Ketamine abuse potential and use disorder

This review (2016) contrasts the therapeutic potential of ketamine as a fast-acting antidepressant to its potential for substance abuse. It specifically examines the social harms, the psycho-physiological and neurochemical effects, reinforcement mechanisms, and the treatment of ketamine abuse. It concludes that ketamine elicits significant reinforcing and toxic effects, which must be weighed against its antidepressant potential, which needs to be investigated in greater depth.

Abstract

“Ketamine is a noncompetitive antagonist of N-methyl-d-asparate (NMDA) receptor and has been long used as an anesthetic agent in humans and veterinary medicine. The present article reviews the epidemiology, pharmacology, neurochemistry, and treatment of ketamine abuse. Ketamine has a unique mood controlling property and a number of studies have demonstrated a significant and rapid antidepressant effect of ketamine. However, the therapeutic value of ketamine to treat psychiatric disorders faces a major challenge that ketamine also owns significant reinforcing and toxic effects. Its abuse has posted severe harms on individuals and society. Disrupted learning and memory processing has long been related with ketamine use. It is hypothesized that ketamine blocks NMDA receptors on gamma-aminobutyric acid (GABA) neurons inside the thalamic reticular nucleus, which leads to disinhibition of dopaminergic neurons and increased release of dopamine. Currently, there is no specific treatment for treating every ketamine patient presenting peripheral toxicity. Interestingly, ketamine psychotherapy has been suggested to be a promising approach to treat addiction of other drugs. Future research can continue to develop creative ways to investigate potential mechanism and treatments related to ketamine abuse that have posted severe individual and social harms.”

Authors: Liu, Yu, Deyong Lin, Boliang Wu & Wenhua Zhou

Summary

Ketamine is a phencyclidine (PCP) derivative that has been used as an anesthetic agent in humans and veterinary medicine. However, due to its reinforcing and rewarding properties, ketamine has become a recreational drug in the context of “raves” and the non-medical use of ketamine has grown steadily worldwide.

Ketamine has become a commonly abused drug in many parts of the world due to its anesthetic and reinforcing properties. Ketamine abuse has been spread over the countries and regions in Asia, and has resulted in the change of ketamine status from a class II to class I psychotropic drug in China. The popularity of ketamine as a club drug has also led to an increased reports of driving under the influence of ketamine.

In Hong Kong, 9% of drivers involving fatal car crash were tested positive for ketamine. Ketamine use has also been linked to increased incidence of unproductive sex among gay men.

Ketamine is used for recreational use in the form of intranasal injection, smoking, and chewing. It is often associated with hallucinations after waking up.

Ketamine’s dissociative anesthetic characteristics greatly contribute to ketamine abuse, and its use is also associated with cognitive impairments, including verbal learning impairment and decreased performance on spatial memory. Ketamine-induced cognitive impairment has been suggested to have therapeutic value, including reduction of suicidal cognition. Ketamine can have systemic effects on a number of organs, including the cardiovascular system, the urinary tract, and the brain. Chronic ketamine use can also cause renal toxicity, including decreased bladder volume, bladder wall thickening, musosal enhancement, dilation of ureter, and perivesical inflammation.

Ketamine abuse results in liver damage, including bile duct dilatation, microscopic bile duct injury, and even significant liver fibrosis. Mitochon- dysfunction has been suggested to result in the underlying hepatotoxcity of ketamine.

Ketamine is rather different from psychostimulants and opioid drugs, but some of its actions are more or less similar to these drugs. The drug self-administration model mimics voluntary drug-taking behavior in animals and has been used widely to assess the reinforcing and motivational aspects drugs. The behavioral paradigm of conditioned place preference (CPP) is also commonly used to evaluate the motivational properties of drugs. Ketamine was found to induce a higher conditioned place preference score in female rats than male rats.

Ketamine has positive reinforcing properties, such as dissociative anesthetic and euphoria effects, which are important to initiate and maintain drug taking behaviors. The negative reinforcing properties of ketamine include fatigue, poor appetite and drowsiness, as well as craving, anxiety, sleeping problems, and dysphoria. Ketamine, like many other psychoactive drugs, activates the rewarding pathway in the brain. Ketamine blocks NMDA receptors on GABA neurons inside the thalamic reticular nucleus, which leads to disinhibition of dopaminergic neurons and increased release of dopamine.

GSK-3 has been implicated in the neurochemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance. It has also been shown to underlie the neuroprotective effect of erythropoietin (EPO) in ketamine-induced neurotoxicity in primary cortical neurons. Ketamine administration results in impaired verbal working and episodic memory, as well as altered activities in the cingulate region, striatum and frontal cortex. Ketamine users also present disrupted frontal and medial temporal functioning, possibly specific to verbal information processing.

Ketamine-induced cognitive impairment may be related to the interaction between nicotinic receptors and GABAergic system, to the modulation of dopaminergic system, to the involvement of AMPA receptors in hippocampus, and to the protective effect of ketamine on electroconvulsive shock-induced memory impairment.

Patients who abuse ketamine presenting peripheral toxicity can be treated with antibiotics, non-steroidal anti-inflammatory drugs, steroids, and anticholingeric drugs. Ketamine psychotherapy has been suggested to be a promising approach to treat addiction of other drugs.

Ketamine psychedelic therapy (KPT) for alcoholism began in the 1950s and 1960s. In two-year follow up studies of heroin addiction, reduced rate of relapse and marginal anti-craving effects were achieved in patients receiving a high dose of intramuscular injection of ketamine.

Ketamine has therapeutic value to treat psychiatric disorders, but it also owns significant reinforcing and toxic effects. Recent mechanistic studies are beginning to investigate neurochemical mechanisms underlying ketamine abuse.