This double-blind, randomised, inpatient study (n=8) evaluates the mystical and dissociative effects of ketamine in the treatment of cocaine dependant individuals. Ketamine led to significantly greater acute mystical-type effects than the active control, and mediated motivation to quit cocaine 24h post-infusion.
Papers cited by this study that are also in Blossom
Griffiths, R. R. · Journal of Psychopharmacology (2008)
Background
Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24 h postinfusion.
Methods
Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions separated by 48 h were received: lorazepam (2 mg) and two doses of ketamine (0.41 mg/kg and 0.71 mg/kg, with the former dose always preceding the latter). Infusions were followed within 15 min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24 h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure).
Results
Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71 mg/kg was associated with significantly higher HMS scores than was the 0.41 mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24 h postinfusion.
Conclusions
These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.
A single sub‑anaesthetic intravenous infusion of ketamine (commonly 0.5 mg/kg over ~40 min) has been shown in prior work to produce rapid antidepressant effects that peak about 24 h after infusion and attenuate by 72 h. Such effects have been attributed to enhanced neuroplasticity, modulation of prefrontal glutamate balance, and changes in default mode network function. Ketamine may therefore also ameliorate dependence‑related deficits by similar biological pathways; the investigators previously reported that ketamine improved low motivation to quit and cue‑induced craving in non‑depressed cocaine‑dependent volunteers. This analysis asks whether the transient psychoactive effects produced by therapeutic ketamine infusions—specifically mystical‑type experiences similar to those elicited by serotonergic hallucinogens—contribute to clinical benefit. Dakwar and colleagues set out to (1) test whether two sub‑anaesthetic intravenous ketamine doses produce dose‑dependent mystical‑type effects measured shortly after infusion, and (2) evaluate whether the intensity of those mystical‑type experiences, as distinct from dissociative symptoms, mediates ketamine’s 24‑hour effects on motivation to quit cocaine and on cue‑induced craving.
Design and participants: The study was a double‑blind, randomised, inpatient experiment involving eight adult cocaine‑dependent individuals actively using freebase cocaine and not seeking treatment. Participants underwent psychiatric screening (including DSM‑IV SCID) and a medical evaluation; those enrolled were in good health, had no history of ketamine use, and had no psychiatric disorders other than substance use disorders. Subjects were hospitalised for nine days and were abstinent on days 1–3 before randomisation to infusion order. Institutional review board approval was obtained. Interventions and procedures: Each participant received three 52‑minute infusions separated by 48 h in a counterbalanced, double‑blind manner: low‑dose ketamine (K1, 0.41 mg/kg: 0.11 mg/kg bolus over 2 min then 0.3 mg/kg over 50 min), higher‑dose ketamine (K2, 0.71 mg/kg: 0.11 mg/kg bolus then 0.6 mg/kg slow drip), and lorazepam 2 mg (LZP: saline bolus then 2 mg over 50 min) as an active control. There were three possible infusion sequences constrained so that K1 always preceded K2 for safety. Participants were monitored for 2 h post‑infusion and interviewed at 20 min and 1 h with attention to persistent sedation, psychosis or dissociation. Assessments: Primary behavioural outcomes were motivation to quit cocaine, assessed by the University of Rhode Island Change Assessment (URICA) at baseline and 24 h post‑infusion, and cue‑induced craving, assessed as the summed visual analogue scale (VAS) ratings collected every 3 min during 15 min of cocaine cue exposure (baseline and 24 h). Acute psychoactive effects were measured within 15 min of infusion termination. Dissociation was measured with the Clinician Administered Dissociative Symptoms Scale (CADSS). Mystical‑type phenomena were measured using a modified, shortened version of Hood’s Mysticism Scale (HMS) adapted to refer specifically to the infusion experience; nine items represented the scale’s dimensions and scores were summed (maximum 36). Other brief psychiatric items and a VAS of drug liking were also collected. Statistical analysis: Given the small sample (n = 8), nonparametric tests were used. HMS scores were compared across medication conditions and infusion order with Friedman’s two‑way ANOVA and paired Wilcoxon signed‑rank tests with Bonferroni correction, two‑tailed α = 0.05. Mediation analyses focused on K1 versus lorazepam because previous work indicated K1 produced a robust ~60% change in the primary outcomes and K2 could not be cleanly evaluated due to order/carryover. Four mediation models were tested (CADSS and HMS each tested as mediators for URICA and for summed VAS craving), using the standard approach whereby mediation is supported if the mediator predicts outcome when controlling for infusion condition and infusion condition ceases to predict the outcome when the mediator is included. To limit Type I error across multiple mediation tests, α was adjusted to 0.0125.
A single sub-anesthetic infusion of ketamine (0.5 mg/kg over 40 min intravenously, IV) has been found to rapidly improve depressive symptoms, with benefits peaking at 24 h postinfusion (when active metabolites are at negligible serum levels) and generally subsiding by 72 h. This unique response has been attributed to enhanced neuroplasticity via various downstream effects, improved prefrontal glutamate homeostasis, and sustained attenuations in default mode network connectivity and activity. Ketamine may address dependence-related deficits through comparable mechanisms. We previously reported that ketamine improves low motivation to quit and cue-induced craving in non-depressed cocaine dependent volunteers). An intriguing but unexplored question is whether the psychoactive effects of ketamine influence its efficacy through psychological mechanisms. At the therapeutic doses studied to date, ketamine elicits an array of psychoactive effects, which tend to resolve entirely within 30 min postinfusion. These effects include dissociative phenomena, as well as alterations in consciousness similar to those engendered by serotonergic hallucinogens. The latter effects may be particularly relevant to therapeutic mechanism. Recent research suggests that the 5HT-2A agonist psilocybin occasions altered states of enduring personal importance and possible benefit in healthy volunteers. These experiences were similar to mystical states that might spontaneously emerge over the normal course of life, and which are imbued with sacred, spiritual, or existential significance. The role of mystical states in robust clinical improvement has been frequently noted in the literature on recovery, with individuals reporting that efforts toward abstinence were promoted by experiences with mystical characteristics. It is, therefore, possible that the improvements in cocaine users we reported previously were influenced by ketamine-induced mystical-type phenomena. This analysis examines the mystical-type effects of the ketamine infusions administered previouslyand investigates whether these phenomena mediate ketamine efficacy, 24 h postin-fusion. We predict that ketamine infusions dose-dependently promote transient mystical-type effects, assessed with items from a widely used mystical experience scale. Further, we predict that the intensity of the mystical experience, but not of dissociative phenomena, serves to mediate the effects of the initial ketamine dose (0.41 mg/kg over 52 min) on motivation to quit cocaine and cue-induced craving.
Create a free account to open full-text PDFs.
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
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)
Krupitsky, E. M., Grinenko, A. Y. · Journal of Psychoactive Drugs (1997)
MacLean, K. A., Leoutsakos, J. S., Johnson, M. W. et al. · Journal for the Scientific Study of Religion (2012)
Studerus, E., Gamma, A., Kometer, M. et al. · PLOS ONE (2012)
Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
Papers in Blossom that reference this study
Gubser, L. P., Trippel, A. S., Zoelch, N. et al. · Brain Research Bulletin (2026)
Dahan, J. D. C., Dadiomov, D., Bostoen, T. et al. · npj Mental Health Research (2024)
Macconnel, H. A., Earleywine, M., Radowitz, S. · OSF Preprints (2024)
Mathai, D. S., Nayak, S., Yaden, D. B. et al. · Psychopharmacology (2023)
Belser, A. B. · Frontiers in Psychology (2022)
Keeler, J. L., Treasure, J., Juruena, M. F. et al. · Nutrients (2021)
Mollaahmetoglu, O. M., Keeler, J., Ashbullby, K. J. et al. · Frontiers in Psychiatry (2021)
Rothberg, R. L., Azhari, N., Haug, N. A. et al. · Journal of Psychopharmacology (2020)
Olson, D. E. · ACS Pharmacology and Translational Science (2020)
Reiff, C. M., Richman, E. E., Nemeroff, C. B. et al. · American Journal of Psychiatry (2020)
Dakwar, E., Levin, F. R., Hart, C. L. et al. · American Journal of Psychiatry (2020)
Dakwar, E., Nunes, E. V., Hart, C. L. et al. · American Journal of Psychiatry (2019)
Best, S. R. D., Pavel, D. G., Haustrup, N. · Heliyon (2019)
Roseman, L., Haijen, E. C. H. M., Idialu-Ikato, K. et al. · Journal of Psychopharmacology (2019)
Sample and safety: Eight participants completed the protocol. Extracted participant characteristics indicate high baseline cocaine use (mean 22 use days in the prior 4 weeks; estimated cost per use day reported as US$158.83). All subjects tolerated the procedures without adverse events, including no unexpected psychiatric disturbances or initiation of ketamine/benzodiazepine misuse. Acute psychoactive effects: All ketamine‑related psychoactive effects, including dissociative and mystical‑type phenomena, resolved within 20 min after infusion termination. Both ketamine doses produced significantly higher HMS scores than lorazepam: median HMS scores were 4 for lorazepam, 22 for K1, and 30 for K2 (overall comparison p = 0.012). The higher ketamine dose (K2) produced greater mystical‑type effects than the lower dose (K1) (median 30 vs 22, p = 0.027). There was no significant effect of infusion order on HMS. A linear regression testing the relationship between HMS and CADSS scores for K1 was non‑significant (R2 = 0.261, p = 0.12), indicating no clear correlation between mystical‑type and dissociative scores for that dose. Mediation analyses: Four mediation models were run (HMS or CADSS mediating changes in URICA or summed VAS craving). The only model meeting the authors’ mediation criteria was HMS mediating the effect of infusion condition (K1 vs lorazepam) on URICA change. The total mediation model for URICA had an adjusted R2 = 0.775 (p < 0.005). In simple regression infusion condition predicted URICA change (β = 0.776, p < 0.001), but when HMS score was included the direct effect of infusion condition fell to β = 0.274 (p = 0.19), consistent with mediation. No mediation was observed for cue‑induced craving, and CADSS did not fulfil mediation criteria for either outcome.
Dakwar and colleagues highlight two principal findings: sub‑anaesthetic intravenous ketamine produced dose‑dependent mystical‑type experiences, and the intensity of those transient experiences statistically mediated ketamine’s 24‑hour enhancement of motivation to quit cocaine but did not mediate reductions in cue‑induced craving. The authors interpret these results as evidence that certain psychoactive effects of ketamine may contribute to its therapeutic impact via psychological mechanisms rather than solely via neurobiological processes. They situate the findings within broader literature on psychedelic and mystical experiences, noting that earlier work with psilocybin linked such experiences to lasting personal significance and therapeutic benefit. A prior intramuscular ketamine study reportedly did not find mystical‑type effects versus placebo; Dakwar and colleagues propose that differences in route and dose might explain that discrepancy because IV administration and the doses used in the present protocol produced clear dose dependence. The authors further draw on historical and psychological theories (for example, writings of William James) to suggest mystical experiences may alter existential dimensions such as self‑identity and purpose, which plausibly explain stronger effects on motivation to quit than on cue‑elicited craving, the latter being only partly influenced by changes in perspective. The discussion also considers clinical translation: approaches such as Ketamine Psychedelic Therapy (KPT), which pair ketamine‑facilitated existential reappraisal with psychotherapy, are mentioned as examples of frameworks that seek to harness and consolidate pharmacologically induced transformative experiences. The investigators suggest that careful screening, preparation, a controlled setting, and post‑infusion support might enhance benefits while minimising risks such as misuse or behavioural toxicity. Several limitations are acknowledged. The sample was small and homogeneous, which limits generalisability and statistical power. The shortened HMS may have reduced sensitivity to nuanced differences between doses. The design could not disentangle mediation from marker effects definitively—although the lack of correlation between HMS and CADSS for K1 and the specificity of mediation for URICA (not craving) provide some support for a mediating role, the authors caution that larger, properly powered studies are required. Other potentially relevant variables (for example, family history of alcoholism or serum ketamine levels) were not examined. Finally, the study was not designed to assess longer‑term drug use outcomes because there was no non‑ketamine control group across follow‑up. The authors conclude that their preliminary results justify further research into whether enhancing and integrating ketamine‑induced mystical‑type experiences can improve clinical outcomes in substance use and related disorders.
Eight cocaine dependent individuals not seeking treatment or abstinence, actively using freebase ("crack") cocaine, and describing a history of cue-induced craving underwent psychiatric screening, including a Structured Clinical Interview for the Diagnostic Statistical Manual, 4th edition (DSM-IV SCID), as well as a medical evaluation. All participants were in good health, had no history of ketamine use, and denied past or current psychiatric disorders other than substance use disorders. Participants were hospitalized for 9 days, and were abstinent on days 1 through 3 before being randomized to one of three infusion orders. Our Institutional Review Board approved all procedures.
Three 52-min infusions (2-min bolus followed by 50 min infusion) separated by 48 h were administered in a randomized double-blind manner to each participant: ketamine 0.41 mg/kg (K1) or 0.71 mg/kg (K2) (0.11 mg/kg over 2 min followed by 0.3 mg/kg or 0.6 mg/kg slowdrip over 50 min, respectively) or lorazepam 2 mg (LZP) (saline bolus over 2 min followed by 2 mg slow-drip over 50 min). There were three possible orders: K1, K2, LZP; LZP, K1, K2; and K1, LZP, K2. K1 always preceded K2 for safety reasons. Participants were monitored for 2 h after the infusion ended, and were interviewed 20 min and 1 h post-infusion, with special attention given to persistent symptomatology that might merit concern, such as sedation, psychosis or dissociation.
Assessments of motivation to quit cocaine and cue-induced craving occurred at baseline and at 24 h post-infusion. Motivation to quit cocaine was assessed using the University of Rhode Island Change Assessment (URICA), a 32-item questionnaire validated to ascertain readiness for change in cocaine users. Cue-induced craving was ascertained by summing serial (every 3 min) visual analogue scale (VAS) assessments of craving over 15 min of cocaine cue exposure.
Acute mystical-type effects were assessed with items from the Hood's Mysticism Scale (HMS;. The questionnaire was modified for the purposes of this study. First, the verb tense of items was changed to focus on infusion-related phenomena rather than on lifetime experience. Second, the questionnaire was shortened. To reduce redundancy and facilitate administration, negative items were removed (e.g., I did not experience a perfectly peaceful state), while each of the eight dimensions, and all three factors, were represented by at least one item, leaving nine items (see Table). Items were administered within 15 min of infusion termination alongside other measures, including a VAS of drug liking, Clinician Administered Dissociative Symptoms Scale (CADSS), and four items pertaining to psychosis from the Brief Psychiatric Rating Scale. Scoring was consistent with the 5-point HMS scale, and HMS scores were calculated as the total sum (maximum possible score = 36).
To evaluate whether ketamine led to mystical-type effects, HMS scores were compared by Friedman's 2-way analyses of variance (ANOVA) (medication (LZP, K1, K2) by order (three possible orders)) and paired Bonferroni-corrected Wilcoxon signed-rank tests. Nonparametric tests were used because of small sample sizes (n = 8), with 2-tailed α = 0.05. Because we have previously shown that K1 (0.41 mg/kg) led to a significant ~60% change from preceding values for both primary outcomes (craving VAS and URICA), while the efficacy of K2 (always received after K1) could not be fully evaluated due to order and carry-over effects, analyses of HMS or CADSS scores as mediators were conducted with data from K1 relative to LZP only. Four mediation analyses were conducted using the approach proposed by. One set of analyses tested CADSS score as a mediator, with URICA or sum VAS alternately designated as dependent variables, and another tested HMS score as a mediator. Mediation was supported if the mediator remained a significant predictor when controlling for infusion condition, and if infusion condition ceased to be a significant predictor when controlling for the mediator. Because multiple comparisons were tested, α was adjusted to 0.0125 to minimize Type I error.
Eight adult participants with high mean baseline cocaine use (22 use days in 4 weeks, at $158.83 per use day) completed the study (seefor other participant characteristics). All participants tolerated study procedures without adverse events, including unexpected psychiatric disturbances and initiation of ketamine or benzodiazepine misuse.
All psychoactive effects, including dissociative and mystical-type phenomena, resolved within 20 min postinfusion. Both doses of ketamine led to significant elevations in HMS score relative to lorazepam (LZP vs. K1, median 4 vs. 22; LZP vs. K2, median 4 vs. 30; p = 0.012; mean values and standard errors of the mean are shown in Fig.). Additionally, K2 led to significantly greater mystical-type effects by HMS compared to K1 (30 vs. 22, p = 0.027). The test for order effects was not significant. A linear regression testing for correlations between HMS and CADSS scores for K1 was non-significant (R 2 = 0.261, p = 0.12).
The only analysis to fulfill the criteria for mediation was that testing the mediating role of HMS score with respect to URICA score (adjusted R 2 for the total model = 0.775, p < 0.005). Infusion condition also ceased to be significant when controlling for HMS score (β = 0.776 in an uncontrolled regression, p < 0.001; β = 0.274 after controlling for HMS score, p = 0.19; Fig.).
Two main findings emerged from this study. The first is that sub-anesthetic ketamine significantly and dose-dependently generated mystical-type phenomena. Second, the intensity of these transient effects was found to mediate (at 24 h postinfusion) the therapeutic effect of ketamine on motivation to quit cocaine, but not on cue-induced craving. These results indicate that the mystical-type effects of ketamine may influence its efficacy, and suggest a psychological mechanism by which ketamine might exert certain benefits. While the dissociative effects of ketamine have been well characterized, its mystical-type effects have not. A single previous studyhad examined the mystical-type effects of ketamine (by the intramuscular, IM, route), and found that it did not significantly generate mystical phenomena relative to placebo. Our data suggest that pharmacologically elicited mystical states may be dose-dependent, as has also been shown with psilocybin. Thus, the lack of observed effect in the previous study might be attributed to the reduced bioavailability of ketamine by the IM route compared to IVas well as the low doses administered (0.2 mg/kg and 0.4 mg/kg;. The finding that HMS score was found to influence the effect of ketamine on motivation to quit is consistent with the hypothesis, first proposed bymore than a century ago, that mystical experience might be psychologically beneficial. According to James and more recent psychologists, mystical experience may impact most directly on the existential dimensions of personhood, such as moral values, self-identity, and purpose. This may explain why HMS score was correlated so robustly with motivation to quit, which implicates many of these dimensions. It also provides a rationale for the failure of HMS score to mediate improvements in cue-induced craving, a deficit only partly influenced by the perspectival shifts) that might result from mystical-type phenomena. Important vulnerabilities that ostensibly involve an existential dimension, and which have responded robustly to ketamine previously, include such depressive symptoms as hopelessness, guilt, and suicidality. This study also suggests that a framework aimed at harnessing the therapeutic potential of these psychoactive effects may optimize efficacy, at least for certain vulnerabilities. Ketamine Psychedelic Therapy (KPT), for example, incorporates 1 or 2 sessions of ketamine-facilitated existential reappraisal into an existential psychotherapy, and preliminary controlled trials suggest that it effectively promotes long-term abstinence in alcohol or opioid dependent individuals. The approach of KPT, as of other therapies aimed at the pharmacological production of a transformative experience, is predicated on two notions: that the quality of the experience is crucial to efficacy, and that efficacy is enhanced by patient preparation and the treatment context. Some research has aimed to clarify how various factors might shape psychoactive responses to other agents, but this has not been studied for ketamine. Our findings suggest that by adequately screening and preparing individuals, administering infusions under controlled conditions, and providing postinfusion support, investigators can effectively minimize the risks of ketamine, such as its abuse liability and behavioral toxicity, while also allowing for its possibly beneficial psychoactive effects to safely emerge. An important limitation is that we cannot conclusively determine from these preliminary results whether mystical-type effects constitute a true mediator or whether they are simply a marker of potency or efficacy. Two findings, however, lend support to the hypothesis of mediation. First, we failed to find a significant correlation between HMS and CADSS scores in individuals receiving K1, suggesting that HMS score did not reflect general psychoactive potency for that dose (though this should be interpreted conservatively in light of a small sample). Similarly, mystical-type effects were not found to mediate general efficacy, even as the improvements in cue-induced craving and motivation to quit were comparable in magnitude. These results, taken together, suggest that a discrete set of psychoactive effects, as ascertained by the HMS, served to influence a particular category of improvements. Larger, adequately powered studies are needed to confirm this hypothesis. Other limitations also reflect the preliminary nature of this study. The sample was small and homogenous. Factors that might impact on the effects of ketamine were not explored, such as a family history of alcoholism or serum levels. In addition, the study was not designed to test how mystical-type effects might mediate drug use reductions in follow-up, because there was no control group that did not receive ketamine. Finally, though the basic dimensions of the HMS were retained, shortening the questionnaire may have impacted on our capacity to obtain more nuanced information on psychoactive effects, particularly when comparing the two ketamine dosages. Despite these limitations, this analysis demonstrates that sub-anesthetic ketamine engenders mystical-type effects in a dose-dependent fashion, and that these transient effects may mediate improvements in motivation to quit cocaine, 24 h postinfusion. Future research can evaluate whether mystical-type effects influence the therapeutic effects of ketamine in larger clinical samples. Researchers can also consider evaluating whether ketamine efficacy is improved by utilizing a clinical framework aimed at enhancing and consolidating the apparent psychological benefits emerging from its psychoactive effects. (A) Regression plot assessing correlation between mystical experience and change in motivation to quit and (B) β values calculated from simple regressions and mediation analyses with respect to change in dependent variables (motivation to quit and cue-induced craving) for ketamine-induced dissociation (CADSS score) or mysticism (HMS score), as well as infusion type (lorazepam vs. ketamine). The correlation between mystical experience and change in motivation to quit is represented in (A), and remained significant when controlling for infusion type (lorazepam vs. ketamine 0.41 mg/kg), β = 0.678, p = 0.005. The relationship between HMS score and motivation to quit was the only association to remain significant after mediation analyses were performed (B). This suggests that mystical-type phenomena might mediate the effect of ketamine on motivation enhancement. * p = 0.001, ** p = 0.012, *** p < 0.001, **** p = 0.005.
Martial, C., Cassol, H., Charland-Verville, V, Erowid, E. et al. · Consciousness and Cognition (2019)
Dakwar, E., Nunes, E. V., Hart, C. L. et al. · Neuropharmacology (2018)
Ezquerra-Romano, I. I., Lawn, W., Krupitsky, E. M. et al. · Neuropharmacology (2018)
Van Schalkwyk, G. I., Wilkinson, S. T., Davidson, L. et al. · Journal of Affective Disorders (2018)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Liu, Y., Lin, D., Wu, B. et al. · Brain Research Bulletin (2016)
Dakwar, E., Hart, C. L., Levin, F. R. et al. · Molecular Psychiatry (2016)
Coyle, C. M., Laws, K. R. · Human Psychopharmacology (2015)
Majic, T., Schmidt, T. T., Gallinat, J. · Journal of Clinical Psychopharmacology (2015)