Ketamine

Substance identification
Ketamine is (±)-2-(o-chlorophenyl)-2-(methylamino)-cyclohexanone. It contains a chiral centre, resulting in two enantiomers: S-(+)-ketamine and R-(–)-ketamine. Usually, the racemate is marketed, but the more active S-(+)-enantiomer is increasingly present in commercially available preparations.

Previous review
Ketamine had been pre-reviewed by the ECDD at its thirty-third meeting, at which a recommendation was made for a critical review. At its thirty-fourth meeting, the ECDD carried out a critical review of ketamine and concluded that the information available was not sufficient to warrant scheduling. Also in view of the activities of the Commission on Narcotic Drugs regarding ketamine in its forty-ninth session held in March 2006, at the thirty-fourth meeting, the ECDD requested the Secretariat to produce an updated version of the critical review and present it to the next Committee meeting. At its thirty-fifth meeting, and on the basis of the critical review undertaken, the Committee decided that bringing ketamine under international control was not appropriate. At its fifty-seventh session in March 2014, the Commission on Narcotic Drugs adopted Resolution 57/10 on preventing the diversion of ketamine from legal sources while ensuring its availability for medical use. The Commission stated a concern regarding the threat to the well-being of people and society posed by the diversion of ketamine and by the rising trend in the abuse and trafficking of that substance. A notification was made by the Government of the People’s Republic of China, under Article 2, paragraph 1 of the Convention on Psychotropic Substances (1971), concerning the proposed recommendation for international control of ketamine. The information provided by China with its notification to the Secretary-General was brought to the Expert Committee’s attention.

Similarity to known substances and effects on the central nervous system
Ketamine is an anaesthetic that binds to the so-called phencyclidine (PCP)-binding site of the NMDA-receptor complex as a non-competitive antagonist. Several studies indicate that opioid receptors are also involved in the pharmacological analgesic effects of ketamine. In non-fatal intoxications, anxiety (especially in first-time users), agitation, changes of perception (e.g. loss of notion of danger or visual disturbances), disorientation and impairment of motor function, such as ataxia and dystonic reaction have been described. Reported intoxications typically involve other drugs and ketamine was the sole intoxicant in only a very limited number of fatalities.

Dependence potential
Ketamine may produce dependence in animal models, but reports of dependence in humans are rare. The short duration of action makes it difficult to maintain intoxication for sustained periods. Tolerance may occur, but there is insufficient evidence to show that ketamine causes a withdrawal syndrome in humans.

Actual abuse and/or evidence of likelihood of abuse
In many countries, levels of abuse in the general population appear to be low. However, some countries report higher levels of abuse. There are reports on ketamine abuse in certain groups with access to the substance (e.g. medical and veterinarian professionals) and by people who use drugs. Ketamine is difficult to synthesize, so illicit manufacture is rare in most countries. The INCB and UNODC have reported that illicit manufacture of ketamine is of increasing concern in east and south-east Asia. Information supplied by China with its notification to the Secretary-General stated that in China "illegal ketamine production is becoming increasingly serious".

Therapeutic usefulness
Ketamine is widely used as an anaesthetic in humans and is the anaesthetic of choice in veterinary medicine. Ketamine is included in the WHO Model List of essential medicines (7) and the WHO Model List of essential medicines for children (9) as well as in many national lists of essential medicines. Ketamine has analgesic, hypnotic and short-term memory loss (amnesic) effects and is useful for induction of anaesthesia, procedural sedation and analgesia. Compelling evidence was presented about the prominent place of ketamine as an anaesthetic in developing countries and crisis situations. The ease of parenteral administration gives ketamine a major advantage when anaesthetic gases are impossible to use owing to limited equipment and a lack of appropriately trained specialists.

Recommendation
Ketamine is a widely used anaesthetic, especially in developing countries, because it is easy to use and has a wide margin of safety when compared with other anaesthetic agents. While the Committee acknowledged the concerns raised by some countries and UN organizations, ketamine abuse currently does not appear to pose a sufficient public-health risk of global scale to warrant scheduling. Consequently, the Committee recommended that ketamine not be placed under international control at this time. Countries with serious abuse problems may decide to introduce or maintain control measures, but should ensure ready access to ketamine for surgery and anaesthesia for human and veterinary care.