A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study

Abstract

Efforts to translate sub-anesthetic ketamine infusions into widespread clinical use have centered around developing medications with comparable neurobiological activity, but with attenuated psychoactive effects so as to minimize the risk of behavioral toxicity and abuse liability. Converging lines of research, however, suggest that some of the psychoactive effects of sub-anesthetic ketamine may have therapeutic potential. Here, we assess whether a subset of these effects - the so-called mystical-type experience - mediates the effect of ketamine on craving and cocaine use in cocaine dependent research volunteers. We found that ketamine leads to significantly greater acute mystical-type effects (by Hood Mysticism Scale: HMS), dissociation (by Clinician Administered Dissociative States Scale: CADSS), and near-death experience phenomena (by the Near-Death Experience Scale: NDES), relative to the active control midazolam. HMS score, but not the CADSS or NDES score, was found to mediate the effect of ketamine on global improvement (decreased cocaine use and craving) over the post-infusion period. This is the first controlled study to show that mystical-type phenomena, long considered to have therapeutic potential, may work to impact decision-making and behavior in a sustained manner. These data suggest that an important direction for medication development is the identification of ketamine-like pharmacotherapy that is selectively psychoactive (as opposed to free of experiential effects entirely), so that mystical-type perspectival shifts are more reliably produced and factors lending to abuse or behavioral impairment are minimized. Future research can further clarify the relationship between medication-occasioned mystical-type effects and clinical benefit for different disorders. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Keywords: Addiction; Cocaine; Hallucinogen; Ketamine; Mystical experience; Psychedelic; Psychoactive effects.

FIGURE 1

Psychoactive and Therapeutic Effects of a Single Sub-anesthetic Ketamine Infusion. Ketamine 0.71 mg/kg over 52 min (Ket) produced greater psychoactive effects on all measures than did midazolam 0.025 mg/kg over 52 min (Mdz) (a–c) as ascertained shortly after the infusion, and was also associated with greater post-infusion global improvement (d), which reflected improvement in subsequent cocaine self-administration, craving, and cocaine use in the natural ecology.

FIGURE 2

(a) Regression plot assessing correlation between mystical experience and global improvement, and (b) β values calculated from univariate regressions examining the effect of ketamine on psychoactive effects, and from univariate/multivariate analyses with respect to change in dependent variable (global improvement) for ketamine-induced dissociation (CADSS score), mystical-type experience (HMS score), and near-death experience related phenomena (NDES), as well as for ketamine dose received, ranging from 0 to 70.5 mg (midazolam vs. ketamine infusions). The correlation between mystical-type experience and global improvement is represented in (a), and was significant in a multivariate analysis, β = 0.431, p = 0.0175 (b), suggesting that mystical-type phenomena mediate the benefits of ketamine in this sample.