This double-blind, randomized, 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.

Abstract

“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.”

Authors: Elias Dakwar, C. Anerella, Carl L. Hart, Frances R. Levin, S. J. Mathew & Edward V. Nunes

Summary

Ketamine may benefit a variety of psychiatric disorders, including addiction. This analysis assesses whether mystical-type effects of ketamine mediate improvements in dependence-related deficits.

Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. They received three counter-balanced infusions separated by 48 h and underwent assessments of motivation to stop cocaine and cue-induced craving.

Ketamine led to greater acute mystical-type effects than lorazepam, and ketamine 0.71 mg/kg was associated with higher motivation to quit cocaine.

1. Introduction

Ketamine has been found to improve depressive symptoms in patients, with benefits peaking at 24 h postinfusion and generally subsiding by 72 h. Ketamine may address dependence-related deficits through comparable mechanisms.

Ketamine elicits an array of psychoactive effects, including dissociative phenomena and altered states of consciousness similar to those engendered by serotonergic hallucinogens. These effects may be particularly relevant to therapeutic mechanism.

The role of mystical states in clinical improvement has been frequently noted in the literature on recovery. The intensity of the mystical experience, but not of dissociative phenomena, mediates the effects of the initial ketamine dose on motivation to quit cocaine and cue-induced craving.

2. Methods

2.1. Participants

Eight cocaine dependent individuals who were not seeking treatment or abstinence, and had a history of cue-induced craving, underwent psychiatric screening and a medical evaluation. They were hospitalized for 9 days and randomized to one of three infusion orders.

2.2. Infusions

Three 52-min infusions of ketamine (0.41 mg/kg K1), lorazepam (2 mg) or saline (0.11 mg/kg over 2 min followed by 0.3 mg/kg or 0.6 mg/kg slow-drip over 50 min, respectively) were administered to each participant.

2.3. Assessments

Motivation to quit cocaine and cue-induced craving were assessed at baseline and 24 h post-infusion.

2.4. Mystical-type Effects

Acute mystical-type effects were assessed with items from the Hood’s Mysticism Scale. The questionnaire was modified to focus on infusion-related phenomena rather than lifetime experience.

Items were administered within 15 min of infusion termination alongside other measures, and HMS scores were calculated as the total sum.

2.5. Statistics

Ketamine led to mystical-type effects in humans. ANOVA and paired Bonferroni-corrected Wilcoxon signed-rank tests were used to evaluate this.

Because the efficacy of K2 could not be fully evaluated due to order and carry-over effects, analyses were conducted with data from K1 relative to LZP only.

Four mediation analyses were conducted using the approach proposed by Baron and Kenny (1986). The CADSS score and HMS score were tested as mediators.

3. Results

3.1. Participants

Eight adult participants with high mean baseline cocaine use completed the study without adverse events.

3.2. Mystical-type Effects

All psychoactive effects of ketamine resolved within 20 min postinfusion, and ketamine led to significantly greater mystical-type effects by HMS compared to lorazepam.

3.3. Mediation

The only analysis to fulfill the criteria for mediation was that testing the mediating role of HMS score with respect to URICA score.

4. Discussion

Two main findings emerged from this study: ketamine significantly generated mystical-type phenomena, and the intensity of these effects mediated the therapeutic effect of ketamine on motivation to quit cocaine.

Ketamine has been shown to produce dissociative effects, but its mystical-type effects have not been well characterized. Our data suggest that ketamine’s mystical-type effects may be dose-dependent, as has also been shown with psilocybin.

The finding that HMS score influenced the effect of ketamine on motivation to quit is consistent with the hypothesis that mystical experience might be psychologically beneficial. This may explain why HMS score was correlated so robustly with motivation to quit, which implicates many of these dimensions.

This study suggests that ketamine-facilitated existential reappraisal can be used to promote long-term abstinence in alcohol or opioid dependent individuals. The study also suggests that by adequately screening and preparing individuals, administering infusions under controlled conditions, and providing postinfusion support, researchers can effectively minimize risks.

A preliminary study of mystical-type effects found that they did not mediate general efficacy, but rather a discrete set of psychoactive effects influenced a particular category of improvements.

This study had several limitations, including a small sample size and homogenous population, lack of a control group, and a questionnaire that was too short to obtain more nuanced information on psychoactive effects.

Despite limitations, this analysis demonstrates that ketamine engenders mystical-type effects in a dose-dependent fashion, and that these effects may mediate improvements in motivation to quit cocaine.

Ketamine-induced dissociation and mysticism were associated with change in motivation to quit, and the relationship between HMS score and motivation to quit was the only association to remain significant after mediation analyses were performed.

The mean hood mystical experience scale (HMS) scores associated with lorazepam were significantly different from those associated with ketamine 0.41 mg/kg and ketamine 0.71 mg/kg, respectively.