Ketamine Pharmacodynamics Entangled: Reply

The authors respond to a critique about how to describe mind-altering drugs like ketamine, psilocybin, and cannabis. They argue that terms like "dissociative" are inadequate because these drugs produce diverse symptoms beyond disconnection from reality. They propose "psychoplastogen" as a better term, focusing on the shared mechanism of promoting rapid neural plasticity and rewiring of brain circuits, which underlies therapeutic effects such as antidepressant and pain relief actions. This term avoids the limitations of describing subjective experiences and instead highlights the neurobiological mechanism responsible for healing.

Study at a glance

Abstract

We thank Bowdle et al.1 for their interest in our article,2 and for the important issue they raise, paraphrased as follows: what is the best anthropocentric description of the "mind-altering" effects of a heterogeneous group of compounds and drugs that act at the brain and cause significant changes in mental state. The group of drugs that we are referring to includes N-methyl-d-aspartate (NMDA) receptor antagonists (ketamine, nitrous oxide, xenon), serotonergic psychedelics (5-HT2a receptor agonists psilocybin and lysergic acid diethylamide and serotonin-releasing 3,4-methylenedioxymethamphetamine), ayahuasca, cannabinoids (CB-1 receptor agonists), and κ-opioid receptor agonists Salvinorin A and B; this list is certainly not complete (see List of Psychedelic Drugs3). During the past two decades we studied ketamine, cannabis, and recently also psilocybin in patients and healthy volunteers and observed several similarities in the subjective expression of feelings and emotions during and after treatment. One important commonality is that these drug consumers display a certain disconnection or dissociation from reality. In this sense, the word "dissociation" and "dissociative drug" have a different meaning than described by Bowdle et al.1 It may indeed not be the correct wording because dissociation does not encompass all of the symptoms experienced and expressed by the users of these drugs (not all symptoms relate to a disconnect with reality). Moreover, there are clear distinctions in symptomatology between these different drugs. For example, the hallucinogenic effects of cannabinoids are very different from those of ketamine or ayahuasca. Hence, it may just not be possible to have one denominator that describes the mind-altering effects of these drugs. The conclusion of Bowdle et al.1 is that it is best to describe the anesthetic drugs that have psychedelic effects by their mechanism of action, for example, the NMDA-receptor antagonist ketamine. However, there is ample evidence that many of the ketamine effects are non-NMDA related. For example, acute pain relief may be related to the μ-opioid receptor and/or specific background potassium channels.4,5 Therefore, we argue that we need another approach. One term that describes both the NMDA-receptor antagonists and serotonergic psychedelics is psychoplastogen. Psychoplastogens are molecules that have a neurotrophic effect and promote rapid neural plasticity in the cortex (rewiring of pathologic neurocircuitry).6 Although this term does not describe the subjective experiences caused by these drugs, it does describe the mechanisms associated with their healing effects, whether it be antidepression or pain relief. Hence, in future studies we will refer to ketamine as a psychoplastogen. We thank Dr. Bowdle et al. for this mental exercise that we hope will result in an improved description of the behavioral effects of psychedelic drugs.The Anesthesia & Pain Research Unit of the Department of Anesthesiology, Leiden University Medical Center (Leiden, The Netherlands), received/receives funding from AMO Pharma Ltd. (Leeds, United Kingdom), Bedrocan BV (Veendam, the Netherlands), Grünenthal GmbH (Aachen, Germany), Medtronic (Minneapolis, Minnesota), MSD Nederland BV (Haarlem, the Netherlands), LTS Lohmann Therapie Systeme AG (Andernach, Germany), and Trevena Inc. (Chesterbrook, Pennsylvania). Dr. Dahan received consultancy and/or speaker fees from Enalare Therapeutics Inc. (Princeton, New Jersey), Grünenthal BV (Woerden, the Netherlands), Medasense Biometrics Ltd. (Ramat Gan, Israel). Dr. Dahan received grants/awards from ZonMW (The Hague, the Netherlands) and US Food and Drug Administration (Silver Spring, Maryland).