Ketamine Pharmacodynamics Entangled: Comment.

The authors argue that the term "dissociative" is outdated and imprecise for describing the subjective effects of ketamine and related drugs. Originally coined in 1966 to describe feelings of being in outer space or lacking limbs, the term does not capture the full range of psychedelic experiences measured by modern rating scales like the Bowdle Visual Analogue Scale and Hallucinogen Rating Scale. The authors suggest that drugs such as phencyclidine, dextromethorphan, salvinorin A, and nitrous oxide—often grouped as "dissociative anesthetics"—produce subjective effects that are not identical to each other and can resemble those of classic psychedelics like dimethyltryptamine or psilocybin. They recommend describing these drugs primarily by their mechanism of action, such as "the NMDA antagonist ketamine," rather than by the term dissociative.

Study at a glance

Abstract

We read with interest the study of ketamine psychedelic and analgesic effects by Olofsen et al.1 and the accompanying editorial by Mashour.2 In both articles, the authors refer to the “dissociative” effects of ketamine. Corssen and Domino3 originally used the term “dissociative” in 1966 to describe “patients and subjects who, during recovery from CI-581 [ketamine], felt as though they were in outer space, or had no arms or legs.” This term has been used ever since, although we know considerably more about the subjective effects of ketamine than we did in the 1960s. Olofsen et al. measured the subjective effects of ketamine using a subset of items from a previously validated rating scale (Bowdle Visual Analogue Scale).1 We first used this rating scale in its entirety in 1998,4 along with the Hallucinogen Rating Scale,5 to establish the relationship between plasma concentrations and the subjective effects of ketamine. The Bowdle Visual Analogue Scale and the Hallucinogen Rating Scale are intended to measure the overall psychedelic effects, not specifically dissociative effects. We would suggest that the term “dissociative” may no longer be the best descriptor of the subjective effects of ketamine.Numerous terms have been used to describe the mind-altering effects of ketamine, including “dissociative,” “psychotomimetic,” “hallucinogenic,” “emergence reaction,” and “psychedelic.” Parsing these terms can be difficult because there is no universal agreement about their meaning. Dissociative experiences as described by Corssen and Domino can occur under the influence of a variety of psychedelic drugs and are not specific to ketamine. Psychotomimetic implies a psychotic state, lacking in insight; psychosis is not typical of psychedelic drug experiences because subjects are usually able to reflect on the nature of the experience. Hallucinogenic effects can occur under the influence of psychedelic drugs but are not an essential or universal element of the psychedelic experience. Emergence reaction refers to mind-altering experiences that occur after awakening from anesthesia with ketamine, and so does not apply to subanesthetic doses of ketamine. Psychedelic, meaning “mind manifesting,” was originally proposed by Osmond in 19576 to describe the effects of a variety of mind-altering drugs, including hashish. Subsequently, the term psychedelic has been applied to diverse mind-altering drugs, although some authors have used the term psychedelic more specifically to refer to lysergic acid diethylamide–like serotonergic receptor agonists.7,8Our current understanding of the psychedelic effects of ketamine and other psychedelic drugs comes primarily from narrative descriptions related by subjects who have experienced the effects, or from rating scales constructed to capture the experiences in a standardized fashion. Although scales are useful for measuring drug effects, the results depend on the nature of the items chosen for inclusion in them.Beyond ketamine, a small group of drugs that produce psychedelic experiences, analgesia, and anesthesia has been referred to as “dissociative anesthetics,” implying a similarity to ketamine. This group usually includes phencyclidine, ketamine analogues, dextromethorphan, salvinorin A (produced by the plant, Salvia divinorum),9 and nitrous oxide. The term “dissociative anesthetics” suggests that the mechanisms of action and the subjective experiences of these drugs are similar to ketamine, similar to each other, and different from other psychedelic drugs. In fact, the subjective experiences induced by dissociative anesthetics are not identical to each other and may be similar to nonanesthetic psychedelic drugs. Distortion of body image (a key feature of dissociation) is not confined to the dissociative anesthetics; other psychedelic drugs may induce a similar experience. For example, the subjective experience of ketamine, when assessed using the Hallucinogen Rating Scale, resembles that of the classic psychedelic serotonin receptor agonist dimethyltryptamine.4 The subjective experience of dextromethorphan assessed using a variety of rating scales resembles that of the classic psychedelic psilocybin.10The mechanism of action of these dissociative anesthetics is not identical. Phencyclidine, ketamine, and dextromethorphan (and its metabolite dextrorphan) are antagonists of the N-methyl-d-aspartate (NMDA) receptor. Salvinorin A is a highly selective κ opioid receptor agonist. The mechanism of action of nitrous oxide is uncertain but may involve antagonism of NMDA receptors11; the subjective effects of nitrous oxide have not been as well characterized as the other drugs.12 It is also worth noting that the recently discovered antidepressant effects of ketamine and other psychedelic drugs may or may not be related to the psychedelic effects, although this remains controversial.13We suggest that anesthetic drugs that also have psychedelic effects should no longer be referred to as dissociative anesthetics. Rather, it may be more useful to describe them primarily by their mechanism of action; for example, “the NMDA antagonist ketamine,” “the serotonin agonist psilocybin,” “the κ agonist salvinorin A.”Dr. Sackett declares a financial interest in Resa Health (Paradise Valley, Arizona). The other authors declare no competing interests.