This report was commissioned by the EMCDDA as part of a risk assessment
on the drug ketamine in accordance with Article 4 of the joint action concerning
the information exchange, risk assessment and control of new synthetic
drugs adopted by the Council of the European Union on 16 June 1997.
This report summarises the relevant data required by the Technical Annexes
A and B of the guidelines for the risk assessment of new synthetic drugs, as
adopted by the Scientific Committee of the EMCDDA.

Introduction

The anaesthetic ketamine was first synthesised by Calvin Stevens at Parke-
Davis laboratories in 1962 (Jansen, 2000a) and patented in Belgium in 1963
and in the US in 1966 (Budavari et al., 1989). Ketamine was first marketed
in the early 1970s (FDA, 1979) and promoted as a more acceptable alternative
to its congener, PCP (‘angel dust’; Dotson et al., 1995). PCP was abandoned,
except for veterinary use, because of its adverse effects, such as hallucinations
and delirium. Although ketamine is not devoid of similar side-effects,
these are less persistent, and ketamine has now achieved a unique place in
medical practice. PCP had become popular as a recreational drug in the
1960s and had caused considerable problems as such. Ketamine abuse was
first noted on the west coast of the United States in 1971 (Siegel, 1978). In
the early 1990s in the United Kingdom, several reports of more widespread
recreational use of ketamine appeared (Hall and Cassidy, 1992; McDonald
and Key, 1992; Jansen, 1993; Dalgarno and Shewan, 1996). An inquiry by
the EMCDDA has shown that recreational use of ketamine is noted in other
Member States as well (e.g. Arditti, 2000).

Since ketamine has existed for 37 years as a chemical entity, it is difficult
to call it a new synthetic drug. Ketamine cannot be considered a drug with
limited therapeutic value, as its pharmacological properties have given it a
unique place in human and veterinary medical practice. Nevertheless, in
light of its current use as a recreational drug in the EU, the Portuguese
Presidency, on behalf of all Member States and in the framework of the
Horizontal Working Party on Drugs of the Council of the European Union,
formally referred the substance ketamine (2-(2-chlorophenyl)-2-(methylamino)-
cyclohexanone) to the EMCDDA for a risk assessment under Article 4 of the
joint action concerning the information exchange, risk assessment and control
of new synthetic drugs adopted by the Council of the European Union on
16 June 1997, on the basis of Article K3 of the Treaty on European Union.
This report summarises the relevant data required by the Technical Annexes
A and B of the principles for risk assessment of new synthetic drugs, as
adopted by the Scientific Committee of the EMCDDA.

Pharmacotoxicological evidence

Chemical information

Ketamine (2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone), an arylcycloalkylamine,
is structurally related to phencyclidine (PCP) and cyclohexamine.
Ketamine hydrochloride is a water-soluble white crystalline and has a
pKa of 7.5 (Budavari et al., 1989). Its free base, ketamine, has a lipid solubility
10 times that of thiopentone. It contains a chiral centre at the C-2 carbon of
the cyclohexanone ring, so that two enantiomers exist, S-(+)-ketamine and
R-(-)-ketamine. Ketamine is used in human and veterinary medicine as an
anaesthetic and analgesic. The commercially available pharmaceutical form is
an aqueous solution for injection of the racemic mixture of the hydrochloride
salt. Clinically, ketamine usually is administered intravenously or intramuscularly.
Recreationally, ketamine is taken intranasally, orally, intramuscularly,
subcutaneously or intravenously. Typical recreational doses are 75–125 mg
intramuscularly or subcutaneously, 60–250 mg intranasally, 50–100 mg
intravenously and 200–300 mg orally. Doses may vary considerably,
depending on the strength of the effect desired, differences in sensitivity and
development of tolerance.

Chemical description (including methods of synthesis, precursors,
impurities if known, type and level)

The chemical names used for ketamine are:

 ketamine;

 ketamine hydrochloride;

 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride;

 2-(o-chlorophenyl)- 2-(methylamino)-cyclohexanone hydrochloride;

 2-(methylamino)-2-(2-chlorophenyl)-cyclohexanone hydrochloride;

 2-(methylamino)-2-(o-chlorophenyl)-cyclohexanone hydrochloride;

 cyclohexanone, 2-(2-chlorophenyl)- 2-(methylamino) hydrochloride;

 cyclohexanone, 2-(o-chlorophenyl)- 2-(methylamino) hydrochloride;

 CI-581;

 CL-369;

 CN-52,372-2.

The chemical formula for ketamine is:

Ketamine contains a chiral centre at the C-2 carbon of the cyclohexanone
ring, so that two enantiomers exist: S-(+)-ketamine and R-(-)-ketamine.

The CAS number for ketamine is:

Free base 6740-88-1
Hydrochloride salt 1867-66-9 (current); 81771-21-3, 96448-41-8, 42551-
62-2 (previous)

The molecular weight of ketamine is:
Free base 237.73
Hydrochloride salt 274.18
1.15 mg of the hydrochloride salt is equivalent to 1 mg of the free base.

The melting point of ketamine is:
Free base 92–93 °C
Hydrochloride salt 262–263 °C

The proprietary names used for ketamine are:

Ketalar, Ketolar, Ketaject, Ketanest, Ketaset, Ketavet, Ketavet 100, Ketalin,
Vetalar, Kalipsol, Calipsol, Substantia, Ketamine Panpharma, Ketamine UVA,
Chlorketam, Imalgene (Budavari et al., 1989; Reynolds et al., 1989; Arditti,
2000).

The most common street names for ketamine currently in use in the EU are
ketamine, K, ket, vitamin K, special K and super K (Jansen, 1993;
Europol/EMCDDA, 2000). Liquid E, a name more often used for GHB
(gamma-hydroxybutyric acid), was mentioned as well (Europol/EMCDDA,
2000). Additionally, the French assessment report on ketamine (Arditti,
2000) mentions kéta K, kit kat, cat valium, flatliners (also in use for 4-MTA),
kaddy, kate, tac et tic, liquid G and spécial la coke. Other names that were
reported earlier in the United States are kay, jet, super acid, 1980 acid,
special LA coke, super C, purple, mauve and green (FDA, 1979; Felser and
Orban, 1982).

Synthesis, precursors, excipients and impurities of ketamine

Ketamine is manufactured by the pharmaceutical industry. The preparation
is described by Stevens, Belgian patent 634208 (1963), which corresponds
to the US patent 3254124 (1966 to Parke-Davis). The synthesis of the optical
isomers is described by Hudyma et al., German patent 2062620 (1971 to
Bristol-Myers) (Budavari et al., 1989).

Ketamine that is used recreationally is mostly diverted from the pharmaceutical
supply to hospitals, veterinary clinics or the pharmaceutical distribution
network. The precursors that are mainly used for its illicit production are
cyclohexanone, methylamine and chlorobenzene (Europol/EMCDDA,
2000). Sources on the Internet rate the synthesis of ketamine as difficult.
A specific route described on rhodium.lycaeum.org involves the precursors
cyclopentyl bromide, o-chlorobenzonitrile and methylamine. Several additional
reagents and solvents are needed for the four-step synthesis described.
The same site mentions that two ketamine analogues have been found on the
black market: the compound missing the 2-chloro group on the phenyl ring,
and its N-ethyl analogue. According to this Internet site, both of these compounds
are considered to be more potent and longer lasting than ketamine.
Using the same synthesis route as described for ketamine, the precursors
benzonitrile and ethylamine would be involved instead of o-chlorobenzonitrile
and methylamine.

Ketamine prepared by the pharmaceutical industry meets the standards of
good manufacturing practice (GMP), which means that the quality and purity
is guaranteed. Ketamine is sold as hydrochloride salt in an aqueous solution
and is packaged in small sealed glass vials. A preservative may also be present.

When the drug is diverted for recreational use, the original pharmaceutical
form is often abandoned. Most users dislike using needles, and the most popular
medium for ketamine is powder form, which is snorted. The powder is
prepared by evaporation of the original solution. This powder is usually sold
in small plastic or paper bags. The ketamine in these bags may be mixed
with other drugs or inactive components. As the effects of ketamine are dosedependent,
the uncertainty about the concentration of ketamine in the powder
poses a risk for overdosing.

Ketamine can also be administered intranasally by transferring the ketamine
solution to a vaporiser, or it may be presented in tablet form, to be taken orally.
Again, the concentration and presence of adulterants are mostly unknown.

Tablets containing ketamine are often sold as ‘ecstasy’. Other substances
reported to be present in ketamine-containing tablets are pseudoephedrine,
ephedrine, caffeine, amphetamine, methamphetamine and MDMA.

Legitimate uses of the product

Ketamine hydrochloride is used as an analgesic and anaesthetic in human
and veterinary medicine, where it has acquired a unique place. Important
clinical applications are brief procedures in paediatric and ambulatory
anaesthesia, the treatment of burning-wound patients, use in obstetrics and
for the induction and maintenance of anaesthesia in hypovolemic pericardial
tamponade, constrictive pericarditis and cardiogenic shock patients (Reich
and Silvay, 1989; Haas and Harper, 1992; Bergman, 1999).

According to the information provided by the EMEA on current use in the EU,
it appears that, in general, medicinal use of ketamine for humans is limited.
Its use is considered useful in special circumstances. Italy had no difficulty
in finding alternatives to ketamine. In Germany, S-ketamine has been
licensed as an anaesthetic in human medicine since 1997.

According to the information provided by the EMEA, the use of ketamine in
veterinary anaesthesia, especially in small animals, as well as in exotic animals,
is currently widespread in the EU. Several Member States (Denmark,
Germany, Portugal, Sweden) indicate that ketamine is indispensable in
veterinary medicine in those countries.

Outside the EU, the use of ketamine as an anaesthetic in human medicine
may have a more prominent place in Third World countries, where facilities
are much poorer. Its ease of use gives ketamine a major advantage under
such difficult circumstances (Green et al., 1996).

Phramaceutical form (powder, capsules, tablets, lquid, injectables, cigarettes)

The pharmaceutical form of the preparations used in medicine is an
injectable solution of the racemic mixture of ketamine hydrochloride in
water (10, 50 or 100 mg/ml). The solution is packaged in small sealed glass
vials.

On the street, ketamine has appeared in various forms. These may be the original
vials containing the ketamine solution, or as a vaporiser, a powder (in bags
or in ampoules) or in tablets.

In powder form, combination with cocaine has been observed (CK, or Calvin
Klein). In tablet form, mixtures of ketamine and a range of other substances
have been reported, including pseudoephedrine, ephedrine, caffeine, amphetamine,
methamphetamine and MDMA. The ketamine content of three
tablets in which ketamine was quantified by a Dutch drug supply monitor
varied from 89 to 114 mg. In these tablets, methamphetamine (6 and 11 mg),
caffeine (31 and 55 mg) and ephedrine were also found.

Routes of administration

Clinically, the drug is usually administered by intramuscular or intravenous
injection. For analgesia, the intrathecal route is used as well. Administration
by the oral and rectal routes has also been reported (Reich and Silvay, 1989).

When ketamine is used recreationally or experimentally, the most popular
route of administration is the intranasal route (i.e. snorting the powder or
inhaling a solution from a vaporiser). Some long-term users may use the
Pharmaceutical form (powder, capsules, tablets, liquid, injectables, cigarettes)
intramuscular, subcutaneous or intravenous route as well. All routes of
administration that involve the use of needles bear the risk of transmitting
diseases like HIV or hepatitis if the needle or syringe is not clean. In the rave
scene, oral administration of ketamine-containing tablets occurs as well.
These may be sold as ecstasy tablets, which poses a risk of inadvertent use
of ketamine by someone expecting to use MDMA.

Dosages by all routes of administration

Adose equivalent to 2 mg of ketamine per kg of body weight given intravenously
over 60 seconds usually produces surgical anaesthesia within 30 seconds
lasting for 5 to 10 minutes (the dose may range from 1 to 4.5 mg/kg). An
intramuscular dose equivalent to 10 mg per kg of body weight (ranging from
6.5 to 13 mg/kg) usually produces surgical anaesthesia within 3 to 4 minutes
lasting for 12 to 25 minutes (Reynolds et al., 1989).

Intravenous administration of 0.2–0.75 mg/kg of ketamine produces analgesia
(Reynolds et al., 1989). Using the oral or intramuscular route, a dosage of
0.5 mg/kg induces analgesia (Grant et al., 1981). Although the time differs,
depending on the route, the similarity of the dosages to obtain analgesia
using different routes might be explained by the analgesic properties of the
primary metabolite norketamine (Reich and Silvay, 1989).

Subanaesthetic intravenous doses inducing psychotropic effects range from
0.1 to 1.0 mg/kg. In clinical studies, this dose may be divided into a bolus of
0.1–0.2 mg/kg and a maintenance infusion of 0.0025–0.02 mg/kg/min
(Krystal et al., 1994; Malhotra et al., 1996; Engelhardt, 1997; Vollenweider
et al., 1997; Oranje et al., 2000).

Intramuscular administration of ketamine in a dose ranging from 25 to 200 mg
has been reported to produce psychotropic effects in humans (Hansen et al.,
1988).

Recreational users who snort the powder describe the dose as a ‘typical line’,
suggesting a quantity between 60 and 250 mg (Dalgarno and Shewan, 1996).
Malinovsky et al. (1996) found that bioavailability of nasally administered
ketamine in children was approximately 50 %, whereas bioavailability of
intramuscularly administered ketamine is approximately 93 % (Grant et al.,
1981). The dose range for intranasally administered ketamine is, therefore,
probably higher than that for the intramuscular route.

Bioavailability is low when ketamine is administered orally (see the section
‘Pharmacokinetics’, page 42). The main active metabolite, norketamine,
which has a potency one third of the parent compound, predominates after
oral administration. Consequently, oral dosages are larger than those administered
by other routes (typical doses may be expected to be around 200–300 mg).

Besides the route dependency of the dose needed to evoke psychotropic
effects, the dose will vary among users, depending on the strength of the
effect desired, differences in sensitivity and development of tolerance.
Commonly, users titrate the quantity individually to achieve the desired
effects.

Toxicology and pharmacology in animals and humans

Pharmacodynamics

A large body of literature exists on the neuropharmacological properties of
ketamine. These studies were performed both in vitro and in vivo. The main
characteristics of ketamine’s action on the central nervous system will be
summarised in this section.

Ketamine is a dissociative anaesthetic (Domino et al., 1966). Originally, the
dissociation component referred to a functional and electrophysiological
dissociation of thalamoneocortical and limbic systems (Reich and Silvay,
1989; Haas and Harper, 1992). More recently, the nature of the subanaesthetic
ketamine experience has led to the use of the term ‘dissociative’ in a
more psychological sense, referring to a feeling of dissociation of the mind
from the body (Jansen, 1990, 2000a).

Ketamine binds to the so-called PCP-binding site, which is a separate site of
the NMDA-receptor complex located within the ion channel, thereby blocking
the transmembranous ion flux. This makes ketamine a non-competitive
NMDA-receptor antagonist. NMDA-receptors are calcium-gated channel
receptors. The endogenous agonists of the receptor are the excitatory amino
acids glutamic acid, aspartic acid and glycine. Activation of the receptor
results in opening of the ion channel and depolarisation of the neurone. The
NMDA-receptor is involved in sensory input at the spinal, thalamic, limbic
and cortical levels. Ketamine would be expected to block or interfere with
sensory input to higher centres of the CNS, with the emotional response to
these stimuli and with the process of learning and memory (Bergman, 1999).

Awakening from ketamine anaesthesia takes place at plasma concentrations
of 0.064 to 1.12 μg/ml (Reich and Silvay, 1989). Psychotropic effects have
been described when plasma concentrations range from 0.05 to 0.3 μg/ml
and with regional brain concentrations higher than 0.5 μg/ml (Hartvig et al.,
1995; Bowdle et al., 1998; Oranje et al., 2000).

Several studies indicated that opioid receptors are also involved and that
the analgesic effect of ketamine may largely be attributed to the activation
of these central and spinal receptors. The plasma levels at which analgesia
is achieved are 0.15 μg/ml following intramuscular administration and
0.04 μg/ml after oral administration. This difference may be explained by a
higher norketamine concentration due to first-pass metabolism. This main
metabolite apparently contributes to the antinociceptive effect (Shimoyama
et al., 1999).

Some of the effects of ketamine may be due to its actions on catecholamine
systems, notably an enhancement of dopamine activity (White and Ryan,
1996; Smith et al., 1998; Vollenweider et al., 2000). A series of experiments
by Hancock and Stamford (1999) on the effects of ketamine on uptake and
efflux of dopamine in the rat nucleus accumbens (NAc) led the authors to
conclude that ketamine increases NAc dopamine efflux not by block of
dopamine uptake, autoreceptors or NMDA receptors, but by mobilisation of
the dopamine storage pool to releasable sites. In the rat, it has been shown
that repeated ketamine administration diminished the initial five-fold
increase in dopamine release in the prefrontal cortex, whereas the increase
in extracellular 5-hydroxyindole acetic acid (5-HIAA, a serotonin metabolite)
levels is enhanced. This suggests that the balance between dopamine and
serotonin neurotransmission in the prefrontal cortex is altered after repeated
exposure to ketamine (Lindefors et al., 1997). The dopaminergic effects
may be of relevance for the euphorigenic, addictive and psychotomimetic
properties of ketamine.

Other neuropharmacological actions are an agonistic effect on α- and -
adrenergic receptors, an antagonistic effect at muscarinic receptors of the
CNS and an agonistic effect at the σ-receptor (Bergman, 1999).

The principal metabolite, norketamine, is pharmacologically active. Its binding
affinity to the NMDA-receptor and its anaesthetic properties are approximately
one third of the parent compound contributing significantly to the
analgesic effect of ketamine (Shimoyama et al., 1999).

The commercially available ketamine is a racemic mixture of two enantiomers.
The S-enantiomer is shown to be the more potent one, with an approximately
three- to fourfold anaesthetic potency compared to R-ketamine. This
correlates to the higher binding affinity for the PCP site of the NMDA-receptor.
The psychotomimetic properties of ketamine are mainly caused by the
S-enantiomer, although subanaesthetic doses of R-ketamine may induce a
state of relaxation (Engelhardt, 1997; Vollenweider et al., 1997).

Secondary pharmacology

EFFECTS ON THE CARDIOVASCULAR SYSTEM

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 (Haas and Harper, 1992). The mechanism is not well
understood, although elevated levels of circulating catecholamines due to
reduced re-uptake may contribute to this phenomenon. On the other hand,
cardiodepressant effects have been noted in critically ill patients. This may
be due to chronic catecholamine depletion preventing any sympathomimetic
effects of ketamine and unmasking a negative inotropic effect which is usually
overshadowed by sympathetic stimulation (Reich and Silvay, 1989; White
and Ryan, 1996). The cardiovascular effects of ketamine usually do not pose
a problem, but its use is contraindicated in patients with significant
ischaemic heart disease and should be avoided in those with a history of
high blood pressure or cerebrovascular accidents (Haas and Harper, 1992).
In recreational ketamine users, presenting to an emergency hospital department,
tachycardia was the most common finding upon physical examination
(Weiner et al., 2000).

EFFECTS ON THE RESPIRATORY SYSTEM

Ketamine is a mild respiratory depressant. Depending on dose, it causes a
shift of the CO2 dose-response curve to the right but does not change the
slope of the curve. Respiratory drive to CO2 may be depressed by as much
as 15 to 22 %. This effect is similar to that of opioids but different to most
sedative hypnotics and anaesthetics, suggesting that opioid receptors may
play a role in the respiratory depressant effect. In clinical studies, these
effects were observed only at high doses. Some case reports describe respiratory
depression after rapid intravenous injection, but also after routine
paediatric use of ketamine administered intramuscularly (Reich and Silvay,
1989; White and Ryan, 1996). It appears that respiratory depression is not
likely to occur at recreational doses, but it cannot wholly be excluded.

Ketamine has a bronchodilatory effect, but pharyngeal and laryncheal reflexes
are maintained (Reich and Silvay, 1989).

OTHER PHARMACOLOGICAL EFFECTS

Other pharmacological effects that have been noted are as follows:

 ketamine increases muscle tone (Reich and Silvay, 1989);

 blood glucose and plasma cortisol and prolactin are increased after ketamine
administration (Reich and Silvay, 1989; Krystal et al., 1994); and

 ketamine may decrease intraocular pressure (Reich and Silvay, 1989).

Pharmacokinetics

The pharmacokinetics of ketamine have been studied in humans (e.g. Grant
et al., 1981; Clements et al., 1982; Malinovsky et al., 1996). The reported
volumes of distribution varied from 1.5 to 3.2 l/kg. The clearance was
in the range 12–28 ml/kg/min. The volume of distribution and clearance for
S-ketamine are 9 and 14 %greater than those for R-ketamine (Engelhardt, 1997).

ABSORPTION

Ketamine is rapidly absorbed when administered through the intramuscular
(Tmax 5–15 min.), nasal (Tmax 20 min.) or oral route (as a solution; Tmax 30
min.). The bioavailability is low when ketamine is given orally (17 %) or rectally
(25 %). Extensive first-pass metabolism in the liver and intestine is largely
responsible for this effect. Bioavailability after nasal administration is
approximately 50 % (Malinovsky et al., 1996). The lower bioavailability
with this route compared to the intramuscular route may partly be caused by
swallowing significant amounts of the intranasal deposit.

DISTRIBUTION

Initially, ketamine is distributed to highly perfused tissues, including the
brain, to achieve levels four to five times those in plasma (distribution halflife
after i.v. 24 sec). CNS effects subside, following redistribution to less
well-perfused tissues (redistribution half-life 2.7 min). Ketamine has a high
lipid solubility and low plasma protein binding (12 %), which facilitates
rapid transfer across the blood–brain barrier.

BIOTRANSFORMATION

Biotransformation primarily takes place in the liver. The most important
pathway is N-demethylation to norketamine. When administered orally or
rectally, initial plasma norketamine concentrations are higher than those
of ketamine, but the plasma area under the curve (AUC) for norketamine is
similar for all routes of administration. Norketamine has one third the anaesthetic
potency of ketamine and has analgesic properties. Norketamine may
be metabolised through multiple pathways, but the majority is hydroxylated
and subsequently conjugated.

ELIMINATION

The predominant route of elimination is by liver metabolism. The high
extraction rate (0.9) makes ketamine clearance susceptible to factors affecting
blood flow. The conjugated hydroxy metabolites are mainly excreted renally.
Reported terminal elimination half-lifes were in the range of 100 to 200 minutes.

Toxicology

The clinical safety profile of ketamine is largely based on extensive clinical
experience. The preclinical data may therefore be of less importance for
clinical safety. However, unlike recreational use, long-term clinical use of
ketamine is rare. Therefore, some preclinical data may be of greater importance
for the recreational drug user than for clinical practice.

SINGLE-DOSE TOXICITY

Single-dose acute toxicity shows an LD50 of between 140 (intraperitoneally
in the neonatal rat) and 616 mg/kg bw orally in the mouse (EMEA, 1997). In
adult mice and rats LD50 values were 224 ± 4 mg/kg and 229 ± 5 mg/kg,
respectively (route not indicated) (Budavari et al., 1989).

In squirrel monkeys (Greenstein, 1975), doses above 25 mg/kg administered
intravenously caused anaesthesia. Return of righting reflex as a function of
the dose administered is shown in the graph in Figure 4.

At the highest concentration tested (350 mg/kg), four out of five monkeys
died. In humans, the lowest recommended intravenous dose to induce
anaesthesia is 1 mg/kg. Applying the same ratio of minimal anaesthetic dose
to highest non-lethal dose to humans implies that doses above 11.3 mg/kg
administered intravenously may be lethal in humans. For a person of 60 kg,
this is equivalent to intravenous doses above 680 mg. This estimate is based
on an experiment with a low number of animals and interindividual and
interspecies differences may exist. For these reasons such estimates always
hold some uncertainty and have to be regarded with caution. Yet, considering
data from case reports of fatal ketamine intoxications in humans, this estimate
seems to be a realistic one (see Table 1).

Several studies investigated the local tolerance of ketamine when administered
intrathecally (e.g. Malinovsky et al., 1996; Errando et al., 1999). Ketamine,
when injected without preservative, did not cause neurotoxicity in the spinal
cord of swine or rabbits. However, when combined with the preservatives
benzethonium chloride or chlorobutanol, it caused discrete histopathological
changes in swine and rabbits.

NEUROTOXICITY

One issue that has been investigated in animals, but that has received little
attention in the clinical literature and may be of importance for the recreational
user of ketamine, is the neurotoxicity as observed in rats (Olney et
al., 1989, 1991). When administered subcutaneously, ketamine (40 mg/kg)
caused vacuolisation in posterior cingulate and retrosplenial cerebrocortical
neurones in the rat. Lower doses (≤ 20 mg/kg) did not cause such pathological
changes. These highly localised neurotoxic effects have also been shown for
other NMDA-antagonists (PCP, tiletamine, MK-801; Olney et al., 1989,
1991; Auer, 1994; O’Callaghan, 1994).

It has been suggested that the mechanism for this neurotoxic response is
based on an NMDA-antagonist-mediated hypofunction of the NMDA-receptor
resulting in a combination of enhancement of excitatory neuronal pathways
and inhibition of inhibitory neuronal pathways that lead to and from specific
groups of neurones in the cingulate and retrosplenial cerebral cortices.
Consistent with this hypothesis, it has been shown that several classes of
drugs effectively inhibit the neurotoxic effects of the NMDA antagonists,
including:

 muscarinic receptor antagonists;

 GABAA-receptor agonists (benzodiazepines and barbiturates);

 σ-receptor antagonists;

 non-NMDA (kainic acid) receptor antagonists;

 α2-adrenergic receptor agonists;

 certain typical antipsychotic agents (haloperidol, thioridazine, loxapine); and

 atypical antipsychotic agents (clozapine, flupefiapine, olanzapine)
(Bergman, 1999).

It may be anticipated that substances with opposite pharmacological actions
to those classes of drugs mentioned here may enhance the neurotoxicity of
ketamine (and related NMDA antagonists). In this context, the following substances
from the recreational drug repertoire should be mentioned: Amanita
muscaria mushrooms (muscarinic agonist), alcohol (NMDA- and partial
GABAA-antagonist), yohimbine (α2-adrenergic receptor antagonist) and other
dissociative drugs (NMDA-antagonists) like PCP and tiletamine.

There may be several reasons why these findings in rats have not led to the
clinical use of ketamine being abandoned. Firstly, ketamine is generally
accepted as a safe anaesthetic without long-term adverse effects (Shorn and
Whitwam, 1980; Reich and Silvay, 1989). Therefore, the preclinical data are
considered to be of limited clinical relevance. Secondly, benzodiazepines
are usually co-administered with ketamine to reduce the occurrence of
emergence phenomena. Benzodiazepines have been shown to protect
against the ketamine-induced neurotoxicity in rats.

On the other hand, there may be reasons why the findings on the neurotoxicity
of ketamine in the rat may be of concern to recreational users of ketamine.
Firstly, drug users do not take ketamine in combination with protective
agents like benzodiazepines. Moreover, compounds increasing the neurotoxic
potency of ketamine may be co-administered. Secondly, recreational
use implies repeated exposure, whereas clinical use is mostly incidental.
Long-term adverse effects in long-term users of ketamine have been reported,
however such data are scarce. Long-term effects that have been noted
include persistent impairment of attention and recall and a subtle visual
anomaly (Jansen, 1990). A review on the Internet (White, 1998) summarises
reports from heavy users of ‘dissociatives’ (i.e. dextromethorphan, ketamine
and PCP). Effects after frequent use that are mentioned include ‘jolts’ or
‘shocks’ when moving the eyes, sharply impaired visual tracking, impaired
recognition of metaphor, impaired language skills and memory problems.
The author relates these adverse effects (that fade with time) to malfunction
of or damage to the cingulate and retrosplenial cortices. To date, there is
insufficient evidence to prove such a relationship in humans. Also, such
Internet reports are bound to be heavily confounded by self-selection bias,
and it is impossible to narrow down the reported effects to a specific drug,
as many subjects are polydrug users.

REPEATED-DOSE TOXICITY

In a toxicological repeated toxicity study carried out on dogs, three groups
of four animals were given daily intramuscular doses of 4, 20 or 40 mg/kg of
body weight over six weeks. At all dose levels there was some degree of
weight loss and anorexia. Some blood parameters were also dose-related
elevated. Histological changes in the liver were minor (EMEA, 1997).

In rats, daily intravenous doses of 2.5, 5 or 10 mg/kg of body weight over six
weeks provoked a slight but not significant decrease in food intake and a
moderate depression in weight gain (EMEA, 1997).

REPRODUCTION FUNCTION

Rats were injected during the premating period (10 mg/kg of body weight
intravenously on days 9, 10 and 11 prior to mating). No effect on litter size
was observed (EMEA, 1997).

EMBRYO-FOETAL AND PERINATAL TOXICITY

Studies were conducted on the teratological effects of ketamine hydrochloride
(25, 50 or 100 mg/kg/day) in rats (Kochhar et al., 1986). Ketamine treatment
had no significant effect on the number of animals per litter. The histological
examination showed focal nuclear hypochromatosis and interfibrillary oedema
of the heart, diffuse hemopoietic cell infiltration and parenchymal cell
degeneration in the liver, and proximal convoluted tubule degeneration in
the kidney. These degenerative effects were dependent upon the dose and
the duration of treatment (days 1–15 or days 5–15 of gestation). The doses
applied in this study are in the subanaesthetic range in rats (Hammer and
Herkenham, 1983).

In another study in rats, doses (in mg/kg of body weight) 10 times the dose
administered to humans for anaesthesia did not result in teratogenic effects
(El-Karim and Benny, 1976).

When rats were treated on days 7 and 8 of gestation with a ketamine dose
of up to 200 mg/kg, no disorders in the pregnancy course and the embryonic
development were induced (Bandazhevskii and Shimanovich, 1991). At the
administration of a dose of 40 mg/kg on days 11, 13 and 15 of pregnancy,
ketamine was shown to exert a marked embryolethal action and administration
of doses of 20 and 40 mg/kg on days 7, 9 and 11 of pregnancy increased the
number of foetuses with haemorrhages in the internal organs.

Abdel-Rahman and Ismail (2000) studied the teratogenic potency of ketamine
hydrochloride in CF-1 mice with and without cocaine. It was shown that
ketamine (50 mg/kg/day) potentiated the teratogenic effects of cocaine
(20 mg/kg/day) but was not teratogenic on its own. Considering the higher
metabolic rate of mice, the authors stated that the doses applied were comparable
to those used by addicted humans and should be toxic to first-time
users. In the absence of toxicokinetic data expressing systemic exposure,
such estimations should be considered rough approximations.

A reproduction study in nine female dogs injected with 25 mg/kg of body
weight intramuscularly six times during one trimester of pregnancy (twice a
week over a three-week period) did not appear to show adverse effects on
the bitch or the pups (EMEA, 1997).

Rats and rabbits were injected during the three fundamental periods of the
reproduction process:

 the premating period (rats 10 mg/kg bw intravenously on days 9, 10 and
11 prior to mating);

 the period of organogenesis (rats and rabbits 20 mg/kg of body weight
intramuscularly on days 6–10);

 day 11–perinatal period (rats 20 mg/kg of body weight intramuscularly on
days 18–21 of gestation).

For all these groups, there were no significant differences in litter size and
delivered pups (EMEA, 1997). These studies, cited from the CVMP
(Committee on Veterinary Medicinal Products) summary report, have limited
value, since the duration and level of exposure do not meet current standards
of toxicity testing. Thus, possible effects may have gone undiscovered.

Olney and co-workers (2000) have suggested that ketamine has the potential
to delete large numbers of neurones from the developing brain by a mechanism
involving interference in the action of neurotransmitters (glutamate and
gamma-amino butyric acid (GABA) at N-methyl-d-aspartate (NMDA)) and
GABAA receptors (see the section ‘Neurotoxicity’, page 44) during the synaptogenesis
period, also known as the brain growth-spurt period. Transient
interference (lasting ≥ 4 hr) in the activity of these transmitters during the
synaptogenesis period (the last trimester of pregnancy and the first several
years after birth in humans) causes millions of developing neurones to commit
suicide (death by apoptosis). Further research will be required to fully
ascertain the nature and degree of risk posed by exposure of the developing
human brain to ketamine.

No data on human pregnancies exposed to ketamine exist (Friedman, 1988),
with the exception of the obstetric use of ketamine during parturition, where
it has been shown that ketamine may depress foetal functions when 2 mg/kg
is administered intravenously to the mother.

In summary, at doses 10 times those used in humans for anaesthesia,
histopathological changes in rat foetuses have been observed. These effects
are dependent on the period of exposure. Based on these preclinical data, in
the absence of sufficient toxicokinetic data in animals, and considering that
rodents have a higher metabolic rate and doses administered were in the
subanaesthetic range in these animals, it cannot be excluded that ketamine
in (sub)anaesthetic doses may adversely affect pregnancy outcome in
humans. However, no data on human pregnancies exposed to ketamine
were found.

MUTAGENIC AND CARCINOGENIC POTENTIAL OF KETAMINE

Bacterial tests: Ketamine was tested in a limited Ames test using two salmonella
strains (TA98 and TA100) and one high test concentration (10 mg/plate)
only. The experiments were done in the presence and absence of rat liver
S9 mix and showed a negative result (Waskell, 1978).

In another bacterial test, ketamine was tested for its ability to inhibit growth
of three bacterial strains with decreased capacity to repair damaged DNA.
No inhibition of growth of DNA-repair deficient strains relative to a strain
with normal DNA-repair was observed, indicating that ketamine did not
induce DNA damage under the test conditions used (Waskell, 1978).

Mammalian cell tests in vitro: Using an SCE test on CHO cells, ketamine at
concentrations of 1.19, 2.38 and 3.66 mg/l was found to induce an increase
in SCE/cell in a concentration-dependent manner (Adhvaryu et al., 1986).
The highest effect (11.20 SCE/cell at 3.66 mg/l) was less than a doubling of
the control value (7.28 SCE/cell).

No relevant in vivo studies with the racemic mixture of ketamine were
performed.

In 1996, study reports of a mutagenicity testing programme with the S(+)
enantiomer of ketamine were submitted to the German Federal Institute for
Drugs and Medical Devices as part of an application for a marketing authorisation.
Since the submission was processed as a new drug application and
the applicant can still claim a period of exclusivity for the marketing authorisation,
we are not authorised to provide any details of these studies.
However, the following general assessment may be given. The mutagenic
and clastogenic potential of the S(+) enantiomer of ketamine was tested both
in vitro and in vivo in a battery of established and validated genotoxicity
studies. The tests were conducted in compliance with GLP regulations and
were in full compliance with recent EU and ICH guidelines regarding the
scope of mutagenicity tests for new chemical entities. This means that the
following test categories, at least, were considered:

 a test for gene mutation in bacteria;

 an in vitro test with cytogenetic evaluation of chromosomal damage with
mammalian cells or an in vitro mouse lymphoma tk assay; and

 an in vivo test for chromosomal damage using rodent hematopoietic cells.

There was no evidence of genotoxicity seen in these studies and it is therefore
concluded that the S(+) enantiomer of ketamine is devoid of genotoxic
properties.

In conclusion, available published data from genotoxicity testing of racemic
ketamine are insufficient and do not allow a reasonable assessment of the
genotoxic potential of ketamine. Whereas negative findings were obtained
in poorly conducted (compared to current standards) bacterial tests, a positive
result was reported from an SCE test in vitro. However, the effects
observed in the SCE study were only weak (i.e. less than a doubling of control
values) and thus the relevance of this finding is questionable. Moreover,
(unpublished) data from genotoxicity testing with the S(+) enantiomer of
ketamine in a standard battery of validated in vitro and in vivo tests did not
reveal any evidence of a genotoxic potential. Provided that the genotoxicity
findings with the S(+) enantiomer of ketamine can be extrapolated to the
racemate, it can be concluded that ketamine is highly unlikely to possess any
relevant genotoxic properties.

No data on the carcinogenic potential of ketamine are available.

Behavioural studies in animals

SELF-ADMINISTRATION

Animal models of addiction are used to test the induction of drug-taking
behaviour which might be similar to the recreational use of ketamine. To
date there are no animal models that incorporate all the elements of addiction.
The observation that animals readily self-administer drugs has led to the
argument of face-validity, and psychologically this is based on the reinforcing
properties of a compound. This animal model also has a high predictive
validity, although there are some limitations (Willner, 1997; Koob et al.,
1998).

Early assessments of the reinforcing properties of ketamine reported that rhesus
monkeys that had been shown to self-administer intravenously methamphetamine
or cocaine also self-administered ketamine (0.0032–1.6 mg/kg/inj)
under limited access conditions at an intense schedule of reinforcement
(fixed ratio 1; i.e. a reward is provided after pressing the lever a fixed number
of times). An inverted U-shaped dose-response curve was observed. A variation
of the fixed ratio to about FR128 (implying that the animals have to
make more effort to obtain their reward) produced an increase in the
response rate with a factor 3 (Moreton et al., 1977). Increasing the fixed ratio
in PCP administration, however, eliminated responding (Marquis and
Moreton, 1987), suggesting a higher intrinsic power of reinforcement for
ketamine, which might be more related to the depressant action of the drugs
than to the psychotomimetic action. In baboons, however, self-administration
was obtained at an FR160 schedule (Lukas et al., 1984) for both ketamine
and PCP, suggesting that the observed difference between ketamine and PCP
might be specific to rhesus monkeys. No obvious behavioural changes
occurred during exposure to doses of 0.010–0.032 mg/kg. A dose of PCP
10 times higher was associated with sedation and ataxia. Food intake was
unaffected by the lower doses.

From data on various species, it appears that drug intake tends to increase
slightly with increases in the unit dose in each species. However, the
increase does not generally occur with the self-administration of CNS
depressants such as pentobarbital and morphine (Marquis and Moreton,
1987).

DRUG DISCRIMINATION

The drug-discrimination paradigm has been developed as a way of enabling
animals to give an indication as to how a drug makes them ‘feel’. This
behavioural method offers the animal a choice, which is reinforced by pelleted
food if they choose correctly, depending on the treatment (drug, saline
or other drug). This drug-discrimination approach is a powerful means of
differentiating between the subjective feelings (referred to as the stimulus)
evoked by various drugs (e.g. between opiates and psychomotor stimulants).
It is well established that such drug-response data can be handled as pharmacological
data showing selectivity and sensitivity.

It is generally recognised that drug-discrimination paradigms can also be
used for non-addictive drugs. However, when carefully designed, such studies
will almost certainly be of value in the assessment of common subjective
states produced by drugs (Schuster and Johanson, 1988).

Drug-discrimination data from a series of stereoisomers of compounds generalising
to PCP or ketamine indicate that compounds exhibiting reinforcing
properties comparable to PCP share similar stimulus properties with this
pharmacological class (Shannon, 1981; Young et al., 1981).

TOLERANCE, DEPENDENCE AND WITHDRAWAL

A number of studies have demonstrated tolerance to the effects of ketamine
(White and Ryan, 1996). This type of acute tolerance is related to changes at
the site of action rather than any increase in the rate of metabolism, as it can
be shown to be induced after one injection, without changing the plasma
concentration.

Continuous intravenous infusion of PCP and ketamine at maximum tolerated
dosages in rats was used to demonstrate whether dependence could be
induced by these compounds. The animals were trained to lever press for
their daily food rations under an FR30 schedule of reinforcement.
Withdrawal of PCP as well as ketamine markedly reduced response rates,
providing evidence of dependence. When the compounds were readministered,
the rates increased rapidly to control rates, providing evidence of
reversal of withdrawal. Cross-dependence from ketamine to PCP was
described.

Observable withdrawal signs have been reported for rhesus monkeys with
unlimited access to ketamine self-administration. Rats chronically exposed
to ketamine exhibited subcortical withdrawal seizures without gross behavioural
manifestations for up to five days after self-administration was discontinued
(White and Ryan, 1996).

Clinical safety

Clinical experience

Ketamine is considered to be an anaesthetic with a good safety profile (Reich
and Silvay, 1989). Its major drawback, limiting its clinical use, is the occurrence
of emergence reactions. Emergence phenomena in patients awakening from
a ketamine narcosis have been described following early clinical experience,
and these include hallucinations, vivid dreams, floating sensations and
delirium. These symptoms were found to be reduced by concurrent use of
benzodiazepines (notably midazolam), putting the patient in a low stimulus
environment, and by providing information preoperatively on the possibility
of emergence reactions. These emergence phenomena appear to occur more
frequently in adults (30–50 %) than in children (5–15 %) (White and Ryan,
1996; Bergman, 1999). Engelhardt (1997), reviewing eight randomised studies
in volunteers and patients, addressed the impact of S-(+)-ketamine on recovery
from anaesthesia compared with racemic ketamine. With only one exception,
the recovery phase was clearly shorter after administration of S-(+)-ketamine
compared to racemic ketamine. However, the incidence of psychic emergence
reactions was lower after S-(+)-ketamine in only a single study.

Both severe respiratory depression and cardiodepressant effects have been
reported, but these adverse effects are rare with ketamine and can be managed
within the clinical setting.

Studies on street users

REPORTED FATALITIES

Table 1 presents an overview of reported deaths involving recreational use
of ketamine.

The circumstances of the death of Case 1 indicated that the victim probably
received around 1 g of ketamine intramuscularly, divided over several doses.
A long period of time may have elapsed between the first dose and the
victim’s death. The last dose was probably administered shortly before death.

Case 2 is another case of ketamine overdose, without the involvement of
other drugs. Case 3, a gunshot victim who was administered ketamine for
anaesthesia during surgery but died as a result of his injuries, was included
only for comparison of ketamine tissue values with Case 2. Blood ketamine
concentrations in Case 2 were only two to three times higher than those in
the gunshot victim. However, tissue concentrations showed that distribution
throughout the body had taken place in the overdose victim and that the
administered dose may have been much higher than an anaesthetic dose.
Based on these data and on circumstantial evidence, the case was ruled to be
caused by an accidental intravenous overdose of ketamine, possibly 900 mg.
Comparison of the data from Case 2 and Case 3 indicates that the presence
of the metabolite norketamine and the tissue distribution are important for
establishing whether a short or a long period of time elapsed between the
administration of the drug and death.

The presence of a number of empty Ketalar bottles and numerous punctures
in the elbow fold indicated that the deceased in Case 4, found dead with a
syringe in his arm, was a repeated intravenous user of ketamine. Tissue levels
indicated that the victim died due to an overdose. Blood, urine and bile concentrations
were not obtainable due to the advanced state of decomposition
of the victim. Pathology showed diffused lung oedema.

In Case 5, ketamine concentrations were low and may not have contributed
to the cause of death. In this case, apart from ketamine, a pharmaceutical
preparation for veterinary use was administered in which tiletamine, which
is another dissociative anaesthetic, is combined with zolazepam, a benzodiazepine.

In Case 6, the victim had been drinking with friends during the evening.
He died early in the morning. Ethanol, a CNS and respiratory depressant,
may have added to the respiratory depressant effect of ketamine and thus
have contributed to this (mixed-drug) fatality.

Case 7 concerns a polydrug addict who was abusing heroin, codeine, ketamine,
cocaine, benzodiazepine and barbiturates. The ketamine blood concentration
was in the anaesthetic range and this may have contributed to the cause of
death. However, the multitude of drugs used by this victim makes it impossible
to determine which drugs were major contributors. Both the respiratory
depressant effects of other substances, notably opioids, barbiturate and benzodiazepine,
and the cardiostimulant effects of cocaine may have exacerbated
the potentially deleterious side-effects of ketamine.

Case 8 was mentioned by Arditti (2000) and Cases 9 and 10 were referred to
in the Europol and EMCDDA joint progress report. However, no details were
provided, so the importance of the role of ketamine in these three deaths
cannot be evaluated. Finally, an Internet site for NIDA mentions three fatal
ketamine cases (Cases 11, 12 and 13 in Table 1), but, again, no details were
provided.

The following conclusions can be drawn from this survey.

 Only three reported fatal ketamine intoxications involving ketamine were
identified. In these cases the intramuscular or intravenous route was used.
Two reports concern mixed-drug fatalities. In one case, ketamine played
only a minor role. For the remaining six cases, insufficient details were
available for a proper evaluation.

 From the cases listed in Table 1, it can be learned that the ketamine blood
concentrations were usually in the anaesthetic range or above. Tissue distribution
data and norketamine concentrations give insight into the total
amount administered and the period of time that elapsed between the first
dose and death. Where clues (usually empty ketamine vials) about the
quantity administered were available, such indicators suggested amounts
of approximately 1 g administered intravenously or intramuscularly in the
absence of other substances. Based on a body weight of 60 kg, such a dose
is 4–17 times the recommended intravenous dose for anaesthesia or
1.3–2.5 times the recommended intramuscular dose for anaesthesia. The
intravenous data are in line with preclinical findings. In squirrel monkeys,
death occurred when ketamine was administered intravenously at a
dosage more than 10 times the dose that produces anaesthesia
(Greenstein, 1975). The relatively small margin of safety for the acute toxicity
that applies to the intramuscular route is unexplained. Based on clinical
experience and pharmacokinetic considerations, the acute toxicity is
lower using the intramuscular route than the intravenous route. It is possible
that the greater prevalence of this route of administration led to the
emergence of fatalities in individuals with increased susceptibility due to
premorbid conditions or deviant pharmacokinetics.

 The reported ketamine concentrations found in multiple drug users are lower
than those found in the few cases involving ketamine only. This indicates
that drug interactions may have contributed to these deaths. In this respect,
substances with CNS/respiratory depressant effects, like ethanol, opioids,
barbiturates and benzodiazepine, or substances with cardiostimulant
effects, like cocaine and amphetamine, are indicated as drugs that may
increase ketamine toxicity.

NON-FATAL INTOXICATION

The pharmacological action of ketamine may produce side-effects, many of
which have been reported by recreational users (Siegel, 1978; Dalgarno and
Shewan, 1996; Weiner et al., 2000). Ataxia, disorientation and anxiety are
the most frequent complaints, especially in first-time users. Other side-effects
were slurred speech, dizziness, blurred vision, palpitations, chest pain, vomiting
and insomnia. The most frequent finding in users that were given a
physical examination at an emergency department was tachycardia (Weiner
et al., 2000). Nystagmus was, unlike with PCP, rather infrequent in this group
of ketamine users. Complications such as hyperthermia, seizure or dysrythmia
were not encountered in Weiner’s study group, but two cases of rhabdomyolysis
were noted (Weiner et al., 2000).

In an overview presented by a French report on ketamine (Arditti, 2000), 19 cases
of non-fatal intoxication were mentioned that were registered by the CEIP
between 1991 and 2000. The majority were recorded during the last four
years. The most frequently observed adverse effects were neurobehavioural:
agitation, delirium, consciousness disturbances (e.g. loss of sense of danger,
sensation of floating, attempts to jump out of a window, amnesia, obsession)
and motor function impairment. Less frequently mentioned adverse effects
were anxiety, neuropathy of the Guillain-Barré type and physical effects such
as general stiffness, raised body temperature (38°C), rhabdomyolysis, hepatic
crisis, myalgia and mydriasis.

Felser and Orban (1982) have described a case of dystonic reaction after
self-administration of ketamine.

A case of hypertension and pulmonary oedema was triggered by ketamine
anaesthesia in an obstetric patient with a history of abusing multiple drugs
(Murphy, 1993). The role of ketamine in this case is not as a drug of abuse
but as an anaesthetic. This case shows that potentially dangerous interactions
may exist when different drugs of abuse are combined. The hypertension
was largely attributed to barbiturate withdrawal, and the use of cocaine
may have predisposed the patient to developing increased pulmonary capillary
hydrostatic pressure, thus causing pulmonary oedema. However, ketamine,
being a sympathomimetic agent, may have triggered the hypertension and
pulmonary oedema.

The following conclusions can be drawn.

 The main effects of non-fatal ketamine intoxication are neurobehavioural:
anxiety (especially in first-time users), agitation, changes of perception
(e.g. loss of sense of danger, visual disturbances) and impairment of motor
function. In such a condition the user will have severely impaired self-control,
which poses a risk of injury of him- or herself or others (e.g. when driving
in traffic).

 Common side-effects reported by users were slurred speech, dizziness,
blurred vision, palpitations, chest pain, vomiting and insomnia. The predominant
symptom found on physical examination of users that went to
an emergency department was tachycardia. Rhabdomyolysis was noted in
several cases. Other physical side-effects appear to be rare.

 Serious side-effects like hypertension and lung oedema have been reported.
Such adverse effects appear to be rare and may be related to the combination
of ketamine with other drugs of abuse.

EMERGENCY TREATMENT

In this section, the treatment of patients presenting to an emergency department
is considered.

The following advice is taken from Weiner et al. (2000):

‘Based on our experience, we offer the following treatment recommendations
for evaluating Emergency Department patients who present
after having abused ketamine. This diagnosis should be suspected
in patients (especially young patients) who present with agitation,
tachycardia, and either visual hallucinations or nystagmus. However,
the absence of the latter two findings does not rule out the possibility
of ketamine abuse. When laboratory confirmation of the diagnosis of
ketamine abuse is critical to the patient’s management (which is hardly
ever the case), one of the aforementioned tests can be used (GC/MS
or HPLC).’

‘Symptomatic patients are best managed with standard supportive
care, as the effects of the drug are usually short-lived. Keeping the
patient in a quiet environment, with a minimum of external stimuli,
may prevent excessive agitation. Benzodiazepines should be used for
sedation in agitated patients who are at risk for self-injury, hyperthermia,
and rhabdomyolysis. Intravenous fluids should be given to agitated
patients at a generous rate until laboratory testing has ruled out rhabdomyolysis.
Activated charcoal is not necessary after ketamine abuse
unless there is evidence that an oral coingestant may be contributing
to the patient’s symptoms. All patients must be observed until their
vital signs and mental status have normalised. Symptoms not improving
within 2 h of presentation should prompt a search for other drugs of
abuse or another disease process. The differential diagnosis of drug- or
toxin-induced hallucinations should include LSD, hallucinogenic
mushrooms, amphetamine, PCP, ketamine, cocaine, anticholinergic
drugs, and a variety of plants, especially morning glory, jimson weed,
and nutmeg.’

The advice given above is comprehensive, although the list of drugs mentioned
at the end for differential diagnosis may vary in time and from region
to region. Amphetamine analogues (e.g. MDMA, DOB) should be included.
Additionally, special attention should be paid to observation of respiratory
and cardiovascular functions. Respiratory depression and cardiovascular
pathology are ketamine-induced side-effects that are rarely serious when
ketamine is used solely, but which may be more serious when other drugs
are used as well. The phenomenon of multiple drug-taking is very prevalent
in patients presenting to emergency departments (Spaans et al., 1999).

DRUG INTERACTIONS

There are no known studies specifically addressing the problems of recreational
use of ketamine and concomitant abuse of other drugs. However,
preclinical data, data from fatal intoxication discussed above, clinical experience
with ketamine as an anaesthetic and general pharmacodynamic and pharmacokinetic
considerations do give some clues about possible interactions
between ketamine and other recreational substances. These will be discussed
below according to type of interaction.

CNS and/or respiratory depression: An early case report mentions severe
respiratory depression in a seven-year-old patient given a subanaesthetic
dose of ketamine (approximately 3.3 mg/kg i.m.) after premedication with
secobarbital (Kopman, 1972).

Opioids have a known respiratory depressant effect (Buck and Blumer, 1991)
and may therefore have an additive effect on the respiratory depression
induced by ketamine.

Ethanol, another respiratory depressant, has been implicated in a mixed-drug
fatality involving ethanol and ketamine (Moore et al., 1997).

Benzodiazepine is known to potentiate respiratory depressant agents.
Flunitrazepam (Rohypnol) is known to induce respiratory depression in
patients with chronic airway obstruction. Fatal cases associated solely with
flunitrazepam have been described. Therefore, it may be anticipated that the
combined use of flunitrazepam and ketamine may also increase the risk of
severe respiratory depression.

These examples show that respiratory depressants like ethanol, opioids, barbiturates
and benzodiazepine (flunitrazepam) may add to the respiratory
depression induced by ketamine and thus may provoke a dangerous interaction
between these substances. Furthermore, these substances are CNS
depressants as well and so may deepen or lengthen the ketamine-induced
anaesthetic state.

Sympathomimetic effects: Ketamine has sympathomimetic properties. Inhibition
of central catecholamine re-uptake and increased levels of circulating catecholamines
are believed to cause the cardiovascular stimulant effects. This
implies that ketamine may add to the sympathomimetic effects of others
drugs such as amphetamine and its analogues, ephedrine and cocaine.
Hypertension, tachycardia and lung oedema have been reported in a patient
receiving ketamine who appeared also to be abusing cocaine (amongst other
substances) (Murphy, 1993). However, barbiturate withdrawal may have
played a major role in this case (see the section, ‘Non-fatal intoxication’,
page 59).

On the other hand, cardiodepressant effects have been noted in critically ill
patients. This may be due to chronic catecholamine depletion inhibiting the
sympathomimetic effects of ketamine and unmasking a negative inotropic
effect which is usually overshadowed by sympathetic stimulation (Reich and
Silvay, 1989; White and Ryan, 1996). It may be hypothesised that drug users
bingeing on stimulatory drugs may provoke a degree of catecholamine
depletion. Therefore, the possibility of ketamine producing a cardiodepressant
effect cannot be excluded under such extreme conditions.

Mixed CNS effects: Benzodiazepines clinically are used to reduce the occurrence
of emergence phenomena (hallucinations, vivid dreams, etc.) associated
with ketamine anaesthesia (Haas and Harper, 1992). Krystal et al.
(1998) studied the interactive effects of subhypnotic doses of lorazepam and
subanaesthetic doses of ketamine. Lorazepam reduced ketamine-associated
emotional distress and there was also a non-significant tendency for it to
decrease any perceptual alterations induced by ketamine. However, it failed
to reduce many of the cognitive and behavioural effects of ketamine, including
psychosis. Furthermore, lorazepam exacerbated the sedative, attentionimpairing,
and amnesiac effects of ketamine.

Potential neurotoxicity: Olney and co-workers (1989, 1991) described how
neurotoxicity was induced in rats by the administration of ketamine (see the
section ‘Neurotoxicity’, page 44). If the postulated mechanism for such a
ketamine-induced neurotoxicity is applicable to the human recreational use
of ketamine, it may be anticipated that several substances from the recreational
drug repertoire might enhance such neurotoxicity: Amanita muscaria
mushrooms (muscarinic agonist), alcohol (NMDA- and (partial) GABAAantagonist),
yohimbine (α2-adrenergic receptor antagonist), and other dissociative
drugs (NMDA-antagonists) like PCP and tiletamine.

Pharmacokinetic interactions: Ketamine and its primary metabolite, norketamine,
are metabolised by enzymes from the cytochrome P450 (CYP) family.
However, in the absence of more detailed information on which CYPs are
involved and whether ketamine may induce or inhibit specific CYPs, it is not
yet possible to evaluate interactions at this level. This point demands further
attention in the future, especially since the possibility of involvement of
CYP3A4, an isozyme that is susceptible to this kind of interaction and that is
involved in the metabolism of medicines (e.g. protease inhibitors used in
HIV therapy), cannot be excluded.

Psychological risk assessment (cognition,
mood and mental functioning)

Acute effects

Studies investigating the pathophysiology of schizophrenia, using ketamine
as a model substance, and studies investigating the psychotropic effects of
ketamine in their own right have provided a good characterisation of the
psychotomimetic action of ketamine (e.g. Krystal et al., 1994; Hartvig et al.,
1995; Malhotra et al., 1996; Vollenweider et al., 1997, 2000; Bowdle et al.,
1998; Adler et al., 1999; Oranje et al., 2000). It appears that ketamine in
subanaesthetic doses induces a state of mind that both neurophysiologically
and behaviourally resembles that of schizophrenic psychosis. This may be
experienced by the experimental or recreational drug user as an altered,
‘psychedelic’, state of mind that allows him to travel beyond the boundaries
of ordinary existence.

Effects on cognitive functioning (neuropsychological assessment)

Ketamine acutely affects cognitive performance, including attention, working
memory and semantic memory.

In a double-blind randomised crossover study with five healthy volunteers,
Hartvig et al. (1995) showed, by means of a word recall test, that short-term
memory could be impaired dose-dependently by intravenous administration
of 0.1 and 0.2 mg/kg. Ketamine binding in the brain correlated well with the
regional distribution of NMDA-receptors.

Ketamine hydrochloride (0.1 or 0.5 mg/kg i.v. during 40 minutes) did not
have a significant effect on the mini-mental state examination (a brief bedside
evaluation of cognition) in healthy subjects (n = 18). However, tests of
vigilance, verbal fluency and the Wisconsin Card sorting test showed a dosedependent
impairment (Krystal et al., 1994). Delayed word recall was
reduced, but immediate and post-distraction recall were spared.

Malhotra et al. (1996) assessed the effects of ketamine (total dose 0.77 mg/kg
i.v. during 1 hour) on attention, free recall of category-related words and
recognition memory of category-related words. All three cognitive functions
showed significant decrements. Memory impairments were not accounted for
by the changes in the subjects’ attention and did not correlate to psychosis
ratings. In further studies, Adler et al. (1998) found that ketamine-induced
thought disorder significantly correlated with decrements in working memory
but did not correlate with ketamine-induced impairments in semantic memory.

Effects on emotional status, behavioural patterns and personality (psychological instruments, rating scales)

Ketamine profoundly affects perception of body, time, surroundings and
reality. A study on 10 psychiatrically healthy volunteers was performed by
Bowdle et al. (1998). The subjects were intravenously administered an escalating
dose of ketamine by infusion with plasma target concentration of
0.050, 0.100, 0.150 and 0.200 μg/ml. Each step was maintained for 20 minutes
and the subjects were asked to rate various aspects of their consciousness on
a visual analogue scale (VAS). A good correlation between the plasma ketamine
concentrations and the VAS ratings was obtained. The following VAS
scores were increased by ketamine, compared with a saline control.

Body: Body or body parts seemed to change their position or shape.
Surroundings: Surroundings seemed to change size, depth or shape.
Time: The passing of time was altered.
Reality: There were feelings of unreality.
Thoughts: There was difficulty controlling thoughts.
Colours: The intensity of colours changed.
Sound: The intensity of sound changed.
Voices: Unreal voices or sounds were heard.
Meaning: Subjects believed that events, objects or other people had particular
meaning that was specific to them.
High: They felt high.
Drowsy: They felt drowsy.
Anxious: They felt anxious.

The intensity of the effects was greatest for High, Reality, Time,
Surroundings, Thought and Sound. They were lowest for Anxiety and
Meaning. There was not a significant difference for Suspicious (subject felt
suspicious).

This study clearly shows that there is a dose–effect relationship between
ketamine dose and intensity of ‘psychedelic’ effects. The quality and type of
effects were exemplified in the following ways: ‘tingling sensation in the
limbs, followed by numbness’; ‘floating, very carefree feelings throughout
entire body’; ‘felt so different. Wasn’t able to describe the way I was feeling’;
‘floating in space’; ‘almost complete annihilation of physical self, shrunken’;
‘dizzy, shaky, light-headed’. One subject wrote the following: ‘The experience
seems to be a mystical experience, an incomprehensible comprehension of
the universe. There seemed to be no past, present or future, no time, just
existence. Life and death at the same time.’ All but one participant spontaneously
reported feelings of intoxication and perceptual distortion during
the ketamine infusion; one of these persons also reported these symptoms
during the placebo infusion. Three participants became moderately dysphoric
during the ketamine infusion, but none of them experienced dysphoria during
the placebo infusion. One participant developed a mildly paranoid state
characterised by multiple questions about the procedure and an intense
affect. Another volunteer, who had experienced emotional stress in the
recent past, experienced tearfulness, a sad mood and moderately intense
ruminations about recent stressful events.

Krystal et al. (1994) also included a VAS of mood states in their study of 18
healthy volunteers after intravenous administration of 0.1 or 0.5 mg/kg
ketamine hydrochloride for 40 minutes. They observed a biphasic effect on
Anxiety, the low dose decreasing anxiety and the high dose increasing anxiety.
The VAS rating for High was increased dose-dependently.

Hartvig et al. (1995) studied the psychotomimetic effect of low intravenous
doses (0.1 and 0.2 mg/kg) of ketamine in a double-blind randomised
crossover study in five healthy volunteers. All subjects having peak plasma
ketamine concentrations of 0.07 μg/ml or above or estimated peak regional
brain ketamine concentrations of 0.5 μg/ml or above experienced psychotomimetic
effects. These consisted of pronounced feelings of unreality,
altered perception of body image, sensations of impaired recognition of the
limbs, detachment from the body, and modulation in hearing, characterised
by preoccupation with unimportant sounds. The intensity of the effects
showed a dose–response relation with the degree of regional brain binding
of ketamine.

Vollenweider and co-workers (1997) investigated the differential effects of
S- and R-ketamine and found that S-ketamine is responsible for the psychotomimetic
effects, whereas R-ketamine induced a state of relaxation.
Results of a mood rating scale for S-ketamine showed increased scores for
‘deactivation’, ‘introversion’, negative and dysphoric feelings and anxiety.
All subjects reported distortion of body image, loosening of ego-boundaries
and alterations of sense of time and space, variously associated with emotional
changes such as euphoria (30 %), indifference (30 %) or heightened
anxiety (40 %).

In an open uncontrolled study (Hansen et al., 1988), seven individuals working
in health care (two psychiatrists, one psychiatrist in training, one anaesthesiologist,
one body therapist, one general practitioner and one medical student)
explored the psychotropic effects of ketamine for its use as a possible adjunct
in psychotherapy by intravenous, intramuscular and oral self-administration
of various subanaesthetic doses. They recorded that their inner experiences
were extremely intense and possessed of a subjective quality which made it
difficult to put them into writing. To a certain extent, their experiences varied
from subject to subject and, even for the same subject, from one session to
another. Nevertheless, all the subjects experienced most of the following
phenomena:

 a sensation of light throughout the body;

 novel experiences concerning ‘body consistency’ (e.g. being described as
made up of dry wood, foam rubber or plastic);

 grotesquely distorted shape or unreal size of body parts (e.g. extremely
large or small);

 a sensation of floating or hovering in a weightless condition in space;

 radiantly colourful visions (e.g. a sense of moving between rooms that are
filled with moving, glowing geometrical patterns and figures);

 complete absence of a sense of time (i.e. an experience of virtual timelessness
or eternity);

 periodic, sudden insight into the riddles of existence or of the self; occasionally,
an experience of compelling emotional consanguinity, at times
extending to sensations of melting together with someone or something in
the environment; and

 an experience of leaving the body (i.e. an out-of-body experience).

In nearly every instance, subjects retained the sense of a sober, witnessing ‘I’
that could both observe and consider as well as be amazed, overjoyed or
perhaps anxious, and that could, to a certain extent, later remember the
unusual phenomena. Music played an important role in their experiences
(synaesthesia), as exemplified by the following remarks:

‘... the music has substance, the music itself made up the very walls
in these endless rooms, it directed both upward and downward flight.’

‘... the music was very nearly material; it could be touched and felt,
as if it had been a sculpture.’

Other examples show that people under the influence of ketamine may have
experiences related to death or expanding consciousness:

‘... I am completely and irrevocably removed from my body and have
this experience: this is death, you will never return. All such reflection
ends, and I am floating out in space. I am in a timeless world filled
with a profusion of light, colour, warmth and joy.’

‘... it was clear that what I was experiencing was from beyond death
— I bounded from insight to insight.’

‘... it felt as if I rolled backward and upward out of my body. My consciousness
rose up in an amazing way, crested upward and spread out
into another dimension, which was ‘I’-less. I was there for only a short
time and went back to the normal dimension in the same way I had
come. The area in which I had been was hazy and lacked structure,
but I noticed that I could return again and learn to understand it and
to spread light into it.’

Effects on psychopathological status — psychiatric comorbidity

Studies in healthy volunteers given ketamine and schizophrenic patients
have shown that ketamine produces a clinical syndrome with aspects that
resemble key symptoms of schizophrenia.

Krystal et al. (1994) assessed four key positive and three key negative symptoms
of schizophrenia in healthy subjects after intravenous administration of
0.1 or 0.5 mg/kg ketamine hydrochloride for 40 minutes. The positive symptoms
were conceptual disorganisation, hallucinatory behaviour, suspiciousness
and unusual thought content. The negative symptoms were blunted affect,
emotional withdrawal and motor retardation. Ketamine produced a dosedependent
increase in scores for both positive and negative symptoms.

Similarly, scores for key symptoms of schizophrenia (conceptual disorganisation
and disorganised speech, unusual thought content, emotional withdrawal,
psychomotor retardation and blunted affect) were increased by
ketamine (Malhotra et al., 1996).

Adler and co-workers (1998, 1999) studied the effects of ketamine on
thought disorder and compared these effects with thought disorder in
patients with schizophrenia. They found similar scores for 19 of 20 items on
the ‘Scale for the assessment of thought, language and communication’.
Only the score for ‘perseveration’ was lower in schizophrenic patients.
However, after Bonferoni correction, this difference was no longer statistically
significant. A total dose of 0.56 mg/kg of ketamine over 125 minutes
was infused in healthy volunteers (n = 19) to obtain a pseudo steady state
plasma ketamine concentration of 0.134 μg/ml. Reduced processing negativity
and P300 amplitude, psychophysiological anomalies commonly
observed in schizophrenic patients, were recorded. However, no drug effect
on mismatch negativity, another parameter that is commonly reduced in
schizophrenic subjects, was found (Oranje et al., 2000).

Vollenweider and co-workers (2000) observed a negative correlation
between raclopride binding potency in the ventral striatum and S-ketamineinduced
euphoria and mania-like symptoms, suggesting a role for elevated
striatal dopamine levels in these positive symptoms.

Chronic effects

Effects on cognition, mood and mental functioning

Short-term exposure to ketamine appears not to induce any long-term
adverse effects on cognition, mood or personality. Long-term heavy use of
ketamine may be associated with persistant deficits in attention and recall.
However, such a condition has been documented only once in the literature.

CLINICAL STUDIES IN VOLUNTEERS

In a follow-up interview in a study by Krystal et al. (1994) of healthy volunteers
given ketamine hydrochloride (0.1 or 0.5 mg/kg), no subject had
lingering or recurrent physiological or psychological effects, such as nightmares,
flashbacks or perceptual alterations, following a test day.

The subjects in the study conducted by Hansen et al. (1988) did not report
long-term side-effects of any kind for up to three years following the
ketamine sessions.

Corssen et al. (1971) studied 30 volunteers from a prison population who
were given either ketamine or thiopentone or served as a control.
Psychological assessment was performed before and at one week, four
weeks and six months after drug administration. The study could not identify
a difference between the three groups.

STUDIES IN PATIENTS

Psychological changes were compared in 221 patients following ketamine
anaesthesia and patients receiving other anaesthetics. Psychometric tests
were applied repeatedly for more than one year (Albin et al., 1970). There
were no significant differences between groups in terms of mental performance,
hallucinations and behavioural factors.

Seven case reports of prolonged (from several weeks up to one year) psychic
phenomena after a single (or, in one case, dual) exposure were reviewed by
Steen and Michenfelder (1979). In one patient, serious effects persisted for
five days and in three others there were only minor disturbances for three
weeks. Severe congenital brain abnormalities were present in two patients.
One patient complained of hallucinations, ‘passing out spells’ and feelings
of unreality and hesitation. These symptoms could have been linked to a
single-dose exposure to ketamine one year earlier, but this seems unlikely.

STUDIES IN RECREATIONAL USERS

Siegel (1978) stated that subjects who reported long-term use of ketamine
sometimes complained of ‘flashbacks’, attention dysfunction and decreased
sociability. Positive effects on mood were mentioned as well, which reinforced
the drug use. However, standard psychometric tests did not reveal
personality changes. The subjects described were mostly polydrug users,
those snorting ketamine also using cocaine. Unlike the PCP group described
in the same paper, a tendency to transient psychosis was not noted.

Amongst 20 recreational drug users studied by Dalgarno and Shewan
(1996), lasting psychological effects were not reported. Eleven of them used
ketamine less than 10 times, eight used it between 10 and 20 times and only
one reported use on approximately 100 occasions. The last subject, who was
an experienced polydrug user, reported ‘a total loss of reality’ during a
month-long ketamine binge, after which he stopped using it completely
without major difficulties. He reported subsequently having very lucid
dreams similar in nature to the ketamine-induced state. These dreams lessened
in intensity and ceased completely within 7 to 10 days of the final ketamine
episode.

Jansen (1990) describes one case in which a subject had persistent impaired
recall and attention and a subtle visual anomaly after cessation of long-term,
high-dose ketamine use.

Psychological effects of drug-using careers

Dependence potential in humans

TOLERANCE

Tolerance to ketamine develops rapidly and can be high. The subject of one
case report related the history of his ketamine use. During the first two years,
his consumption developed from an occasional oral dose of 50 mg to 500 mg
four to five times a day. Switching to intramuscular injection, he was injecting
300–750 mg five to six times a day within a month. The tolerance dissipated
on stopping the habit, but redeveloped at the same rate (within a month)
after restarting intramuscular injections (Kamaya and Krishna, 1987).

ABSTINENCE SYMPTOMS
There is no evidence that ketamine causes an abstinence syndrome in
humans. The subject described in the case report by Kamaya and Krishna
(1987) found stopping the habit extremely difficult but never experienced a
withdrawal syndrome.

Of 20 recreational ketamine users described by Dalgarno and Shewan
(1996), 11 never experienced mental after-effects and eight never experienced
physical after-effects following a ketamine episode. Of those that did
experience mental after-effects, three reported a general feeling of wellbeing,
two had a desire for physical contact, two felt mildly depressed and
‘flat’ and two said they felt ‘dopey’ (like being under the influence of
cannabis). Of those that experienced physical after-effects, three reported a
general feeling of contentment and happiness, four said they felt mildly
‘hung over’ or drained, three experienced vomiting, one said he felt physically
and positively changed and one felt nauseous.

Jansen (2000b) states that an elevated mood after a ketamine binge is a common
experience, whereas a cocaine-like swing into depression is rare.
He suggests that high levels of norketamine can take days to subside, thereby
providing a ‘deflating cushion’. However, no evidence is provided for such
a theory. In rats, norketamine-induced anaesthesia and locomotor activity
are of shorter duration than when these effects are induced by ketamine.
Both ketamine and norketamine are rapidly cleared from blood and brain
(Leung and Baillie, 1986).

DRUG-SEEKING BEHAVIOUR AND ADDICTION

A distinction may be drawn between experimental (Ahmed and
Petchkowsky, 1980) and dependent ketamine use (Kamaya and Krishna,
1987; Hurt and Ritchie, 1994). In dependent users, use of the drug continues
despite increasingly apparent effects on their work or on their health. Of the
20 users described by Dalgarno and Shewan (1996), 7 had used ketamine
once or twice and only 3 had used it 15 times or more. One user in this
group reported that he had believed the experience was ‘never going to end’
and another experienced extreme dissociation. These two never repeated
their first-time use. It appears that this dissociative experience discourages
some experimental users. Another reason for limited use mentioned in this
study was the scarcity of the drug. On the other side of the spectrum, one
user in this study group said he believed he had been addicted to using
ketamine during his heaviest period of its use.

According to Jansen (2000b), tolerance to the effects of ketamine soon develops
and, with higher doses, the ability to remember the experience is sharply
reduced. Where many stop at this point, others carry on with compulsive
binges which result in cocaine-like stimulation, opiate-like calming,
cannabis-like imagery (which also disappears), alcohol-like intoxication,
and relief from anxiety, depression and mental craving (Jansen, 2000b).
Jansen states that repeated users of ketamine may rapidly become addicted.
This addictive side of ketamine (in the sense of psychological dependence)
may be more pronounced for those who persist in compulsive binges.
No reliable data on the prevalence of long-term use are available.

Three well-known ketamine histories are those of John Lilly (1978), Marcia
Moore (1978) and D.M. Turner (1994). The first was still using ketamine at
the age of 83, even though at some point in his life he had elected to be
hospitalised for ketamine withdrawal. The second, according to her husband,
Howard Altounian, became addicted and committed suicide. The third slipped
below the waterline in his bathtub, with a half-empty bottle of ketamine at
his side.

Psychological factors that increase the probability of harm

No systematic studies were found on personality traits or other psychological
factors which could lead to ketamine use or affect the probability of harm.

Jansen (2000b) describes several conditions that may motivate ketamine use.
Amongst these is a characteristic of the ketamine experience which may be
described as escape from reality. Few drugs offer such a powerful experience
of entering a different reality, which is experienced as no less real than
reality without the drug. This possibility for escape and discovery may
appeal to some individuals, especially those who are discontented with their
ordinary existence and are looking for meaning in their life. In this way, the
ketamine experience offers a psychological reward, which contributes to the
development of addiction.

For those interested in taking as much and as many drugs as possible, the
sensation-seeking factor will certainly be important (Laviola et al., 1999).
Ketamine, advertised as the ultimate psychedelic journey (Turner, 1994),
will appeal to drug users looking for extreme experiences.

Conclusions

 Ketamine has existed for 37 years and is a registered medicine in EU
Member States. It cannot be regarded as a new synthetic drug.

 Ketamine is in use in human and veterinary medicine as an anaesthetic
and analgesic agent.

 Ketamine is a dissociative anaesthetic. It binds to the PCP-site of the
NMDA-receptor, thus acting as a non-competitive NMDA-antagonist.
Ketamine enhances striatal dopaminergic activity.

 Therapeutic use of ketamine in humans is limited due to the occurrence of
emergence reactions (patients experiencing vivid dreams, hallucinations,
and disorientation when emerging from anaesthesia). Veterinary use of
ketamine is widespread in the EU and it would be difficult to replace it
with another drug.

 Administration of ketamine for recreational use is predominantly by the nasal
route, but it is also taken orally and by injection (usually intramuscular).

 Taken orally, the bioavailability of ketamine is low. However, the primary
metabolite, norketamine, still has one third of the pharmacological activity
of the parent compound.

 The main psychological effects are as follows:
— ketamine acutely affects cognitive performance, including attention,
working memory and semantic memory;
— it profoundly affects perception of body, time, surroundings and reality;
and
— it produces a clinical syndrome with effects that resemble key symptoms
of schizophrenia.

 The main risks associated with the recreational use of ketamine are as
follows.
— Ketamine has the potential to cause psychological dependence in
some individuals. Self-administration and generalisation to other compounds
of the PCP class in drug-discrimination tests have been
demonstrated in animals. There is evidence of physical dependence in
animals, but this is not severe. Cases of psychological dependence in
humans have been described. The prevalence is unknown.

— The acute psychological effects of ketamine may lead to loss of self
control and subsequently increase the risk of self-injury and accidents.

— Acute ketamine intoxication presents itself clinically with tachycardia,
agitation, hallucinations, anxiety, changes in perception of reality,
impaired motor function, rhabdomyolysis, slurred speech, dizziness,
blurred vision, palpitations, chest pain, vomiting and insomnia.
Not all of these symptoms need to be present. In serious cases, hypertension
and lung oedema have been observed. Several cases have
been described in which death was attributed to the recreational use
of ketamine, either alone or in combination with other substances.

— Preclinical data that may be relevant for the recreational ketamine
user are findings concerning neurotoxicity and reproductive toxicity.
However, to date there are no clinical data to support these findings.

 The following conditions, which increase the risks associated with the use
of ketamine, should be regarded as contraindications:

— psychiatric disorders;

— history of substance abuse; and

— cardiovascular pathology.

 Substances that result in pharmacological interactions with ketamine and
therefore increase the risks associated with the use of ketamine are:

— CNS and respiratory depressants; notably, ethanol, opioids, barbiturates
and benzodiazepines (flunitrazepam);

— sympathomimetic agents; notably, cocaine, amphetamine and its
congeners, and other substances causing inhibition of central catecholamine
re-uptake or increasing levels of circulating catecholamines

(7) This report was written by L.A.G.J.M. van Aerts and J.W. van der Laan of the Laboratory for
Medicines and Medical Devices, National Institute of Public Health and Environment, the Netherlands.
Valuable help and advice was contributed by Dr Peter Kasper of the Federal Institute for Drugs and
Medical Devices, Berlin, Germany.