissociative anesthetic” in the 1960s, noted for its minimal impact on respiratory drive (Domino et al., 1965). In recent years, a large evidence base has bolstered ketamine’s use in off-label psychiatric treatment at subanesthetic doses. Since the 1990s, researchers have consistently observed ketamine’s swift effect on depression symptoms (Alnefeesi et al., 2022; Coyle et al., 2015; Fond et al., 2014). Yet, newer studies examining its impact on PTSD have generated conflicting results. For example, intravenous ketamine significantly improved PTSD symptoms in a randomized controlled trial with 30 participants (Feder et al., 2021). In contrast, the largest RCT to date failed to find a significant effect over placebo in 158 veterans with the disorder (Abdallah et al., 2022), which highlights the necessity for additional research.

Amid these challenges, researchers are pursuing a range of innovative new drug-assisted therapies for PTSD. Recently, shifting regulatory attitudes have inspired a “psychedelic renaissance,” enabling renewed efforts to explore the safety and efficacy of psychedelics and related compounds for treatment-resistant health conditions. Across a wide range of studies, MDMA-assisted psychotherapy has shown substantial promise for patients who have found little relief in conventional PTSD therapies. The treatment received FDA breakthrough therapy status in 2017, proved highly efficacious in Phase 3 trials (Mitchell et al., 2023), and was broadly expected to see FDA approval by 2024. However, in the wake of a Phase 2 trial participant’s abuse by study therapists, and several consequent research retractions, the FDA declined to approve MDMA and instead requested an additional Phase 3 trial. Furthermore, MDMA therapy itself is not without its limitations. Due to MDMA’s serotonergic activity, patients must cease SSRI usage throughout the course of treatment, posing potential psychiatric risks for those discontinuing the drug in anticipation of an uncertain MDMA response. Additionally, current protocols call for two therapists to remain in the treatment room with patients for 8 h or more for multiple MDMA dosing sessions (Mithoefer et al., 2013). While this model has proven beneficial for many study participants, its complexities raise questions of cost and access for real-world implementation—and its regulatory hurdles put its future in question.

The term “psychedelic renaissance” typically refers to renewed scientific and popular interest in 5-HT2A agonists (so-called “classic psychedelics”), as well as MDMA. Meanwhile, both researchers and clinicians have frequently regarded ketamine as an unrelated substance, despite its markedly psychoactive effects (Bennett, 2019; Dore et al., 2019). Frequently, ketamine trials employ a dose at the low end of the subanesthetic dose range, typically 0.5 mg/kg, to mitigate dissociative or “psychotomimetic” effects—a practice which first became commonplace in ketamine dosing for depression (Andrade, 2017). Indeed, in analyses of multiple depression trials, a subset of ketamine’s subjective effects—dissociative “floating”—failed to predict therapeutic outcomes, while broader measures of acute dissociation predicted positive outcomes up to a week later (Acevedo-Diaz et al., 2020; Luckenbaugh et al., 2014).

In sharp contrast, psychedelic therapy research commonly employs intensely mind-altering doses in pursuit of self-transcendent, unitive, ineffable states—a validated construct known as mystical-type experience (Barrett et al., 2015). At long-term follow-up, samples of both healthy volunteers and psychiatric patients have frequently rated these transient, egoless states among the top most meaningful experiences of their lives (Fischman, 2019). Researchers have associated this effect profile with a wide range of beneficial, long-term outcomes spanning months to years following a single drug administration (Kangaslampi, 2023).

Despite the prevailing usage of ketamine as a primarily biological agent, converging research demonstrates that ketamine, under specific conditions, at sufficient subanesthetic doses, can produce a range of mystical-type effects that overlap with those of classic psychedelics in magnitude and kind (Marguilho et al., 2023). Research thus far reveals that ketamine’s mystical-type experiences mediate robust therapeutic outcomes for depression and substance use disorders (Dakwar et al., 2014; Krupitsky et al., 1997; Mathai et al., 2020; Rothberg et al., 2021). Nevertheless, ketamine’s research and clinical paradigms have frequently excluded “set and setting” considerations common in psychedelic therapy, such as psychological preparation and integration, music, eye shades, moderately high dose ranges, and a welcoming clinician stance toward intense and unpredictable effects. This approach to psychedelic therapy has been an established best practice for decades, across a range of substances, including ketamine (Leary et al., 1963; Gukasyan et al., 2022; Hartogsohn, 2016; O’Donnell et al., 2023; Wolfson, 2014). Attending to these “set and setting” factors commonly decreases challenging experiences and increases positive outcomes with classic psychedelic compounds (Borkel et al., 2024; Hartogsohn, 2017; Kaelen, 2018).

In light of mounting evidence, ketamine therapy outcomes may greatly benefit from a paradigm most commonly reserved for classic psychedelics and MDMA. However, the relevance of these factors to intravenous ketamine for treatment-resistant PTSD is unknown. Given this discrepancy, we sought to better understand the effects of ketamine on PTSD symptoms in a setting more closely resembling psychedelic therapy. The present study retrospectively reports the clinical outcomes of patients treated at Nushama Psychedelic Wellness Center, a clinic in New York City that has adapted a psychedelic treatment model to ketamine infusions for chronic mental health conditions. With 117 patients in the final sample, this analysis is, to the authors’ knowledge, the largest real-world study of intravenous ketamine for treatment-resistant PTSD to date.

Methods

Clinic process

Screening

The clinic provides ketamine treatment for individuals grappling with severe mental health conditions resistant to other treatments, such as major depressive disorder (MDD), bipolar disorder, anxiety, and PTSD. After a psychiatric and medical assessment, patients review and sign a consent for ketamine treatment that emphasizes that ketamine is not approved by the US FDA for depression and other mood disorders, and is provided off label, in addition to potential risks and benefits. Individuals with a history of psychosis, current mania, or uncontrolled medical conditions do not qualify for participation. Anonymized patient charts provided data on demographics, trauma type, PCL scores, diagnoses, past medications, psychotherapy history, suicidal ideation history, number of infusions, and infusion dosages. An institutional review board at University at Albany declared this study exempt, due to the retrospective, de-identified, and pre-consented nature of its data collection.

Dosing procedure

A medical team, including a physician, nurse practitioner, nurse, medical assistant, and integration coach, monitors each patient during visits. This team also administers the nursing assessment, places the IV, reviews medical history, and discusses ketamine dosing. Dosing discussions occur at each session. Integration coaches spend 15–30 min with patients both before and after the session to aid in preparation and processing, totaling 30–60 min. After this preparation session, patients receive eye shades and headphones, to listen to evocative music during the duration of their infusion and minimize external distraction, in line with common psychedelic therapy protocols. The initial dose usually stands at 0.8 mg/kg over 60 min. In consultation with recipients, subsequent doses are progressively escalated by 0.1–0.2 mg/kg to achieve a psychedelic dose range with documented efficacy and safety across a range of conditions (Bowdle et al., 1998; Dore et al., 2019; Krupitsky et al., 1997; Kolp et al., 2014). Staff treat occasional nausea—at rates in line with previous research (Dore et al., 2019)—with ondansetron or meclizine and offer them prophylactically to patients with a history of motion sickness or discomfort after anesthesia. Additional psychotropic medications, such as benzodiazepines for acute stress reactions, are not employed. Staff monitor blood pressure before and 30 min after starting infusions, administering intravenous labetalol, metoprolol, or oral clonidine to patients with significant pressure increases. Patients can leave once they return to their baseline mental state, free from gait disturbances and nausea, and with normal blood pressure. The clinic prohibits patients from driving until the next day. Infusions in this sample were provided between 9a.m. and 4p.m. The initial protocol includes twice-weekly infusions over 3 weeks, followed by a tailored maintenance schedule. Maintenance doses depend on the interval since the last treatment and previous dose responses, with adjustments for medical conditions or changes in medications. Patients generally continue other pharmacological and psychotherapeutic treatments. The clinic staff does recommend pausing lamotrigine for 24 h before treatment and withholding stimulants, benzodiazepines, and gabapentin on the morning of administration sessions. Staff members and clinic written material also advise against alcohol, marijuana, and other non-prescribed drugs for 48 h before and 24 h after administration sessions.

Statistical analyses

Researchers screened 337 patients with intakes between November 2021 to August 2023 who had completed the PTSD Checklist for DSM-5 (PCL-5), a self-report measure comprising 20 items that correspond to DSM-5 PTSD symptoms (Weathers et al., 2013). Of these patients, 257 started ketamine treatment, 170 of whom at intake scored over 31 on the PCL. Among these 170 patients, 117 completed at least one more PCL, allowing for a pre- and post-treatment analysis in this study.

A 10-point or greater reduction in the PCL defined a clinically significant change in PTSD symptoms. Researchers used this threshold to distinguish between responders and nonresponders. Furthermore, they identified patients as remitters or non-remitters using a cut-off score of 33 or lower on the PCL-5 at the time of the last recorded measure.

A repeated-measures analysis of covariance (ANCOVA) revealed the effect of ketamine therapy on PTSD symptomatology across two time points: baseline (FirstPCL) and follow-up (LastPCL). The within-subjects factor was time with two levels, and the PTSD Checklist (PCL) score served as the dependent variable. This analysis controlled for the following covariates: age, gender, days between PCL assessments, number of past psychiatric medication trials, concomitant psychotherapy at intake, current suicidal ideation at intake, and past suicidal ideation. The distribution of residuals was assessed for normality using the Shapiro-Wilk test, which was nonsignificant for both FirstPCL, W = 0.988, p = 0.393, and LastPCL, W = 0.978, p = 0.051, suggesting the residuals were normally distributed. Visual inspection of Q-Q plots further corroborated these findings, displaying a predominantly linear pattern with minor deviations at the tails, indicative of approximate normality. A two-tailed p-value of <0.05 qualified as statistically significant, based on analyses using Statistical Package for Social Science (SPSS) version 29.0 for Mac (IBM Corporation, Armonk, NY, USA).

Results

Subject characteristics

The final sample included 117 outpatients treated and assessed between 27 September 2021, and 11 October 2023. Among these participants, 72.6% identified as female with an average age of 41.9 years (SD = 13.1, range: 20–74). 45.3% of participants did not report their race or ethnicity at intake, while the remaining were: 45.3% caucasian; 5.98% Asian; 2.56% Black or African American; and 0.85% American Indian/native Alaskan. The majority, 96.58%, had at least one psychiatric comorbidity. On average, patients had previously undergone 4.68 psychiatric medication trials (SD = 1.97, range: 0–13). A small number of patients (n = 7) reported no history of medication trials but had a history of nonresponse to psychotherapy. At intake, 17% reported active suicidal ideation, while 62% had a history of suicidal ideation.

Patients received an average of 4.79 ketamine infusions (SD: 1.7; range: 2–9; mode: 3) from the first to the last PCL in their records. The mean ketamine dose across all infusion series was 1.28 mg/kg (SD: 0.20 mg/kg; range: 0.50–2.40 mg/kg), with the highest dose averaging 1.62 mg/kg (SD: 0.27 mg/kg; range: 0.7–2.4 mg/kg). Table 1 presents complete demographic and clinical characteristics of the patients.

Treatment outcomes

A total of 117 patients recorded a PCL-5 over 31 at intake, initiated ketamine treatment, and completed at least one subsequent PCL-5 to analyze over the course of treatment. Patients tolerated treatment well, with no serious adverse events. Rates of adverse effects, including nausea, vomiting, and agitation were low, very rarely led to discontinuation of treatment, and paralleled previous research (Dore et al., 2019). Of these patients, 111 (94%) finished the full course of ketamine treatment. (See Figure 3 for full attrition analysis). Of the 117 patients’ final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms. Time points for final PCL measures ranged between 1 and 44 weeks, an average of 55 days after the first (SD: 60 days; range: 7–314 days; mode: 14 days).

PCL scores showed significant mean decreases from the first to the last recording, with an initial mean at intake of 52.54 (SD = 12.010) and a subsequent mean of 28.78 (SD = 16.608). The main effect of time was significant, F (1, 103) = 10.737, p = 0.001, partial η² = 0.094, demonstrating a substantial reduction in PTSD symptoms post-treatment. No significant interaction effects appeared for time * age, time * gender, time * days between PCL assessments, time * psychiatric medication count, time * current suicidal ideation, or time * past suicidal ideation. However, time and concomitant psychotherapy status at intake did interact, F (1, 103) = 4.957, p = 0.028, partial η² = 0.046, suggesting a moderating effect of concomitant psychotherapy on ketamine treatment outcome for PTSD.

In tests of between-subjects effects, age was significantly associated with the average PCL scores, F (1, 103) = 8.175, p = 0.005, partial η² = 0.074 but no significant effects appeared for gender, previous psychiatric medication count, days between PCL assessments, current therapy status, or suicidal ideation.

Multivariate tests confirmed the time effect, with Pillai’s trace, Wilks’ lambda, Hotelling’s trace, and Roy’s largest root yielding an F value of 196.651, all p < 0.001, partial η² = 0.656, based on the linearly independent pairwise comparisons among the estimated marginal means. Pairwise comparisons of the estimated marginal means between the two time points indicated a significant reduction in PTSD symptoms, mean difference = −23.757, 95% CI (−27.117, −20.397), p < 0.001.

Cohen’s d effect sizes quantified the standardized difference in PTSD symptom severity, as measured by the PCL, from pre- to post-ketamine therapy. The mean PCL score decreased from 52.54 (SD = 12.01) at the first assessment to 29.42 (SD = 16.52) at the last assessment. This change represents a Cohen’s d of 1.64, a large effect size according to Cohen’s conventions (Cohen, 1988). These results suggest that, while the ANCOVA revealed a modest partial eta squared for time, the raw change in symptom severity reflected a robust overall treatment effect when standardized to the variability in the sample.

Exploratory analysis of follow-up periods

To better understand the potential impacts of a wide variance in follow-up periods, we conducted additional exploratory analyses of common follow-up periods within the range of recorded data: 0–14 days, 15–30 days, 31–90 days, and 91–365 days. Sub-analyses grouped patients by the days elapsed between their first and last PCL assessments. Independent samples t-tests confirmed large and significant reductions in mean PCL scores within each group (See Figure 2 for statistics). Visual inspection of these pre-post results by follow-up period offers more intuitive confirmation of a statistical finding in the primary ANCOVA analysis: when days between PCL assessments were controlled for as a covariate, they did not significantly interact with the main treatment effect. Altogether, these analyses reveal both rapid and sustained PTSD symptom reductions following treatment.

Exploratory analysis of therapist effects

Independent samples t-tests confirmed large, significant pre-post mean reductions in PCL scores in participants who received concomitant psychotherapy (68.4% of the sample) as well as those who did not (31.6% of the sample). However, an absolute effect size difference reveals a moderately large between-group effect favoring those who did receive concomitant psychotherapy, d = 0.51.

In participants who received concomitant psychotherapy the mean PCL score decreased from 53.74 (SD = 11.64) at the first assessment to 28.40 (SD = 16.66) at the last assessment, t(79) = 10.88, p < 0.0001, resulting in a large effect size of d = 1.76. In participants who did not receive concomitant psychotherapy, the mean PCL score decreased from 49.49 (SD = 12.10) at the first assessment to 31.62 (SD = 16.23) at the last assessment, t(36) = 4.64, p < 0.0001, also resulting in a large effect size of d = 1.25. Lastly, we calculated an absolute effect size difference between groups, indicating a moderate difference favoring those who received concomitant psychotherapy, d = 0.51

Discussion

This retrospective chart review examined the largest set of real-world outcomes to date for treatment-resistant PTSD patients receiving intravenous ketamine (Ragnhildstveit et al., 2023). A total of 117 outpatients received ketamine therapy in a highly supportive, real-world clinic environment, with the hallmarks of psychedelic therapy—including eye shades, headphones, intention setting, preparation and integration, a supportive care team, and moderately high doses. Patients received an average of 4.79 infusions (SD: 1.7; range: 2–9; mode: 3) from the first to the last PCL in their records, with an average dose of 1.28 mg/kg (SD: 0.20 mg/kg; range: 0.50–2.40 mg/kg).

Treatment preceded large reductions in PTSD symptom severity over a wide range of follow-up periods, spanning 7–314 days (mean between first and last PCL: 55 days, SD = 60; mode: 14 days). Out of 117 patients, 88 (75.21%) measures suggested a clinically meaningful improvement, and 72 (61.54%) measures suggested remission of PTSD symptoms on their final PCL. After controlling for covariates—age, gender, days between PCL assessments, number of past psychiatric medication trials, concomitant psychotherapy at intake, current suicidal ideation at intake, and past suicidal ideation—the main treatment effect remained significant. The mean PCL score decreased from 52.54 (SD = 12.01) at the first assessment to 28.78 (SD = 16.61) at the last assessment, resulting in a Cohen’s d effect size of d = 1.64.

Further, patients who received concomitant psychotherapy from an external provider (68.4% of the sample) had significantly greater PCL reductions than those who did not, d = 0.51. Previous studies of intravenous ketamine for PTSD included participants receiving concomitant psychotherapy but did not consistently report rates or moderating effects (Abdallah et al., 2022; Feder et al., 2021). Further investigation of concomitant psychotherapy’s moderating effects in randomized controlled designs would be a welcome confirmation of the present study’s preliminary findings.

Given the wide variance in follow-up periods, spanning 1–44 weeks, we conducted additional exploratory analyses of various common follow-up periods: 2 weeks, 1, 3, and 12 months. These sub-analyses revealed large and statistically significant effects within groups, with modest variation among them. This provides additional evidence for the primary ANCOVA result, that days between PCL assessments were not significantly associated with treatment outcome.

Patients in the present study tolerated treatment well, with no serious adverse events. Rates of dropout were not dissimilar from PTSD psychotherapy trials: 170 patients with a PCL over 31 began treatment, 117 completed at least one post-infusion PCL, and 111 finished, representing a 35% dropout rate. Whereas dropout frequently results from poor treatment tolerability in exposure-based psychotherapies for PTSD, dropout in the present data mostly resulted from scheduling conflicts and other unspecified reasons, versus adverse events. Given insufficient insurance coverage for generic ketamine treatments, we cannot rule out cost as a possible contributing factor to early discontinuation. Further, while the study clinic adapted a 6-infusion protocol from clinical research—based in turn on early depression trials—the necessity of this number of infusions has not been rigorously validated in PTSD samples.

The treatment approach in the present study aimed to enhance the magnitude and salience of ketamine’s subjective effects while promoting psychological safety. These factors—preparation, integration, and mystical-type experiences—are established correlates of therapeutic outcomes in converging psychedelic and ketamine literature (Dakwar et al., 2014; Haijen et al., 2018; Marguilho et al, 2023; Mathai et al., 2020; Rothberg et al., 2021). While the retrospective nature of this study requires cautious interpretation, the data suggest that intravenous ketamine delivered in a psychedelic paradigm, unlike typical research protocols, may produce significantly larger effects than those documented previously (Ragnhildstveit et al., 2023).

These results further suggest the potential for unifying treatment approaches to ketamine, psychedelics, and related compounds. With this integrative aim, we hope to temper premature conclusions that certain substances hold singular promise for curing PTSD. Instead, we might consider if contextual aspects of psychedelic-type drug delivery suggest more similarities than differences. Prospective studies comparing ketamine directly with MDMA, psilocybin, and other substances can establish more definitive comparisons. Nevertheless, noteworthy similarities appear to unify an overall treatment paradigm, including psychological preparation, moderately high doses, sensory immersion with music and eyeshades, psychological integration of significantly altered experiences, and concomitant psychotherapy. The impact of these various factors can be further established with dismantling studies.

The uniqueness of ketamine meanwhile lies in its affordability as a generic drug, current FDA approval, safety profile, relative brevity as a 60-min infusion, and minimal-to-no interactions with common psychiatric drugs such as SSRIs. Many prospective patients, including those in the present study, take these medications, and tapering off of them can prove challenging and risky. Ketamine’s accessible and flexible nature shows unique promise for expanding access to individuals across socioeconomic lines and psychiatric complexities. By increasing clinical education for providers in diverse community settings, best practices can spread, enhancing the uptake of these treatments for individuals who need options.

The present study, similar to many other ketamine and psychedelic studies, reveals a wide variance in outcomes. Despite the large aggregate effects, subsequent work could improve treatment by addressing the range of impact. Rigorous inquiry into active ingredients of treatment may further reduce nonresponse rates. Adjunctive psychotherapy shows considerable promise (Mathai et al., 2022). Varying frequency, modality, and timing of sessions relative to ketamine dosing could prove illustrative. Even tailored music selection may prove salient (Barrett et al., 2017).

Meanwhile, research has yet to conclude if ketamine therapy for PTSD represents a new method of exposure-based treatment, a neuroplastic enhancement of psychotherapy, or more novel mechanisms of change still undefined. Although these present data do not specifically detail patients’ subjective effects or their psychotherapeutic interventions, it is likely that priming of trauma memory occurred during treatment, whether intentionally or not. Recent brain imaging research suggests that explicit priming of traumatic memory immediately before ketamine infusion induces uniquely beneficial neural changes compared to priming with a midazolam placebo (Duek et al., 2023). Further studies are needed to establish the tolerability and efficacy of this approach in larger, diverse PTSD patient samples.

Alternatively, the mediating impact of mystical-type experiences in other ketamine and psychedelic research samples may suggest that positive psychology constructs such as awe, insight, self-transcendence, and emotional breakthrough could have uniquely beneficial effects in ketamine for PTSD (Kangaslampi, 2023). Over the course of repeated dosing and psychotherapy sessions, patients could potentially benefit from a range of therapeutic vectors within a single treatment. Even in resolved cases of PTSD, long-term follow-up reveals significantly reduced quality of life in multiple domains of function relative to controls, despite the remission of symptoms (Bryant et al., 2016). The need for more integrative, restorative PTSD treatment and aftercare is urgent; randomized controlled trials can help clarify ketamine’s emerging and varied role.

Limitations

Although these results suggest that PTSD symptoms can decline in conjunction with ketamine administrations in a psychedelic paradigm, they have several limitations that suggest future studies.

As a naturalistic, observational study, the absence of a placebo group inherently restricts our ability to draw firm conclusions about specific treatment effects. The naturalistic design also limits our understanding of possible confounders driving the enhanced response associated with concomitant psychotherapy in the community. While we report large absolute effect sizes in the present study, we also note that placebo-controlled studies of psychiatric interventions frequently reveal more modest relative treatment effects after accounting for large effects in the placebo arms. For instance, in a well-powered RCT of I.V. ketamine for PTSD, when CAPS-5 scores were measured at 4 weeks post last infusion, the placebo group registered a Cohen’s d of 1.01, while two ketamine groups ranged from 1.41–1.68 (Abdallah et al., 2022), representing a small-to-medium relative treatment effect size. This scale of PTSD-specific relative efficacy closely parallels recent meta-analytic research on placebo response in trials of ketamine and esketamine for MDD; across 14 studies, placebo response accounted for up to 72% of the overall treatment effect (Matsingos et al., 2024). Large placebo effects may be the rule, rather than the exception, in psychiatric treatments more broadly. In a meta-analysis of placebo effects across nine common psychiatric disorders, placebos induced significant symptom reductions in all conditions, including an average effect size of 0.84 in 10 pharmaceutical RCTs for PTSD (Bschor et al., 2024). Furthermore, specific treatment modifications that appear substantial in the abstract may be more incremental under controlled scrutiny. For instance, in one Cochrane review, trauma-focused cognitive behavioral therapy (CBT) with exposure showed a large effect size of 1.62 compared to treatment-as-usual waitlist control, but only a small effect size of 0.27 compared to generic CBT (Bisson et al., 2013). In sum, we reiterate the need for well-powered, randomized, placebo-controlled studies to clarify the precise treatment effects of I.V. ketamine delivered in a psychedelic paradigm for PTSD.

This study has several other limitations. While the preconditions for psychedelic-type experience were consistent across patients, the variance of effects was not recorded with standardized measures employed in trial settings. These measures are relatively lengthy and would benefit from shorter forms to deploy in real-world settings. The follow-up periods varied widely among participants. The sample, 70% female patients with sufficient economic support, limits the generalizability to a broader population. In contrast, a previous study of veterans with antidepressant-resistant PTSD contained only 23% females and failed to demonstrate a superior effect of ketamine over placebo (Abdallah et al., 2022). Additionally, inconsistent ethnicity reporting in the clinic data set hinders our understanding of the treatment’s efficacy across diverse demographic groups. These limitations underscore the need for more comprehensive studies to validate and extend these findings. Nevertheless, the current results offer preliminary support that ketamine-assisted approaches can improve PTSD symptoms in highly supportive settings with the hallmarks of psychedelic therapy.

Demographics

Table 1.

Participant demographics and clinical characteristics (N = 117).

Variable	Data	N
Age, mean ± SD (range)	41.9 ± 13.1 (20–74)	117
Gender
Female	70.09% (n = 82)	117
Male	26.50% (n = 31)
Genderfluid	0.85% (n = 1)
Female/nonbinary	0.85% (n = 1)
Transgender	0.85% (n = 1)
Genderqueer	0.85% (n = 1)
Race/ethnicity
Unspecified/not reported	45.3% (n = 53)	117
Caucasian	45.3% (n = 53)
Asian	5.98% (n = 7)
Black or African American	2.56% (n = 3)
American Indian/native Alaskan	0.85% (n = 1)
Trauma type
Unspecified	33.33% (n = 39)	117
Sexual assault	32.48% (n = 38)
Physical assault	17.09% (n = 20)
Accident	4.27% (n = 5)
Death of someone close	3.42% (n = 4)
Sudden death	3.42% (n = 4)
Illness/injury	1.71% (n = 2)
Captivity	1.71% (n = 2)
Combat	1.71% (n = 2)
Natural disaster	0.85% (n = 1)
Psychiatric medication trials, mean ± SD (range)	4.68 ± 1.97, (0–13)	117
Currently sees a psychotherapist
Yes	68.4% (n = 80)	117
No	31.6% (n = 37)	117
Current suicidal ideation
Yes	17% (n = 20)	117
No	83% (n = 97)	117
Past suicidal ideation
Yes	62% (n = 73)	117
No	34% (n = 40)
N/A	3% (n = 4)
Psychiatric comorbidity
GAD	74.36% (n = 87)	117
MDD	69.23% (n = 81)
Dysthymia	14.53% (n = 17)
ADHD	11.11% (n = 13)
Panic	7.69% (n = 9)
SUD	7.69% (n = 9)
Eating disorder	5.13% (n = 6)
OCD	3.42% (n = 4)
Borderline personality disorder	2.56% (n = 3)
Bipolar disorder	2.56% (n = 3)
Adjustment disorder	1.71% (n = 2)
Developmental disorder	0.85% (n = 1)
Body dysmorphic disorder	0.85% (n = 1)

Footnotes

Acknowledgements

The authors wish to thank Samantha Gomez and Carl Erik Fisher for their thoughtful edits and suggestions. They also thank Alexandra Clements and the clinic nursing staff for their careful attention to patient progress tracking.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HAM and ME have no conflicts to declare. SR is a shareholder and Chief Medical Officer of Nushama.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Henry A MacConnel

Mitch Earleywine

References

Acevedo-Diaz

Cavanaugh

Greenstein

, et al. (2020) Can ‘floating’ predict treatment response to ketamine? Data from three randomized trials of individuals with treatment-resistant depression. J Psychiatric Res 130: 280–285.

Alnefeesi

Chen-Li

Krane

, et al. (2022) Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review and meta-analysis. J Psychiatric Res 151: 693–709.

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th edn. USA: American Psychiatric Association.

Andrade

(2017). Ketamine for depression, 4: In what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry 78: 10106.

Abdallah

Roache

Gueorguieva

, et al. (2022) Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: A double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology 47: 1574–1581.

Barrett

Johnson

Griffiths

(2015) Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol 29: 1182–1190.

Barrett

Robbins

Smooke

, et al. (2017) Qualitative and quantitative features of music reported to support peak mystical experiences during psychedelic therapy sessions. Front Psychol 8: 1238.

Bennett

(2019) Paradigms of ketamine treatment. MAPS Bull Spring 29: 48–49.

Bisson

Roberts

Andrew

, et al. (2013) Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. Cochrane Database System Rev 2013: CD003388.

10.

Biskin

Paris

(2012) Diagnosing borderline personality disorder. CMAJ 184: 1789–1794.

11.

Borkel

Rojas-Hernández

Henríquez-Hernández

, et al. (2024) Set and setting predict psychopathology, wellbeing and meaningfulness of psychedelic experiences: a correlational study. Expert Rev Clin Pharmacol 17: 165–176.

12.

Bowdle

Radant

Cowley

, et al. (1998) Psychedelic effects of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. J Am Soc Anesthesiol 88: 82–88.

13.

Bryant

McFarlane

Silove

, et al. (2016) The lingering impact of resolved PTSD on subsequent functioning. Clin Psychol Sci 4: 493–498.

14.

Bschor

Nagel

Unger

, et al. (2024) Differential outcomes of placebo treatment across 9 psychiatric disorders: A systematic review and meta-analysis. JAMA Psychiatry 81: 757–768.

15.

Cohen

(1988) Statistical power analysis for the behavioral sciences (2nd ed.). Lawrence Erlbaum Associates.

16.

Coyle

Laws

(2015) The use of ketamine as an antidepressant: A systematic review and meta-analysis. Human Psychopharmacol Clin Exp 30: 152–163.

17.

Dakwar

Anerella

Hart

, et al. (2014) Therapeutic infusions of ketamine: Do the psychoactive effects matter? Drug Alcohol Depend 136: 153–157.

18.

Diamond

Airdrie

Hiller

, et al. (2022) Change in prevalence of post-traumatic stress disorder in the two years following trauma: A meta-analytic study. Eur J Psychotraumatol 13: 2066456.

19.

Domino

Chodoff

Corssen

(1965) Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Therap 6: 279–291.

20.

Dore

Turnipseed

Dwyer

, et al. (2019) Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoact Drugs 51: 189–198.

21.

Duek

Korem

, et al. (2023) Long term structural and functional neural changes following a single infusion of Ketamine in PTSD. Neuropsychopharmacology 48: 1648–1658.

22.

Feder

Costi

Rutter

, et al. (2021) A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry 178: 193–202.

23.

Fischman

(2019) Seeing without self: Discovering new meaning with psychedelic-assisted psychotherapy. Neuropsychoanalysis 21: 53–78.

24.

Fond

Loundou

Rabu

, et al. (2014) Ketamine administration in depressive disorders: A systematic review and meta-analysis. Psychopharmacology 231: 3663–3676.

25.

Goetter

Bui

Ojserkis

, et al. (2015) A systematic review of dropout from psychotherapy for posttraumatic stress disorder among Iraq and Afghanistan combat veterans. J Trauma Stress 28: 401–409.

26.

Gukasyan

Nayak

(2022) Psychedelics, placebo effects, and set and setting: Insights from common factors theory of psychotherapy. Transcult Psychiatry 59: 652–664.

27.

Haijen

Kaelen

Roseman

, et al. (2018) Predicting responses to psychedelics: A prospective study. Front Pharmacol 9: 897.

28.

Hartogsohn

(2016) Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. J Psychopharmacol 30: 1259–1267.

29.

Hartogsohn

(2017) Constructing drug effects: A history of set and setting. Drug Science Policy Law 3: 2050324516683325.

30.

Imel

Laska

Jakupcak

, et al. (2013) Meta-analysis of dropout in treatments for posttraumatic stress disorder. J Consult Clin Psychol 81: 394.

31.

Kaelen

Giribaldi

Raine

, et al. (2018) The hidden therapist: Evidence for a central role of music in psychedelic therapy. Psychopharmacology 235: 505–519.

32.

Kangaslampi

(2023) Association between mystical-type experiences under psychedelics and improvements in well-being or mental health–A comprehensive review of the evidence. J Psyched Stud 7: 18–28.

33.

Kilpatrick

Resnick

Milanak

, et al. (2013) National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Traum Stress 26: 537–547.

34.

Kolp

Friedman

Krupitsky

, et al. (2014) Ketamine psychedelic psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. Int J Transpers Stud 33: 8.

35.

Krupitsky

Grinenko

(1997) Ketamine psychedelic therapy (KPT): A review of the results of ten years of research. J Psychoact Drugs 29: 165–183.

36.

Leary

Litwin

Metzner

(1963) Reactions to psilocybjn administered in a supportive environment. J Nerv Ment Dis 137(6): 561–573.

37.

Luckenbaugh

Niciu

Ionescu

, et al. (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders 159: 56–61.

38.

Marguilho

Figueiredo

Castro-Rodrigues

(2023) A unified model of ketamine’s dissociative and psychedelic properties. J Psychopharmacol 37: 14–32.

39.

Mathai

Meyer

Storch

, et al. (2020) The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. J Affect Disord 264: 123–129.

40.

Mathai

Mora

Garcia-Romeu

(2022) Toward synergies of ketamine and psychotherapy. Front Psychol 13: 868103.

41.

Matsingos

Wilhelm

Noor

, et al. (2024) Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: A systematic review and meta-analysis. Front Psychiatry 15: 1346697.

42.

Mitchell

Bogenschutz

Lilienstein

, et al. (2023) MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Focus 21: 315–328.

43.

Mithoefer

Jerome

Ruse

, et al. (2013) A Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder. Multidisciplinary Association for Psychedelic Studies. Available at: https://maps.org/research-archive/mdma/MDMA-Assisted-Psychotherapy-Treatment-Manual-Version7-19Aug15-FINAL.pdf (accessed 24 November 2023)

44.

Morina

Wicherts

Lobbrecht

, et al. (2014) Remission from post-traumatic stress disorder in adults: A systematic review and meta-analysis of long term outcome studies. Clin Psychol Rev 34: 249–255.

45.

National Center for PTSD (2020) How common is PTSD in adults? U.S. Department of Veterans Affairs. Available at: https://www.ptsd.va.gov/understand/common/common_adults.asp (accessed 24 November 2023).

46.

O’Donnell

Roberts

Ching

, et al. (2023) What is in a name? The many meanings of “psychedelic.” Psyched Med 1: 187–189.

47.

Ragnhildstveit

Roscoe

Bass

, et al. (2023) The potential of ketamine for posttraumatic stress disorder: A review of clinical evidence. Therap Adv Psychopharmacol 13: 20451253231154125.

48.

Rothberg

Azhari

Haug

, et al. (2021) Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial. J Psychopharmacol 35: 150–158.

49.

Schottenbauer

Glass

Arnkoff

, et al. (2008) Nonresponse and dropout rates in outcome studies on PTSD: Review and methodological considerations. Psychiatry Interpers Biol Proc 71: 134–168.

50.

Stein

Ipser

Seedat

(2006) Pharmacotherapy for post-traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews (1): CD002795.

51.

Tucker

Chandler

Witkiewitz

(2020) Epidemiology of recovery from alcohol use disorder. Alcohol Res Curr Rev 40: 2.

52.

Weathers

Litz

Keane

, et al. (2013) The PTSD Checklist for DSM-5 (PCL-5). Scale available from the National Center for PTSD. Available at: https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp (accessed 24 November 2023).

53.

Wolfson

(2014) Psychedelic experiential pharmacology: Pioneering clinical explorations with Salvador Roquet (how I came to all of this: Ketamine, admixtures and adjuvants, Don Juan and Carlos Castaneda too): An interview with Richard Yensen. IJTS 33: 160–174.