Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
Ketamine
The ketamine story–past, present and future
The history of ketamine begins in the 1950s at Parke-Davis and Company’s laboratories in Detroit, Michigan, USA. At that time, Parke-Davis were searching among cyclohexylamines for an ‘ideal’anaesthetic agent with analgesic properties.
Ketamine: 50 Years of Modulating the Mind
Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top down”) distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications.
Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity
Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’. Keywords: GluN2D subunit; Ketamine; LTP; Long-term potentiation; Memory; NMDA receptors; PCP; Phencyclidine; Psychedelics; STP; Short-term potentiation; Working memory.
Ketamine use: a review
Aims: Ketamine remains an important medicine in both specialist anaesthesia and aspects of pain management. At the same time, its use as a recreational drug has spread in many parts of the world during the past few years. There are now increasing concerns about the harmful physical and psychological consequences of repeated misuse of this drug. The aim of this review was to survey and integrate the research literature on physical, psychological and social harms of both acute and chronic ketamine use. Method: The literature on ketamine was systematically searched and findings were classified into the matrix of Nutt et al.’s (2007) rational scale for assessing the harms of psychoactive substances. Results: A major physical harm is ketamine induced ulcerative cystitis which, although its aetiology is unclear, seems particularly associated with chronic, frequent use of the drug. Frequent, daily use is also associated with neurocognitive impairment and, most robustly, deficits in working and episodic memory. Recent studies suggest certain neurological abnormalities which may underpin these cognitive effects. Many frequent users are concerned about addiction and report trying but failing to stop using ketamine. Conclusions: The implications of these findings are drawn out for treatment of ketamine-induced ulcerative cystitis in which interventions from urologists and from addiction specialists should be coordinated. Neurocognitive impairment in frequent users can impact negatively upon achievement in education and at work, and also compound addiction problems. Prevention and harm minimization campaigns are needed to alert young people to these harmful and potentially chronic effects of ketamine.
Ketamine: teaching an old drug new tricks
Ketamine has a special position among anesthetic drugs. It was introduced into clinical practice >30 yr ago with the hope that it would function as a “monoanesthetic” drug: inducing analgesia, amnesia, loss of consciousness, and immobility. This dream was not fulfilled because significant side effects were soon reported. With the introduction of other IV anesthetic drugs, ketamine’s role diminished rapidly. However, it is still used clinically for indications such as induction of anesthesia in patients in hemodynamic shock; induction of anesthesia in patients with active asthmatic disease; IM sedation of uncooperative patients, particularly children; supplementation of incomplete regional or local anesthesia; sedation in the intensive care setting; and short, painful procedures, such as dressing changes in burn patients. However, recent insights into ketamine’s anesthetic mechanism of action and its neuronal effects, as well as a reevaluation of its profound analgesic properties, offer the potential of expanding this range of indications. In addition, studies with the S(+) ketamine isomer suggest that its use may be associated with fewer side effects than the racemic mixture. In this article, we review the mechanism of action of ketamine anesthesia, the pharmacologic properties of its stereoisomers, and the potential uses of ketamine for preemptive analgesia and neuroprotection. Several aspects discussed herein have been reviewed previously [1-4].