This further analysis of a randomized, double-blind, active-placebo controlled study (n=40) of ketamine (50mg/70kg) found that the mystical-type experiences (not dissociation) mediated the effect of ketamine on drinking behavior.

Abstract

“Background: Sub-anesthetic ketamine administration may be helpful for substance use disorders. Converging evidence suggests that the efficacy of ketamine for certain conditions may implicate a subset of its psychoactive effects.

Aims: The aim of this analysis is to evaluate whether the mystical-type effects of ketamine are critical for clinical efficacy in alcohol-dependent individuals. In this secondary analysis, we determine if a subset of the psychoactive effects of ketamine, the so-called mystical-type experience, mediates the effect of ketamine, when combined with motivational enhancement therapy, on at-risk drinking behavior in alcohol-dependent individuals interested in treatment.

Methods: Forty alcohol dependent adults were randomized to either a 52-minute infusion of ketamine or midazolam, which they received on a designated quit-day during the second week of a five-week motivational enhancement therapy regimen. Psychoactive effects were assessed following the infusion, and alcohol use was monitored for the subsequent 3 weeks at each twice-weekly visit.

Results: We found that ketamine leads to significantly greater mystical-type effects (by Hood Mysticism Scale) and dissociation (by Clinician Administered Dissociative States Scale) compared to the active control. Ketamine also led to significant reduction in at-risk drinking. The Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior.

Conclusions: This trial adds evidence to the literature on the importance of mystical-type experiences in addiction treatment. Future research should continue to investigate the relationship between the psychoactive effects of psychedelic therapeutics and clinical outcomes for other substance use and mental health disorders.”

Authors: Rebecca L. Rothberg, Nour Azhari, Nancy A. Haug & Elias Dakwar

Summary

Introduction

Alcohol misuse is a significant problem in the USA, and current treatment includes both behavioral health interventions and medication treatment. Ketamine, a N-methyl-D-aspartate antagonist, promoted sustained abstinence in individuals engaged in a five-week course of motivational enhancement therapy.

Ketamine may help individuals work towards recovery by improving mood and anxiety, improving craving and motivation to quit, increasing resilience, and dampening reactivity.

Sub-anesthetic ketamine administration may be helpful for substance use disorders.

A secondary analysis of ketamine uses in alcohol-dependent individuals determined that a subset of its psychoactive effects, the mystical-type experience, mediates the effect of ketamine on at-risk drinking behavior.

Forty alcohol dependent adults received ketamine or midazolam.

Ketamine was used to treat alcohol dependence in a five-week motivational enhancement therapy regimen. Ketamine was found to lead to significantly greater mystical-type effects and dissociation compared to the active control.

Other mechanisms might pertain to the psychoactive effects that emerge at sub-anesthetic doses, such as dissociative, psychotomimetic, and mystical-type effects, which are comparable to phenomena associated with spontaneous “spiritual” experiences.

Ketamine has been shown to have mystical-type effects that mediate the effects of ketamine on motivation to quit drug use and on drug use and craving, in two human laboratory studies with cocaine-dependent volunteers.

In the trial mentioned above, ketamine (0.71/kg) had a positive impact on problem drinking, and mystical-type effects were found to be the main mechanism.

Methods

A five-week, randomized, double-blind, placebo-controlled trial was conducted at the New York State Psychiatric Institute to evaluate the impact of a subanesthetic ketamine infusion on drinking behavior in healthy adults seeking treatment for alcohol dependence.

Participants

A sample of 40 healthy adults seeking treatment for alcohol dependence was studied. All participants tolerated study procedures without adverse events, including initiation of ketamine or benzodiazepine misuse.

Study design and procedures

Forty individuals seeking treatment for alcohol dependence were enrolled in a five-week trial where they received an intravenous (IV) infusion of either ketamine or of the active control midazolam and came in twice weekly for 5 weeks for monitoring and measures, physician visits, and MET.

Infusion procedures

Patients were randomized to receive an IV infusion of either ketamine or midazolam on day 2, week 2 of the trial. They were not told which drug they would receive, and were given a quit day to minimize expectancy effects.

Participants were guided through relaxation and mindfulness-based exercises prior to the start of the infusion, and were also asked questions about any subjective psychoactive effects they may have experienced.

Drinking outcome measures

At-risk drinking post-infusion was measured using urine toxicology and self-reported drug use. This dependent variable pertained to the entire three-week follow-up period.

We used a time right-censored variable to measure the number of days post-infusion until a participant engaged in a heavy drinking day or dropped out of the study.

Assessment of psychoactive effects

Participants’ mystical experiences were assessed via the HMS, which is a 32-item questionnaire concerning eight dimensions of mystical experience initially conceptualized by Stace (1960).

The eight dimensions of mystical experience are represented by eight subscales on the HMS, and each of these scales was analyzed separately in relation to post-infusion treatment outcomes.

Statistical analyses and calculation

SPSS version 24 was used to carry out the analyses, which used listwise deletion to treat missing data. The CADSS variable had a positive skew and was therefore treated with robust regression.

Ketamine leads to higher levels of mystical and dissociative experiences than midazolam, but decreases the odds of at-risk drinking post-infusion. A mediation analysis was performed to examine the relationship between ketamine and at-risk drinking.

To test if mystical and/or dissociative experiences mediated the relationship between treatment group and time to relapse, a Kaplan-Meier survival model was used. Additionally, Cox proportional hazard models were used to examine the full mediation model.

Participants

Thirty-five participants had baseline data on drinking patterns and no adverse events were reported as a result of either the ketamine or midazolam infusions.

Infusion effects

Ketamine led to significantly greater levels of both mystical-type and dissociative effects than midazolam, and decreased the odds of engaging in at-risk drinking by approximately five times. Ketamine also led to significantly longer time to relapse compared to midazolam.

HMS subscale analysis

The correlations between the HMS subscales relating to ineffability and positive affect were significant in those randomized to the ketamine arm.

Discussion

Ketamine-occasioned mystical-type experiences may play a critical role in the efficacy of ketamine-assisted behavioral treatment for alcohol use disorder, and provide support for a psychological mechanism of action for the therapeutic effects of ketamine on substance use disorder.

The impact of mystical-type phenomena on motivation to quit smoking was studied in a previous study, and we assumed that a psychotherapy platform aimed at enhancing motivation and promoting change might provide a framework for focusing these psychoactive effects into more fruitful engagement with behavioral modification.

Other therapeutic mechanisms of mystical-type phenomena include psychospiritual explanations, which invoke the “revelation” of a non-ordinary mode of being. These revelatory experiences might include: developing a relationship to an immaterial and sacred dimension, or finding redemption from sin, or freedom from suffering.

Studies have found a correlation between spirituality and fewer relapses and longer-term recovery, as well as a negative correlation with frequent binge-drinking. The mystical-type dimension of ineffability was significantly correlated with percentage of heavy drinking days.

Psychedelics are substances that produce shifts in consciousness comparable to trance, meditation, mystical experience, and other non-ordinary experiences. These shifts in consciousness are often accompanied by a sense of peace and joy, unity, sacredness, ineffability, a sense of transcending space and time, and an experience of tapping into some more universal aspect of reality.

There has been a resurgence of research examining the possible impact of psychedelics on mental health issues, and on addiction and SUDs in particular. LSD, psilocybin, ayahuasca, and ketamine may decrease alcohol misuse and cravings in those with AUDs. Ketamine has been investigated in terms of its neurobiological mechanisms of action, but Krupitsky recognized that its psychoactive effects might be impactful. He therefore evaluated ketamine in the context of “psychedelic therapy” for alcohol and opioid use disorders.

Limitations

It is not possible to conclusively determine whether the mystical type experience was responsible for the therapeutic outcomes observed. It is possible that neurobiological mechanisms associated with ketamine are responsible for both its observed therapeutic effects and mystical type experiences.

Nevertheless, mystical-type effects are not merely an epiphenomenon of neurobiological action, or a marker of potency, as only mystical experiences were found to mediate the effects. Furthermore, the broader literature suggests that mystical experiences have long-lasting, meaningful impacts on individuals.

Our research revealed that positive affect associated with ketamine-induced mystical experience was significantly correlated with drinking outcomes. This suggests that the mood-boosting effects of ketamine may interact with other aspects of mysticism in a meaningful way that impacts on treatment outcomes.

The present study had several limitations, including a small sample size and using a non-depressed alcohol-dependent population. It is unknown whether these results would generalize to a broader population of alcohol-dependent individuals with psychiatric comorbidity.

Conclusion

This analysis adds significant evidence to the literature supporting the importance of mystical-type phenomena in addiction treatment. Further research should explore the relationship between psychedelic therapeutics, psychotherapy, and treatment outcomes.