To use or not to use: an update on licit and illicit ketamine use

Abstract

Ketamine, a derivative of phencyclidine that was developed in the 1960s, is an anesthetic and analgesic with hallucinogenic effects. In this paper, the pharmacological and toxicological effects of ketamine are briefly reviewed. Ketamine possesses a wide safety margin but such a therapeutic benefit is somewhat offset by its emergence phenomenon (mind-body dissociation and delirium) and hallucinogenic effects. The increasing abuse of ketamine, initially predominantly in recreational scenes to experience a "k-hole" and other hallucinatory effects but more recently also as a drug abused during the workday or at home, has further pushed governments to confine its usage in many countries. Recently, urinary tract dysfunction has been associated with long-term ketamine use. In some long-term ketamine users, such damage can be irreversible and could result in renal failure and dialysis. Although ketamine has not yet been scheduled in the United Nations Conventions, previous studies using different assessment parameters to score the overall harms of drugs indicated that ketamine may cause more harm than some of the United Nations scheduled drugs. Some countries in Southeast and East Asia have reported an escalating situation of ketamine abuse. Dependence, lower urinary tract dysfunction, and sexual impulse or violence were the most notable among the ketamine-associated symptoms in these countries. These results implied that the danger of ketamine may have been underestimated previously. Therefore, the severity levels of the ketamine-associated problems should be scrutinized more carefully and objectively. To prevent ketamine from being improperly used and evolving into an epidemic, a thorough survey on the prevalence and characteristics of illicit ketamine use is imperative so that suitable policy and measures can be taken. On the other hand, recent findings that ketamine could be useful for treating major depressive disorder has given this old drug a new impetus. If ketamine is indeed a remedy for treating depression, more research on the risks and benefits of its clinical use will be indispensable.

Keywords: anti-depressant; cognitive impairment; epidemiology; ketamine; psychedelic effects; urinary tract dysfunction.

Figure 1

Schematic diagram of NMDA receptor complex. The NMDA receptor is an ionotropic glutamate receptor for controlling synaptic plasticity and memory function., Glutamate (and NMDA) binds to the agonist site on the NMDA receptors. PCP, ketamine, and dizocilpine bind to the PCP receptor in the inside of the NMDA receptors. Glycine and D-serine bind to a glycine modulatory site on the NMDA receptors. The NMDA receptor is blocked by Mg²⁺ in a voltage sensitive manner. Activation of NMDA receptor by binding of both glutamate and glycine results in the opening of the channel. This allows voltage-dependent flow of Na⁺ and small amounts of Ca²⁺ ions into the cell and K⁺ out of the cell. The symbol (−) denotes inhibitory effect. Abbreviations: NMDA, N-methyl-D-aspartate; 7-CK, 7-chlorokynurenic acid; L689,560, trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonyl; AP5, 2-amino-5-phosphonovaleric acid; CGS-19775, cis-4-phosphonomethyl-2-piperidinecarboxylic acid.

Figure 2

The pathway of ketamine metabolism in phase I. Ketamine is N-demethylated by liver cytochrome P450 enzymes (major: CYP3A4; minor: CYP2B6 and CYP2C9) into norketamine., CYP2B6 and CYP2A6 have been identified to hydroxylate norketamine into 5-hydroxynorketamine. The chemical structures are depicted for S-ketamine and its metabolites.