This post hoc analysis (n=576) examined the relationship between acute dissociation and the antidepressant efficacy of esketamine in treatment-resistant depression by combining data from the TRANSFORM-1 and TRANSFORM-2 clinical trials. It found no clinically significant association between dissociation and antidepressant effect for esketamine, suggesting the need for improved characterization of drug experiences relevant to therapeutic outcomes.
Rationale
The relationship between subjective drug experience and antidepressant outcomes for ketamine derivatives is poorly understood but of high clinical relevance. Esketamine is the patented (S)-enantiomer of ketamine and has regulatory approval for psychiatric applications.
Objectives
We examined the relationship between acute dissociation, as measured by the Clinician-Administered Dissociative States Scale (CADSS), and antidepressant efficacy, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), for esketamine across the 4-week induction phase of treatment.
Methods
This post hoc analysis combined data (N = 576) from the TRANSFORM-1 and TRANSFORM-2 clinical trials of esketamine for treatment-resistant depression. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables: baseline MADRS score, treatment condition × time interaction, and CADSS × time interaction. To assess whether initial dissociation predicted rapid antidepressant benefit with esketamine, a separately planned regression was performed with day 2 MADRS as the outcome variable with the following dependent variables: baseline MADRS, treatment condition, and day 1 CADSS.
Results
The linear mixed model did not show any effect of a CADSS × time interaction (p = 0.7). Looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a − .04 [95% CI − .08, − .002] (p = .04) decrease in MADRS score.
Conclusions
We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine. Our findings suggest that subsequent inquiry in this area will benefit from improved characterization of drug experiences relevant to therapeutic outcomes.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Chen, G., Chen, L., Zhang, Y. et al. · International Journal of Neuropsychopharmacology (2022)
Dakwar, E., Anerella, C., Hart, C. L. et al. · Drug and Alcohol Dependence (2014)
Mathai and colleagues place this study in the context of longstanding uncertainty about whether subjective drug effects—particularly drug-induced “dissociation”—are mechanistically related to the antidepressant effects of ketamine and its enantiomer, esketamine. They review historical and conceptual debates about dissociation, noting its roots in 19th- and early 20th-century accounts and its later operationalisation in instruments such as the Clinician-Administered Dissociative States Scale (CADSS). Previous clinical work with ketamine has produced inconsistent findings: some studies report that greater acute dissociation predicts better antidepressant response, while others do not. The authors also note that classic psychedelics show clearer links between particular qualities of the acute experience (for example, mystical-type experiences) and clinical benefit, and that the subjective profile of dissociatives may differ meaningfully from that of classic psychedelics. The present paper aims to clarify whether acute dissociation predicts antidepressant efficacy for esketamine by conducting a pooled, post hoc analysis of two Phase III trials (TRANSFORM-1 and TRANSFORM-2). Specifically, the investigators test whether CADSS-measured dissociation interacts with time to predict change in depression severity during the 4-week induction phase, and whether dissociation after the first dose predicts rapid antidepressant benefit within 24–48 hours. The authors frame this as the largest formal assessment to date of dissociation’s therapeutic relevance for esketamine and argue that a comprehensive, across-trials approach is warranted given prior mixed results.
This secondary, pooled analysis combined de-identified data from two randomised, double-blind Phase III trials of intranasal esketamine plus an oral antidepressant versus intranasal placebo plus oral antidepressant: TRANSFORM-1 (fixed-dose arms: 56 mg, 84 mg, and placebo) and TRANSFORM-2 (flexible-dose arm: 56 mg or 84 mg and placebo). Participants were adults aged 18–64 with treatment-resistant depression, defined as lack of response to at least two adequate antidepressant trials in the current episode. Study drug was administered twice weekly over an initial 4-week induction phase. The Yale Open Data Access (YODA) Project provided the datasets; the Johns Hopkins IRB determined the secondary analysis did not constitute human subjects research. Depression severity was measured with the Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale (range 0–60) assessed by independent remote raters blind to protocol details. Dissociation was assessed on-site using a 23-item clinician-administered version of the CADSS, administered before dosing, at 40 minutes post-dose (approximate peak), and at 1.5 hours post-dose. The authors selected the 40-minute CADSS score for primary analyses and included CADSS data from all eight induction doses. Statistical analyses were conducted in R (version 3.6.3). The primary model was a linear mixed-effects model with total MADRS score as the outcome and baseline MADRS, treatment condition-by-time interaction, and CADSS-by-time interaction as fixed effects. Random intercepts for participant accounted for repeated measures, and random intercepts for study accounted for clustering within trials. Significance of the CADSS-by-time interaction was assessed with type II Wald chi-square tests (ANOVA in the car package). The team also generated model-predicted MADRS means at days 1 and 28 for a range of CADSS values (0, 2, 4, 8, 16) to visualise relationships. Separately, a planned simpler regression tested whether day 1 CADSS predicted day 2 MADRS, controlling for baseline MADRS and treatment condition.
The pooled analysis included 576 participants: placebo (TRANSFORM-1 + TRANSFORM-2) N = 227; fixed-dose esketamine 56 mg (TRANSFORM-1) N = 115; fixed-dose esketamine 84 mg (TRANSFORM-1) N = 116; flexible-dose esketamine 56/84 mg (TRANSFORM-2) N = 118. Mean baseline MADRS for the placebo group was reported as 37.6 (SD = 5.14). The extracted text does not clearly report mean baseline MADRS values for the other groups. Plots of raw MADRS and CADSS scores over time and scatterplots of individual CADSS values versus change in MADRS were described but not reproducible from the extracted text. In the primary linear mixed model, the CADSS-by-time interaction was not significant (p = 0.7), indicating no evidence that time-varying dissociation scores, as measured by CADSS at 40 minutes, predicted change in MADRS across the 4-week induction phase. Model-predicted MADRS values were generated across CADSS values from 0 to 16 for days 1 and 28, but the main inferential result was null for the interaction term. In the separate regression examining rapid benefit, each additional point on day 1 CADSS was associated with a -0.04 change in day 2 MADRS score (95% CI -0.08 to -0.002; p = 0.04). The authors present this as a statistically significant but very small effect size. They also note that dissociation levels observed in these esketamine trials were lower than those reported in many ketamine studies, although numerical comparisons are not provided in the extracted text.
Mathai and colleagues interpret their findings as providing no evidence that acute dissociation, as measured by the CADSS in the specific context of the TRANSFORM trials, either facilitates or interferes with esketamine’s antidepressant effects. They emphasise that this pooled analysis is the largest formal assessment to date and that its null findings are broadly consistent with a prior industry analysis that reached similar conclusions despite methodological differences. The authors argue that pooling both TRANSFORM-1 and TRANSFORM-2 and examining dissociation across all induction sessions provides a more comprehensive test than analyses limited to one trial or to fewer time points. Several explanations and caveats are discussed. The investigators note that dissociation levels in the esketamine trials were relatively low compared with many racemic ketamine studies, which could reflect pharmacological, dosing, or delivery differences; however, variable findings across ketamine studies with similar administration methods suggest other factors may also matter. The potential influence of researcher and site attitudes on patient expectancies and experiences is raised as a possible modifier of subjective effects and outcomes, and the authors highlight the broader importance of contextual and extra-pharmacological variables. They further observe that the CADSS was developed to index pathological, trauma-related dissociation and may insufficiently capture other acute subjective phenomena—such as trance-like states, absorption, or mystical-type experiences—that could plausibly relate to therapeutic change. Subcomponents of the CADSS (for example, depersonalisation items) have in some studies been more predictive of outcome, and qualitative data hint that experiences of detachment may promote perspective shifts relevant to therapy. The authors acknowledge several limitations of the current analysis. Flexible dosing in TRANSFORM-2 precluded distinguishing between 56 mg and 84 mg doses in that trial, reducing the ability to probe dose-related effects across the pooled sample. Differences between ketamine and esketamine in pharmacology, delivery, and patient preference are noted as undercharacterised in the present data. The authors recommend future research that employs instruments better tailored to capture the full range of acute subjective effects, includes subgroup and dose-response analyses, and considers the role of psychological support and therapeutic context. They also note the clinical imperative to understand and mitigate any dissociative phenomena that may pose safety risks while, conversely, attending to subjective experiences that might promote benefit. Overall, the authors conclude that more nuanced conceptualisations and measurement of subjective drug experience are needed to clarify whether—and how—acute states relate to antidepressant response with ketamine derivatives.
Ketamine was first discovered in 1962 as a phencyclidine (PCP) derivative suitable for anesthetic use in humans. The drug's dreamlike and hallucinogenic properties were quickly observed and experienced by patients as feeling "disconnected" from their environment, leading to the classification of ketamine as a "dissociative anesthetic". To this day, ketamine and other dissociatives are often categorized by the subjective experience elicited during intoxication, typically involving feelings of detachment from one's sense of self or reality). However, the study of drug-induced "dissociation" and its implications has been limited by substantial confusion around this term. Historically, one of the earliest known descriptions of dissociation (désagrégation) as it is presently understood comes from the French psychiatrist Jacques-Joseph Moreau and his research on the psychological effects of hashish in the mid-1800s (van der Hart and Horst 1989). Moreau saw drug intoxication as a model of mental illness at large and described the function of hashish as disrupting an otherwise coherent "mental power," which "rules ideas and associates and connects them together". The most comprehensive theory of dissociation, however, can be attributed to psychologist Pierre Janet and his work involving non-drug states. Janet thought of dissociation as a divided state of consciousness, precipitated by traumatic or overwhelming experiences that gave rise to characteristic forms of psychopathology in at-risk patients. While these concepts have evolved with time, modern evidence supports the relationships Janet observed between trauma exposure, dissociation, and clinical presentations such as post-traumatic stress disorder. Importantly, from different vantage points and in ways that would endure, both Moreau and Janet proposed dissociation as a breakdown of the unified psychological functioning necessary for health. Dissociative disorders were not formally recognized in the DSM until 1980 but were similarly characterized then as involving, "sudden, temporary alteration in the normally integrative functions of consciousness, identity, or motor behavior" (American Psychiatric. This acknowledgement led to renewed scientific interest in dissociative phenomena and the development of instruments like the Clinician-Administered Dissociative States Scale (CADSS), which could be used toward symptom measurement. The CADSS was used by, the team of researchers credited for modern applications of ketamine in psychiatry, who first explored the drug as a glutamatergic model for acute dissociative and psychotic symptomatology before inadvertently discovering its rapid-acting antidepressant properties. As ketamine was repurposed as an intervention for depression, dissociation was recharacterized as an undesirable side effect rather than a primary aim of drug administration, and scales such as the CADSS were preserved as a way of assessing drug tolerability. In contrast with this view, some evidence suggests that greater drug-induced dissociation predicts antidepressant efficacy for ketamine, although observations of this relationship are inconsistent across clinical trials. While it is not clearly understood why such a relationship might occur, or the extent to which these data can be explained by functional unblinding, it has been proposed that the subjective effects of ketamine mediate its therapeutic benefit). This appears to be the case for other psychedelic treatments under investigation such as psilocybin-assisted interventions, where therapeutic outcomes for anxiety, mood, and substance use disorders have shown significant association with qualities of the acute drug experience, such as mysticaltype effects, broadly defined as feelings of unity, sacredness, ineffability, and positive mood. While overlapping, the subjective effects of classic psychedelics (e.g., LSD, psilocybin, DMT/ayahuasca, mescaline) are also thought to meaningfully diverge from those of dissociative hallucinogens (e.g., ketamine, dextromethorphan). This may explain in part why few clinical studies of classic psychedelics have examined the CADSS. One study of the analgesic properties of low-dose (5-20 µg) LSD utilized this scale as a measure of cognitive interference at 6 h postdosing, finding that LSD doses of 10 and 20 µg only slightly increased symptoms of dissociation relative to placebo, albeit with evidence of a significant association between increased dissociation and pain tolerance. Another randomized controlled trial of ayahuasca (containing 0.36 mg/kg of N,N-DMT) for treatment-resistant depression included the CADSS as a safety/tolerability measure at 1:40 h, 2:40 h, and 4 h after intake. Changes in CADSS score did not significantly differ between ayahuasca and placebo, nor did dissociation correlate with improvements in depression after treatment. The relevance of dissociation may vary among highly psychoactive interventions but is ultimately worth considering from a broader explanatory context. While dissociative-type phenomena have often been considered pathological, as initially proposed by Moreau and Janet, they have also been considered historically in terms of their non-pathologic, and even therapeutic value. It thus remains an open and critical question whether dissociation facilitates or interferes with the psychiatric use of ketamine and its derivatives, or whether it is an altogether unrelated pharmacological epiphenomenon. To further explore this question, the present study was conducted to examine the relationship between dissociation and antidepressant efficacy in a pooled post hoc analysis of data from TRANSFORM-1) and TRANSFORM-2, two-phase 3 shortterm trials of esketamine (a patented enantiomer of ketamine) for treatment-resistant depression. At the time of this writing, only esketamine, and not ketamine, is approved for the treatment of depression by the US Food and Drug Administration (U.S. Food and Drug Administration 2019), though ketamine is often administered off-label for psychiatric indications. A similar analysis was conducted recently by the Janssen Research and Development team and found no relationship between dissociation and antidepressant efficacy, though it did not formally test this across trials and excluded dissociation data for key study time points. In the present study, we test across trials and time points in a comprehensive manner. The current investigation is, to our knowledge, the largest formal assessment of the therapeutic relevance of dissociation for esketamine to date.
This post hoc analysis combines data from two clinical trials (total N = 576) of esketamine for treatment-resistant depression in adults ages 18 to 64, TRANSFORM-1) and TRANSFORM-2, which were made available through The Yale University Open Data Access (YODA) Project. Treatmentresistant depression (TRD) was defined as nonresponse to an adequate trial (dose, duration, and adherence) of ≥ 2 antidepressants in the current major depressive episode. Full descriptions of these trials, including inclusion criteria and study design, are available in these publications. In TRANSFORM-1, participants with TRD were randomized to receive intranasal placebo, fixed-dose esketamine 56 mg, or fixed-dose esketamine 84 mg, each combined with an open-label oral antidepressant administered daily. In TRANSFORM-2, participants with TRD were randomized to receive intranasal placebo or a flexible dose (56 mg or 84 mg) of esketamine in addition to an openlabel oral antidepressant. In both studies, the study drug was administered in a double-blind fashion twice weekly over the course of an initial 4-week induction phase.
The primary efficacy endpoint for these studies was a change in total depression score across the induction phase of treatment, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS)) and performed by independent, remote (by telephone) raters who were blind to the protocol details. The MADRS has been psychometrically validated as a clinician-rated scale consisting of 10 items rated from 0 to 6, resulting in a maximum total score of 60 points, with higher scores indicative of greater depressive symptomatology. Previous studies have recommended the following severity estimates based on MADRS score: 0 to 6 = no depression, 7 to 19 = mild depression, 20 to 34 = moderate depression, > 35 = severe depression. Both the TRANSFORM-1 and TRANSFORM-2 studies classified dissociation as an adverse event and utilized the CADSS as an on-site safety assessment of present-state dissociative symptoms at all drug administration visits (measured before dosing, at 40 min, and 1.5 h after dosing). The initial version of the CADSS consisted of 27 clinician-administered questions and clinical observations scored from 0 to 4, although a 23-item version of the instrument including only clinicianadministered questions was used in TRANSFORM-1 and TRANSFORM-2, consistent with other ketamine trials) and including subscale items for "depersonalization," "derealization," and "amnesia." The CADSS has been psychometrically validated as an instrument for the measurement of present-state dissociative symptoms with the ability to discriminate patients with dissociative disorders, including severe forms of posttraumatic stress disorder, from patients with other psychiatric disorders and healthy subjects. While preliminary studies have explored the validity of the CADSS in the measurement of ketamine-induced dissociation, this application of the CADSS has also been criticized for insufficiently measuring the acute psychoactive effects attributed to ketamine.
The present secondary analysis of de-identified datasets from TRANSFORM-1 and TRANSFORM-2 was acknowledged by the Johns Hopkins Medicine Institutional Review Board as not constituting human subjects research. The primary outcome of interest was the effect of the CADSS by time interaction on MADRS scores. CADSS scores at the 40-min post-dose time point were used for analysis, representing the approximate peak of post-dose dissociation associated with esketamine. Data from all eight induction doses of esketamine were included in these analyses. All analyses were performed in R, version 3.6.3. Linear mixed models were performed using total MADRS score as the outcome variable with the following independent variables: baseline MADRS score, a condition (fixed-dose esketamine 56 mg, fixed-dose esketamine 84 mg, flexible-dose esketamine 56 mg or 84 mg, or placebo) by time interaction, and CADSS by time interaction. These specific conditions were selected according to the format of data made available through the YODA analytic platform. Random intercepts for subject were included to account for repeated measures, and random intercepts for study were included to account for clustering within trials. Statistical significance for the CADSS by time interaction was assessed with type II Wald chi-square tests using the ANOVA function of the package car. To visually demonstrate the relationship between CADSS and MADRS, model-predicted means for MADRS days 1 and 28 were performed using the fitted function and the following CADSS values: 0, 2, 4, 8, and 16. To assess whether initial dissociation predicted rapid antidepressant benefit (i.e., occurring within 24-48 h) with esketamine, a simpler regression was also performed with day 2 MADRS as the
The analysis set included 576 patients from both trials grouped across four conditions: placebo (TRANSFORM 1 + TRANSFORM 2; N = 227), fixed-dose esketamine 56 mg (TRANSFORM 1; N = 115), fixed-dose esketamine 84 mg (TRANSFORM 1; N = 116), or flexible-dose esketamine 56 or 84 mg (TRANSFORM 2; N = 118). For these respective groups, mean baseline MADRS scores were 37.6 [SD = 5.14], 37.9), the treatment groups in each trial were similar with respect to demographic and baseline characteristics. Figureshows raw MADRS and CADSS scores combined from both studies and plotted over time. The linear mixed model did not show any effect of a CADSS × time interaction (p = 0.7). Figureshows model-predicted MADRS scores for each group at baseline and follow-up for CADSS values ranging from 0 to 16. Figureshows individual participant data as scatterplots of CADSS values at each time point by change in MADRS score from baseline to final follow-up. A separate, planned regression looking solely at the effect of day 1 CADSS on day 2 MADRS revealed that each additional CADSS point was associated with a -0.04 [95% CI -0.08, -0.002] (p = 0.04) decrease in MADRS score.
We found no evidence of a clinically significant positive (treatment-facilitating) or negative (treatment-interfering) association in this secondary analysis testing the relationship between dissociation and antidepressant effect for esketamine across two clinical trials. These findings represent the largest formal assessment of the therapeutic relevance of dissociation for esketamine. A similar, previous analysis that was unknowingly conducted in parallel to the present study found comparable results but did not test the relationship between dissociation and antidepressant effect across TRANSFORM-1 and TRANSFORM-2. The authors' rationale for the limited analysis was that only TRANSFORM-2 demonstrated a statistically significant antidepressant effect for esketamine over placebo, such that the analysis of TRANSFORM-1 was unwarranted. However, as this approach significantly limits the data that could be used toward the question of interest, and because the studies themselves have been considered sufficiently comparable to allow for pooled analyses, we combined data from both trials. The prior analysis also examined a reduced number of time points, while we considered dissociation across all induction dosing sessions. Despite these methodological differences in approach, our findings are broadly consistent with those of. We extend the previous findings by demonstrating that dissociation does not predict an antidepressant effect when the TRANSFORM-1 and TRANSFORM-2 samples are pooled, and when dissociation is examined across all time points. Across different studies involving ketamine, dissociation has been found to either positively predict or, more consistently, not predict its therapeutic efficacy. Interestingly, several experiments showing evidence of a positive correlation appear to have also hypothesized that dissociation would predict antidepressant benefit. However, in most other studies, as well as the esketamine trials used in the present analysis, dissociation has been narrowly characterized as an adverse event: in other words, an undesirable side effect of treatment. While demonstrating no relationship between druginduced dissociation and efficacy, the TRANSFORM-1 and TRANSFORM-2 trials are also notable for levels of dissociation that are markedly lower than those reported in other studies involving ketamine). This could, on one hand, reflect differences in pharmacologic, dosing, and delivery-related parameters for ketamine and esketamine). However, dissociation is also variably predictive of antidepressant benefit for studies of racemic ketamine with similar methods of administration. As such, it is worth considering that researcher attitudes toward dissociation could affect patient expectancies, experiences, and even outcomes around treatment-a possibility that should be considered in future prospective study designs involving ketamine and its derivatives. Contextual and extrapharmacological variables have indeed been described as crucial, though often underemphasized, aspects of psychopharmacology research. Similarly, the impact of acute dissociation could vary among individuals or patient subpopulations, suggesting the importance of considering trait variables that predict drug trajectories. Fig.CADSS/MADRS over time; split by treatment condition (placebo = placebo condition, esketamine 56 mg = fixed-dose esketamine 56 mg, esketamine 84 mg = fixed-dose esketamine 84 mg, esketamine = flexible-dose esketamine 56 mg or 84 mg) ◂ While specific features of dissociation have not been predictive of antidepressant efficacy for esketamine, other data suggest that certain subscales of the CADSS, such as depersonalization, are uniquely predictive of therapeutic benefit with ketamine. The CADSS items related to depersonalization capture detachment from one's typical sense of self, with wording including "sense of your own body feel changed," "some experience that separate you from what is happening," "disconnected from your own body," "watching the situation as an observer," and "looking at things from outside your body." Qualitative interview data also suggest a potential link between acute experiences of detachment during ketamine dosing and subsequent changes in perspective that may facilitate therapeutic effects. If there are experimental contexts for which and individuals for whom depersonalization reliably predicts therapeutic outcomes, this mechanism could overlap with the therapeutic changes in narrative selfhood that are thought to be implicated with psychedelics. The larger question posed is whether the subjective experiences of ketamine or esketamine are relevant to their benefit. Our findings suggest that acute dissociation, as approximated by the CADSS and in one particular therapeutic context, may not be. It is notable that the CADSS was developed for the direct measurementor modelingof pathological and trauma-related dissociation. However, the construct of dissociation has been tasked, historically, with describing a much broader spectrum of experiences. While often relegated to pathology, this spectrum has extended to psychological functions considered normal and even adaptive in certain contexts, including processes such as absorption and hypnotismconsidered by some to be a "form of structured and controlled dissociation". From this perspective, drug-induced ratings of "happiness" or "lightness" that have correlated with the antidepressant effects of ketamine) might be seen as highlighting the mechanistic action and therapeutic value of trance-likeand self-transcendent) states, which are poorly characterized by the CADSS. While study in this area is limited, it has been proposed that the trance state associated with lower doses of ketamine might facilitate processes of meditative self-reflection or, in drug-assisted therapy models, various qualities of effective psychotherapy. The latter implies that the benefits of some druginduced phenomena may not be fully realized in the absence of relational, psychologically oriented interventions. Sufficiently high doses of ketamine may elicit a different experience altogether, more akin to the mystical-type experiences that have been attributed to classic psychedelics and associated with lasting transformative impact. This range of possible experiences might be optimized in a variety of ways, such as implementing forms of psychological support that emphasize the meaning and insight that may be present during drug dosing sessions). However, for now, it remains inconclusive whether the unique therapeutic value ketamine depends on, or exists independently from, how it is subjectively experienced. Nevertheless, we propose that this area should be highly prioritized in future research efforts, using instruments that are more appropriately designed for hypotheses of interest. The current investigation has several important limitations. Given the procedure of flexible dosing used by TRANS-FORM-2, we did not distinguish between esketamine doses of 56 and 84 mg for that trial data, limiting our ability to detect dose-related differences in the relationship between dissociation and antidepressant benefit to the data from TRANSFORM-1. While briefly addressed here, it is also worth further characterizing the relevant differences between ketamine and esketamine, ranging from pharmacological activity, clinical delivery, and even patient preference. Future studies could benefit from these considerations and further subgroup analyses, to probe whether there are differences in how dissociation mediates treatment for specific populations. Consistent with prior research, we found that dissociation neither facilitates nor interferes with therapeutic efficacy, though additional investigation is needed. If certain dissociative phenomena are indeed related to risks for psychiatric decompensation, then it is critical that these risks are understood and mitigated in adequately supportive clinical settings. Conversely, if particular acute subjective effects are found to promote therapeutic outcomes, it is of high priority to tend to these types of experiences within the established treatment context. Ultimately, our findings suggest that subsequent inquiry involving ketamine or esketamine will be well-served by more nuanced conceptualizations of dissociation and the subjective drug experience.
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Dakwar, E., Nunes, E. V., Hart, C. L. et al. · Neuropharmacology (2018)
Davis, A. K., Barrett, F. S., May, D. G. et al. · JAMA Psychiatry (2021)
Garcia-Romeu, A., Griffiths, R. R., Johnson, M. W. · Current Drug Abuse Reviews (2015)
Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Haarsma, J., Harmer, C. J., Tamm, S. · Brain and Neuroscience Advances (2021)
Hartogsohn, I. · Journal of Psychopharmacology (2016)
Hull, T. D., Malgaroli, M., Gazzaley, A. et al. · Journal of Affective Disorders (2022)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Krupitsky, E. M., Burakov, A. M., Romanova, T. N. et al. · Journal of Substance Abuse Treatment (2002)
Abdallah, C. G., Charney, D. S., Duman, R. S. et al. · Neuron (2019)
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Mathai, D. S., Meyer, M. J., Storch, E. A. et al. · Journal of Affective Disorders (2020)
Mathai, D. S., McCathern, A. G., Guzick, A. G. et al. · Journal of Child and Adolescent Psychopharmacology (2021)
Mcinnes, L. A., Qian, J. J., Gargeya, R. S. et al. · Journal of Affective Disorders (2022)
Mollaahmetoglu, O. M., Keeler, J., Ashbullby, K. J. et al. · Frontiers in Psychiatry (2021)
Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Palhano-Fontes, F., Barreto, D., Onias, H. et al. · Psychological Medicine (2018)
Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2023)
Ramaekers, J. G., Hutten, N. P. W., Mason, N. L. et al. · Journal of Psychopharmacology (2020)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Rothberg, R. L., Azhari, N., Haug, N. A. et al. · Journal of Psychopharmacology (2020)
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Sumner, R. L., Chacko, E., Mcmillan, R. et al. · Journal of Psychopharmacology (2021)
Turkoz, I., Daly, E. J., Singh, J. B. et al. · Journal of Clinical Psychiatry (2021)
Van Schalkwyk, G. I., Wilkinson, S. T., Davidson, L. et al. · Journal of Affective Disorders (2018)
Yaden, D. B., Griffiths, R. R. · ACS Pharmacology and Translational Science (2020)
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