This randomised controlled trial (n=116) investigated the psychological mechanisms of ketamine's antidepressant effects. Participants receiving ketamine reported significantly heightened feelings of awe compared to those receiving a placebo. Awe experiences, as measured by the Awe Experience Scale (AWE-S), mediated depression outcomes (% improvement in MADRS scores) at multiple time points (24 hours and 5, 12, 21, and 30 days) post-infusion, indicating a potential role of awe in ketamine's therapeutic efficacy for depression.
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Background
Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research.
Methods
One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery-Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison.
Results
We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery-Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery-Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point.
Conclusions
Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.
Depression is a major global health burden and many patients do not respond to first-line treatments. Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects but these are typically transient and questions remain about how to prolong or amplify clinical benefit. Prior research has emphasised ketamine's molecular and circuit-level actions, whereas acute psychological effects—often labelled dissociative—have been treated as side effects and measured with instruments such as the Clinician-Administered Dissociative States Scale (CADSS). The authors note that CADSS may not sensitively capture the full range of ketamine's subjective effects and that more specific psychological constructs might help explain clinical outcomes. Aepfelbacher and colleagues therefore tested whether the acute subjective experience of awe, measured with the Awe Experience Scale (AWE-S), occurs during a ketamine infusion and whether it relates to antidepressant response. Using data from a randomised controlled trial of a single 0.5 mg/kg ketamine infusion versus saline, the study asked three primary questions: does ketamine induce awe relative to saline, are AWE-S scores associated with clinician-rated depression improvement up to 30 days postinfusion, and do AWE-S scores statistically mediate ketamine's antidepressant effects? For comparison, the investigators ran parallel analyses using CADSS scores to index general dissociative symptoms.
The study used data from a parent trial (ClinicalTrials.gov: NCT03237286) that randomised adults with moderate-to-severe depression (baseline MADRS ≥25) to receive a single intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) or saline, with a 2:1 allocation ratio stratified by sex and level of prior treatment resistance. Participants had to have failed at least one prior antidepressant (45% had failed three or more) and to have stable background treatments for at least 4 weeks before and during the 30-day follow-up. Of 154 participants randomised in the parent trial, the AWE-S was added to the assessment battery midway through recruitment; 116 participants (77 ketamine, 39 saline) completed the AWE-S at approximately 40 minutes after infusion start and constitute the analytic sample reported here. Immediately prior to the AWE-S at that same timepoint, a trained rater administered the CADSS. The primary clinical outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS), clinician-rated at baseline and at five postinfusion time points (24 hours and days 5, 12, 21, and 30). For interpretability the investigators expressed outcomes as percentage improvement from baseline MADRS at each time point. The AWE-S is a validated 30-item measure capturing six subdomains of awe: connectedness, time, vastness, accommodation, self-diminishment, and physiological changes. Statistical analyses used JMP and MATLAB. Because some scale distributions were non-normal, nonparametric tests were employed: Wilcoxon rank-sum tests compared AWE-S (total and subscales) between treatment groups and Spearman correlations tested associations between AWE-S and MADRS % improvement. Mediation testing used a standard three-variable path model implemented in a Multilevel Mediation and Moderation Toolbox with bootstrap testing of the indirect (a*b) pathway; false discovery rate correction adjusted for multiple comparisons across the five MADRS time points. Parallel analyses replaced AWE-S with CADSS and Fisher r-to-z tests compared correlation strengths within the ketamine group. Sensitivity analyses and further details, including the adjunct digital therapy (automated self-association training, ASAT) and CONSORT information, are reported in the Supplement.
This study utilized data from a parent study (Clinicaltrials.Gov: NCT03237286) investigating 1) the neurocognitive mechanisms of ketamine treatment, and 2) the efficacy of ketamine combined with a novel digital therapy (automated selfassociation training [ASAT]). All patients reported moderate to severe levels of depression (indicated by a score $ 25 on the Montgomery-Åsberg Depression Rating Scale [MADRS]) and had previously undergone at least one unsuccessful trial of a U.S. Food and Drug Administration-approved antidepressant (45% had failed 3 or more trials). Patients' existing depression treatment regimens were required to remain stable for at least 4 weeks before screening and throughout the 30-day trial. See the Supplement for additional trial details including full inclusion/exclusion criteria and CONSORT (Consolidated Standards of Reporting Trials) information. Participants were randomly assigned at a 2:1 ratio (stratifying randomization on sex and level of prior treatment resistance) to receive either ketamine (at a dose of 0.5 mg/kg) or saline (50 mL of 0.9% sodium chloride) through a 40-minute infusion. The assessment of awe (detailed below) was completed approximately 40 minutes after infusion start. The following day, patients began 4 consecutive days of an additional, digital intervention (either active ASAT or sham ASAT, delivered by computer, according to the patient's random assignment). Due to our principal interest in the impacts of ketamine on awe, the current analyses focus on comparisons of the ketamine versus saline groups, irrespective of ASAT allocation. Please refer to the Supplement for additional details of the active and sham ASAT conditions and sensitivity analyses exploring the impact of ASAT allocation on the current findings. To measure the specific psychological experience of awe during ketamine infusion, we utilized the AWE-S, which was added to the trial's assessment battery midstudy (after approximately 25% of participants had enrolled) based on the authors' growing familiarity with and interest in this construct. The AWE-S is a 30-item, validated tool designed to quantify the feeling of awe using 6 different subdomains: connectedness, time, vastness, accommodation (representing the need to mentally attempt to accommodate unusual experiences into existing mental schemas), self-diminishment (representing a shrinking of self in the setting of something larger), and physiological changes. Of the total of 154 participants who were randomized in the parent study, 116 (n = 77 for ketamine arm, n = 39 for saline) were administered the AWE-S at a 40minute postinfusion time point and were subsequently included in this substudy. Immediately prior to the administration of the AWE-S (i.e., also at the 40-minute timepoint), the CADSS was administered by a trained rater. The CADSS quantifies general dissociative symptoms (e.g., out-of-body sensations, derealization, shifts in the perception of time and surroundings), measuring a range of possible cognitive experiences without specific links to the subjective experience of awe, and has been used widely in prior ketamine research to measure dissociative side effects. The primary clinician-rated clinical outcome for the trial was the MADRS, which was administered by a single experienced masters-level rater, blinded to treatment condition, at preinfusion baseline and the following 5 time points postinfusion: 124 hours, 15, 112, 121, and 130 days. Total MADRS scores were used to calculate the percentage improvement from preinfusion baseline at each time point to enhance the clinical relevance and interpretability of posttreatment scores. Statistical analyses were performed using JMP16.0 and MATLAB (version 2019b; The MathWorks, Inc.). Nonparametric tests were used to compare AWE-S results (total scores and each subdomain score) for study participants who received ketamine with saline-treated control participants. Additionally, the relationship between awe-inspiring experiences of ketamine (defined by higher AWE-S total scores, collapsing across the 6 subscales) and percentage improvement in MADRS scores at each available time point was assessed with Spearman's correlations to assess the clinical significance and impact of acute experiences of awe during the infusion. To Awe Mediates Ketamine's Effects on Depression assess for possible statistical mediation effects of the AWE-S in mediating the relationship between the ketamine intervention and MADRS outcomes, the Multilevel Mediation and Moderation Toolbox implemented in MATLAB was used to perform mediation analyses based on a standard 3-variable path model with a bootstrap test of the statistical significance of the mediational pathway (path a 3 b). A statistically significant a 3 b mediation pathway indicates the presence of mediation, reflecting that the indirect effect of treatment group on the outcome (MADRS % improvement) when controlling for the mediator (path c 0 ) is significantly reduced compared to the total effect of treatment on MADRS improvement (path c). See Figurefor a depiction of the hypothesized mediational model that was tested in these analyses. Each set of analyses was corrected for multiple comparisons across the 5 discrete MADRS outcome time points using false discovery rate correction. To probe the specificity of findings to the experience of awe versus general dissociation effects of ketamine, all analyses above were repeated using CADSS scores in place of AWE-S scores. In the ketamine-treated group, the strength of correlation coefficients linking MADRS improvement to each measure (AWE-S vs. CADSS) was compared using Fisher's r-to-z transformation tests within dependent samples.
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The AWE-S was completed by 116 participants (77 ketamine, 39 saline). Baseline characteristics were reported as comparable to the parent trial; the extracted text does not present the full table. Distribution checks showed AWE-S scores were approximately normal in the ketamine group but skewed in the saline and total samples, prompting the use of nonparametric tests. In a Wilcoxon rank-sum comparison, total AWE-S scores and all subdomain scores were significantly higher in the ketamine group than in the saline group (p < .0001). The accommodation subscale yielded the highest subscale scores in both groups. Spearman correlations within the ketamine arm revealed significant associations between total AWE-S scores and percentage MADRS improvement at all five postinfusion time points after false discovery rate correction (i.e. 24 hours and days 5, 12, 21, and 30). Exploratory analyses found that each of the six AWE-S subscales correlated with MADRS improvement at one or more time points. Mediation analyses showed that total AWE-S scores statistically mediated the relationship between ketamine treatment and MADRS % improvement at every assessed time point (reported a*b p-values: 24 hours p = .0028; day 5 p = .0154; day 12 p = .0027; day 21 p = .0018; day 30 p = .0052; all FDR-corrected p < .05). A direct (main) effect of ketamine on MADRS remained at 24 hours and day 5 (24 hours p < .0001; day 5 p < .001) but was not significant from day 12 onward. The investigators interpret this pattern to indicate that a subset of ketamine-treated patients who reported particularly strong awe showed larger and more persistent antidepressant responses. In parallel, CADSS total scores at 40 minutes were also significantly higher in the ketamine group than saline (p < .0001). Unlike the AWE-S, CADSS scores did not correlate with MADRS improvement in the ketamine arm at any time point and did not mediate outcomes (a*b mediation tests non-significant, ps > .372). From day 12 onward, correlations between AWE-S and MADRS were significantly stronger than CADSS-MADRS correlations. The extracted text notes a few modest CADSS correlations in the saline group that did not survive multiple comparison correction.
Aepfelbacher and colleagues conclude that ketamine infusions elicited strong self-reported experiences of awe and that these acute awe experiences statistically mediated clinician-rated antidepressant improvements from 24 hours up to 30 days postinfusion. The mediation effects persisted beyond the time when a significant group-level effect of ketamine on depression was detectable, suggesting that individuals who experienced pronounced awe during infusion retained benefit for longer than those who did not. By contrast, CADSS scores, commonly used to index ketamine-associated dissociation, did not predict or mediate depression outcomes and were generally unrelated to clinical improvement in the ketamine-treated sample. The investigators situate their findings within broader literature indicating ketamine can produce psychedelic or mystical-type experiences not fully captured by dissociation scales. They note parallels with studies where measures of mystical or unitive experiences predicted benefit in substance use disorders and with research showing ketamine can elicit spiritual or unitive experiences comparable to classical psychedelics on some scales. The authors posit that acute awe may reflect a psychologically meaningful component of ketamine's action that operates alongside neurobiological mechanisms such as increased neuroplasticity; awe has been linked previously to enhanced cognitive flexibility and altered neural connectivity, which could plausibly interface with ketamine's known effects. Practical implications discussed include the possibility that treatment context, mindfulness, or adjunctive psychotherapeutic techniques could be used to foster awe and thereby augment ketamine's therapeutic impact, although the investigators emphasise that randomised trials are needed to validate such adjunctive strategies. The authors acknowledge multiple limitations. Effect sizes for AWE-S–depression associations were small to medium, indicating other sources of variance in outcomes. The AWE-S was added mid-study so only a subset of the parent trial completed it; CADSS was always administered before the AWE-S, introducing a possible order effect; and no baseline measure of trait propensity for awe or expectancy was collected. Use of saline as an inert placebo leaves open the possibility of functional unblinding and expectancy influences. The sample excluded bipolar disorder and some comorbidities, and lacked racial and ethnic diversity, limiting generalisability. Finally, because no active psychoactive comparator was included, the design cannot prove that the observed relationships are specific to ketamine rather than to acute psychoactive interventions more broadly. The authors recommend further research integrating psychological and neurobiological levels of analysis and testing whether deliberate fostering of awe in the treatment context enhances clinical outcomes.
The study suggests that experiences of awe during a single ketamine infusion mediated both rapid and sustained antidepressant effects over a 1-month period. Individuals reporting very strong awe-like experiences were comparatively protected against relapse for at least 30 days after a single infusion, whereas a commonly used dissociation measure (CADSS) did not mediate clinical outcomes. These randomised controlled trial data indicate that awe may be a clinically relevant component of the subjective experience unfolding during ketamine treatment for depression and warrant further investigation.
In this study, we found that ketamine strongly induced heightened feelings of awe in patients with depression. In addition, the self-reported strength of the experience of awe during a ketamine infusion statistically mediated ketamine's effect on clinician-rated improvements in depression symptoms. Mediation effects were present both for rapid depression outcomes (at 24 hours and 5 days, when robust group-level effects of ketamine were observed) as well as mediating the level of enduring antidepressant effects observed up to 30 days postinfusion. Despite the fact that a notable improvement in symptoms due to ketamine was no longer evident (in the entire group) at this point in time, patients who reported experiencing a high level of awe immediately after the infusion continued to exhibit greater persistent antidepressant benefits (Figure, left panel). In contrast, CADSS, a tool often used to capture the dissociative effects of ketamine, did not mediate depression outcomes, and correlations with depression improvements among ketamine-treated patients were nonsignificant and substantially weaker than for the AWE-S, particularly at later time points (postinfusion day. Our results highlight the potential role of awe, a specific component of the psychological experience during the infusion, in the efficacy of ketamine treatment for depression. Over the past 20 years, there has been mounting evidence that ketamine is a fast-acting and effective treatment option for treatment-resistant depression. Research aimed at understanding this therapeutic effect has focused largely on the molecular-, cellular-, and circuit-level mechanisms of action, while relatively few studies have thoroughly explored potential psychological components. As a result, there has been widespread adoption in the academic research community of a biological model in which the acute cognitive and psychological (e.g., dissociative) experiences of ketamine are often seen as undesirable side effects. Studies that have examined ketamine's acute psychological or cognitive impacts among patients with depression have largely focused on general dissociative or psychotomimetic symptoms, such as those captured by the CADSS. Studies using the CADSS have yielded inconsistent results, with some finding that dissociative experience is correlated with lower depression scores following ketamineand others finding no association at all. Unexpectedly, CADSS scores in the current trial Awe Mediates Ketamine's Effects on Depression were modestly (and nonsignificantly) correlated with reductions in depression in the saline group only (Table), suggesting that nonspecific factors (e.g., demand characteristics, placebo effects), rather than specific drug actions, may sometimes result in CADSS responses and depression outcomes being linked. Other work suggests that ketamine's acute effects on consciousness extend beyond dissociation. In a recent qualitative exploration of the experience of ketamine based on patient interviews, the researchers posited that ketamine may cause psychedelic experiences, which in turn helps participants improve their outlook on challenges in their lives. Additionally, the interviews suggested that the psychological and mystical properties of ketamine are not fully captured by scales that measure dissociative symptoms. The same study also found that 3 subfactors of the 11-dimensions Altered States of Consciousness rating scale, unity, spirituality, and insight, were correlated with improved antidepressant outcomes among patients treated with ketamine. These findings are consistent with studies that have compared ketamine to psilocybin, a known psychedelic. Vollenweider and Kometer (32) administered the 5-dimensions Altered States of Consciousness rating scale to healthy participants alongside different dosages of ketamine and psilocybin. Both substances caused dose-dependent psychological experiences ranging from feelings of connectedness and an enjoyable blurring of ego boundaries to a more fear-invoking ego dissolution similar to psychosis (32). Studerus et al.later found more nuanced differences between the 2 substances using the 11dimensions version of the Altered States of Consciousness scale. Importantly, ketamine enabled spiritual and unitive experiences on par with psilocybin. Our findings that awe experiences, but not general dissociation, statistically mediated improvements in depression are also consistent with findings from studies that were not focused on depression treatment. Ketamine-induced mystical experiences, measured by the Hood Mysticism Scale, have been shown to be associated with improved outcomes in cocaine use disorderand alcohol use disorder. Similar to our findings, both these studies found that the Hood Mysticism Scale mediated the relationship between ketamine and improvements in symptoms of substance disorders, while CADSS scores did not. More broadly, our findings are consistent with a growing literature documenting the therapeutic and/or quality-of-life benefits of awe experiences, which can be invoked through a wide range of stimuli, including contact with nature, art, moral total scores are presented. However, nonparametric (for group comparisons and correlations) and bootstrapping (for mediation) tests were used for statistical inferences, which are robust tests that can be applied even when scales are non-normally distributed or skewed, including to manage the presence of outliers. These tests minimize the impact of anomalies or discrepancies in the range and distribution of the absolute (raw) scores because prior to analysis, all raw values are first converted to rank-ordered values.