Ketamine Pharmacodynamics Entangled: Reply
Albert Dahan, Erik Olofsen, Thomas K. Henthorn, Monique van Velzen, Marieke Niesters
Anesthesiology September 12, 2022 DOI: 10.1097/aln.0000000000004350 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Ketamine Esketamine |
| Keywords | Pharmacodynamics Pharmacology Anesthesia |
| Citations | 3 |
| Key points | Argues that the term "psychoplastogen" better describes drugs like ketamine and psilocybin by focusing on their shared mechanism of promoting neural plasticity, rather than subjective dissociative effects. |
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).
Comparable studies
Other theoretical and historical papers on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. | 2014 | Historical analysis | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Neuroscience and the Near-Death Experience: Roles for the NMSA-PCP receptor, the sigma receptor and the endopsychosins | 1990 | Theoretical or philosophical paper | |
| A unified model of ketamine's dissociative and psychedelic properties. | 2022 | Theoretical or philosophical paper | |
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper |
Citations in the library
Cites 3
- Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth ACS Pharmacology & Translational Science September 11, 2020
- Ketamine Psychedelic and Antinociceptive Effects Are Connected Anesthesiology February 21, 2022
- Ketamine Pharmacodynamics Entangled: Comment. Anesthesiology December 1, 2022