The dissociative psychedelic renaissance

Abstract

With all the recent excitement about the resurgence of clinical research on the classic serotonergic psychedelics, in what has been labeled the psychedelic renaissance, it is easy to overlook a concurrent revolution taking place in the field of ketamine research. More than 50 years have passed since the synthesis of ketamine, and it remains today the most widely available compound with psychedelic properties – nearly ubiquitously approved for both research and clinical use. Ketamine has recently proved to be highly effective for depression and suicidality, with a rapid onset of effect. Despite currently being the leading cause of disability in the world, there have been no major advances in depression treatment, since the selective serotonin reuptake inhibitors of the 1980s. In the context of this stagnation, research on ketamine has been met with understandable enthusiasm, typified by former director of the National Institute of Mental Health (NIMH) Thomas Insel’s proclamation that ketamine “might be the most important breakthrough in antidepressant treatment in decades.” Two books, Ketamine for Treatment-Resistant Depression: The First Decade of Progress edited by Sanjay J. Mathew and Carlos A. Zarate, Adis, 2016, and The Ketamine Papers: Science, Therapy and Transformation edited by Phil Wolfson and Glenn Hartelius, Multidisciplinary Association for Psychedelic Studies, 2016, explore in depth the fascinating history and clinical background of using ketamine for depression. These two books are the most comprehensive works to date that summarize the progress made on ketamine research in the field of mental health. While both cover the major milestones in the history of ketamine’s development, safety, and clinical data, they have substantially different approaches and foci. They ultimately complement one another, each filling in gaps where the other is more cursory. Both Ketamine for TRD and The Ketamine Papers are essential reading for any researcher or health care provider interested in understanding the history and science behind the use of ketamine for the treatment of mental health disorders. Ketamine is an arylcyclohexylamine derivative that is primarily a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. It was first synthesized in 1962 to replace phencyclidine as a surgical anesthetic with a better safety profile and fewer adverse effects. It was tested on human prisoners in 1964, FDA approved in 1970, and subsequently gained widespread use for battlefield anesthesia during the Vietnam War. Ketamine’s unique psychoactive effects at subanesthetic doses were noted early on by Edward Domino during his first experiments on humans. Patients reported both significant changes in mood as well as a sense of “disconnection” from their bodies, which led him to coin a new and unique drug class: “dissociative.” Ketamine is now classified as the penultimate dissociative anesthetic, describing the dosedependent continuum leading to eventual dissociation of the conscious state from awareness of the physical self prior to complete anesthesia. At a subanesthetic dose, ketamine reliably produces alterations in consciousness, including positive mood, altered perception and cognition, transcendence of space and time, a sense of awe, ineffability, depersonalization, and derealization often coexistent with a conscious awareness of a sense of unity. These psychoactive effects were not lost on psychedelic researchers, as the FDA approval of ketamine in 1970 coincided with the global shutdown of research on the classic serotonergic agents as a consequence of the 1971 UN Convention on Psychotropic Substances. Beginning in the 1970s, Khorramzadeh and Lofty (1973) and Roquet, Favreau, Ocana, and Velasco (1975) began to experiment with ketamine in the tradition of drug-assisted psychotherapy as narco-analysis, abreactive, psycholytic, and psychedelic therapy, describing cases of sustained psychological benefits and improved mood using psychoactive doses. While The Ketamine Papers dedicates a full six chapters to this first stage of research and clinical exploration, Ketamine for TRD mentions that same early work over several decades in just one paragraph of the book (even announcing this omission in its subtitle “The First Decade of Progress” a full 20 years after initial reports of clinical use). The Ketamine Papers starts the story with formal clinical trials begun in the 1990’s. To some extent, the different approaches could be tracked to the semantic history of early psychedelic research. Whereas The Ketamine Papers both acknowledges and explores the potential “mind-manifesting” properties of ketamine (in the