ChapterPDF AvailableLiterature Review

Drug Abuse and Addiction in Medical Illness

May 2012
CNS Drugs 20(3):201-211

May 2012
20(3):201-211

DOI:10.1007/978-1-4614-3375-0_15

In book: Drug Abuse and Addiction in Medical Illness (pp.201-211)

Authors:

Kim Wolff

King's College London

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

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AUTHOR PROOF

Approval for publication Signed Date Number of amended pages returned

CNS Drugs 2006; 20 (1): 1

EVIEW

RTICLE

1172-7047/06/0001-0001/$39.95/0

Ketamine

From Medicine to Misuse

Kim Wolff1 and Adam R. Winstock2

1 National Addiction Centre, Institute of Psychiatry, Kings College, London, England

2 South Western Sydney Area Health Service, Area Drug Health Services, Liverpool, New

South Wales, Australia

Contents

Abstract ..................................................................................... 1

1. Pharmacodynamics ....................................................................... 2

1.1 Mechanisms of Action ................................................................. 4

1.2 Optical Isomers of Ketamine ........................................................... 5

2. Pharmacokinetics ......................................................................... 7

3. Medical Uses ............................................................................. 7

4. Research Uses ............................................................................ 8

5. Recreational Uses ......................................................................... 9

5.1 Ketamine and the Dance Scene .......................................................10

5.2 Sought-After Effects of Ketamine .......................................................11

5.3 Ketamine and Sexual Assault ..........................................................12

5.4 Toxicological Testing for Ketamine ......................................................12

6. Adverse Effects ...........................................................................12

6.1 Long-Term Effects .....................................................................14

6.2 Tolerance and Dependence...........................................................15

7. Conclusions ..............................................................................15

This review describes the medical, research and recreational uses of ketamine,

Abstract an anaesthetic derivative of phencyclidine that has dissociative, analgesic and

psychedelic properties. Ketamine has a complex mechanism of action that is

further complicated by stereo selectivity. However, antagonism of glutamate

NDMA receptors is thought to underlie it analgesic, dissociative and neuroprotec-

tive 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.

AUTHOR PROOF

2Wolff & Winstock

The potential of ketamine as a novel clinical and research tool is matched by its

abuse potential outside medical settings.

((Author: please confirm that our rewording of the Abstract is acceptable

to you. Thank you))

((Author: the order of the text and tables has trolled under the Misuse of Drugs Act. It is possible

been re-arranged somewhat to improve flow and that the British Home Office may consider

readability. We hope that these changes are ac- rescheduling, but that is usually a prolonged pro-

ceptable to you)) cess. However, possession of ketamine is illegal

without a prescription. Ketamine was made a con-

Ketamine (2-[2-chlorophenyl]-2-[methylamino- trolled drug (Schedule III) in the US in 1999.

]-cyclohexanone) is an anaesthetic derivative of

In this article we will review the medical, re-

phencyclidine (1-[1-phenylcyclohexyl] piperidine;

search and recreational (particularly within the

PCP; ‘Angel dust’) with dissociative, analgesic and

dance scene) uses of ketamine, its pharmacodynam-

psychedelic properties. As an arylhexylalkyamine, it

ics, pharmacokinetics and adverse effects.

is also related to dizocilpine (MK 801) and

tiletamine. Parke Davis Laboratories developed

ketamine in 1962 after worries about the range of 1. Pharmacodynamics

aggressive behavioural problems and adverse psy-

chological reactions associated with its earlier prod- Ketamine is almost unique as an anaesthetic in its

uct, phencyclidine.[1] Ketamine is also known as ability to produce a dissociative state. This term was

Ketalar, Ketaset, Ketamex ((Author: please con- first phrased by Domino et al.[4] in 1965 to describe

firm spelling, Ketotal, Ketamine 500((Author: is the mental state produced by anaesthetic action with

this a trade name – or a popular name for As- sympathomimetic properties and cerebral dissocia-

trapin’s brand?))) and Imalgen ((Author: please tive actions. Such action results in higher centres in

indicate if these names are registered or trade the brain being prevented from perceiving auditory,

marks. Thank you )).visual or painful stimuli, leading to ‘a lack of re-

Not surprisingly, phencyclidine and ketamine sponsive awareness’. The effects of ketamine have

have similar properties; the main difference is the been likened to sensory deprivation, dreamlike vi-

shorter half-life of ketamine and its less problematic sion, a sense of isolation and often the feeling that

‘emergence phenomena’((Author: for the benefit the ‘self’ has been separated from the body.[5]

of general readers, please add a brief definition of The loss of contact with ordinary reality and the

‘emergence phenomena’ at this point. Thank sense of participation in another reality are more

you)). Despite its unusual clinical effect and mul- pronounced than is usually the case with LSD

tifaceted mechanism of action, ketamine has found (lysergide) ((Author: please reference)). Pro-

its place within several areas of medicine, including longed and frequent use of ketamine can induce

paediatric analgesia and anaesthesia, emergency an- psychotic reactions and a gradual loss of contact

aesthesia, obstetrics and on the battlefield.[2] with the every-day world ((Author: please refer-

((Author: please confirm that rewording of ence)). Ketamine is not alone in this respect, and the

this paragraph is okay)) However, while ketamine, psychological effects of the common general anaes-

which has been described as the ‘ultimate thetics (ether, chloroform and nitrous oxide [NO])

psychedelic’,[3] has a good safety record within all produce experiences that could be described as

clinical settings, the increase in its unregulated use psychedelic.[6] Overall, the ketamine effect has been

outside such controlled environments is a cause for described as a somatesthetic sensory blockade with

concern. In the UK, ketamine is not currently con- amnesia and analgesia.[4]

AUTHOR PROOF

Use and Misuse of Ketamine 3

Table I. Clinical physiological effects of ketamine [10-15]((Author: please check and correct these references – ref[15] is a 1958 paper))

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, parenthesis ((Author:

“paresis”?)), ataxia, convulsions, temporary paralysis

Other Skin rash, analgesia, hypersensitivity to sound or light, amnesia, pyrexia

As described in section 1.1, it is an action at seconds and 4 minutes following intravenous and

glutamate NMDA receptors that underlies the anal- intramuscular induction doses, respectively ((Au-

gesic, dissociative and neuroprotective qualities of thor: please reference)). However, anaesthesia is

ketamine.[7] NO also produces dissociative anaes- short-lived and persists for only 5–10 minutes, re-

thesia due to NMDA receptor blockade.[7] There is a quiring frequent re-administration through an infu-

growing body of research that indicates that alcohol sion to maintain the clinical effect ((Author: please

also acts in this way, blocking the effects of gluta- reference)).

mate at the NMDA receptor in a noncompetitive and One-off sub-anaesthetic doses of ketamine have

concentration-dependent fashion; blockade occurs led to disrupted attentional performance and im-

across the range of alcohol concentrations associat- paired performance on tests of vigilance, recogni-

ed with human alcohol intoxication (5–100 mmol/ tion memory, verbal fluency, working memory, and

L).[8] episodic memory (a deficit seen in schizophrenia)

Unlike inhalational agents and narcotics, which [table II] ((Author: please confirm that rewording

suppress the reticular activating system, ketamine is okay)). On tests of higher executive function,

induces a functional and electrophysiological disso- such as the Wisconsin Card Sorting Test, ketamine

ciation between the thalamo-neocortical and limbic use leads to an increase in perseverative errors and

systems. The ensuing prevention of the higher cen- preferentially disrupts delayed word recall, sparing

tres from perceiving auditory, visual and/or painful immediate recall and post-distraction recall.[8,16,17]

stimuli is potentially hazardous outside clinical set- Indeed, the acute amnesic effects can be so marked

tings. There is great risk of injuries being masked that they can make it difficult for subjects to de-

and the risk of accidents increased.[6] scribe their experience to researchers attempting to

record the episode.[18] Dysfunction seen in episodic

With doses of ketamine that are adequate to bring memory (personal life event) is of particular note,

about anaesthesia, a trance-like cataleptic state with since it is highly correlated with everyday memory

amnesia is produced, without impairment of laryn- difficulties.[9,19,20]

geal and pharyngeal reflexes or depression of respi-

ration or cardiac function.[6] Typically, the eyes tend The perceptual and mood changes observed in

to remain open with a disconnected stare and nys- those who have used ketamine ((Author: are you

tagmus is usually observed; the recreational drug referring to clinical or recreational use here?))

user may appear to be awake but is dissociated from are, as with other effects, highly sensitive to age,

the environment, immobile and unresponsive to pain dose, route, previous experience (expectations, per-

(table I). Ketamine also produces analgesic effects sonality, motivation and mood) and setting (social,

and is remarkable in being able to produce potent physical and emotional environment).[29,30] At low

analgesia at sub-anaesthetic concentrations.[9] Prob- doses of ketamine, stimulant effects predominate

lematic emergence phenomena and other unpleasant and environmental conditions are significant. How-

experiences appear maximal in early adolescence ever, with higher doses, psychedelic effects become

((Author: please reference)). Within clinical set- the primary experience and the effect of the environ-

tings, anaesthesia is usually induced within 30 ment diminishes. Auditory hallucinations are fairly

AUTHOR PROOF

4Wolff & Winstock

Table II. Clinical psychopathological effects of ketamine[2,21-28]]((Author: please check all references – they may relate to an earlier

version of the manuscript))

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, poor recognition memory, 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

rare following ketamine use and have been reported (norepinephrine), serotonin, and muscarinic cholin-

much less consistently.[31] ergic receptors elsewhere.[36,37]It also has multiple

actions at numerous other receptor sites, particularly

While psychedelic effects may be dose-related,

those affecting glutamatergic and monoaminergic

idiosyncratic adverse responses can occur at low

neurotransmission, and there is growing evidence to

doses. Some recreational users report taking issues

substantiate the role of such receptor activity in the

of set and setting ((Author: please clarify the dif-

clinical effects of ketamine.[38] Ketamine has also

ference between set and setting. Thank you)) into

been found to significantly inhibit the uptake of

careful consideration prior to using ketamine.[32]

noradrenaline, dopamine and serotonin in a dose-

Such preparation cannot be performed if the drug is

dependent fashion in human embryonic kidney cells

consumed unwittingly when it has been marketed ((Author: please provide a reference)). It has been

under the guise of another drug, such as ‘ecstasy’

postulated that the psychotomimetic and sympatho-

(methylenedioxymetamfetamine).[33,34] The range of

mimetic effects are thus mediated through this en-

experiences for ketamine used in non-medical cir-

hancement of monoaminergic neurotransmission in

cumstances may be perceived quite differently (bi-

the brain.[39]

zarre, intense, extreme or vivid imagery) by differ-

ent individuals. Expectation of effect and the indi- The most significant pharmacological action of

vidual’s personality are thought to exert a significant ketamine is its non-competitive antagonistic binding

influence upon the experience, though predicting at the cation channel of the NMDA receptor and its

proneness to such unpleasant/undesired experiences consequent interference with the excitatory amino

with ketamine is difficult, particularly in hidden acid transmitters, glutamate and aspartate.[11,22,40,41]

populations (clubbers). Action at the NMDA receptor is considered to un-

derlie the analgesic and dissociative effects of

1.1 Mechanisms of Action ketamine and to have important effects on memory.

Early work postulated that antagonism of the

It has been established that the distinctive effects NMDA receptor would disrupt long-term potentia-

of ketamine are due to antagonism of the NMDA tion and synaptic growth, which are crucial in the

receptor.[35] Ketamine, as a first generation excitato- development of synaptic plasticity, learning and

ry amino acid ((Author: is it correct to describe memory.[23,24,42] However, a recent study investigat-

ketamine as an EAA?)), is now characterised as ing the effects of subdissociative doses of ketamine

having low affinity for blocking the NMDA mul- on executive processes during a working memory

timeric receptor complex.[35] It is also well estab- task found a highly specific task pattern of impair-

lished that ketamine has effects on opioid receptors ment.[43] Impairments were restricted to a subgroup

at central and spinal sites and noradrenaline of verbal working memory tasks (the manipulation

AUTHOR PROOF

Use and Misuse of Ketamine 5

of information within working memory). The pro- 1.2 Optical Isomers of Ketamine

cess-specific effect of ketamine did not affect visio- In clinical use, ketamine is a racemic mixture of

spatial working memory. This specificity of effect two optical isomers (enantiomers), S-(+)-ketamine

suggests that the earliest effect of NMDA receptor and R-(–)-ketamine.[50] There appears to be some

blockade is on higher order control of executive clinically relevant stereo selectivity regarding the

function rather than on more basic maintenance effects of the drug, with S-(+)-ketamine being 2-fold

processes. More study in this area would be useful. more potent as an analgesic and hypnotic than the

Clinical studies also implicate glutamate in the racemic mixture.[51] The stereo-specific binding of

S-(+)-ketamine to opioid receptors in vitro appears

mediation of the dissociative symptoms of

to be associated with a more rapid emergence from

ketamine, with acute administration leading to a anaesthesia and a lower incidence of emergence

transient hyperglutaminergic state.[44] Indeed, the sequelae ((Author: compared to the other enanti-

pre-administration of drugs that reduce glutamate omer or the racemic mixture – or both?)).[52]

release partly negate the perceptual disturbances More rapid recovery of psychomotor skills after

seen with ketamine,[45] which can, in turn, be anaesthesia has also been reported with S-(+)-

blocked ((Author: “reversed” rather than ketamine than with R-(–)-ketamine ((Author: re-

“blocked”?)) by the administration of glutamate. wording okay? Also, please provide a reference)).

Additional evidence supporting the significant role The anaesthetic potency of S-(+)-ketamine was

of glutamate in the clinical effects of the drug comes found to be 3-fold higher than that of R-(–)-

from preclinical data. This suggests that ketamine ketamine ((Author: please provide a reference)).

may, in part, produce psychotomimetic effects Its higher anaesthetic potency and minor

psychotomimetic adverse effects suggest S-(+)-

through an increase in glutamate release that, in

ketamine has a better therapeutic efficacy compared

turn, acts on the AMPA subtype of glutamate recep- to the racemic form ((Author: please confirm that

tor in the prefrontal cortex to induce a rewording is okay)).[2] In healthy young volunteers,

hyperdopaminergic state.[46]

endocrine and cardiovascular parameters of racemic

Additionally, ketamine binds to α-receptors (κ)and S-(+)-ketamine were similar, but S-(+)-

and opioid µ-receptors ((Author: please clarify the ketamine offered clear advantages as an anaesthetic,

receptors that you are referring to here - opioid κwith significant improvement in recovery ((Author:

and µ-receptors?)) but with only 10% and 20% of time?))and a reduced quantitative drug load ((Au-

its NMDA receptor affinity, respectively.[47] There- thor: please confirm that rewording is okay)).[53]

fore, the opioid receptor antagonist naloxone has There is also evidence that S-(+)-ketamine offers

up to 50% better performance in terms of faster

only a limited capacity to reverse the effects of recovery of cognitive performance, greater accept-

ketamine and could not reverse key effects in ance by healthy volunteers and identical depth of

vivo.[25] Ketamine may also have a modulating effect anaesthesia after injection, compared with racemic

on opioid receptors, thought to be responsible for its ketamine.[54] In early human studies, S-(+)-ketamine

analgesic and dysphonic effects. In animal models, was presumed to produce the desired anaesthetic

ketamine and other NMDA antagonists, such as effects and R-(–)-ketamine the undesired emergence

methadone, have been demonstrated to inhibit the reactions.((Author: please provide a reference))

development and acquisition of opioid dependence However, when given as a single bolus, a bolus

and tolerance,[48] while small doses of ketamine followed by continuous infusion or an intramuscular

have been shown to prevent tolerance developing injection, the incidence of perceptual emergence

acutely on repeated administration of the potent, reactions was pronounced with S-(+)-ketamine.[52,53]

short-acting opioid, alfentanil.[10,49] It appears that subanaesthetic doses of S-(+)-

AUTHOR PROOF

6Wolff & Winstock

Table III. Affinity of ketamine enantiomers for various receptors (adapted from Nishimura & Sato, 1999)[37]((Author: reference changed –

okay? Also, please confirm that re-arranged table is okay))

Receptor Ki(µmol/L)

S-(+)-ketamine R-(–)-ketamine

NMDA 0.9a2.5a

Opioid µ28.6a83.8

Opioid κ23.7a60.0

Opioid δ205.0 286.0

Opioid σ131.0 19.0a

Muscarinic acetylcholine 125.0 91.0

Dopamine transporter 46.9a390.0

Noradrenaline (norepinephrine) transporter 64.8 68.9

Serotonin transporter 156.0 148.0

a High affinity for the site.

Ki = inhibition constant.

ketamine produce distortion of the body image, receptors[31] and muscarinic receptors[59] than S-(+)-

loosening of ego boundaries and alterations of the ketamine. The molecular interactions of S-(+)-

sense of time and space, which are associated with ketamine and R-(–)-ketamine with their various

emotional changes including heightened feelings of targets are summarised in table III.

euphoria, indifference and anxiety.[55] This has lead It has been speculated that the psychotomimetic

to the recommendation that S-(+)-ketamine should effects results from binding to the σ-receptor site.

always be combined with a hypnotic or sedative Since R-(–)-ketamine has a higher affinity for this

drug in clinical anaesthesia.[56] receptor than S-(+)-ketamine, it would be thought

In rat corticostriatal slices, it was observed that that the R-isomer would be associated with a higher

the neuroprotective effect of ketamine was both incidence of hallucinations ((Author: rewording

region- and isomer-dependent ((Author: please okay?)). However, studies with S-(+)-ketamine in

provide a reference, and expand this sentence –healthy volunteers indicate that S-(+)-ketamine is

which isomer was associated with greater more likely to have hallucinogenic effects that R-

neuroprotection and in which region?)).(–)-ketamine.[60] This finding is conducive with the

It is known that pharmacological differences ex- much higher affinity of S-(+)-ketamine for the

ist between the enantiomers of ketamine with re- NMDA receptor (table III). Since psychotomimetic

spect to several targets (transporter proteins) of the effects are generally considered to be caused by a

drug.[57] Recently, it has been shown that the relative relative excess of dopamine, it is possible that the

potency of subanaesthetic doses of the S-(+)- and R- stereo-selective inhibition of dopamine reuptake

(–)-ketamine enantiomers parallels their relative af- might also add to ketamine-induced

finity at the NMDA receptor complex[58] and their psychotomimetic effects. However, the inability of

relative potency to block NMDA-mediated neuro- haloperidol to block these effects suggests that other

transmission in animal studies.[26] In particular, it transmitters are involved.[58] This would imply that

was found that S-(+)-ketamine binds to the noradrenergic systems are more strongly activated

phencyclidine binding site of the NMDA receptor in those individuals who have greater R-(–)-

complex in human brain with a 4- to 5-fold higher ketamine activity ((Author: your meaning in this

affinity than R-(–)-ketamine.[31] It was also found sentence is not clear - how does an individual

that subanaesthetic doses of racemic ketamine have have greater R-ketamine activity? Please reword

a weak affinity for σ-receptor sites, whereas S-(+)- this sentence. Thank you)). The over-stimulation

ketamine binds only negligibly.[58] On the other of noradrenergic and serotonergic pathways by R-

hand, the R-isomer exhibits a higher affinity for σ-(

–)-ketamine might contribute to the adverse effects

AUTHOR PROOF

Use and Misuse of Ketamine 7

observed as a result of ketamine-induced overdose provide a reference)). Less than 4% appears in

in those who use the drug at raves (dance parties) or urine as the parent compound or as the primary

for other non-medical purposes ((Author: please metabolite norketamine. The duration of action of

confirm that rewording is okay)). ketamine is not affected by decreased renal func-

tion.[2]

((Author: please confirm that rewording in

this paragraph is okay)) As stated previously, Ingested ketamine is poorly absorbed, and

commercial preparations of ketamine are most com- bioavailability may be as low as 16%.[65] Plasma

monly a racemic mixture, in equal amounts, of its concentrations are detected about 30 minutes after

enantiomers. Illicit manufacture of ketamine is al- administration ((Author: please confirm that re-

most unknown, because it is very difficult to synthe- wording is ok)).[65] Peak plasma concentrations af-

sise, so misappropriated legitimate pharmaceutical ter ingestion occur more slowly than and are only

sources most commonly supply recreational users. 20% of that observed with equivalent doses admin-

For example, ketamine has been reported to be istered intramuscularly ((Author: please provide a

smuggled into North America from Mexico and reference)). Additionally, with oral administration,

India.[52] Furthermore, ketamine is not a controlled first pass metabolism of ketamine results in a 2-fold

substance in many countries (e.g. Germany [S-(+)- higher concentration of norketamine than is ob-

ketamine] and The Netherlands, where it can be served following intramuscular administration

purchased legitimately). It is, therefore, highly prob- ((Author: please provide a reference)).

able that recreational users administer a racemic Norketamine is pharmacologically active with an-

mixture, although those selling the drug for non- aesthetic potency approaching one-third that of the

medical use reportedly add various adulterants to parent compound ((Author: please provide a ref-

make the drug go further. erence)). Hence, although the onset of effects fol-

lowing ingestion may be somewhat slower than with

parenteral administration, the duration of the effects

2. Pharmacokinetics

may be longer.

Ketamine may be effectively administered by a Intravenous administration of ketamine, as ex-

number of routes including oral, intranasal, intrave- pected, produces a rapid onset of action (within 30

nous, subcutaneous, intramuscular and intrathecal, seconds). Ketamine is rapidly distributed to highly

all of which permit adequate absorption and excel- perfused tissues, such as the brain, heart and lungs.

lent bioavailability.[61] Reports of clinical use via the Intramuscular administration of ketamine produces

rectal[62] and transdermal routes[63] have also been similar effects, being well absorbed, with a bioavai-

described. Such a plethora of potential routes of lability of up to 93% ((Author: please provide a

administration of ketamine is of concern when as- reference)). Intranasal use of ketamine is common

sessing its abuse potential, as uncomplicated and amongst recreational users, and this route is likely to

innocuous modes of delivery may favour non-medi- be associated with a rapid onset of action, with an

cal use. estimated duration of action of 2–3 hours.[66]

Ketamine has a short half-life that is dependent

upon the route of administration, but is generally 3. Medical Uses

1–3 hours.[64] Most of the parent drug is metabolised

via N-demethylation by the cytochrome P450 en- Ketamine is used selectively in both European

zyme CYP2B6, and eliminated from the body with- and American hospitals in a variety of procedures in

in 24 hours, although prolonged effects, due to the paediatric, obstetric and geriatric patients to provide

presence of active metabolites, may occur ((Au- a range of functions, from analgesia for minor pro-

thor: please provide a reference)). The majority of cedures, such as bone marrow aspiration, to opera-

a ketamine dose is excreted in the form of hydroxyl- tive analgesia and use in intensive care units.[2]

ated and conjugated metabolites ((Author: please Within adult medicine, it has been used to augment

AUTHOR PROOF

8Wolff & Winstock

opiate-induced analgesia, preventing the develop- bling subjects to become emotionally aware of their

alcohol dependence, resulting in the “harmonisation

ment of tolerance and dose escalation[10] and is

of personality and changes in life values, spirituality

effective transdermally and intra-articularly.[67]

and purpose, with these values favouring a sober

Doses for intravenous analgesia are <1 mg/kg, with

lifestyle” ((Author: which paper is this quote

oral doses being much higher (100–300mg). Anaes-

from?)). More recently, ketamine-enhanced psy-

thesia is achieved at doses of 5–10 mg/kg, though in

chotherapy has been used for heroin addiction. High

such cases it is often combined with

dose intramuscular ketamine (2.0 mg/mg/kg) report-

benzodiazepines to reduce cardiovascular stimula-

edly reduced craving and achieved longer periods of

tion and emergence phenomena. Dissociation occurs

abstinence ((Author: than what other treat-

at doses as low as 50–100mg.[2,66,68]

ment?)).[80]

This novel range of effects has allowed ketamine As well as having clinical utility in humans,

to be used in entrapment situations,[69] high altitude ketamine is also widely used in veterinary practice,

anaesthesia[70] and war zones.[50] Potential new uses especially where large animals may be uncoopera-

are continually being explored; recently ketamine tive and may require the administration of sedation

was found to be useful in reducing prolonged aura in at a distance (e.g. free-ranging giraffes and goril-

some patients with migraine,[71] in controlling status las).[21,81,82]

epilepticus[72] and, perhaps more surprisingly, in the

treatment of major depression.[73] It was also found

to be useful in the management of neuropathic and 4. Research Uses

cancer pain,[36,74] although a review of ketamine in

chronic pain management reported that the evidence The psychotogenic and cognitive effects of

for its efficacy was moderate-to-weak.[75] It has been ketamine have led to the drug being used as a

regarded by some as the anaesthetic agent of choice pharmacological model for studying transitory

in several specific clinical conditions, for example schizophrenic-thought disorder in healthy sub-

in children undergoing radiotherapeutic procedures jects.[83] Given to healthy volunteers, subanaesthetic

and for repeated anaesthesia in difficult circum- doses of ketamine result in a range of positive and

stances, such as patients with burns.[76] Additionally, negative schizophrenic-like symptoms,[17,84] as well

a major benefit of ketamine use is that it is one of the as perceptual disturbances similar to those found in

rare anaesthetic agents that does not cause hypoten- dissociative states.[16]This has led to the so-called

sion; this benefit is used to best advantage in emer- ‘NMDA hypothesis’ of schizophrenia,[85] which has

gency departments in treating patients with serious been a subject of debate for >25 years.[86] Reports

trauma and hypovoleamic shock.[73] suggest that diminished glutaminergic neurotrans-

mission may contribute to the dysfunction seen in

In a qualitative Iranian study,[77] ketamine was

schizophrenia, especially positive symptoms,[87]

investigated for its ‘releasing’ effect on 100 patients

through modulation of the dopaminergic sys-

with neurotic and psychosomatic symptoms. The

tem.[88,89]

majority of patients reportedly reacted with symp-

toms of regression, introversion and emotional in- Furthermore, in stable patients with schizophre-

stability, and subsequent psychotherapy proceeded nia, ketamine administration has been demonstrated

more easily. Ketamine has also been used in combi- to provoke a relapse of acute positive symptomatol-

nation with psychotherapy with the explicit aim of ogy.[90] Recent positron emission tomography (PET)

making use of its psychedelic effects. The studies of induced psychotic states in human volun-

‘psychedelic therapy’ of ketamine has been used in teers suggest that the pre-frontal cortex may be

Russia with purported success for >10 years.[29] involved in mediating the psychotogenic capacity of

Ketamine was reported[78,79] to enhance psychother- NMDA antagonists, as they demonstrate a relation-

apy in the treatment of alcohol dependence by ena- ship between ketamine-induced increases in pre-

AUTHOR PROOF

Use and Misuse of Ketamine 9

frontal metabolic activity and conceptual organisa- The use of ketamine as a research tool to study

the pathophysiology of psychosis and as a screen to

tion.[90]

evaluate new drug action[98] has raised concerns in

Other PET studies have demonstrated the signifi- terms of possible distress inflicted on patients. The

cant role of dopamine in mediating the psychoactive potential for adverse effects and the serious long-

effect of ketamine.[88] Using healthy volunteers, term effects that might be induced by the symptom-

some studies have demonstrated that ketamine leads stimulating action of ketamine have led to the view

to an increase in dopamine levels in the ventral that its use for this purpose is unethical ((Author:

striata ((Author: please provide a reference)),please confirm that rewording is okay)). This has

which correlates well with heightened mood. Other led to several review papers that address the ques-

studies have demonstrated an increase in nucleus tion of prolonged psychological effects as a result of

accumbens dopaminergic activity.[91] The release of the administration of ketamine in the general popu-

dopamine within the ventrotegmental dopaminergic lation[99,100] and in North American institutions;

pathway (the ‘reward circuit’) is considered as cen- these reviews concluded that there was no evidence

tral in the mediation of dependence and is seen with for long-lasting events nor increased distress.[101]

most drugs of abuse.[64] Preclinical studies in rats ((Author: please check referencing in this sen-

suggest that receptors other than dopamine D2 are tence -the earlier clause mentions ‘these reviews’,

involved in the mediation of the effect of ketamine, then the latter clause has a singular reference,

as clozapine, but not haloperidol or risperidone, which is different again.)) Lahti et al.,[102] conclud-

block the metabolic effect ((Author: please clarify ed that in controlled environments, in which there is

what you mean by “metabolic effect”. Thank a high regard for subject safety, ketamine as an

you)) of ketamine in the brain.[58] High ((Author: investigative probe caused no adverse long-term

okay?))doses of olanzapine, however, are known to (9-month follow up) events. Work is urgently re-

achieve blockade of the metabolic effect ((Author: quired in areas where ketamine is used in uncon-

see previous query about this term)) of trolled environments ((Author: please confirm

ketamine.[92] that rewording is okay)).

Ketamine is also useful as a research probe in

studies of the modulation of opioid neurobiology, 5. Recreational Uses

where it has been found to attenuate the develop-

ment of tolerance to opioids ((Author: “interfer- The recreational use of ketamine was first report-

ence” with what?)).[93] It has also been found to ed in 1971 in North America ((Author: please

suppress morphine withdrawal in experimental set- reference the report. Thank you)), although Jan-

tings (e.g. in a preclinical study in rats) without sen[61] reported that as early as 1967 ketamine was

interference.[94] In addition, Krystal et al.[8] reported being used for non-medical purposes. Some have

that the production of ethanol-like subjective effects suggested that recreational use in North America

by ketamine supports the potential clinical impor- may have been linked to returning Vietnam veterans

tance of NMDA receptor antagonism among the who had experienced it on the battlefield.[103,104]

mechanisms underlying the subjective effects of Intellectual hedonism with ketamine was popu-

ethanol in humans. larised in the 1970s and 1980s, particularly in the

NMDA receptor antagonists, including ketamine, US, and periodic reports of its abuse by healthcare

appear to protect neurons against toxic assault such professionals gradually appeared.[12,105] Used in a

as ischaemia through the inhibition of calcium in- wide variety of settings by users seeking different

flux[95,96] and in certain clinical situations may be experiences, ketamine has been reported to have the

neuroprotective, as in the case of dopaminergic advantage of being easy to consume, with the clear

metamfetamine toxicity.[97] dose response effect and relatively short half-life

AUTHOR PROOF

10 Wolff & Winstock

reportedly making the effects easier to titrate than 5.1 Ketamine and the Dance Scene

LSD.[103]

Ketamine first appeared in the UK in the gay

Over the past decade there have been a growing dance scene during the early 1990s. Gay media

number of reports on the non-medical, unauthorised observers noted that with many early users adhering

use of ketamine in the UK,[13] Sweden,[14] Austra- to strict set and setting rituals ketamine was consid-

lia[27] and in the US (particularly, ((Author: ered by some to be an elitist drug.[108,109]In the dance

okay?))New York).[106] scene setting, ketamine has been used in two forms,

as a powder (under various pseudonyms such as K,

Ketamine can be obtained for recreational use in Super K, Special K, Vitamin K, Green, Mean Green

a number of preparations: as crystalline powder for and Jet) and as capsules and ampoules specifically

intranasal use (100–400mg per dose) and in liquid, sold with ketamine as the marketable content.

powder or capsular form (350–500mg per dose) for In the UK, a substantial quantity of ketamine for

ingestion. Ketamine has also been smoked and has non-medical use is brought in from countries where

been reportedly available as an intranasal spray. The it is legally manufactured (e.g. China and India).[110]

favoured route of administration is nasal, with users The remainder is diverted from hospitals and veteri-

inhaling a powdered formulation. nary clinics or purchased entirely legally from a

A standard street dose of ketamine in a Scottish wide range of chemical companies in Amsterdam,

Germany and France ((Author: please reference)).

study was typically one-eighth of a gram usually

In the US, ketamine now tends to originate from

taken intranasally, with effects lasting for approxi- legitimate Mexican pharmacies, although up until

mately 1 hour. Unlike dance-scene users, partici- the late 1990s most ketamine was reportedly divert-

pants in this study reported using ketamine in a ed from legitimate medical supplies at Fort Dodge

carefully pre-planned setting, emphasising comfort laboratories in Illinois.[111]

and familiarity.[107] There is wide variation in con- Ketamine has also appeared as a constituent of

sumption patterns among users. Experienced con- tablets purporting to be ‘ecstasy’, often in combina-

sumers, who have developed tolerance to the drug, tion with a stimulant drug, such as ephedrine, usual-

use ≥1g of ketamine over the course of an evening/ ly legally purchased from a German chemical com-

weekend ((Author: please confirm that reword- pany. The surprise of experiencing immobility or

ing is okay)).hallucinations when empathy and euphoria were

expected must come as a shock to unassuming rav-

The particular brand of pharmaceutical ketamine

ers.[108]

may make a difference to the drug effects. KetalarAlong with sodium oxybate (gamma hydrox-

contains a preservative (an anticholinergic agent, ybutyrate; GHB), ketamine has become a recent

benzethonium chloride) that has a significant effect addition to the thriving ‘polypharmacy’ of club-land

upon the brain and Ketamine 500 ((Author:  or drug use ((Author: please confirm that rewording

? Reference to “Astrapin” removed, as manu- is okay)). The frequent use of more than one drug

facturers of other brands have not been identi- consumed over a relatively short period of time is

fied – is this okay, or is the drug also known as common in the dance scene. Drug-drug interactions

“Astrapin”?)) contains the toxic organic preserva- resulting from poly-substance use with a combina-

tive (chlorobutanol), which has shown harmful ef- tion of drugs from the same drug class or with the

fects in some animal experiments.[15] There are some same physiological effects (e.g. respiratory depres-

reports of ‘freebasing’ ketamine, produced by the sion) are cumulative. There are few reports, howev-

removal of benzethonium chloride and salts from er, about the effects of ketamine used in combina-

Ketalar to achieve fewer unwanted adverse effect- tion with other compounds ((Author: please con-

s.((Author: please provide a reference)) firm that rewording is okay)). Combining

AUTHOR PROOF

Use and Misuse of Ketamine 11

psychoactive substances is the single most risk- the US, seizures of ketamine by the Drug Enforce-

producing behaviour of club drug users and usually ment Administration in 2001 increased by >500%

involves alcohol.[112] ((Author: compared to what?)),[114] while in Hong

Kong, ketamine has unseated use of ecstasy ((Au-

Estimating the prevalence of ketamine use within thor: as what – the most frequently used illegal

a recreational-use population is difficult. Appealing drug?)). Of all reported drug users in Hong Kong in

and available to certain populations only and not 2002 under the age of 21, 59% were using

routinely asked about in household or community ketamine.[110]

surveys, ketamine users are a hidden group. Within

the dance scene there are some estimates, which at 5.2 Sought-After Effects of Ketamine

least suggest that although ketamine is not as popu-

lar as cocaine or ecstasy (methylenediox- Ketamine is most frequently used for its

ymetamfetamine), its increasing availability and use psychedelic properties, sometimes as a dance drug

is attractive to some polydrug users.[108] In 1996, a and sometimes to ‘explore the mind’.[115] Others

study by the British-based charity organization, Re- have reported using ketamine to ‘experiment’ or to

lease, reported that 30% of 520 clubbers surveyed in ‘feel good’ and to enhance social activities.[116]

the UK had tried ketamine.[13]

Ketamine use for recreational purposes has been

A survey of Australian ecstasy users in 1997 described as a “collection of paradoxes” because of

found that ketamine was identified as one of the its many effects otherwise associated with other

‘other drugs’ having been used, with 6% of respon- substances. For instance, ketamine has been associ-

dents using the drug within the previous 6 ated with ‘cannabis-like imagery’, ‘alcohol-like in-

months;[28] in 2001, ketamine use had increased to toxication’, ‘cocaine-like stimulation’ and ‘opiate-

15% of respondents.[113] like calming’.[117] Some users describe being put

In 1999 ((Author: please clarify this date, as into ‘overdrive’ and will seek this particular state.

the reference that you give at the end of this Further exploration of the reasons for ketamine use

sentence was published in 2001)), a survey of over may help provide information on the growth of use

1100 UK clubbers reported a lifetime prevalence of of this drug.

ketamine use of 25% (half of these in combination As described by Tim Leary, the ‘godfather’ of

with ecstasy). The level of use tended to be low with hallucinatory hedonism, ketamine is “the ultimate

only 13% of respondents reporting use of >20 occa- psychedelic journey”.[118] The collective term for the

sions and <5% reporting use on >100 occasions; use myriad of experiences associated with the use of

within the last month was only reported by 4%.[108] higher doses of ketamine is the “K hole”, which

Another study of a similar population, but with a refers to the place ‘where users are’ when under the

slightly smaller sample group, suggested that the use influence of ketamine.[106] Reported experiences are

of ketamine had become more widespread, with wide ranging and include emergence and toxic ef-

35% of respondents reporting use ((Author: on how fects, such as out-of-body experiences; temporal and

many occasions?)) and 30% reporting use within spatial distortion; a sense of floating, rebirthing and

the last month ((Author: please confirm that re- experiencing evolution; sudden insights into the

wording is okay)).[104] Although ketamine may ini- meaning of one’s existence; tactile and visual distor-

tially be thought of as an odd choice of drug, given tion; and hallucinations (table II). Sometimes the K

its dissociating and immobilising effects, the drug hole can reproduce the features of a ‘near-death’

has marked stimulatory effects at low doses and any experience, including buzzing, ringing and

immobility may be reduced by the concurrent use of whistling sounds at the beginning and travel through

amfetamine, cocaine or ecstasy. a dark tunnel into light at a high speed with intense

Seizures of ketamine intended for non-medical visions.[117] The spectrum of effects is reflected in

use indicate the growth in popularity of this drug. In the different groups of users who choose ketamine

AUTHOR PROOF

12 Wolff & Winstock

for different reasons. For instance, communal troscopy and high-performance liquid chromatogra-

events, where individual or small groups of users phy in order to provide quantitative analytical infor-

participate in sequential administration of the drug mation. However, the results from these confirmato-

throughout the evening, are preferred by some and ry tests are not normally immediately available.

may well evoke different events to the overstimula- Immunoassay tests, which would provide a more

tion of a dance club venue.[103] immediate (non-quantitative) result, are not current-

ly available for ketamine and those available for

5.3 Ketamine and Sexual Assault phencyclidine (the structural analogue) have pro-

duced false-positive results due to cross-reactivity

The media has made great deal of the concept of with ketamine.[123] Consequently phencyclidine im-

“date rape” or “acquaintance rape”, i.e. the use of munoassay tests are not considered reliable as an

drugs by friends or acquaintances of the victim to alternative for when ketamine detection is sought in

facilitate sexual assault. A number of drugs have populations that have access to both drugs.[124]

been implicated in such alleged criminal activities, Postmortem testing for ketamine is relatively

among them sodium oxybate,[119] flunitrazepam[120]

simple and it is picked up on routine screening by

and ketamine.[121] Proven cases are extremely rare, gas chromatography with a nitrogen phosphorous

however. Studies have indicated that alcohol is usu- detector. However, problems can arise with toxico-

ally the predominant drug in such cases, followed by logical testing in the acutely intoxicated live person.

marijuana and benzodiazepines.[119]

Since there is no rapid screen for ketamine intoxica-

Ketamine, however, is a potent anaesthetic with a tion, treating physicians often do not know that the

rapid onset of action particularly when used in- person is under the influence of the drug. The ac-

tranasally, a route favoured recreationally. The dis- counts by the patient or patient’s friends about what

sociative state, which results from ketamine admin- has been consumed may not help further.

istration with amnesia and analgesia, suggests that However, clinicians should consider possible

ketamine might ((Author: or “could” or ketamine use in patients presenting with physical

“should”?)) be included in any forensic examina- damage due to an unexplained accident, disor-

tion of sexual assault cases. Providing specimens for ganised speech, confusion and agitation ((Author:

analysis are collected within 24 hours of the inci- rewording okay?)). Blurred vision, nystagmus,

dent, current technologies allow the detection of body detachment and a lack of awareness of time

most drug classes. However, in patients with a histo- and place may also indicate use (see table IV for

ry of stimulant use, ketamine given in trauma set- further details).

tings has been reported to be associated with pulmo- Development of an assay to screen for ketamine

nary oedema and hypertension ((Author: please would be a useful clinical development, serving

provide a reference. Also, it is unclear how this both staff in accident and emergency departments

relates to discussion on sexual assault – would and those involved in the treatment of addicted

you consider clarifying?)), thus careful history tak- healthcare professionals.

ing and urine toxicological drug screening may be

useful. 6. Adverse Effects

5.4 Toxicological Testing for Ketamine Ketamine use outside clinical supervision is not

Testing for the presence of ketamine in an intoxi- without risks. The effects of the drug are influenced

cated individual is difficult because of the short- by various factors including the route of administra-

acting properties of the drug ((Author: do you tion, the constitution of the individual and any other

mean the short half-life of the drug?)). Neverthe- drugs consumed ((Author: rewording okay?)). Al-

less ketamine can be detected in both plasma and though ketamine has a wide margin of safety in

urine,[122] using gas chromatography and mass spec- clinical practice,[125] and most adverse effects do not

AUTHOR PROOF

Use and Misuse of Ketamine 13

Table IV. Short-term adverse effects of ketamine[17,51,53] ((Author: please check all references – they may relate to an earlier version of

the manuscript))

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

((Author: ok?)) weightlessness

require an overnight admission, recreational use pharmacokinetics of the drug, with the vast majority

may lead to overdosing, which has occasionally (18 of 20) of patients in the Connecticut study

been life threatening.[115] Ketamine has also been discharged from emergency departments within 5

reported in accidental autoerotic deaths in Germa- hours of presentation.[67,71]

ny.[126] In children, inadvertent overdose has been re-

The short duration of effect and rapid onset of ported with 5–100 times the recommended clinical

action when ketamine is taken by intranasal or intra- dose ((Author: please provide a reference)). Ad-

venous routes often leads recreational users to ad- verse effects were reported to include brief respira-

minister repeated doses over the course of a session tory depression without residual effect, implying a

in order to maintain a desired psychoactive effect. wide margin of safety in overdose. This is supported

Being an amnesic it may become difficult to remem- by a review of ketamine deaths in recreational users

ber the total number of doses of ketamine and other in New York, which reported in all cases polysub-

drugs consumed over a session, thus increasing the stance use, most commonly opioids and amphet-

likelihood of an overdose and unwanted prolonged amines, as the cause of overdose rather than

intoxication. ketamine per se.[128] The risks of adverse effects

following polysubstance use has been highlighted in

The principal physical dangers of most non-med- section 5.1. The risk of cardiac overstimulation and

ical usage of ketamine are believed to arise mainly respiratory depression are potential consequences of

from the setting, or an interaction between the user combining ketamine with stimulant drugs (e.g.

and the setting of use,[12] as ketamine can leave the amfetamine, cocaine) and CNS depressants (alco-

user in a confused state. This can result in falls hol, benzodiazepines and opioids), respectively.

(sometimes fatal), drowning and road traffic acci-

dents. The user can also become a victim of crimes, Recreational users of ketamine have reported ex-

such as sexual assault.[103] periencing significant negative effects, to such a

degree that some have either reduced their dose or

The most common complaints in an US case stopped use altogether. In an Australian study,

series of 20 patients who had taken ketamine and which surveyed 100 long-term ketamine users,

presented to a Connecticut hospital[118] were related many reported regularly experiencing an inability to

to sympathetic hyperactivity, such as anxiety, chest speak, blurred vision, lack of co-ordination and in-

pain and palpitations. Not unsurprisingly, tachycar- creased body temperature ((Author: both refs okay

dia was the most common physical finding (table here?)).[28,113] Employment problems were reported

IV). Nystagmus, a common finding after in 20% of the respondents, including vagueness

phencyclidine use, was seen in only three cases. The affecting work performance. Others have reported

most frequent complications reported following residual effects 3 days after use, including semantic

ketamine overdose were severe agitation and memory impairment.[129]

rhabdomyolysis. There have also been case reports

of dystonic reactions ((Author: with over- Recreational users also report a number of ad-

dose?)).[127] The symptoms of ketamine intoxication verse psychological experiences (table IV). Al-

appear to be short-lived and in line with the though the onset of psychological effects occurs

AUTHOR PROOF

14 Wolff & Winstock

more quickly and recedes faster than with LSD, the upon a wide range of cognitive processes, most

notably memory. With disruptive effects mediated

effects are similar, including hallucinations, synaes-

largely through the inhibition of long-term potentia-

thesia, euphoria, depersonalisation and confusion

tion, ketamine has been shown to impair, in an acute

((Author: please reference)). Additionally, power-

sense, both episodic and semantic memory.[29,53,56,79]

ful dissociative or ‘out-of-body’ sensations, which

appear specific to ketamine, have been reported In hospital settings, reassurance and cardiorespi-

((Author: please reference)). Ketamine has a ratory examination are required. The effects of con-

greater propensity than LSD to induce feelings of comitant benzodiazepines are inconsistent, varying

agitation, aggression, and stimulation consistent between compounds and dose. For instance, while

with its stimulant properties, which both preclinical- lorazepam may reduce emotional distress, it appears

ly and clinically have been shown to resemble the to have little impact upon the psychosis or perceptu-

al changes observed with ketamine.[137] Midazolam,

physical effects of phencyclidine.[130-132]

on the other hand, is able to negate the effect of

Very often it is the interpretation of the experi- ketamine on thought process and perceptual disor-

ence by the user, not the effects of the drug per se, der, but has little impact upon mood problems.[118]

that is the problem. The short half-life of the drug Interestingly, haloperidol also has little effect upon

may limit the potential risk of a prolonged ‘bad trip’, the psychosis associated with ketamine, suggesting

although one such episode has been described in the a role for receptors other than D2.[58] Pre-administra-

scientific literature by Johnstone[133] as “cycling into tion with lamotrigine (a drug known to inhibit gluta-

and out of awareness – a frightening experience”. mate release) potentiates the mood elevating quali-

Observers reported a panicked look, defensive ties of ketamine and significantly reduces perceptu-

thrashing of the arms and marked nystagmus. John- al, cognitive and positive and negative symptoms

stone, at the time, warned against giving ketamine to associated with its use.[45]

a patient as a sole anaesthetic agent. It was consid- Predictors of adverse or psychotic episodes with

ered likely that sequential administration, variations ketamine come from studies of anaesthetic patient

in purity, intravenous administration, tolerance and case series. A study of ketamine-induced anaesthe-

the amnesic effects of the drug (which may impair sia in >300 subjects identified premorbid anosogno-

recall of the total dose consumed) could result in sia and paranoia (as assessed by the Minnesota

acute episodes of paranoia, panic and psychosis.[134]

Multiphasic Personality Inventory) ((Author:

Ketamine produces a syndrome of effects in okay?)) as risk factors for experiencing psychotic

healthy individuals who take sub-therapeutic doses disorders after ketamine administration.[138,139]

in a recreational manner. Reactions to low sub-

anaesthetic doses have been illustrated in a number 6.1 Long-Term Effects

of texts[3] and describe disoriented perceptions and

the total loss of an observer consciousness. Accord- The literature on the long-term consequences

ing to the DSM-IV,[124] a ketamine-induced psycho- ketamine use, in isolation from other drugs of abuse,

sis would best fit the criteria for the disorganised or is rather sparse. However, in the late 1970s the long-

the undifferentiated subtype model of schizophre- term effects of ketamine were reviewed,[140] fol-

nia.[135,136] lowed by an editorial 1 year later.[141] These papers

Recreational use of ketamine has been shown to reported prolonged ‘psychic’ phenomena occurring

result in an acute state that has features of positive for periods of ≤1 year in seven separate case reports,

and negative psychopathology, resembling those following the administration of a single dose or two

seen in schizophrenia. In addition, ketamine use also doses of ketamine. However, a larger study (221

produces symptoms that mirror the frontal lobe defi- adults), which investigated psychological changes

cits in cognitive functioning seen in schizophre- following anaesthesia with ketamine compared with

nia.[16] In fact, ketamine exerts significant effects other anaesthetics, found no long-term impairment

AUTHOR PROOF

Use and Misuse of Ketamine 15

of personality or intellectual function, even after 6.2 Tolerance and Dependence

repeated exposures to the drug.[142] ((Author: Animal studies demonstrate the ability of intrave-

please confirm that rewording is okay)) nous ketamine to produce dependence in rat models,

A study nearly 25 years ago[143] of social users of with disruption of operant behaviour on withdraw-

ketamine who had administered the drug nasally, al.[130] Ketamine demonstrates reinforcing efficacy

intravenously or intramuscularly found that long- in animal self-administration models and is found to

be a discriminative stimuli in operant tasks.[137] The

term effects included ‘flashbacks’, attentional dys-

effects of the drug are thus readily distinguishable

function and decreased sociability. Future research from other drugs, indicating that it may be liable to

into the long-term consequences of use should in- abuse ((Author: please confirm that rewording is

clude investigation of social-psychological as well okay)). Ketamine has the ability to release

as physiological parameters. Flashbacks reported dopamine within the reward pathway, which has a

following repetitive use[66] may only be ‘a graininess role in reinforcement ((Author: please confirm

of vision’ under anxiety-provoking circum- that rewording is okay)).[91]

stances.[144] Other long-term consequences of chron- However, ketamine is somewhat unusual in its

ic use have been reported, including anxiety and pharmacodynamics, almost acting as a partial antag-

social withdrawal.[145] Conversely, however, many onist with regard to brain reward enhancements,

users report positive long-term effects, such as being stimulatory at low doses and inhibiting brain

chronic elevation in mood and deeper insights into reward centres at higher doses. Gardener[144] has

self and others.[66]Long-term users also reportedly suggested this paradoxical effect at higher doses

experience stimulant-like weight loss and loss of parallels the experiences of street users of the drug.

appetite during periods of heavy use ((Author: Heavy habitual use has been described,[145] and

please reference)).cases of dependence have also been reported among

anaesthetic staff.[147-149] To date, only one review

Subjective reports of prolonged effects on cogni- has been conducted on ketamine dependence in

tion have also recently been observed. In a study of humans.[150]

37 ketamine users (18 chronic, frequent users and 19 Nevertheless, there is some evidence suggesting

infrequent users), chronic users were significantly the development of tolerance to the behavioural

impaired on tests of semantic and episodic memory effects of ketamine in animals.[151,152] In addition,

3 days after a dose of ketamine.[142] Regular use of several reports have suggested that tolerance to

ketamine may, therefore, lead to long-term cogni- ketamine may develop in individuals who have un-

tive impairment, but this study relied upon self- dergone repeated anaesthesia with ketamine[153-155]

reporting and did not confirm psychoactive drug use and in recreational users.[103,107,156] However, toler-

on the night ((Author: of testing?)). Systematic ance to the analgesic effects of ketamine does not

research is required in this area to support animal seem to develop.[157,158]

evidence that indicates ketamine and phencyclidine, 7. Conclusions

as NMDA antagonists, may be potent neurotox-

ins.[140] ((Author: please confirm that rewording Ketamine is a dissociative anaesthetic with a

is okay))At present, there is no substantial evidence wide range of clinical applications and a wide mar-

that permanent changes in intellectual function or gin of safety in overdose. As a research probe in the

personality can occur as a result of regular ketamine study of schizophrenia, ketamine has given increas-

use,[145] although long-term intravenous use by the ing prominence to the role of glutamate in the aeti-

American psychiatrist Lilly[146] in 1978 did lead to ology of this illness. The marked perceptual and

several admissions for paranoid psychosis, self-re- cognitive psychedelic effects of ketamine have led

ported attentional difficulties and social withdrawal. to a recent rise in its use in the recreational drug

AUTHOR PROOF

16 Wolff & Winstock

3. Stafford P. Contrasting profiles. In: Stafford P, editors.

scene. Somewhat complex in its pharmacology, the Psychedelics encyclopedia. 3rd ed. Berkeley (CA): Ronin Pub

effects of ketamine are highly sensitive to its iso- Inc, 1991: 392-395

4. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of

meric form, which can exert a significant influence C1-581, a new dissociative anesthetic, in man. Clin Pharmacol

upon both monoaminergic and glutaminergic neuro- Ther 1965; 6 (3): 279-86

transmission. When ketamine is administered acute- 5. Adams HA, Wener C. From the racemate to the enantiomers (S)

Ketamine: renaissance of a substance? Anaesthesia 1997; 46:

ly it induces significant disturbance in semantic and 1026-42

episodic memory as well as in attention and higher 6. Grinspoon L, Bakalar JB. The major psychedelic drugs. In:

executive functioning. Long-term use may be asso- Grinspoon L, Bakalar JB, editors. Sources and effects. Ch 2.

New York: Basic Books Inc Pub, 1981: 32-36

ciated with more prolonged deficits in episodic

7. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Ni-

memory, perhaps related to the effects of ketamine trous oxide (laughing gas) is an NMDA antagonist, neuropro-

on synaptic plasticity, long-term potentiation and tectant and neurotoxin. Nat Med 1998; 4: 460-3

neurotoxic effects. Diverted illicit clinical sources of 8. Krystal JH, Petrakis IL, Webb E, et al. Dose-related ethanol-like

effects of the NMDA antagonist, ketamine, in recently detoxi-

ketamine are the main source for recreational non- fied alcoholics. Arch Gen Psychiatry 1998; 55 (4): 354-60

medical ketamine use. Snorted or swallowed, the 9. Ghonheim MM, Hinrichs JV, Mewaldt SP, et al. Ketamine:

drug may be associated with acute cardiorespiratory behavioural effects of subanaesthetic doses. J Clin

Psychopharmacol 1985; 5: 70-7

problems, especially when combined with other 10. Kissin I, Bright CA, Bradley Jr EL. The effect of ketamine on

stimulant drugs and may lead to accidental injury. opioid-induced acute tolerance: can it explain reduction of

Acute adverse psychological reactions may also oc- opioid consumption with ketamine-opioid analgesic combina-

tions? Anaesth Analg 2000; 91 (6): 1483-8

cur and many regular users report ‘grainy’ flash- 11. Gao KM, Saku K, Roberts RC, et al. Ionotropic glutamate

backs following the consumption of ketamine. Al- receptors and expression of N-methyl-D-aspartate receptor

though numbers involved in repeated long-term use subunits in subregions of human hippocampus; effects of

schizophrenia. Am J Psychiatry 2000; 157: 1141-9

appear small, case reports, especially among health- 12. Jansen KL. Non medical use of ketamine. BMJ 1993; 306

care professionals, are cited in the literature. The (6878): 601-2

potential of ketamine as a novel clinical and re- 13. ((Author: please confirm details))Release 1997. Release drugs

and dance survey: an insight into the culture. Release, London

search tool is matched by its abuse potential outside (Contact: Release, 388 Old Street, London EC1V 9LT, UK)

medical settings. 14. ((Author: is this an abstract or a letter?))Skovmand K.

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Clinical outcomes of augmentation cystoplasty in patients suffering from ketamine-related bladder contractures

Article

Jul 2013
INT UROL NEPHROL

To evaluate the outcomes of augmentation cystoplasty in patients with bladder contractures secondary to chronic ketamine abuse. Patients who had received augmentation cystoplasty to treat ketamine-related bladder contractures in two hospitals in our region were reviewed retrospectively. Their history of ketamine consumption, presenting symptoms, history of treatment, surgical information and post-operative conditions were retrieved from clinical records and then summarized. Between 2006 and 2011, four patients (three women and one man), aged 21-30 years (mean 27 years), underwent augmentation cystoplasty for ketamine-related bladder contractures. The duration of ketamine consumption ranged from 3 to 15 years, and all four patients resumed ketamine consumption after surgery. The mean maximal baseline and post-operative bladder capacity was 37.5 cc (range 25-50 cc) and up to 400-500 cc, respectively. Three patients experienced a further deterioration in renal function that was secondary to new-onset ureteral strictures in two cases and to sepsis in the other. At the time of the last follow-up, three patients could void spontaneously and one required regular intermittent catheterization. Ketamine cystitis is an emerging medical condition that requires a multi-disciplinary approach to manage the patients. Simple surgical management of the physical component of the contracted bladder may produce only suboptimal results, and could even cause further problems in some patients. The importance of compliance with post-operative care and abstinence from drug use should be stressed to the patients before surgery. In view of the high complication rate, the option of a simple ileal conduit should also be discussed prior to surgical intervention.

Ketamine and international regulations

Article

Full-text available

Feb 2017

Background: Ketamine is an anesthetic commonly used in low-income countries and has recently been shown to be effective for treatment-resistant depression. However, the illicit manufacturing, trafficking, and nonmedical use of ketamine are increasing globally, and its illicit use poses major public health challenges in many countries. Objectives: To review the nonmedical use of ketamine in selected countries and its regulatory control. Methods: We conducted a review of literature identified from searches of the China National Knowledge Infrastructure (CNKI) (1979-2016) and PubMed databases, supplemented by additional references identified by the authors. Special attention was given to the regulation of ketamine. Results: Illicit manufacturing, trafficking, and use of ketamine appear to have begun on a large scale in several Asian nations, and it has subsequently spread to other regions. Regulations governing availability of ketamine vary across countries, but there is a clear trend toward tighter regulations. Conclusions: As nonmedical use of ketamine and its harmful consequences have worsened globally, stricter controls are necessary. Appropriate regulation of ketamine is important for international efforts to control ketamine's cross-border trafficking and its nonmedical use.

Ketamine in the Treatment of Depressive Disorder

Article

Full-text available

Jan 2014

Peter Šóš

This literature review begins with a rationale for the development of new therapeutic approaches for the treatment of depressive disorder. In the following sections the history of the finding of ketamine‘s antidepressant effect, its pharmacological properties and application routes are summarized. The following is an overview of the existing scientific evidence of ketamine’s efficacy in patients with unipolar and bipolar depression, suicidality and the adjuvant use in electroconvulsive therapy. Finally, the author discusses acute and chronic side effects, safety of repeated administration of ketamine and possibilities of extending the antidepressant effect. The last section summarizes recent findings on the mechanism of the antidepressant effect of ketamine on the molecular level and its effect on neuronal plasticity.

Neuropharmacological basis of vestibular system disorder treatment

Article

Full-text available

Nov 2013

This work reviews the neuropharmacology of the vestibular system, with an emphasis on the mechanism of action of drugs used in the treatment of vestibular disorders. Clinicians are confronted with a rapidly changing field in which advances in the knowledge of ionic channel function and synaptic transmission mechanisms have led to the development of new scientific models for the understanding of vestibular dysfunction and its management. In particular, there have been recent advances in our knowledge of the fundamental mechanisms of vestibular system function and of drug action. In this work, drugs acting on vestibular system have been grouped into two main categories according to their primary mechanisms of action: those with effects on neurotransmitters and neuromodulators dynamics and those that act on voltage-gated ion channels. Particular attention is given in this review to drugs that may provide additional insight into the pathophysiology of vestibular diseases. The critical analysis of the literature reveals that there is a significant lack of information defining the real utility of diverse drugs used in clinical practice. The development of basic studies addressing drug actions at the molecular, cellular and systems level, combined with reliable and well controlled clinical trials, would provide the scientific basis for new strategies for the treatment of vestibular disorders.

Effect of ketamine on oxidative stress following lipopolysaccharide administration

Article

Dec 2013

The aim of this study was to determine the effect of ketamine on oxidative stress and inflammation in the brain and liver in basal state and during systemic inflammation induced by intraperitoneal (i.p.) lipopolysaccharide (LPS) administration. Rats were treated with subcutaneous ketamine (15 or 30 mg/kg) alone, LPS (300 μg/kg, i.p.) or with ketamine (30 mg/kg) and LPS (300 μg/kg, i.p.) and euthanized 4 h later. Lipid peroxidation (malondialdehyde: MDA), reduced glutathione (GSH), nitric oxide (nitrite) concentrations and paraoxonase 1 (PON1) activity were measured in the brain (in the striatum and in the cerebral cortex) and liver. Tumour necrosis factor alpha (TNF-α) was determined in brain tissue. Histopathological assessment and immunohistochemical expression of the apoptotic marker caspase-3 were performed as well. Results: LPS increased oxidative stress in both the brain and liver tissue. Rats treated with ketamine alone exhibited higher MDA concentrations in the brain and liver, whereas brain and liver GSH and nitric oxide concentrations and PON1 activities were depressed compared with the saline control group. Ketamine given to LPS-treated rats resulted in increased MDA compared with either agent alone. GSH concentrations and PON1 activities were markedly depressed in rats given ketamine and LPS. Ketamine decreased the LPS-induced elevation in nitric oxide. Ketamine resulted in increased TNF-α in brain in saline-treated rats and increased LPS-induced TNF-α production. Ketamine resulted in minimal histological damage in cortex, striatum and liver. In rats given ketamine and LPS, both brain injury and liver damage as well as the expression caspase-3 due to endotoxin were increased. Thus, ketamine increased oxidative stress in brain and liver and the release of TNF-α in brain and enhanced the tissue injury during systemic inflammation.

The chiral forms of ketamine as probes for NMDA receptor functions in humans

Chapter

Full-text available

Jan 1991

On Atoms and Human Knowledge

Chapter

Jan 1996

Af Niels Bohr

Effects of Noncompetitive N-Methyl-D-Aspartate Receptor Antagonists on Opiate Tolerance and Physical Dependence

Article

Dec 1995

Keith A. Trujillo

Recent research has demonstrated that N-methyl-D-aspartate (NMDA) receptors, a class of excitatory amino acid receptors, may have an important role in opiate tolerance and physical dependence. Much of the evidence for this has arisen from studies that have examined the effects of NMDA receptor antagonists on these phenomena. This article summarizes research from our laboratory on the effects of NMDA receptor antagonists on opiate tolerance and dependence in rats.

On atoms and human knowledge

Article

Jan 1958
DAEDALUS-US

N. Bohr

Brain reward mechanisms

Article

Jan 2005

E.L. Gardner

NMDA-Sensitive Glutamate Antagonism A Human Model for Psychosis

Article

Dec 1999

A Lahti

The use of animal models for the study of psychosis and new treatment development is inadequate in assessing target psychotic symptoms because animals lack an ability to use language. Despite this deficiency, new antidopaminergic antipsychotic drugs have still become available. However, even these new antipsychotics, although substantially better than the conventional compounds, do not “cure” psychosis or normalize schizophrenic symptoms. The need for new treatment strategies is apparent. The value of a human model, where language is available to describe target symptoms, is clear. Currently, there is an opportunity to use the mild psychotomimetic symptoms induced by a minimal dose of ketamine in normal humans as a model of psychosis. The mental symptoms in this model resemble some of the symptoms of schizophrenia, suggesting the additional possibility that parallel mechanisms of psychosis may occur in schizophrenia and in a ketamine state, creating a potentially viable psychosis model for pathophysiology. This paper includes arguments in support of this human model's application. Several potential outcome measures that can be used to evaluate potentially novel antipsychotics are described. This model has the potential for identifying novel therapeutics because it does not primarily utilize the dopaminergic system. Further delineation of ketamine pharmacology in humans is pivotal to the eventual application of this ketamine model in drug development.

Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans

Article

Mar 1994
ARCH GEN PSYCHIAT

John H. Krystal

Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor.Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured.Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure.Conclusions: These data indicate that N-methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

S05.04 Effect of a subanesthetic dose of ketamine on memory and awareness in healthy volunteers

Article