Short communicationTherapeutic infusions of ketamine: Do the psychoactive effects matter?
Introduction
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 (Mathew et al., 2012, Skolnick et al., 2009, Zarate et al., 2006). This unique response has been attributed to enhanced neuroplasticity via various downstream effects (Li et al., 2010, Maeng et al., 2008), improved prefrontal glutamate homeostasis (Salvadore et al., 2009), and sustained attenuations in default mode network connectivity and activity (Scheidegger et al., 2012). 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 (Dakwar et al., 2013).
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 (Perry et al., 2007). These effects include dissociative phenomena, as well as alterations in consciousness similar to those engendered by serotonergic hallucinogens (Perry et al., 2007, Vollenweider and Kometer, 2010). 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 (Griffiths et al., 2006, Griffiths et al., 2008). 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 (Griffiths et al., 2006, Hoffer, 1970, Miller and C’de Baca, 2001).
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 (Miller and C’de Baca, 2001, Miller, 2004). 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 previously (Dakwar et al., 2013) and investigates whether these phenomena mediate ketamine efficacy, 24 h postinfusion. We predict that ketamine infusions dose-dependently promote transient mystical-type effects, assessed with items from a widely used mystical experience scale (Hood, 1975, Hood et al., 2001). 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.
Section snippets
Participants
Eight cocaine dependent individuals not seeking treatment or abstinence, actively using free-base (“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
Eight adult participants with high mean baseline cocaine use (22 use days in 4 weeks, at $158.83 per use day) completed the study (see Dakwar et al., 2013 for other participant characteristics). All participants tolerated study procedures without adverse events, including unexpected psychiatric disturbances and initiation of ketamine or benzodiazepine misuse.
Mystical-type effects
All psychoactive effects, including dissociative and mystical-type phenomena, resolved within 20 min postinfusion. Both doses of ketamine
Discussion
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
Conflict of interest
Dr. Mathew has been named as an inventor on a pending use-patent of ketamine for the treatment of depression. Dr. Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine were approved for this use. Dr. Mathew has received consulting fees or research support from AstraZeneca, Bristol-Myers Squibb, Naurex, Noven, Roche Pharmaceuticals, and Takeda. The other authors have no conflicts to report.
Author disclosures
Role of funding sources: The authors thank the National Institutes of Health for supporting this study with the following grants: MH081870, DA022412, DA031771, DA035472, DA009236, and DA007294.
Drs. Dakwar, Hart, Levin, and Nunes also acknowledge the support of Columbia College of Physicians and Surgeons, and the New York State Psychiatric Institute. Dr. Mathew is supported by the Brown Foundation, Inc., and the Michael E. DeBakey VA Medical Center, Houston, TX.
Contributors: ED devised the
References (32)
- et al.
Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans
J. Pharm. Sci.
(1982) - et al.
Stages of change profiles in outpatient alcoholism treatment
J. Subst. Abuse
(1990) - et al.
Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up
J. Subst. Abuse Treat.
(2002) - et al.
Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors
Biol. Psychiatry
(2008) - et al.
Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression
Biol. Psychiatry
(2009) - et al.
Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine
Biol. Psychiatry
(2009) - et al.
Glutamate-based antidepressants: 20 years on
Trends Pharmacol. Sci.
(2009) - et al.
The moderator–mediator variable distinction in social psychological research: conceptual, strategic and statistical considerations
J. Pers. Soc. Psychol.
(1986) - et al.
The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers
Biol. Psych.
(2013) - et al.
Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later
J. Psychopharmacol.
(2008)
Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance
Psychopharmacology
Therapeutic uses
The construction and preliminary validation of a measure of reported mystical experience
J. Sci. Study Relig.
Dimensions of the mysticism scale: confirming the three-factor structure in the United States and Iran
J. Sci. Study Relig.
The Varieties of Religious Experience: A Study in Human Nature
Human hallucinogen research: guidelines for safety
J. Psychopharmacol.
Cited by (74)
The role of non-ordinary states of consciousness occasioned by mind-body practices in mental health illness
2023, Journal of Affective DisordersActive mechanisms of ketamine-assisted psychotherapy: A systematic review
2022, Journal of Affective DisordersPsychedelic Therapy: A Primer for Primary Care Clinicians - Ketamine
2024, American Journal of Therapeutics