CNS Drugs 2006; 20 (3): 199-218

REVIEW ARTICLE 1172-7047/06/0003-0199/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Ketamine
From Medicine to Misuse
Kim Wolff1 and Adam R. Winstock2
1 King’s College London National Addiction Centre, Institute of Psychiatry, London, England
2 South Western Sydney Area Health Service, Area Drug Health Services, Liverpool, New
South Wales, Australia

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
1. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
1.1 Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
1.2 Optical Isomers of Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
3. Medical Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
4. Research Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
5. Recreational Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
5.1 Ketamine and the Dance Scene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
5.2 Sought-After Effects of Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
5.3 Ketamine and Sexual Assault . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
5.4 Toxicological Testing for Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
6. Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
6.1 Long-Term Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
6.2 Tolerance and Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Abstract This review describes the medical, research and recreational uses of ketamine,
an anaesthetic derivative of phencyclidine that has dissociative, analgesic and
psychedelic properties. Ketamine has a complex mechanism of action that is
further complicated by stereoselectivity; however, antagonism of glutamate
NDMA receptors is thought to underlie its analgesic, dissociative and neuropro-
tective effects.
While ketamine use in medical and veterinary settings is well documented and
has a good safety record, the increase in its unregulated use outside of such
controlled environments is a cause for concern. The impact on higher centres in
the brain, particularly altered perception of auditory, visual and painful stimuli,
results in a general lack of responsive awareness that puts the recreational user at
(often unrecognised) risk of personal harm. The perceptual and mood changes
observed in those who have consumed ketamine are highly sensitive to age, dose,
route of administration, previous experience and setting. At low doses, stimulant
effects predominate and the effect of environmental conditions are significant;
with higher doses, psychedelic effects predominate and the effect of the environ-
ment diminishes.
200 Wolff & Winstock

The potential of ketamine as a novel clinical and research tool is matched by its
abuse potential outside medical settings.

Ketamine (2-[2-chlorophenyl]-2-[methylamino]- In this article we review the medical, research

cyclohexanone) is an anaesthetic derivative of
phencyclidine (1-[1-phenylcyclohexyl] piperidine;
PCP; ‘Angel dust’) with dissociative, analgesic and
psychedelic properties. As an arylhexylalkyamine, it
is also related to dizocilpine (MK 801) and
tiletamine. Parke Davis Laboratories developed
ketamine in 1962 after worries about the range of
aggressive behavioural problems and adverse psy-
chological reactions associated with its earlier prod-
uct, phencyclidine.[1] Ketamine is also known as
Ketofen™ 1, Ketalar®, Ketanest®, Ketaset®,
Ketaject®, Ketamine 500® (manufactured by As-
trapin, Pfaffen-Schwabenhiem, Germany) and
Imalgen® (manufactured by Merial, Lyon, France).
Not surprisingly, phencyclidine and ketamine
have similar properties; the main difference is the
shorter half-life of ketamine and its less problematic
‘emergence phenomena’ 2. Despite its unusual
clinical effect and multifaceted mechanism of ac-
tion, ketamine has found its place within several
areas of medicine, including paediatric analgesia
and anaesthesia, emergency anaesthesia, obstetrics
and on the battlefield.[2]
However, while ketamine, which has been de-
scribed as the ‘ultimate psychedelic’,[3] has a good
safety record within clinical settings, the increase in
its unregulated use outside such controlled environ-
ments is a cause for concern. In the UK, ketamine is
not currently controlled under the Misuse of Drugs
Act. It is possible that the British Home Office may
consider rescheduling, but this is usually a pro-
longed process. However, possession of ketamine is
illegal without a prescription. Ketamine was made a
controlled drug (Schedule III) in the US in 1999.
and recreational (particularly within the dance
scene) uses of ketamine, its pharmacodynamics,
pharmacokinetics and adverse effects.
1. Pharmacodynamics
Ketamine is almost unique as an anaesthetic in its
ability to produce a dissociative state. This term was
first phrased by Domino et al.[4] in 1965 to describe
the mental state produced by anaesthetic action with
sympathomimetic properties and cerebral dissocia-
tive actions. Such action results in higher centres in
the brain being prevented from perceiving auditory,
visual or painful stimuli, leading to ‘a lack of re-
sponsive awareness’. The effects of ketamine have
been likened to sensory deprivation, dreamlike vi-
sion, a sense of isolation and often the feeling that
the ‘self’ has been separated from the body.[5]
The loss of contact with ordinary reality and the
sense of participation in another reality are more
pronounced than is usually the case with LSD
(lysergide).[6] Prolonged and frequent use of
ketamine can induce psychotic reactions and a grad-
ual loss of contact with the every-day world.[7]
Ketamine is not alone in this respect and the psycho-
logical effects of the common general anaesthetics
(ether, chloroform and nitrous oxide [NO]) all pro-
duce experiences that could be described as
psychedelic.[8] Overall, the ketamine effect has been
described as a somatesthetic sensory blockade with
amnesia and analgesia.[4]
As described in section 1.1, it is an action at
glutamate NMDA receptors that underlies the anal-
gesic, dissociative and neuroprotective qualities of
ketamine.[9] NO also produces dissociative anaes-
thesia due to NMDA receptor blockade.[9] There is a

1 The use of trade names is for product identification purposes only and does not imply endorsement.
2 ‘Emergence phenomena’ is the term used to describe recovery (waking up) from anaesthesia following the
administration of a drug. In the case of ketamine, the emergence phenomena involve psychological manifestations,
which vary in severity from pleasant dream-like states to vivid imagery to hallucinations and emergence delirium. In
some cases, these states are accompanied by confusion, excitement and irrational behaviour.

© 2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine 201

Table I. Clinical physiological effects of ketamine[14,15]

System Physiological effects
Cardiovascular Tachycardia, increased pulse, hypertension
Gastrointestinal Anorexia, nausea, vomiting, hypersalivation, increased tracheobronchial secretions
Ocular Nystagmus, diplopia, lacrimation, dilatation, increased intraocular pressure, blurred vision
Musculoskeletal Myoclonus, twitching, vocalisation, fasciculations, hypertonicity, spasms, paresis, ataxia, convulsions
Other Skin rash, analgesia, hypersensitivity to sound or light, amnesia, pyrexia

growing body of research that indicates that alcohol
also acts in this way, blocking the effects of gluta-
mate at the NMDA receptor in a noncompetitive and
concentration-dependent fashion; blockade occurs
across the range of alcohol concentrations associ-
ated with human alcohol intoxication (5–100
mmol/L).[10]
Unlike inhalational agents and narcotics, which
suppress the reticular activating system, ketamine
induces a functional and electrophysiological disso-
ciation between the thalamo-neocortical and limbic
systems. The ensuing prevention of the higher cen-
tres from perceiving auditory, visual and/or painful
stimuli is potentially hazardous outside clinical set-
tings. There is great risk of injuries being masked
and the risk of accidents increased.[8]
With doses of ketamine that are adequate to bring
about anaesthesia, a trance-like cataleptic state with
amnesia is produced, without impairment of laryn-
geal and pharyngeal reflexes or depression of respi-
ration or cardiac function.[8] Typically, the eyes tend
to remain open with a disconnected stare and nys-
tagmus is usually observed; the recreational drug
user may appear to be awake but is dissociated from
the environment, immobile and unresponsive to pain
(table I). Ketamine also produces analgesic effects
and is remarkable in being able to produce potent
analgesia at sub-anaesthetic concentrations.[11]
Problematic emergence phenomena and other un-
pleasant experiences have been reported in an early
study of young adolescents.[11] However, recent evi-
dence suggests no serious psychic recovery reac-
tions in young adults aged 15–21 years.[12] Within
clinical settings, anaesthesia is usually induced
within 30 seconds and 4 minutes following intrave-
nous and intramuscular induction doses, respective-
ly.[13] However, anaesthesia is short-lived and per-
sists for only 5–10 minutes, requiring frequent re-
administration through an infusion to maintain the
clinical effect.[13]
One-off sub-anaesthetic doses of ketamine have
led to disrupted attentional performance and im-
paired performance on tests of vigilance, recogni-
tion memory, verbal fluency, working memory, and
episodic memory (a deficit seen in schizophrenia)
[table II]. On tests of higher executive function, such
as the Wisconsin Card Sorting Test, ketamine use
leads to an increase in perseverative errors and pref-
erentially disrupts delayed word recall, sparing im-
mediate recall and post-distraction recall.[10,16,17] In-
deed, the acute amnesic effects can be so marked
that they can make it difficult for subjects to de-

Table II. Clinical psychopathological effects of ketamine[2,17-19,21]

Category Effects
Emergence phenomena Vivid dreams and/or imagery, hallucinations, delirium, floating sensations, extra corporeal experiences,
‘weird trips’, misperception of visual stimuli, auditory misperception, synaesthesia, temporal and
spatial disorder, body detachment, dissociative state, sensation of being separated from environment
and/or body and enhanced colour vision
Cognitive Concrete thinking, impaired episodic memory, deficit prepulse inhibition, reduced verbal recall,
reduced attentional performance, impaired performance on tests of vigilance, acute amnesic effects,
poor recognition memory (verbal), inhibition of long-term potentiation, impaired verbal fluency and
perseveration
Psychotic Emotional withdrawal, lack of interest, disorganised speech, blunted affect, formal thought disorder,
paranoid ideation, lack of responsive awareness, ideas of reference, time delusion, mistrust, raised
suspiciousness and unusual thought content

© 2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (3)
202
scribe their experience to researchers attempting to
record the episode.[18] Dysfunction seen in episodic
memory (personal life event) is of particular note,
since it is highly correlated with everyday memory
difficulties.[11,19,20]
The perceptual and mood changes observed in
those who have used ketamine recreationally are, as
with other effects, highly sensitive to age, dose,
route, previous experience (expectations, personali-
ty, motivation and mood) and setting (social, physi-
cal and emotional environment).[22,23] At low doses
of ketamine, stimulant effects predominate and en-
vironmental conditions are significant. With higher
doses, psychedelic effects become the primary expe-
rience and the effect of the environment diminishes.
Auditory hallucinations are fairly rare following
ketamine use and have been reported much less
consistently.[24]
While psychedelic effects may be dose-related,
idiosyncratic adverse responses can occur at low
doses. Some recreational users report taking issues
of set (who) and setting (where) into careful consid-
eration prior to using ketamine.[25] Such preparation
cannot be performed if the drug is consumed unwit-
tingly when it has been marketed under the guise of
another drug, such as ‘ecstasy’ (methylene-
dioxymetamfetamine).[26,27] The range of exper-
iences for ketamine used in non-medical circum-
stances may be perceived quite differently (bizarre,
intense, extreme or vivid imagery) by different indi-
viduals. Expectation of effect and the individual’s
personality are thought to exert a significant influ-
ence upon the experience, though predicting prone-
ness to such unpleasant/undesired experiences with
ketamine is difficult, particularly in hidden popula-
tions (clubbers).
1.1 Mechanisms of Action
It has been established that the distinctive effects
of ketamine are due to antagonism of the NMDA
receptor.[28] Ketamine blocks, with low affinity, the
NMDA multimeric receptor complex.[28] It is also
well established that ketamine has effects on opioid
receptors at central and spinal sites and nora-
drenaline (norepinephrine), serotonin and muscarin-
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
ic cholinergic receptors elsewhere.[29,30] It also has
multiple actions at numerous other receptor sites,
particularly those affecting glutamatergic and
monoaminergic neurotransmission, and there is
growing evidence to substantiate the role of such
receptor activity in the clinical effects of
ketamine.[31] Ketamine has also been found to sig-
nificantly inhibit the uptake of noradrenaline,
dopamine and serotonin in a dose-dependent fashion
in human embryonic kidney cells.[32] It has been
postulated that the psychotomimetic and sympatho-
mimetic effects are thus mediated through this en-
hancement of monoaminergic neurotransmission in
the brain.[32]
The most significant pharmacological action of
ketamine is its non-competitive antagonistic binding
at the cation channel of the NMDA receptor and its
consequent interference with the excitatory amino
acid transmitters, glutamate and aspartate.[33-36] Ac-
tion at the NMDA receptor is considered to underlie
the analgesic and dissociative effects of ketamine
and to have important effects on memory. Early
work postulated that antagonism of the NMDA re-
ceptor would disrupt long-term potentiation and
synaptic growth, which are crucial in the develop-
ment of synaptic plasticity, learning and memo-
ry.[37-39] However, a recent study investigating the
effects of subdissociative doses of ketamine on ex-
ecutive processes during a working memory task
found a highly specific task pattern of impair-
ment.[40] Impairments were restricted to a subgroup
of verbal working memory tasks (the manipulation
of information within working memory). The pro-
cess-specific effect of ketamine did not affect visio-
spatial working memory. This specificity of effect
suggests that the earliest effect of NMDA receptor
blockade is on higher order control of executive
function rather than on more basic maintenance
processes. More study in this area would be useful.
Clinical studies also implicate glutamate in the
mediation of the dissociative symptoms induced by
ketamine, with acute administration leading to a
transient hyperglutaminergic state.[41] Indeed, the
pre-administration of drugs that reduce glutamate
release partly negate the perceptual disturbances
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
seen with ketamine,[42] which can, in turn, be re-
versed by the administration of glutamate. Addition-
al evidence supporting the significant role of gluta-
mate in the clinical effects of the drug comes from
preclinical data. This suggests that ketamine may, in
part, produce psychotomimetic effects through an
increase in glutamate release that, in turn, acts on the
AMPA subtype of glutamate receptor in the
prefrontal cortex to induce a hyperdopaminergic
state.[43]
Additionally, ketamine binds to opioid α-recep-
tors and μ-receptors but with only 10% and 20% of
its NMDA receptor affinity, respectively.[44] There-
fore, the opioid receptor antagonist naloxone has
only a limited capacity to reverse the effects of
ketamine and could not reverse key effects in
vivo.[45] Ketamine has a modulating effect on opioid
receptors, thought to be responsible for its analgesic
and dysphonic effects. In animal models, ketamine
and other NMDA antagonists, such as methadone,
have been demonstrated to inhibit the development
and acquisition of opioid dependence and toler-
ance,[46] while small doses of ketamine have been
shown to prevent tolerance developing acutely on
repeated administration of the potent, short-acting
opioid, alfentanil.[47,48]
1.2 Optical Isomers of Ketamine
In clinical use, ketamine is a racemic mixture of
two optical isomers (enantiomers), S-(+)-ketamine
and R-(–)-ketamine.[14] There appears to be some
clinically relevant stereo selectivity regarding the
effects of the drug, with S-(+)-ketamine being 2-fold
more potent as an analgesic and hypnotic than the
racemic mixture.[49] The stereo-specific binding of
S-(+)-ketamine to opioid receptors in vitro appears
to be associated with a more rapid emergence from
anaesthesia and a lower incidence of emergence
sequelae compared to the racemic mixture.[50]
More rapid recovery of psychomotor skills after
anaesthesia has also been reported with S-(+)-
ketamine than with R-(–)-ketamine.[51] The anaes-
thetic potency of S-(+)-ketamine was found to be 3-
fold higher than that of R-(–)-ketamine.[52] Its higher
anaesthetic potency and minor psychotomimetic ad-
© 2006 Adis Data Information BV. All rights reserved.
203
verse effects suggest S-(+)-ketamine has a better
therapeutic efficacy compared to the racemic
form.[2] In healthy young volunteers, endocrine and
cardiovascular parameters of racemic and S-(+)-
ketamine were similar, but S-(+)-ketamine offered
clear advantages as an anaesthetic, with significant
improvement in recovery time and a reduced quanti-
tative drug load.[5]
There is also evidence that S-(+)-ketamine offers
up to 50% better performance in terms of faster
recovery of cognitive performance, greater accept-
ance by healthy volunteers and identical depth of
anaesthesia after injection, compared with racemic
ketamine.[53] In some human studies, S-(+)-ketamine
was reported to produce the desired anaesthetic ef-
fects and R-(–)-ketamine the undesired emergence
reactions.[13] However, when given as a single bolus,
a bolus followed by continuous infusion or an intra-
muscular injection, the incidence of perceptual
emergence reactions was pronounced with S-(+)-
ketamine.[50,51] It appears that subanaesthetic doses
of S-(+)-ketamine produce distortion of the body
image, loosening of ego boundaries and alterations
of the sense of time and space, which are associated
with emotional changes including heightened feel-
ings of euphoria, indifference and anxiety.[54] This
has lead to the recommendation that S-(+)-ketamine
should always be combined with a hypnotic or seda-
tive drug in clinical anaesthesia.[55]
In rat corticostriatal slices, it was observed that
the neuroprotective effect of ketamine was both
region- and isomer-dependent.[56] That is, both the
striatal and cortical areas of the brain were sensitive
to the neuroprotective effect of ketamine. Similarly,
the (+) and (–) enantiomers of ketamine attenuated
the loss of metabolic activity in the striatum, but
only S-(+)-ketamine was neuroprotective in the cor-
tex.[56]
It is known that pharmacological differences ex-
ist between the enantiomers of ketamine with re-
spect to several targets (transporter proteins) of the
drug.[57] Recently, it has been shown that the relative
potency of subanaesthetic doses of the S-(+)- and R-
(–)-ketamine enantiomers parallels their relative af-
finity at the NMDA receptor complex[58] and their
CNS Drugs 2006; 20 (3)
204
Table III. Affinity of ketamine enantiomers for various receptors[30]
Receptor
NMDA
Opioid μ
Opioid κ
Opioid δ
Opioid σ
Muscarinic acetylcholine
Dopamine transporter
Noradrenaline (norepinephrine) transporter
Serotonin transporter
a High affinity for the site.
Ki = inhibition constant.
relative potency to block NMDA-mediated neuro-
transmission in animal studies.[59] In particular, it
was found that S-(+)-ketamine binds to the
phencyclidine binding site of the NMDA receptor
complex in human brain with a 4- to 5-fold higher
affinity than R-(–)-ketamine.[54] It was also found
that subanaesthetic doses of racemic ketamine have
a weak affinity for σ-receptor sites, whereas S-(+)-
ketamine binds only negligibly.[58] On the other
hand, the R-isomer exhibits a higher affinity for σ-
receptors[54] and muscarinic receptors[60] than S-(+)-
ketamine. The molecular interactions of S-(+)-
ketamine and R-(–)-ketamine with their various
targets are summarised in table III.
It has been speculated that the psychotomimetic
effects result from binding to the σ-receptor site.
Since R-(–)-ketamine has a higher affinity for this
receptor than S-(+)-ketamine, it would be thought
that the R-isomer would be associated with a higher
incidence of hallucinations. However, studies with
S-(+)-ketamine in healthy volunteers indicate that S-
(+)-ketamine is more likely to have hallucinogenic
effects that R-(–)-ketamine.[61] This finding is con-
ducive with the much higher affinity of S-(+)-
ketamine for the NMDA receptor (table III). Since
psychotomimetic effects are generally considered to
be caused by a relative excess of dopamine, it is
possible that the stereo-selective inhibition of
dopamine reuptake might also add to ketamine-
induced psychotomimetic effects. However, the in-
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
Ki (μmol/L)
S-(+)-ketamine R-(–)-ketamine
0.9a 2.5a
28.6a 83.8
23.7a 60.0
205.0 286.0
131.0 19.0a
125.0 91.0
46.9a 390.0
64.8 68.9
156.0 148.0
ability of haloperidol to block these effects suggests
that other transmitters are involved.[58] Haloperidol
pretreatment reduced impairments in executive cog-
nitive functions produced by ketamine, but failed to
block the capacity of ketamine to produce psycho-
sis, perceptual changes, negative symptoms or eu-
phoria in healthy adults. These findings suggest that
the effects of ketamine are functionally modulated
by dopamine D2 receptors and other sites at which
haloperidol has effects. The over-stimulation of
noradrenergic and serotonergic pathways by R-(–)-
ketamine might contribute to the adverse effects
observed as a result of ketamine-induced overdose
in those who use the drug at raves (dance parties) or
for other non-medical purposes.
As stated previously, commercial preparations of
ketamine are most commonly a racemic mixture, in
equal amounts, of its enantiomers. Illicit manufac-
ture of ketamine is almost unknown, because it is
very difficult to synthesise, so misappropriated le-
gitimate pharmaceutical sources most commonly
supply recreational users. For example, ketamine
has been reported to be smuggled into North
America from Mexico and India.[50] Furthermore,
ketamine is not a controlled substance in many
countries (e.g. Germany [S-(+)-ketamine] and The
Netherlands, where it can be purchased legitimate-
ly). It is, therefore, highly probable that recreational
users administer a racemic mixture.
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
2. Pharmacokinetics
Ketamine may be effectively administered by a
number of routes including oral, intranasal, intrave-
nous, subcutaneous, intramuscular and intrathecal,
all of which permit adequate absorption and excel-
lent bioavailability.[62] Reports of clinical use via the
rectal[63] and transdermal[64] routes have also been
described. Such a plethora of potential routes of
administration of ketamine is of concern when as-
sessing its abuse potential, as uncomplicated and
innocuous modes of delivery may favour non-medi-
cal use.
Ketamine has a short half-life that is dependent
upon the route of administration, but is generally
1–3 hours.[65] Most of the parent drug is metabolised
via N-demethylation by the cytochrome P450 en-
zyme CYP2B6, and eliminated from the body with-
in 24 hours, although prolonged effects, due to the
presence of active metabolites, may occur.[66,67] The
majority of a ketamine dose is excreted in the form
of hydroxylated and conjugated metabolites, mainly
norketamine and dehydronorketamine.[68] Less than
4% appears in urine as the parent compound. The
duration of action of ketamine is not affected by
decreased renal function.[2]
Ingested ketamine is poorly absorbed, and
bioavailability may be as low as 16%.[69] Plasma
concentrations are detected about 30 minutes after
administration.[69] Peak plasma concentrations after
ingestion occur more slowly than and are only 20%
of that observed with equivalent doses administered
intramuscularly.[2] Additionally, with oral adminis-
tration, first pass metabolism of ketamine results in a
2-fold higher concentration of norketamine than is
observed following intramuscular administration.[70]
Norketamine is pharmacologically active with an-
aesthetic potency approaching one-third that of the
parent compound. Hence, although the onset of ef-
fects following ingestion may be somewhat slower
than with parenteral administration, the duration of
the effects may be longer.[70,71] A further factor that
should be taken into account is the variability of
digestive absorption of ketamine between individu-
als, which in some cases may lead to poor quality of
© 2006 Adis Data Information BV. All rights reserved.
205
anaesthesia and adverse effects, such as vomiting
and hallucinations.[71]
Intravenous administration of ketamine, as ex-
pected, produces a rapid onset of action (within 30
seconds). Ketamine is rapidly distributed to highly
perfused tissues, such as the brain, heart and lungs.
Intramuscular administration of ketamine produces
similar effects, being well absorbed, with a bioavai-
lability of up to 90%.[72] Intranasal use of ketamine
is common amongst recreational users, and this
route is likely to be associated with a rapid onset of
action, with an estimated duration of action of 2–3
hours.[73] However, the bioavailability of ketamine
has been reported to be poor (45%) when adminis-
tered via a nasal spray and even lower following
administration via sublingual tablets.[74]
3. Medical Uses
Ketamine is used selectively in both European
and American hospitals in a variety of procedures in
paediatric, obstetric and geriatric patients to provide
a range of functions, from analgesia for minor pro-
cedures, such as bone marrow aspiration, to opera-
tive analgesia and use in intensive care units.[2]
Within adult medicine, it has been used to augment
opiate-induced analgesia, preventing the develop-
ment of tolerance and dose escalation[47] and is
effective transdermally and intra-articularly.[75]
Doses for intravenous analgesia are <1 mg/kg, with
oral doses being much higher (100–300mg). Anaes-
thesia is achieved at doses of 5–10 mg/kg, though in
such cases it is often combined with benzodi-
azepines to reduce cardiovascular stimulation and
emergence phenomena. Dissociation occurs at doses
as low as 50–100mg.[2,73,76]
This novel range of effects has allowed ketamine
to be used in entrapment situations,[77] high altitude
anaesthesia,[78] war zones and natural disaster
zones.[14,79] Potential new uses are continually being
explored; recently ketamine was found to be useful
in reducing prolonged aura in some patients with
migraine,[80] in controlling status epilepticus[81] and,
perhaps more surprisingly, in the treatment of major
depression.[82] It was also found to be useful in the
management of neuropathic and cancer pain,[29,83]
CNS Drugs 2006; 20 (3)
206
although a review of ketamine in chronic pain man-
agement reported that the evidence for its efficacy
was moderate-to-weak.[84] It has been regarded by
some as the anaesthetic agent of choice in several
specific clinical conditions, for example in children
undergoing radiotherapeutic procedures and for re-
peated anaesthesia in difficult circumstances, such
as patients with burns.[85] Additionally, a major ben-
efit of ketamine use is that it is one of the rare
anaesthetic agents that does not cause hypotension;
this benefit is used to best advantage in emergency
departments in treating patients with serious trauma
and hypovoleamic shock.[82]
In a qualitative Iranian study,[86] ketamine was
investigated for its ‘releasing’ effect on 100 patients
with neurotic and psychosomatic symptoms. The
majority of patients reportedly reacted with symp-
toms of regression, introversion and emotional in-
stability, and subsequent psychotherapy proceeded
more easily. Ketamine has also been used in combi-
nation with psychotherapy with the explicit aim of
making use of its psychedelic effects. The
‘psychedelic therapy’ of ketamine has been used in
Russia with purported success for >10 years.[22]
Ketamine was reported[87,88] to enhance psychother-
apy in the treatment of alcohol dependence by ena-
bling subjects to become emotionally aware of their
alcohol dependence, resulting in the “harmonisation
of personality and changes in life values, spirituality
and purpose, with these values favouring a sober
lifestyle”.[87] More recently, ketamine-enhanced
psychotherapy has been used for heroin addiction.
High dose intramuscular ketamine (2.0 mg/kg) re-
portedly reduced craving and achieved longer peri-
ods of abstinence than low doses of the drug.[89]
As well as having clinical utility in humans,
ketamine is also widely used in veterinary practice,
especially where large animals may be uncoopera-
tive and may require the administration of sedation
at a distance (e.g. free-ranging giraffes and goril-
las).[90-92]
4. Research Uses
The psychotogenic and cognitive effects of
ketamine have led to the drug being used as a
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
pharmacological model for studying transitory
schizophrenic-thought disorder in healthy sub-
jects.[21] Given to healthy volunteers, subanaesthetic
doses of ketamine result in a range of positive and
negative schizophrenic-like symptoms,[17,93] as well
as perceptual disturbances similar to those found in
dissociative states.[16] This has led to the so-called
‘NMDA hypothesis’ of schizophrenia,[94] which has
been a subject of debate for >25 years.[95] Reports
suggest that diminished glutaminergic neurotrans-
mission may contribute to the dysfunction seen in
schizophrenia, especially positive symptoms,[96]
through modulation of the dopaminergic sys-
tem.[97,98]
Furthermore, in stable patients with schizophre-
nia, ketamine administration has been demonstrated
to provoke a relapse of acute positive symptomatol-
ogy.[99] Recent positron emission tomography (PET)
studies of induced psychotic states in human volun-
teers suggest that the pre-frontal cortex may be
involved in mediating the psychotogenic capacity of
NMDA antagonists, as they demonstrate a relation-
ship between ketamine-induced increases in pre-
frontal metabolic activity and conceptual organisa-
tion.[99]
Other PET studies have demonstrated the signifi-
cant role of dopamine in mediating the psychoactive
effect of ketamine. Using healthy volunteers, some
studies have demonstrated that ketamine leads to an
increase in dopamine levels in the ventral striata,[97]
which correlates well with heightened mood. Other
studies have demonstrated an increase in nucleus
accumbens dopaminergic activity.[100] The release of
dopamine within the ventrotegmental dopaminergic
pathway (the ‘reward circuit’) is considered as cen-
tral in the mediation of dependence and is seen with
most drugs of abuse.[65] Preclinical studies in rats
suggest that receptors other than dopamine D2 are
involved in the mediation of the effect of ketamine,
with clozapine, but not haloperidol or risperidone,
blocking the metabolic activity of ketamine in the
brain.[58] High doses of olanzapine, however, are
known to achieve inhibition of the metabolic effects
of ketamine.[101]
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
Ketamine is also useful as a research probe in
studies of the modulation of opioid neurobiology,
where it has been found to attenuate the develop-
ment of tolerance to opioids.[102] Co-treatment with
NMDA receptor antagonists, such as ketamine, has
been shown to dramatically suppress the morphine-
induced rewarding effect of the mesolimbic
dopaminergic pathway projecting from the ventral
tegmental area to the nucleus accumbens.[103]
Ketamine has also been found to suppress morphine
withdrawal in experimental settings (e.g. in a
preclinical study in rats).[104] In addition, Krystal et
al.[10] reported that the production of ethanol-like
subjective effects by ketamine supports the potential
clinical importance of NMDA receptor antagonism
among the mechanisms underlying the subjective
effects of ethanol in humans.
NMDA receptor antagonists, including ketamine,
appear to protect neurons against toxic assault such
as ischaemia through the inhibition of calcium in-
flux[105,106] and in certain clinical situations may be
neuroprotective, as in the case of dopaminergic
metamfetamine toxicity.[107]
The use of ketamine as a research tool to study
the pathophysiology of psychosis and as a screen to
evaluate new drug action[95,108] has raised concerns
in terms of possible distress inflicted on patients.
The potential for adverse effects and the serious
long-term effects that might be induced by the
symptom-stimulating action of ketamine have led to
the view that its use for this purpose is unethical.
This has led to several review papers that address the
question of prolonged psychological effects as a
result of the administration of ketamine in the gener-
al population[109,110] and in North American institu-
tions; these reviews concluded that there was no
evidence for long-lasting events nor increased dis-
tress.[95] Lahti et al.,[111] concluded that in controlled
environments, in which there is a high regard for
subject safety, ketamine as an investigative probe
caused no adverse long-term (9-month follow up)
events. Work is urgently required in areas where
ketamine is used in uncontrolled environments.
© 2006 Adis Data Information BV. All rights reserved.
207
5. Recreational Uses
The recreational use of ketamine was first report-
ed in 1971 in North America,[112] although Jansen[62]
reported that as early as 1967 ketamine was being
used for non-medical purposes. Some have suggest-
ed that recreational use in North America may have
been linked to returning Vietnam veterans who had
experienced it on the battlefield.[113,114] Intellectual
hedonism with ketamine was popularised in the
1970s and 1980s, particularly in the US, and period-
ic reports of its abuse by healthcare professionals
gradually appeared.[115,116] Used in a wide variety of
settings by users seeking different experiences,
ketamine has been reported to have the advantage of
being easy to consume, with the clear dose response
effect and relatively short half-life reportedly mak-
ing the effects easier to titrate than LSD.[113]
Over the past decade there have been a growing
number of reports on the non-medical, unauthorised
use of ketamine in the UK,[117] Sweden,[118] Austra-
lia[119] and in the US (particularly New York).[120,121]
Ketamine can be obtained for recreational use in
a number of preparations: as crystalline powder for
intranasal use (100–400mg per dose) and in liquid,
powder or capsular form (350–500mg per dose) for
ingestion. Ketamine has also been smoked and is
reportedly available as an intranasal spray. The
favoured route of administration is nasal, with users
inhaling a powdered formulation (insufflation). In-
formation on the internet suggests ketamine is often
used recreationally in ‘bumps’ or as small amounts
of powder insufflated from either a specialised
micro-spoon, a specialised ‘bullet’ or eyeballed
small piles (commonly 30–50mg).[13]
A standard street dose of ketamine in a Scottish
study was typically one-eighth of a gram, usually
taken intranasally, with effects lasting for approxi-
mately 1 hour. Unlike dance-scene users, partici-
pants in this study reported using ketamine in a
carefully pre-planned setting, emphasising comfort
and familiarity.[122] There is wide variation in con-
sumption patterns among users. Experienced con-
sumers, who have developed tolerance to the drug,
use ≥1g of ketamine over the course of an evening/
weekend.
CNS Drugs 2006; 20 (3)
208
The particular brand of pharmaceutical ketamine
may make a difference to the drug effects. Ketalar®
contains a preservative (an anticholinergic agent,
benzethonium chloride) that has a significant effect
upon the brain and Ketamine 500® contains the
toxic organic preservative (chlorobutanol), which
has shown harmful effects in some animal experi-
ments.[123] There are some reports of ‘freebasing’
ketamine, produced by the removal of benzethoni-
um chloride and salts from Ketalar® to achieve
fewer unwanted adverse effects.[13]
5.1 Ketamine and the Dance Scene
Ketamine first appeared in the UK in the gay
dance scene during the early 1990s. Gay media
observers noted that with many early users adhering
to strict set and setting rituals ketamine was consid-
ered by some to be an elitist drug.[124,125] In the dance
scene setting, ketamine has been used in two forms,
as a powder (under various pseudonyms such as K,
Super K, Special K, Vitamin K, Green, Mean Green
and Jet) and as capsules and ampoules specifically
sold with ketamine as the marketable content.
In the UK, a substantial quantity of ketamine for
non-medical use is brought in from countries where
it is legally manufactured (e.g. China and India).[126]
The remainder is diverted from hospitals and veteri-
nary clinics or purchased entirely legally from a
wide range of chemical companies in Amsterdam
and Germany. From 2001 the theft of medical and
veterinary trade marks for ketamine in France have
to be declared to the authorities.[127] In the US,
ketamine now tends to originate from legitimate
Mexican pharmacies, although up until the late
1990s most ketamine was reportedly diverted from
legitimate medical supplies at Fort Dodge laborato-
ries in Illinois.[128]
Ketamine has also appeared as a constituent of
tablets purporting to be ‘ecstasy’, often in combina-
tion with a stimulant drug, such as ephedrine, usual-
ly legally purchased from a German chemical com-
pany. The surprise of experiencing immobility or
hallucinations when empathy and euphoria were
expected must come as a shock to unassuming rav-
ers.[124]
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
Along with sodium oxybate (gamma hydrox-
ybutyrate; GHB), ketamine has become a recent
addition to the thriving ‘polypharmacy’ of club-land
drug use. The frequent use of more than one drug
consumed over a relatively short period of time is
common in the dance scene. Drug-drug interactions
resulting from poly-substance use with a combina-
tion of drugs from the same drug class or with the
same physiological effects (e.g. respiratory depres-
sion) are cumulative. There are few pharmacologi-
cal reports, however, about the effects of ketamine
used in combination with other compounds. Com-
bining psychoactive substances is the single most
risk-producing behaviour of club drug users and
usually involves alcohol.[129] Future research should
be directed towards developing a more comprehen-
sive description of the risks associated with combin-
ing ketamine with other drugs – risks such as drug
overdoses, the transmission of bloodborne viruses
(HIV, hepatitis C virus) and effects on cognitive
functioning.[121]
Estimating the prevalence of ketamine use within
a recreational-use population is difficult. Appealing
and available to certain populations only and not
routinely asked about in household or community
surveys, ketamine users are a hidden group. Within
the dance scene there are some estimates, which at
least suggest that although ketamine is not as popu-
lar as cocaine or ecstasy, its increasing availability
and use is attractive to some polydrug users.[124] In
1996, a study by the British-based charity organisa-
tion, RELEASE, reported that 30% of 520 clubbers
surveyed in the UK had tried ketamine.[117]
A survey of Australian ecstasy users in 1997
found that ketamine was identified as one of the
‘other drugs’ having been used, with 6% of respon-
dents using the drug within the previous 6
months;[130] in 2001, ketamine use had increased to
15% of respondents.[131]
In 1999, a survey of over 1100 UK clubbers
reported a lifetime prevalence of ketamine use of
25% (half of these in combination with ecstasy). The
level of use tended to be low with only 13% of
respondents reporting use of >20 occasions and
<5% reporting use on >100 occasions; use within
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
the last month was only reported by 4%.[124] Another
study of a similar population, but with a slightly
smaller sample group, suggested that the use of
ketamine had become more widespread, with 35%
of respondents reporting ever using and 30% report-
ing use within the last month.[27] Although ketamine
may initially be thought of as an odd choice of drug,
given its dissociating and immobilising effects, the
drug has marked stimulatory effects at low doses
and any immobility may be reduced by the concur-
rent use of amfetamine, cocaine or ecstasy.
Seizures of ketamine intended for non-medical
use indicate the growth in popularity of this drug. In
the US, seizures of ketamine by the Drug Enforce-
ment Administration in 2001 increased by >500%
compared to the previous year,[132] while in Hong
Kong, ketamine has unseated use of ecstasy as the
most frequently used illegal recreational drug. Of all
reported drug users in Hong Kong in 2002 under the
age of 21 years, 59% were using ketamine.[126]
5.2 Sought-After Effects of Ketamine
Ketamine is most frequently used for its
psychedelic properties, sometimes as a dance drug
and sometimes to ‘explore the mind’.[133] Others
have reported using ketamine to ‘experiment’ or to
‘feel good’ and to enhance social activities.[134]
Ketamine use for recreational purposes has been
described as a “collection of paradoxes” because of
its many effects otherwise associated with other
substances. For instance, ketamine has been associ-
ated with ‘cannabis-like imagery’, ‘alcohol-like in-
toxication’, ‘cocaine-like stimulation’ and ‘opiate-
like calming’.[135] Some users describe being put
into ‘overdrive’ and will seek this particular state.
Further exploration of the reasons for ketamine use
may help provide information on the growth of use
of this drug.
As described by Tim Leary, the ‘godfather’ of
hallucinatory hedonism, ketamine is “the ultimate
psychedelic journey”.[136] The collective term for the
myriad of experiences associated with the use of
higher doses of ketamine is the ‘K hole’, which
refers to the place ‘where users are’ when under the
influence of ketamine.[120] Reported experiences are
© 2006 Adis Data Information BV. All rights reserved.
209
wide ranging and include emergence and toxic ef-
fects, such as out-of-body experiences;[137] temporal
and spatial distortion; a sense of floating, rebirthing
and experiencing evolution; sudden insights into the
meaning of one’s existence; tactile and visual distor-
tion; and hallucinations (table II). Sometimes the K
hole can reproduce the features of a ‘near-death’
experience, including buzzing, ringing and
whistling sounds at the beginning and travelling
through a dark tunnel into light at a high speed with
intense visions.[135] The spectrum of effects is re-
flected in the different groups of users who choose
ketamine for different reasons. For instance, com-
munal events, where individual or small groups of
users participate in sequential administration of the
drug throughout the evening, are preferred by some
and may well evoke different events to the over-
stimulation of a dance club venue.[113]
5.3 Ketamine and Sexual Assault
The media has made great deal of the concept of
‘date rape’ or ‘acquaintance rape’, i.e. the use of
drugs by friends or acquaintances of the victim to
facilitate sexual assault. A number of drugs have
been implicated in such alleged criminal activities,
among them sodium oxybate,[15] flunitrazepam[138]
and ketamine.[139] Proven cases are extremely rare,
however. Studies have indicated that alcohol is usu-
ally the predominant drug in such cases, followed by
marijuana and benzodiazepines.[15]
Ketamine, however, is a potent anaesthetic with a
rapid onset of action particularly when used in-
tranasally, a route favoured recreationally. The dis-
sociative state, which results from ketamine admin-
istration with amnesia and analgesia, suggests that
ketamine should be included in any forensic exami-
nation of sexual assault cases. Providing specimens
for analysis are collected within 24 hours of the
incident, current technologies allow the detection of
most drug classes; thus, careful history taking and
urine toxicological drug screening may be useful.
5.4 Toxicological Testing for Ketamine
Testing for the presence of ketamine in an intoxi-
cated individual is difficult because of the short half-
CNS Drugs 2006; 20 (3)
210
Table IV. Short-term adverse effects of ketamine[17,50,71,136,145]
Category Effects
Psychological Anxiety, severe agitation, thought disorder, dissociation (K hole confusion), insomnia, excitement,
euphoria, oneirogenia
Physical Chest pain, palpitations, tachycardia, temporary paralysis, slurring of speech, blurred vision
Psychoactive Hallucinations, out-of-body feeling, increased suspiciousness, paranoia, time delusion, feeling of
weightlessness
life of the drug. Nevertheless ketamine and its me-
tabolites, norketamine and dehydronorketamine, can
be detected in plasma, hair and urine,[140] using gas
chromatography and mass spectroscopy and high-
performance liquid chromatography in order to pro-
vide quantitative analytical information.[141] Howev-
er, the results from these confirmatory tests are not
normally immediately available. The detection win-
dow for the analytes is highly dependent on the
method used for determination and varies between
individuals.[142]
Immunoassay tests, which would provide a more
immediate (non-quantitative) result, are not current-
ly available for ketamine and those available for
phencyclidine (the structural analogue) have pro-
duced false-positive results due to cross-reactivity
with ketamine.[143] Consequently phencyclidine im-
munoassay tests are not considered reliable as an
alternative for when ketamine detection is sought in
populations that have access to both drugs.[144]
Postmortem testing for ketamine is relatively
simple and the drug can be detected on routine
screening by gas chromatography with a nitrogen
phosphorous detector. However, problems can arise
with toxicological testing in the acutely intoxicated
live person. Since there is no rapid screen for
ketamine intoxication, treating physicians often do
not know that the person is under the influence of
the drug. The accounts by the patient or patient’s
friends about what has been consumed may not help
further.
However, clinicians should consider possible
ketamine use in patients presenting with physical
damage due to an unexplained accident, disor-
ganised speech, confusion and agitation. Blurred
vision, nystagmus, body detachment and a lack of
awareness of time and place may also indicate use
(see table IV for further details).
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
Development of an assay to screen for ketamine
would be a useful clinical development, serving
both staff in accident and emergency departments
and those involved in the treatment of addicted
healthcare professionals.
6. Adverse Effects
Ketamine use outside clinical supervision is not
without risks. The effects of the drug are influenced
by various factors including the route of administra-
tion, the constitution of the individual and any other
drugs consumed. Although ketamine has a wide
margin of safety in clinical practice,[146] and most
adverse effects do not require an overnight admis-
sion, recreational use may lead to overdosing, which
has occasionally been life threatening.[133] Ketamine
concentrations in a 26-year-old man whose death
was attributed to ketamine intoxication were 6.9 and
1.8 mg/L in heart and femoral blood, respective-
ly.[147] Ketamine has also been reported in accidental
autoerotic deaths in Germany.[148]
The short duration of effect and rapid onset of
action when ketamine is taken by intranasal or intra-
venous routes often lead recreational users to admin-
ister repeated doses over the course of a session in
order to maintain a desired psychoactive effect. Be-
ing an amnesic it may become difficult to remember
the total number of doses of ketamine and other
drugs consumed over a session, thus increasing the
likelihood of an overdose and unwanted prolonged
intoxication. In patients with a history of stimulant
use, ketamine given in trauma settings has been
reported to be associated with pulmonary oedema
and hypertension.[149]
The principal physical dangers of most non-med-
ical usage of ketamine are believed to arise mainly
from the setting, or an interaction between the user
and the setting of use,[116] as ketamine can leave the
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
user in a confused state. This can result in falls
(sometimes fatal), drowning and road traffic acci-
dents. The user can also become a victim of crimes,
such as sexual assault.[113]
The most common complaints in an US case
series of 20 patients who had taken ketamine and
presented to a Connecticut hospital[136] were related
to sympathetic hyperactivity, such as anxiety, chest
pain and palpitations. Not unsurprisingly, tachycar-
dia was the most common physical finding (table
IV). Nystagmus, a common finding after phencycli-
dine use, was seen in only three cases. The most
frequent complications reported following ketamine
overdose were severe agitation and rhabdomyolysis.
There have also been case reports of dystonic reac-
tions during intoxication.[150] The symptoms of
ketamine intoxication appear to be short-lived and in
line with the pharmacokinetics of the drug, with the
vast majority (18 of 20) of patients in the Connecti-
cut study discharged from emergency departments
within 5 hours of presentation.[75,80]
In children, inadvertent overdose has been re-
ported with 5–100 times the recommended clinical
dose.[151] Adverse effects were reported to include
brief respiratory depression without residual effect,
implying a wide margin of safety in overdose. This
is supported by a review of ketamine deaths in
recreational users in New York, which reported in
all cases polysubstance use, most commonly opioids
and amphetamines, as the cause of overdose rather
than ketamine per se.[152] The risks of adverse ef-
fects following polysubstance use has been high-
lighted in section 5.1. The risk of cardiac overstimu-
lation and respiratory depression are potential con-
sequences of combining ketamine with stimulant
drugs (e.g. amfetamine, cocaine) and CNS depres-
sants (alcohol, benzodiazepines and opioids), re-
spectively.
Recreational users of ketamine have reported ex-
periencing significant negative effects, to such a
degree that some have either reduced their dose or
stopped use altogether. In an Australian study,
which surveyed 100 long-term ketamine users,
many reported regularly experiencing an inability to
speak, blurred vision, lack of co-ordination and in-
© 2006 Adis Data Information BV. All rights reserved.
211
creased body temperature.[130,131] Employment
problems were reported in 20% of the respondents,
including vagueness affecting work performance.
Others have reported residual effects 3 days after
use, including semantic memory impairment.[23]
Recreational users also report a number of ad-
verse psychological experiences (table IV). Al-
though the onset of psychological effects occurs
more quickly and recedes faster than with LSD, the
effects are similar, including hallucinations, synaes-
thesia, euphoria, depersonalisation and confu-
sion.[13] Additionally, powerful dissociative or ‘out-
of-body’ sensations, which appear specific to
ketamine, have been reported.[145] Ketamine has a
greater propensity than LSD to induce feelings of
agitation, aggression, and stimulation consistent
with its stimulant properties, which both preclinical-
ly and clinically have been shown to resemble the
physical effects of phencyclidine.[2,73,153]
Very often it is the interpretation of the experi-
ence by the user, not the effects of the drug per se,
that is the problem. The short half-life of the drug
may limit the potential risk of a prolonged ‘bad trip’,
although one such episode has been described in the
scientific literature by Johnstone[154] as “cycling into
and out of awareness – a frightening experience”.
Observers reported a panicked look, defensive
thrashing of the arms and marked nystagmus. John-
stone, at the time, warned against giving ketamine to
a patient as a sole anaesthetic agent. It was consid-
ered likely that sequential administration, variations
in purity, intravenous administration, tolerance and
the amnesic effects of the drug (which may impair
recall of the total dose consumed) could result in
acute episodes of paranoia, panic and psychosis.[155]
Ketamine produces a syndrome of effects in
healthy individuals who take sub-therapeutic doses
in a recreational manner. Reactions to low sub-
anaesthetic doses have been illustrated in a number
of texts,[3] which describe disoriented perceptions
and the total loss of an observer consciousness.
According to the DSM-IV,[144] a ketamine-induced
psychosis would best fit the criteria for the disor-
ganised or the undifferentiated subtype model of
schizophrenia.[156,157]
CNS Drugs 2006; 20 (3)
212
Recreational use of ketamine has been shown to
result in an acute state that has features of positive
and negative psychopathology, resembling those
seen in schizophrenia. In addition, ketamine use also
produces symptoms that mirror the frontal lobe defi-
cits in cognitive functioning seen in schizophre-
nia.[16] In fact, ketamine exerts significant effects
upon a wide range of cognitive processes, most
notably memory. With disruptive effects mediated
largely through the inhibition of long-term potentia-
tion, ketamine has been shown to impair, in an acute
sense, both episodic and semantic memory.[22,51,55,88]
In hospital settings, reassurance and cardiorespi-
ratory examination are required in patients exper-
iencing adverse reactions to ketamine. The effects of
concomitant benzodiazepines are inconsistent, vary-
ing between compounds and dose. For instance,
while lorazepam may reduce emotional distress, it
appears to have little impact upon the psychosis or
perceptual changes observed with ketamine.[158]
Midazolam, on the other hand, is able to negate the
effect of ketamine on thought process and perceptu-
al disorder, but has little impact upon mood
problems.[136] Interestingly, haloperidol also has lit-
tle effect upon the psychosis associated with
ketamine, suggesting a role for receptors other than
D2.[58] Pre-administration with lamotrigine (a drug
known to inhibit glutamate release) potentiates the
mood elevating qualities of ketamine and signifi-
cantly reduces perceptual, cognitive and positive
and negative symptoms associated with its use.[42]
Predictors of adverse or psychotic episodes with
ketamine come from studies of anaesthetic patient
case series. A study of ketamine-induced anaesthe-
sia in >300 subjects identified premorbid anosogno-
sia and paranoia (as assessed by the Minnesota
Multiphasic Personality Inventory) as risk factors
for experiencing psychotic disorders after ketamine
administration.[159,160]
6.1 Long-Term Effects
The literature on the long-term consequences of
ketamine use, in isolation from other drugs of abuse,
is rather sparse. However, in the late 1970s the long-
term effects of ketamine were reviewed,[161] fol-
© 2006 Adis Data Information BV. All rights reserved.
Wolff & Winstock
lowed by an editorial 1 year later.[162] These papers
reported prolonged ‘psychic’ phenomena occurring
for periods of ≤1 year in seven separate case reports,
following the administration of a single dose or two
doses of ketamine. However, a larger study (221
adults), which investigated psychological changes
following anaesthesia with ketamine compared with
other anaesthetics, found no long-term impairment
of personality or intellectual function, even after
repeated exposures to the drug.[163]
A study nearly 25 years ago[73] of social users of
ketamine who had administered the drug nasally,
intravenously or intramuscularly found that long-
term effects included ‘flashbacks’, attentional dys-
function and decreased sociability. Future research
into the long-term consequences of use should in-
clude investigation of social-psychological as well
as physiological parameters. Flashbacks reported
following repetitive use[73] may only be ‘a graininess
of vision’ under anxiety-provoking circum-
stances.[164] Other long-term consequences of chron-
ic use have been reported, including anxiety and
social withdrawal.[165] Conversely, however, many
users report positive long-term effects, such as
chronic elevation in mood and deeper insights into
self and others.[73] Long-term users also reportedly
experience stimulant-like weight loss and loss of
appetite during periods of heavy use.[116]
Subjective reports of prolonged effects on cogni-
tion have also recently been observed. In a study of
37 ketamine users (18 chronic, frequent users and 19
infrequent users), chronic users were significantly
impaired on tests of semantic and episodic memory
3 days after a dose of ketamine.[163] Regular use of
ketamine may, therefore, lead to long-term cogni-
tive impairment, but this study relied upon self-
reporting and did not confirm psychoactive drug use
on the night of testing. Systematic research is re-
quired in this area to support animal evidence that
indicates ketamine and phencyclidine, as NMDA
antagonists, may be potent neurotoxins.[161] At pre-
sent, there is no substantial evidence that permanent
changes in intellectual function or personality can
occur as a result of regular ketamine use,[165] al-
though long-term intravenous use by the American
CNS Drugs 2006; 20 (3)
Use and Misuse of Ketamine
psychiatrist Lilly[7] in 1978 did lead to several ad-
missions for paranoid psychosis, self-reported atten-
tional difficulties and social withdrawal. More data
are needed to define the possible long-term effects
of ketamine.
6.2 Tolerance and Dependence
Animal studies demonstrate the ability of intrave-
nous ketamine to produce dependence in rat models,
with disruption of operant behaviour on withdraw-
al.[153] Ketamine demonstrates reinforcing efficacy
in animal self-administration models and was found
to be a discriminative stimuli in operant tasks.[158]
The effects of the drug are thus readily distinguisha-
ble from other drugs, indicating that it may be liable
to abuse.[166] Ketamine has the ability to release
dopamine within the reward pathway, which has a
role in reinforcement.[100]
However, ketamine is somewhat unusual in its
pharmacodynamics, almost acting as a partial antag-
onist with regard to brain reward enhancements,
being stimulatory at low doses and inhibiting brain
reward centres at higher doses. Gardener[164] has
suggested this paradoxical effect at higher doses
parallels the experiences of street users of the drug.
Heavy habitual use has been described,[165] and
cases of dependence have also been reported among
anaesthetic staff.[167-169] To date, only one review
has been conducted on ketamine dependence in
humans.[170] Nevertheless, there is some evidence
suggesting the development of tolerance to the
behavioural effects of ketamine in animals.[171,172] In
addition, several reports have suggested that toler-
ance to ketamine may develop in individuals who
have undergone repeated anaesthesia with
ketamine[173-175] and in recreational users.[113,122,166]
However, tolerance to the analgesic effects of
ketamine does not seem to develop.[176,177]
7. Conclusions
Ketamine is a dissociative anaesthetic with a
wide range of clinical applications and a wide mar-
gin of safety in overdose. As a research probe in the
study of schizophrenia, ketamine has given increas-
ing prominence to the role of glutamate in the aeti-
© 2006 Adis Data Information BV. All rights reserved.
213
ology of this illness. The marked perceptual and
cognitive psychedelic effects of ketamine have led
to a recent rise in its use in the recreational drug
scene. Somewhat complex in its pharmacology, the
effects of ketamine are highly sensitive to its iso-
meric form, which can exert a significant influence
upon both monoaminergic and glutaminergic neuro-
transmission. When ketamine is administered acute-
ly it induces significant disturbance in semantic and
episodic memory as well as in attention and higher
executive functioning. Long-term use may be asso-
ciated with more prolonged deficits in episodic
memory, perhaps related to the effects of ketamine
on synaptic plasticity, long-term potentiation and
neurotoxic effects. Diverted illicit clinical sources of
ketamine are the main source for recreational non-
medical ketamine use. Snorted or swallowed, the
drug may be associated with acute cardiorespiratory
problems, especially when combined with other
stimulant drugs and may lead to accidental injury.
Acute adverse psychological reactions may also oc-
cur and many regular users report ‘grainy’ flash-
backs following the consumption of ketamine. Al-
though numbers involved in repeated long-term use
appear small, case reports, especially among health-
care professionals, are cited in the literature. The
potential of ketamine as a novel clinical and re-
search tool is matched by its abuse potential outside
medical settings.
Acknowledgements
Huge thanks must go to Anthea Hawley for her consistent
efforts in putting together this complicated review and earlier
drafts that were attended to by Marina Lye. Thanks to both for
their input. There were no sources of funding used in the
preparation of this review. Neither author is employed by the
manufacturers of ketamine.
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Correspondence and offprints: Dr Kim Wolff, National Ad-
diction Centre, Institute of Psychiatry, 4 Windsor Walk,
London, SE5 8AF, England.
E-mail: k.wolff@iop.kcl.ac.uk
CNS Drugs 2006; 20 (3)