3.1. Individual health risks

(a) Acute effects: Ketamine is a dissociative anaesthetic. The term ‘dissociative’
has two meanings. 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 somaesthetic (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 themselves 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 this 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 some 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 these include persistent impairment of attention and recall
and a subtle visual anomaly. The Report on the 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 to be an anaesthetic with a good
safety profile, based on extensive clinical experience. The major drawback,
which limits 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, unlike clinical practice,
may present cases of long-term use.

A total of 12 deaths in which ketamine was identified were noted between
1987 and 2000, including seven from the United States. 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 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 indicate 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 amphetamine
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: The recreational user of ketamine may experience
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 and 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 sense of danger, visual disturbances),
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 (3). Seizure data suggest mostly low levels
of availability of ketamine for illicit use within different Member States, with
a decrease occurring in the United Kingdom 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 is often used for 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 pseudoephedrine, MDMA,
methamphetamines and amphetamines. In Belgium, 89 kg of pure ketamine
powder was seized in September 1999 and a further 3 kg in January 2000.
Four Member States (Belgium, Ireland, the Netherlands and the United
Kingdom) 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.

(b) Knowledge and perception of ketamine among users: There appears to be
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 United Kingdom
indicate growing awareness among consumers about how to manage doses
to achieve the desired effects and to avoid negative ones. A survey in a
dance setting in Austria found that the respondents who regularly use
MDMA and amphetamines considered the psychological risks attached to
ketamine to be very high.

At low doses, ketamine is sometimes reported to have a stimulant effect. This
could be the result of the 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 upmarket 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 that 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 that
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-year-old children and 2 % of 15/16-yearolds
had tried ketamine compared to 2 and 5 % respectively who had tried
cocaine.

The most popular routes of administration are to snort ketamine as a powder
and to inject liquid preparations. There have also 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 traveller 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 group is those who take ketamine under the illusion
that 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: Four deaths in the EU in which ketamine
was found by laboratory analysis have been reported to the EMCDDA since
1996, of which two occurred in 1996, in Ireland. In neither of the Irish
cases was ketamine considered to be the main cause of death. The 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 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 phenomenon of ketamine entering the recreational
drug market in the guise of ecstasy or other stimulant drugs means that someone
expecting to take MDMA, cocaine or amphetamine may find themselves
inadvertently taking ketamine, without warning, knowledge or support.

Compared to the effects of stimulants, the rapid physical incapacity induced
by ketamine consumption has serious implications for driving.

(3) Classification for the supply of medicinal products for human use is regulated by Directive 92/26/EEC
of 31 March 1992. 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.