Ketamine and phencyclidine: the good, the bad and the unexpected

Abstract

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. ACh receptors (muscarinic) GluN2BCannabinoid receptors GluN2C D2 receptor GluN2DMetabotrophic glutamate receptors Kainate receptors These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,d Alexander et al., 2013a. PreambleIn April 1981, Nabil Anis and David Lodge showed for the first time that ketamine was a selective antagonist of the NMDA subtype of glutamate receptor. Unlike the discovery of bicuculline as a GABA antagonist, reported by Graham Johnston in an earlier publication in this series of historical reviews (Johnston, 2013), the editors of Nature were not impressed, the finding 'not being of sufficient general interest'. Fortunately, the British Journal of Pharmacology took a different view and the resulting paper has now over 1000 citations . Both before and since this discovery, ketamine and its congener, phencyclidine, have captured the interest of clinicians, basic scientists and sections of the general public. This review will attempt to describe some of this history and bring the reader up to date with the latest twists of this fascinating story in the context of these drugs as NMDA receptor antagonists. Discovery of phencyclidine and ketamine: early observationsAbout 27 years earlier, phencyclidine had been synthesized by chemists at Parke Davis Company but not published for some 10 years (Maddox et al., 1965). Initial pharmacology, however, was described by Chen et al. (1959) who noted lack of sensation, hyperlocomotion, ataxia and catalepsy in rats and pigeons. They ascribed these to monoaminergic mechanisms and showed partial reversal by the neuroleptic chlorpromazine (Chen et al., 1959). At about the same time, Ed Domino commenced a fuller study of the neuropharmacology of phencyclidine (Domino, 1964). In rats, he described a 'drunken state' with increased locomotor activity leading to ataxia and catatonia at higher doses. Dogs also showed a similar state called 'canine delirium, although in monkeys a more satisfactory anaesthetic state was ...

Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties

“…Many voltage-dependent uncompetitive NMDA antagonists, such as ketamine, PCP and dextromethorphan, also show schizophrenia-like effects in man (Lodge and Mercier, 2015). Although ephenidine is not described as a psychotomimetic agent in the scientific literature, anecdotal descriptions of the dissociative effects of ephenidine (see above) suggest that, in high enough doses, it mimics some of the symptoms of schizophrenia.…”

“…Such compounds, although structurally distinct from arylcyclohexylamines, like PCP and ketamine, are well documented in on-line anecdotal reports, as having potent and long lasting dissociative effects in man (http://www.bluelight.org/vb/threads/668291-The-Big-amp-Dandy-Diphenidine-Thread; http://www.erowid.org/chemicals/methoxphenidine/methoxphenidine_timeline.php; http://drugs-forum.com/forum/showthread.php?t=273812). Like the original dissociative anesthetics (Anis et al., 1983) and other dissociative hallucinogens (Lodge and Mercier, 2015), these tricyclic 1,2-diarylethylamines have proved to be potent and selective NMDA antagonists (Wallach et al., 2016). …”

GluN2D N-Methyl-d-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…However, the relationships between specific NMDAR subtypes and schizophrenia symptom components are not well understood. Psychotomimetic agents, such as ketamine and PCP, produce many of the symptoms of schizophrenia by modulating the neuronal systems known to underlie schizophrenia (for reviews, see Lahti et al, 1995;Javitt, 2007;Lodge and Mercier, 2015). Hence, resolving how these agents act on specific NMDAR subtypes to produce psychotomimetic symptoms should help define mechanisms of drug action as well as neurobiologic mechanisms underlying schizophrenia.…”

Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action

“…High doses of ketamine have long been used medically to produce anesthesia (Haas and Harper, 1992) and the recreational use of ketamine as a dissociative drug of abuse also has a lengthy history (Lodge and Mercier, 2015). For the past two and a half decades, ketamine has been used as a pharmacological model for schizophrenia, as sub-anesthetic doses have been shown to produce temporary schizophrenia-like symptoms in healthy humans (Krystal et al, 1994; Olney and Farber, 1995).…”