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EUROPEAN MONITORING CENTRE FOR DRUGS AND DRUG ADDICTION



Report on the Risk Assessment of ketamine
in the Framework of the
Joint Action on New Synthetic Drugs
Report on the Risk Assessment of ketamine in the Framework of
the Joint Action on New Synthetic Drugs
On 17 April 2000, the Portuguese Presidency of the European Council formally notified KETAMINE (2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) to the EMCDDA for risk assessment under Article 4 of the Joint Action on new synthetic drugs of 16 July 1997. A meeting of the Scientific Committee of the EMCDDA extended with experts nominated by the Member States and representatives of the European Commission, Europol and the EMEA to assess the health and social risks as well as the possible consequences of prohibition of ketamine, was held on 25-26 September 2000. The meeting considered the following documents: I. Technical Annexes A and B: The Pharmacotoxicological Report on ketamine, Report to the EMCDDA Technical Annex D: public health risks: epidemiological evidence, EMCDDA Technical Annex C: sociological/criminological evidence, EMCDDA Europol contribution to the risk assessment of ketamine EMEA contribution to the risk assessment of ketamine
These documents, in conjunction with further information and comments from the expert
participants, formed the basis of the Risk Assessment reported below.

1. CHEMICAL
DESCRIPTION

The chemical name of ketamine is 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone,
an arylcycloalkylamine. It is structurally related to phencyclidine (PCP–‘angel dust’) and
cyclohexamine. It occurs in racemic form and also as the S-enantiomer.
Registered names (human use) are: KETALAR, Ketamine PANPHARMA, KETOLAR,
KETANEST-S.
Registered names (veterinary use) are: KETALAR, Ketaminol Vet., Clorketam,
Imalgene, Anesketin, Ketamine Ceva, Vetalar Vet., NARKETAN, KETASET.

Ketamine is known in Member States under the street names: K, Special K, KitKat, Tac
et Tic, Cat Valium, Vitamine K, Ket, Super K, and others.
2. PHARMACEUTICAL DESCRIPTION

Ketamine was first synthesised in 1962 and patented in Belgium in 1963. As an
anaesthetic and analgesic, ketamine has a recognised unique therapeutic value in
veterinary practice and, to a lesser extent, in human medicine. For therapeutic
purposes, ketamine usually is administered intravenously or intramuscularly.

In recreational use, typical doses are: 75-125 mg intramuscularly or subcutaneously; 60-
250 mg intranasally; 50-100 mg intravenously; and 200-300 mg orally.

Ketamine is manufactured by the chemical industry for use in the manufacture of
pharmaceutical products using as precursors cyclopentyl bromide, o-chlorobenzonitrile,
and methylamine. Due to the complicated multi-step synthesis, and the difficulty of
purchasing the necessary precursors and numerous solvents and reagents, ketamine
sold illicitly for recreational use appears to be mostly obtained by diversion of legitimate
supplies of either the bulk drug or of pharmaceutical preparations containing it.

Pharmaceutical products may be injected or may be modified by evaporation after which
the resultant powder may be snorted in pure form or mixed with other drugs and/or
inactive components. In powder form, combination with cocaine has been observed. In
the form of tablets, the concentration of ketamine and other substances are mostly
unknown by users. These tablets are sold as ‘ecstasy’ in some Member States. Other
substances reported to be present in ketamine-containing tablets are pseudoephedrine,
ephedrine, caffeine, amphetamine, methamphetamine and MDMA. As the effects of
ketamine are dose-dependent, the uncertainty about ketamine concentration in the
powder, and a fortiori in fake ‘ecstasy’ tablets, poses a risk in recreational use.

Preparations containing ketamine hydrochloride are used as an anaesthetic and
analgesic agent in human and veterinary medicine, with important clinical applications in
paediatric and ambulatory anaesthesia, treatment of burned wound patients, and for
short anaesthetic procedures. However, the human use of ketamine in the EU is
restricted to special indications, due to the occurrence of emergence reactions. Outside
the EU, the ease of use gives ketamine a major advantage under difficult circumstances
(developing countries and remote areas). Its use in veterinary anaesthesia, especially in
small animals, is widespread and considered by several Member States and by the
Federation of Veterinarians of Europe as indispensable in veterinary medicine.

3. HEALTH

3.1 Individual health risks
(a) Acute effects

Ketamine is a dissociative anaesthetic. The term ‘dissociative’ has a twin meaning.
Firstly, it refers to an effect on the brain, inducing a lack of responsive awareness, not
only to pain but also to the general environment. Secondly, it refers to a feeling of
dissociation of the mind from the body (‘out of body experience’). Ketamine would be
expected to block or interfere with sensory input to centres of the central nervous system
(CNS) in a way the drug selectively interrupts association pathways of the brain before
producing somesthetic (sensation of having a body) sensory blockade.
Ketamine differs from most anaesthetic agents in that it appears to stimulate the
cardiovascular system, producing changes in heart rate, cardiac output and blood
pressure. In recreational ketamine users, presenting to an emergency department,
tachycardia was the most common finding. As a mild respiratory depressant, ketamine

is unlikely to produce respiratory depression at recreational doses, even if it cannot be
wholly excluded. Cardiovascular effects usually do not pose a problem in patients
without cardiovascular problems, but ketamine is contraindicated in patients with
significant ischaemic heart disease and is to be avoided in those with a history of high
blood pressure or cerebrovascular disorders.
The findings of neurotoxicity in the rat may indicate cause for concern in recreational
users of ketamine. These users may not take ketamine in combination with protective
agents like benzodiazepines as is usually the case in the clinical setting. Moreover,
compounds increasing the neurotoxic potency of ketamine (like alcohol) might be co-
administered. Recreational use also implies repeated exposure, whereas clinical use is
mostly incidental. Long-term adverse effects in chronic users of ketamine have been
reported, though rarely, and include persisting impairment of attention and recall and a
subtle visual anomaly. The Report on Risk Assessment of 4-MTA noted that ketamine
increased the neurotoxicity of 4-MTA in mice. Neurotoxicity of repeated exposure to
ketamine in primates including humans has not been studied.
(b) Clinical effects
Ketamine is considered as an anaesthetic with a good safety profile, based on extensive
clinical experience. The major drawback, limiting clinical use, is the occurrence of
emergence reactions in patients awakening from ketamine anaesthesia. These
reactions include hallucinations, vivid dreams, floating sensations and delirium.
However, preclinical data on the effects of repeated ketamine administration may be of
greater importance for recreational use which, contrary to clinical practice, may present
cases of long-term use.

A total of 12 deaths in which ketamine was identified, have been noted between 1987-
2000 including seven from the USA. Only three reported fatal cases involving ketamine
alone were identified. Two reports concern mixed drugs fatalities. In one case,
ketamine had only a minor role. For the remaining six cases, insufficient details were
available to be evaluated properly. In the three cases involving only ketamine, the
routes of administration were intramuscular or intravenous and the cause of death was
mainly due to overdose (multiple intramuscular doses or accidental intravenous
overdose), in line with preclinical findings. In the other cases involving ketamine mixed
with other drugs, the observed lower ketamine concentrations indicates that drug
interaction may have contributed to these deaths. Substances with CNS/respiratory
depressant effects, like ethanol, opioids, barbiturates, and benzodiazepines or drugs
with cardiostimulant effects, like cocaine or amphetamines, may increase ketamine
acute toxicity.
Regarding non-fatal intoxications, potential dangerous interactions may also arise when
different drugs are combined. ketamine has sympathomimetic properties. Inhibition of
central catecholamine re-uptake and increased levels of circulating catecholamines are
believed to cause the cardiovascular stimulant effects. Serious side effects such as
hypertension and pulmonary oedema have been reported, but such adverse effects
appear to be rare and may be related to the combination of ketamine with other drugs,
such as amphetamines and its analogues, ephedrine and cocaine.

(c) Dependence
Tolerance, dependence and withdrawal signs have been observed in a number of
animal studies. Tolerance to the desired effects of ketamine develops quickly and may
result in an escalation of the dose, the toxicological implications of which are unknown. A
risk associated with the recreational use of ketamine, is the potential of the drug to
cause psychological dependence in some individuals based on case reports and
information from users. The prevalence of long-term use is unknown. There is no
evidence that ketamine causes an abstinence syndrome in humans.
(d) Psychological effects

Ketamine may be experienced by the recreational user as an altered, ‘psychedelic’ state
of mind (‘the K-hole’) that allows the user to travel beyond the boundaries of ordinary
existence. The intensity of ‘psychedelic effects’ is dose-related. Ketamine in
subanaesthetic doses produces a clinical syndrome which both neurophysiologically and
behaviourally resembles that of a schizophrenic psychosis. Ketamine acutely affects
cognitive performance, profoundly affects perception of the body, time, surroundings and
reality.
The main effects of ketamine are neurobehavioural: anxiety, agitation, changes of
perception (e.g., loss of notion of danger, visual disturbance) and impairment of motor
function and the analgesic effects. In such a condition, the user may be at risk of injury
to themselves (burns, falls) or to others (accidents).
3.2 Public health risks

(a) Availability and Quality
Ketamine preparations have marketing authorisations in most countries of the EU,
except in Greece where the marketing authorisation was recalled in 1998 .
Seizure data suggest mostly low levels of availability of ketamine for illicit use within
different Member States, with a decrease occurring in the UK and an increase in two
other Member States. A large proportion of ketamine seizures are in tablet form and the
tablets carry the same logo as those often found in ecstasy tablets. It may also be found
in powder form and sold as a stimulant such as amphetamine or cocaine. Forensic
laboratories have found ketamine in variable doses mixed with manitol, caffeine,
ephedrine and pseudo-ephedrine, MDMA, methamphetamines and amphetamines. In
Belgium, 89 kilos of pure ketamine in powder were seized in September 1999 and a
further 3 kg in January 2000. Four Member States (Belgium, Ireland, the Netherlands
and the UK) seized significant amounts of ketamine. However, seizures of ketamine are
small when compared to seizures of ‘regular’ types of synthetic drugs such as
amphetamine, MDMA and MDA.
1 Classification for the supply of medicinal products for human use is regulated by Directive 92/26/EEC of 31 March 1992 and Article 12 of Directive 75/319/EEC of 20 May 1975 regulates through the Committee for Proprietary Medicinal Products (CPMP) the suspensions, withdrawal or variations to the terms of the marketing authorisation, in particular to take account of the information collected in accordance with Pharmacovigilance.
(b) Knowledge and Perception of ketamine Among Users

There is apparently low awareness of and experimentation with ketamine in Europe
compared with drugs such as cannabis, MDMA, amphetamine and cocaine. Lack of
information about the dose content of the ketamine on the market may be an important
factor. Anecdotal reports from France and the UK indicate growing awareness among
consumers about how to manage doses to achieve sought after effects and to avoid
negative ones. A survey in a dance setting in Austria found that the respondents, using
regularly MDMA and amphetamines, considered the psychological risks attached to
ketamine as very high.
At low doses, ketamine is sometimes reported to have a stimulant effect: this could be
the result of stimulant effect of other drugs or active cutting agents (like caffeine)
because ketamine is often snorted with amphetamines and/or cocaine or taken with
other drugs in the illicit drug scene. There is some indication that ketamine has an up-
market image as an esoteric drug for experienced drug users.
(c) Prevalence and Patterns of Use
Surveys of selected groups of drug users in dance settings have shown that a significant
number of people experiment with ketamine but the level varies between sub-
populations and geographical areas. A London club survey in 1997 found that up to
40% of the 200 respondents had experimented with ketamine and were to use it the
same evening. A large French survey conducted the same year found that 15% of the
900 respondents in techno party settings had experimented with ketamine. Recently, a
large school survey conducted in the North East of England found that 1% of 13/14
years old children and 2% of 15/16 years old had ever tried ketamine compared to 2%
and 5% respectively who had tried cocaine.
The most popular route of administration is to snort ketamine as a powder and to inject
liquid preparations, and there have been reports of it being swallowed, smoked or
inserted rectally.

(d) Characteristics and Behaviours of Users
Although there is evidence of use by younger people, targeted surveys and anecdotal
reports indicate that prevalence may be higher in older, highly educated, experienced,
MDMA users, particularly in the free party/new age travellers scene, in the gay club
scene, and among small groups of self-exploratory individuals. Among ‘closed’ groups
in Europe, initiation into ketamine use is often ritualised.
The most vulnerable groups are those who take ketamine under the illusion they are
taking MDMA or some other stimulant drug. The volume of seizures of ketamine in
tablet form with ecstasy-type logos reflects the scope for this scenario and the need for
better information about drug contents and harm reduction. Ketamine does not react
with commonly used field tests (e.g., Marquis reagent) although other drugs present in
the tablet may produce a positive reaction.

(e) Indicators of Health Consequences
In the EU since 1996, there have been four deaths reported to the EMCDDA in which
ketamine was found by laboratory analysis, of which two occurred in 1996 in Ireland. In
neither of the Irish cases, ketamine was considered to be the main cause of death. One
death of a 19 year-old-male has been reported in France where ketamine, LSD and
ecstasy were implicated. The fourth death, also reported from France, was a polydrug
user.
There has been a notable lack of reporting about hospital emergencies in Europe. A
recent report in France presents some data on 17 cases of intoxication associated with
ketamine.
An important factor of health risk is the lack of reliable indications of dose accompanying
sales of ketamine at street level. In the absence of advice, first time users of ketamine
will tend to follow similar consumption patterns as those previously adopted for other
drugs. This uninformed use of ketamine increases the risk of both physical and
psychological problems. The existence of tolerance may increase a tendency to move
from snorting to injecting ketamine, with the risks associated with injection.
.
(f) Context of Use

The implications for the non-ketamine using population appears to be phenomenon of
ketamine entering the recreational drug market in the guise of ecstasy, or other stimulant
drugs. This means that someone expecting to take MDMA, cocaine or amphetamine
may find themselves taking ketamine inadvertently, without warning, knowledge or
support.
Compared with the effects of stimulants, the rapid physical incapacity rendered by
ketamine consumption has serious implications for driving.
4 SOCIAL RISKS: sociological/criminological aspects

4.1 Sociological aspects
4.1.1 Social Consequences

Social consequences for the user stem firstly from its anaesthetic properties and loss of
physical control if too high a dose is taken, and secondly from reported psychological
effects of regular, or heavy, use which include dependency. In addition to the loss of
physical control it may cause tension due to the introspective quality of effects, other
psychological symptoms, and compulsive use by a small minority
4.1.2 Consequences for the Social Behaviour of the User

Main consequences on social behaviour stem directly from ketamine’s effects and a
tendency towards compulsive use by some users.

4.1.3 Other Social Consequences

In dance settings ketamine often appears in the form of well-made tablets, which are
visually similar to MDMA and usually mixed with a stimulant ranging from caffeine to
amphetamine. It is also found as liquid, powder and capsules. Ketamine has also been
used as a cutting agent for drugs such as cocaine, amphetamines and heroin and may
be taken by problem opiate users. The chosen route of administration for a small
minority is by injection which raises a value conflict in a drug using culture which is
strongly against injecting.
A range of social factors increase the probability of use, such as the existence of a large
market of long term ecstasy users seeking new drug experiences, a rather intellectual
trend-setting image and low price. However, other factors mitigate against widespread
diffusion, such as the anaesthetic effects, marked discomfort with intranasal use, the
short action, acute psychological reactions when taken without due knowledge about
dose or effects, psychological dependence, and negative effects on social relationships.
In view of potential anaesthetic and numbing effects, psychological disturbances and
compulsive use there are implications for: drug services, research institutes, hospital
emergency departments and the press.
4.2 Criminological aspects

The seizure of considerable amounts in Belgium, Ireland, the Netherlands and the UK
could suggest an involvement of organised crime. In the UK, it is believed that ketamine
raw material is imported in bulk from legitimate suppliers in Europe. A number of
sources, close to the user, suggest that there may be diversion from licit sources or
foreign purchase, particularly from Asia.
5. POSSIBLE CONSEQUENCES OF PROHIBITION
5.1 Legal Status
Ketamine is subject to control in five Member States: Belgium, France, Greece, Ireland
(to be scheduled in the Misuse of Drugs Act) and Luxembourg. It is controlled through
general medicines legislation in all Member States. Due to the fact that ketamine
preparations, as medical and veterinary products, have marketing authorisation in most
Member States and have a recognised unique therapeutic value, the major concern
appears to be the diversion from legitimate supply to the black market.
The complex routes of synthesis for manufacturing illegally ketamine reduce the
potential impact on the illegal market for ketamine of targeted measures to control
ketamine precursors. Illegal production of ketamine is unlikely to develop due to these
conditions. However, the implication of organised crime in the production and supply of
ketamine in tablet form, with the possible health risks due to sales of ketamine tablets
with ecstasy logos, represents a particular matter of concern.

5.2 Possible Consequences of Prohibition

The possible consequences of prohibition discussed at the meeting included the
following:
• The EMEA highlighted the fact that changes in the conditions of marketing
authorisations for ketamine containing medicinal products proposed by the meeting should be dealt with at national level or referred to the CPMP and CVMP. • Introducing penalties for use would be unlikely to deter use in groups where illegal • Concern was expressed about the effects of prohibition and control measures on informal information and harm-reduction networks. • One opinion was that control measures might draw unnecessary attention to the drug thus increasing its attractiveness to potential users. • In discussions on possible mechanisms of control, differences between control of the bulk drug and of medicinal products containing ketamine were mentioned. In this regard, there was a strong support that the view of the chemical and pharmaceutical industry about possible measures of control be sought. • The view that as a common minimum approach, medicines legislation should be used as a control measure received strong support. • Another opinion expressed at the meeting was that, in addition to the medicines legislation, stronger measures of control to deal with diversion, trafficking and inadvertent exposure (i.e. through fake ‘ecstasy’-tablets) were necessary. It was also stated that control of import and export of ketamine requires such measures. • The meeting noted the concern of the Federation of Veterinarians of Europe that placing ketamine under the same stringent restrictions as opioids could be detrimental to good veterinary medicine. It was noted that the same concern could apply to the use of ketamine in human medicine. 2 I.e. EU Regulation based upon Council Directive of 26 January 1965, 65/65/EEC, as amended by Directives 83/570/EEC, 87/21/EEC, 89/341/EEC and 93/39/EEC, as well as Decisions of the Court of Justice of the European Communities, especially case C-112/89.
6. CONCLUSIONS

The Scientific Committee of the EMCDDA enlarged with experts from the Member
States and representatives of the Commission, Europol and EMEA have considered the
health and social risks as well as the possible consequences of prohibition of ketamine
and in accordance with Article 4 of the Joint Action submit the following conclusions:
6.1
Ketamine is not a new synthetic drug. While it has a significant therapeutic use, it is also being used in recreational settings. The meeting noted the main risks of the recreational use of the drug, such as the psychological dependence, loss of self-control, and the risk of acute intoxications. To date, the use of ketamine has been reported as associated with mortality or morbidity in a small number of cases. An opinion, which received strong support at the meeting, was that as a common minimum ketamine should be subject to control under the medicines legislation in Member States. Another opinion firmly expressed at the meeting was that, in addition to the medicines legislation, stronger measures of control to deal with diversion, trafficking and inadvertent exposure to the drug were necessary. The meeting recommends that both the EMCDDA and Europol should further monitor the manufacture, trafficking, distribution, patterns of use and health consequences of ketamine, particularly the fatalities and non-fatal emergencies. The meeting recommends that a study on possible neurotoxicity of ketamine in primates should be considered in the context of the 5th Framework Research Programme of the European Commission. The possibility for improving control of diversion should be discussed with the chemical and pharmaceutical industry in order to ensure the continued availability of ketamine for medical and veterinary use. The meeting recommends that consideration should be given to how appropriate information be disseminated to the most vulnerable risk groups.

Source: http://www.m.legaliser.nu/sites/default/files/files/ketamine_final_riskassessment_report.pdf