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REVIEW
published: 29 November 2016
doi: 10.3389/fnhum.2016.00612
Ketamine: 50 Years of Modulating
the Mind
Linda Li1and Phillip E. Vlisides2*
1Department of Internal Medicine, St. Joseph Mercy Hospital, Ann Arbor, MI, USA , 2Department of Anesthesiology,
University of Michigan Medical School, Ann Arbor, MI, USA
Edited by:
Mikhail Lebedev,
Duke University, USA
Reviewed by:
Axel Hutt,
German Weather Service, Germany
Fabio Sambataro,
Fondazione Istituto Italiano di
Technologia, Italy
Yingtang Shi,
University of Virginia, USA
*Correspondence:
Phillip E. Vlisides
pvliside@med.umich.edu
Received: 06 September 2016
Accepted: 15 November 2016
Published: 29 November 2016
Citation:
Li L and Vlisides PE (2016) Ketamine:
50 Years of Modulating the Mind.
Front. Hum. Neurosci. 10:612.
doi: 10.3389/fnhum.2016.00612
Ketamine was introduced into clinical practice in the 1960s and continues to be
both clinically useful and scientifically fascinating. With considerably diverse molecular
targets and neurophysiological properties, ketamine’s effects on the central nervous
system remain incompletely understood. Investigators have leveraged the unique
characteristics of ketamine to explore the invariant, fundamental mechanisms of
anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may
occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top
down”) distribution. This proposed mechanism of general anesthesia has since been
demonstrated with anesthetics in other pharmacological classes as well. Ketamine
remains invaluable to the fields of anesthesiology and critical care medicine, in large part
due to its ability to maintain cardiorespiratory stability while providing effective sedation
and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of
refractory depression and Post-Traumatic Stress Disorder. In this article, we review the
history of ketamine, its pharmacology, putative mechanisms of action and current clinical
applications.
Keywords: ketamine, neuropharmacology, consciousness, anesthesia, functional connectivity, depression,
post-traumatic stress disorder
INTRODUCTION
Fifty years ago, Corssen and Domino (1966) published the first clinical study of ketamine as a
human anesthetic. Ketamine produces an unusual state, sometimes referred to as ‘‘dissociative
anesthesia’’, which was a term coined by Domino’s (2010) wife. During this dissociative state,
patients might appear awake with preserved airway reflexes and respiratory drive, but they are
unable to respond to sensory input (Domino et al., 1965). Ketamine additionally provides excellent
analgesia with an impressive safety profile, making it a popular anesthetic induction agent in a
variety of patient populations and settings.
Although initially developed as an anesthetic, over the past several decades ketamine has been
revealed to have greater potential in the field of medicine. A growing body of literature has
demonstrated the clinical value of ketamine across diverse settings, with emerging roles in pain
medicine and treatment-resistant depression. Concurrently, efforts to uncover the mechanisms
underlying ketamine’s actions are providing researchers with new insights into the relationship
between consciousness and anesthesia.
Since the first clinical report in 1966, ketamine has become arguably the most unique anesthetic
agent used today and also one of the most promising and exciting in terms of its potential. The
purpose of this article is to provide an overview of ketamine’s history, pharmacology, putative
mechanisms and clinical applications.
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Li and Vlisides Ketamine Update
HISTORY
Ketamine’s history begins with phencyclidine, which was first
synthesized in 1956 by chemists at Parke Davis Company
(Maddox et al., 1965) who discovered ketamine’s unique and
fascinating pharmacology. Phencyclidine was capable of causing
the appearance of drunkenness in rodents, delirium in dogs,
cataleptoid states in pigeons and anesthesia in monkeys (Domino
and Luby, 2012). Although demonstrated to be a safe and reliable
anesthetic in humans, it also caused an intense, prolonged
emergence delirium that ultimately made it undesirable for
human use (Greifenstein et al., 1958; Johnstone et al., 1959;
Domino and Luby, 2012).
Efforts were subsequently redirected towards synthesizing
shorter-acting analogs of phencyclidine that would have
similar anesthetic potential but cause less emergence delirium.
Ketamine, then identified as CI-581, was one such agent
developed by Parke Davis consultant and organic chemist
Calvin Stevens in 1962 (Domino, 1980). A structural analog
at one-tenth the potency of its parent drug phencyclidine,
ketamine was subsequently selected for human trials, and the
first human anesthetic dose was administered on August 3,
1964 by two University of Michigan professors: Dr. Edward
Domino of Pharmacology (Figure 1) and Dr. Guenter Corssen
of Anesthesiology. In their initial pharmacological study of
ketamine in 20 humans, Domino and Corssen found evidence
that the drug could be safe and effective for clinical anesthetic
use (Domino et al., 1965). In 1966, they published findings
FIGURE 1 | Dr. Edward Domino as a young faculty at the University of
Michigan. Dr. Domino is now in his 90s, an Emeritus Professor, and still active
as a scientist in the field of neuropharmacology. Photograph provided
courtesy of the University of Michigan Bentley Historical Library.
from the first clinical experiences with ketamine, reporting its
anesthetic effects in 130 patients, aged 6 weeks to 86 years,
undergoing a total of 133 surgical procedures (Corssen and
Domino, 1966). They found that ketamine could rapidly
produce profound analgesia with a unique state of altered
consciousness and a limited duration of effect that could be safely
prolonged with repeated administration. They also reported
minimal side effects and a lack of severe emergence delirium
compared to phencyclidine (Corssen and Domino, 1966). Ketalar
(1970) became the first preparation of ketamine approved by the
food and drug administration (FDA) for human use.
PHARMACOLOGY
Structure
Ketamine is an arylcycloalkylamine that exists as S(+) and
R(−) isomers and is commonly marketed as a racemic mixture
of the two (Figure 2). Isolated S(+) ketamine, which is not
currently available in the United States but marketed in other
parts of the world, has a higher affinity to the binding
site on N-methyl-D-aspartate (NMDA)-receptors and produces
3–4 times greater anesthetic potency than the R(−) isomer
(White et al., 1985). When used intraoperatively, the S(+) isomer
is associated with less cardiac stimulation, less spontaneous
motor activity, better analgesia, more rapid recovery, fewer
psychotomimetic side effects, and a decreased incidence of
emergence delirium (White et al., 1980, 1985). In the more recent
use of ketamine as an antidepressant, mouse studies have shown
the R(−) isomer to be more potent and with less side effects than
the S(+) isomer (Zhang et al., 2014).
Pharmacokinetics and Pharmacodynamics
Administration and Bioavailability
Soluble in both water and lipids, ketamine can be safely
administered through multiple routes: intravenous (IV),
intramuscular (IM), oral, nasal, rectal, subcutaneous and
epidural. IV administration is 100% bioavailable and considered
FIGURE 2 | Structure of Ketamine.
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Li and Vlisides Ketamine Update
the ideal route of administration. However, in certain settings
such as emergencies or with uncooperative patients, IM ketamine
is commonly used and has only a slightly lower bioavailability of
93% (Clements et al., 1982). A summary of ketamine’s common
routes of administration and their respective pharmacologic
profiles is provided in Table 1.
Other routes of administration are less commonly used but
exist as feasible options nonetheless. Intraosseous ketamine,
for instance, has slightly slower anesthetic onset compared
to IV administration (71.3 s and 56.3 s, respectively; Aliman
et al., 2011) but may be used in emergency settings. Ketamine
can also be administered intranasally, though it has a lower
bioavailability of approximately 45% (Yanagihara et al., 2003)
and can vary depending on the amount absorbed through
nasal mucosa and the amount swallowed. Due to ketamine’s
extensive first-pass metabolism, rectal and oral formulations
have limited bioavailability with relatively high concentrations of
the active (but less-potent) metabolite norketamine (Malinovsky
et al., 1996; Chong et al., 2009; Rolan et al., 2014). Historically,
these routes are used infrequently in humans, though increasing
efforts are being made to develop suitable oral and sublingual
formulations given the recent move towards using low-dose
ketamine for pain and depression in the outpatient setting
(Chong et al., 2009; Rolan et al., 2014).
Distribution, Metabolism and Excretion
Due to ketamine’s high lipid solubility and relatively limited
protein binding, it is rapidly taken up by the brain and
redistributed, with a distribution half-life of only 10–15 min
(Wieber et al., 1975; Domino et al., 1984). Ketamine has a
large volume of distribution of nearly 3 L/kg (Clements and
Nimmo, 1981). Once in the body, ketamine undergoes liver
metabolism to several metabolites (Clements and Nimmo, 1981).
Of note, metabolism through cytochrome systems forms the
active metabolite norketamine, which retains anesthetic activity
but at one-third the potency of ketamine (Cohen and Trevor,
1974; Domino et al., 1984). Inactive ketamine conjugates and
metabolites are renally excreted (Wieber et al., 1975), and
elimination half-life is 2–3 h (Domino et al., 1984).
Dosing
Ketamine’s wide therapeutic range makes it one of the safest
anesthetics available. General anesthesia can be induced with
both IV and IM routes (Table 1) and maintained with repeated
doses of 0.5–1 mg/kg (Domino et al., 1984). Good analgesia
and sedation can also be achieved at subanesthetic doses (e.g.,
0.2–0.8 mg/kg IV, 2–4 mg/kg IM), and infusions at subanesthetic
doses (e.g., 0.5 mg/kg/h) may also provide continuous sedation
and analgesia (Allen and Macias, 2005; Miller et al., 2011).
Systemic Effects
Cardiovascular
At both subanesthetic and anesthetic doses, ketamine is
predominantly a sympathomimetic, producing increased arterial
pressures and heart rate (Corssen and Domino, 1966) through
direct stimulation of central nervous system structures (Traber
et al., 1970). At higher doses (e.g., 20 mg/kg), however, ketamine
also acts as direct myocardial depressant (Traber et al., 1968), and
in the setting of compromised autonomic control (e.g., spinal
cord transection, catecholamine depletion), these depressive
effects may be unmasked. Ketamine also causes direct relaxation
of vascular smooth muscle, though due to its sympathetically-
mediated vasoconstriction, it has a relatively stable net effect on
systemic vascular resistance (Diaz et al., 1976; Akata et al., 2001;
Jung and Jung, 2012).
Pulmonary
Ketamine does not cause clinically significant respiratory
depression in patients (Corssen and Domino, 1966), though
arterial hypoxemia following rapid IV infusion of ketamine
has been reported (Zsigmond et al., 1976). In fact, low-dose
TABLE 1 | Basic pharmacologic profiles of ketamine.
Route Dose∗Bioavailability Tmax(minutes) References
IV 1–4.5 mg/kg 100% 3 Weber et al. (2004)
IM 6.5–13 mg/kg 93% 5–10 Clements et al. (1982)
Intranasal 0.5–1 mg/kg 8–45%†10–20 Yanagihara et al. (2003)
Huge et al. (2010)
Andolfatto et al. (2013)
Yeaman et al. (2014)
PO 0.25–0.5 mg/kg 17–29%†30 Grant et al. (1981)
Clements et al. (1982)
Chong et al. (2009)
Blonk et al. (2010)
Rolan et al. (2014)
Rectal 9–10 mg/kg 11–25% 30–45 Idvall et al. (1983)
Pedraz et al. (1989)
Malinovsky et al. (1996)
∗Dosages may vary depending on clinical setting; anesthetic doses provided per manufacturer labeling for intravenous (IV) and intramuscular (IM) routes. Representative
analgesic doses and bioavailability data are outlined for intranasal, oral (PO) and rectal routes. †Intranasal and PO absorption vary significantly. Tmax, time to maximum
plasma concentration; mg, milligram; kg, kilogram.
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Li and Vlisides Ketamine Update
ketamine may actually stimulate respiration and is observed
to produce higher flow-rates, respiratory rates and duty-cycle
(inspiratory time divided by total respiratory cycle time) in
animal models (Eikermann et al., 2012). Ketamine is also unique
in its ability to preserve upper airway reflexes during anesthesia,
uncoupling the loss of consciousness with the loss of upper
airway dilator muscle activity (Eikermann et al., 2012). Ketamine
further increases genioglossus muscle activity (Eikermann et al.,
2012); this elevates and pushes the tongue forward, increasing
upper airway diameter to further prevent its collapse (Oliven
et al., 2003).
Despite the fact that a patent airway is usually maintained
during exposure to ketamine, attention to airway protection
remains essential, as partial obstruction and aspiration are still
possible. Ketamine may increase salivary secretions (Corssen and
Domino, 1966) and potentially increase the risk of laryngospasm,
but this is rarely reported (Green et al., 2010). Other respiratory
effects of ketamine include bronchodilation, likely through
vagolytic and other neurally mediated mechanisms (Brown and
Wagner, 1999). At high doses, ketamine may also directly affect
airway smooth muscle, but this effect is unlikely to be of clinical
importance (Brown and Wagner, 1999).
Neurological
Because ketamine increases cerebral metabolism, it can
potentially increase intracranial pressure (ICP) and has been
used cautiously in patients with space-occupying cerebral lesions
brain injury (Gardner et al., 1971; Shaprio et al., 1972; Wyte
et al., 1972). However, when used in combination with propofol
or midazolam, effects on cerebral perfusion are comparable to
other commonly used, opioid-based combinations (Bourgoin
et al., 2003, 2005; Wang et al., 2014). Ketamine has also been
safely used in patients with elevated ICP while helping to
maintain optimal hemodynamic profiles (Bourgoin et al., 2003;
Schmittner et al., 2007). In fact, in some cases, ketamine’s
cerebral effects may be neuroprotective and potentially
beneficial for brain trauma patients (Albanèse et al., 1997;
Bar-Joseph et al., 2009). This includes ketamine’s inhibition
of spreading cortical depolarizations after traumatic brain
injury (TBI), an effect that may attenuate the extension of
ischemic damage to healthier peri-ischemic tissue (Hertle et al.,
2012).
Side Effects, Toxicities, Interactions and
Abuse
Ketamine has multiple dose-dependent side effects, though
most of which are self-resolving. Adverse effects include
hypersalivation, hyperreflexia and transient clonus (Corssen and
Domino, 1966). Ketamine may also cause vestibular-type
symptoms including dizziness, nausea and vomiting.
Cardiopulmonary toxicity is rare, with effects limited to
those caused by the transient sympathetic activation such as
tachycardia, hypertension and palpitations (Weiner et al., 2000;
Strayer and Nelson, 2008). Given ketamine’s wide therapeutic
range, death by overdose is rare and usually involves other
intoxicants or in the setting of trauma (Moore et al., 1997; Gill
and Stajic, 2000).
The psychoactive properties associated with ketamine
limit widespread clinical use. Even at subanesthetic doses
(i.e., 0.1–0.4 mg/kg; Krystal et al., 1994), patients may experience
perturbing dissociative symptoms. One study described
ketamine at such doses producing four main psychological
effects (Pomarol-Clotet et al., 2006): (1) a feeling of intoxication,
comparable to the effects of other anesthetics and sedatives;
(2) perceptual alterations in visual, auditory and somatosensory
domains concomitant with symptoms of depersonalization
or derealization; (3) referential ideas and delusions, often
of misinterpretation and thought disorder; and (4) negative
symptoms such as poverty of speech.
More recently, cystitis and various lower urinary tract
pathologies (e.g., detrusor over-activity) have also been reported
in long-term ketamine users (Chu et al., 2008; Tsai et al.,
2009). Ketamine abuse is also associated with gastrointestinal
symptoms, including biliary dysfunction, epigastric pain and
hepatic injury (Poon et al., 2010; Lo et al., 2011; Wong et al., 2014;
Yu et al., 2014), though these adverse effects may be reversible
with abstinence (Zhou J. et al., 2013; Wong et al., 2014; Yu et al.,
2014).
While ketamine’s psychedelic effects limit clinical use, they
have made ketamine a popular recreational drug. At lower
doses, stimulant effects predominate, and users experience mild
dissociation with hallucinations and a distortion of time and
space. Higher doses induce more severe, schizophrenia-like
symptoms and perceptions that are completely separate
from reality (Wolff and Winstock, 2006; Niesters et al.,
2014). Although these effects resolve approximately 2 h
after acute ketamine use, long-term use can cause more
pronounced and persistent neuropsychiatric symptoms,
including schizophrenia-like symptoms, cognitive impairment
and poor psychological well-being (Morgan et al., 2009, 2010;
Liu et al., 2016).
Finally, given its CNS modulatory activity, ketamine
should be used cautiously with other drugs that alter mood
and perception, including alcohol, opioids, benzodiazepines
and cannabis. Ketamine metabolism involves cytochrome
P450 enzymes (Hijazi and Boulieu, 2002), and thus, concomitant
use with drugs that inhibit cytochrome P450 metabolism may
lead to inhibited ketamine metabolism and supratherapeutic
toxicity.
PROPOSED MECHANISMS OF ACTIONS
Molecular Targets
Unlike the IV and inhaled anesthetics in common clinical use,
ketamine is not thought to act primarily through the potentiation
of gamma-aminobutyric acid (GABA) transmission. Early work
on the mechanisms of ketamine found that it reduced neuronal
excitation by NMDA, the agonist for which the glutamatergic
receptor type is named (Anis et al., 1983). Ketamine was
found to block excitatory postsynaptic potentials in rat cortical
pyramidal cells (Thomson et al., 1985) and frog spinal cord
neurons (Martin and Lodge, 1985) in a manner consistent
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Li and Vlisides Ketamine Update
with NMDA antagonism; these data were supported by studies
in the central nervous system of the lamprey (Yamamura
et al., 1990). Subsequently, mouse models with altered NMDA
receptor subunits showed attenuated responses to ketamine
(Petrenko et al., 2004; Sato et al., 2004). In fact, ketamine-
mediated NMDA receptor antagonism of GABAergic inhibitory
interneurons is a postulated mechanism of disinhibition and
psychosis (Homayoun and Moghaddam, 2007; Brown et al.,
2011).
Ketamine non-competitively antagonizes the NMDA receptor
by at least two distinct mechanisms: as an open-channel blocker,
binding to a site within the channel pore to occlude the
channel and reduce mean open time, and through an allosteric
mechanism to decrease channel opening frequency (Orser et al.,
1997). Ketamine also has a slow off-rate (86% trapping) and
is an example of a high-trapping antagonist of the NMDA
receptor, similar to MK-801 (dizocilpine, nearly 100% trapping).
Thus, even after glutamate dissociates from the NMDA receptor,
ketamine remains trapped in the closed ion channel and causes
continued blockade. Conversely, NMDA receptor antagonists
with a fast off-rate (low-trapping), such as memantine, (50–70%
trapped) escape the channel before it closes, producing less
blockade of physiological NMDA function. This results in fewer
side effects (e.g., sedative or psychotomimetic) and an NMDA
antagonist without ‘‘appreciable anesthetic effects’’ (Sleigh et al.,
2014).
In addition to NMDA-antagonism, ketamine acts on a
wide-range of other targets, contributing to its unique effects and
uses (Table 2). For instance, ketamine’s relaxant effect on airway
smooth muscle has been attributed to its inhibition of L-type
voltage-dependent Ca2+channels (Yamakage et al., 1995).
Inhibition of calcium channels may also contribute to observed
psychodysleptic effects such as dysphoria, psychosis, altered
perception and impaired verbal fluency (Baum and Tecson,
1991). A block on monoamine transport systems is also thought
to contribute to psychotomimetic and sympathomimetic
effects (Nishimura et al., 1998), and recently, a compelling
case has been made that hyperpolarization-activated cyclic
nucleotide (HCN) channels—sometimes referred to as neuronal
pacemaker channels—significantly contribute to ketamine-
induced hypnosis (Chen et al., 2009; Zhou C. et al., 2013).
These channels may mediate the hypnotic effects of volatile
anesthetics as well (Zhou et al., 2015). Although ketamine
appears to play a role in opioid potentiation (Finck and Ngai,
1982; Smith et al., 1987; Pacheco et al., 2014), antinociceptive
effects mediated by opioid receptors may vary based on receptor
subtype (Mikkelsen et al., 1999; Pacheco et al., 2014). Inhibition
of serotonin reuptake is another suggested as a mechanism
by which ketamine may confer analgesic effects (Martin et al.,
1982), and ketamine’s block of large-conductance KCa channels
(BK channels) preferentially suppresses spinal microglia
hyperactivation after nerve injury and may explain its potent
effects on neuropathic pain (Hayashi et al., 2011). More recently,
a novel mechanism for activation of α-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid (AMPA) receptors by the
(R,S)-ketamine metabolite (2S,6S;2R,6R)-hydroxynorketamine
has been implicated in the rapid, antidepressant-like properties
TABLE 2 | Receptor and channel targets of ketamine and related clinical
effects.
Antagonism/Inhibition
NMDA receptors •Dissociative anesthesia, amnesia
(Oye et al., 1992)
•Inhibited sensory perception
(Oye et al., 1992)
•Analgesia (Oye et al., 1992)
HCN channels •Hypnosis
(Chen et al., 2009; Zhou C. et al., 2013)
Calcium channels (L-type
voltage-dependent)
•Negative cardiac inotropy (Baum and
Tecson, 1991)
•Airway smooth muscle relaxation
(Yamakage et al., 1995)
Voltage-gated sodium channels •Decreased parasympathetic activity
(Irnaten et al., 2002)
•Local anesthetic effect (Frenkel and
Urban, 1992; Haeseler et al., 2003)
BK channels •Analgesic effects on neuropathic pain
(Hayashi et al., 2011)
Agonism/Activation
Opioid receptors (particularly µ,δ)•Central antinociception (Finck and Ngai,
1982; Pacheco et al., 2014)
AMPA receptors •Rapid antidepressant effects (Zanos et al.,
2016)
GABAAreceptors •Anesthetic properties (Irifune et al., 2000)
NMDA, N-methyl-D-aspartate; HCN, Hyperpolarization-activated cyclic nucleotide;
BK, Large-conductance potassium channels; AMPA, α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid; GABAAR, γ-aminobutyric acid A receptor.
observed with ketamine (Zanos et al., 2016). Gonadal hormones,
such as estrogen and progesterone, may also potentiate the
rapidity and potency of ketamine’s antidepressant effects, as
demonstrated in preclinical models (Carrier and Kabbaj, 2013;
Franceschelli et al., 2015; Hashimoto, 2016). Lastly, ketamine
interaction with GABA receptors has been implicated in various
clinical pathologies, including obsessive-compulsive disorder
(Rodriguez et al., 2015), depression (Perrine et al., 2014) and
learning disabilities following chronic exposure (Tan et al.,
2011).
Not surprisingly, ketamine’s immediate effects on its various
targets cause altered downstream processes. Ketamine’s block of
Ca2+influx through NMDA antagonism may, for instance, lower
the activity of protein kinase C (PKC) and other intracellular
signals, which could then induce altered protein phosphorylation
or signaling. In rodent models, systemic ketamine administration
suppresses immediate early gene expression (zif/268, c-fos, junB,
fosB, c-jun, junD) in the cortex and hippocampal dentate gyrus
after mechanical brain injury (Belluardo et al., 1995). It also
decreases NMDA receptor 1 phosphorylation (Mei et al., 2010)
and affects mRNA expression implicated in rodent models of
hyperalgesia (Ohnesorge et al., 2013). Ketamine acutely increases
hippocampal proteins brain-derived neurotrophic factor (BDNF;
Garcia et al., 2008; Yang et al., 2013) and mammalian target
of rapamycin (mTOR; Yang et al., 2013), which may also help
to explain the mechanism for its rapid antidepressant effects.
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Li and Vlisides Ketamine Update
Indeed, investigation into ketamine’s antidepressant effects
have led to several reports that ketamine may affect various
brain regions through epigenetic mechanisms, such as histone
deacetylase modulation (Reus et al., 2013; Choi et al., 2015) and
increased BDNF mRNA expression (Duman and Voleti, 2012).
Systems Neuroscience
At the systems neuroscience level, ketamine’s mechanisms
are markedly distinct from drugs such as propofol or the
halogenated ethers. Unlike most anesthetics, ketamine does
not appear to activate the sleep-promoting ventrolateral
preoptic nucleus of the hypothalamus; rather, ketamine activates
subcortical wake-promoting nuclei (Lu et al., 2008). This
is paralleled in ketamine’s unique neurochemistry. Unlike
most other inhaled and IV anesthetics, ketamine increases
levels of the arousal-promoting neurotransmitter acetylcholine
in the cortex (Pal et al., 2015) and it depends, in part,
on noradrenergic transmission for its full effect (Kushikata
et al., 2011). Ketamine is the only sedative-hypnotic that
maintains or increases thalamic metabolism (Langsjo et al.,
2005). Neurophysiologically, ketamine—unlike propofol and
sevoflurane—increases electroencephalographic activity around
40 Hz (Lee et al., 2013), but—like other anesthetics—suppresses
high gamma activity (Pal et al., 2015) and increases delta power
(Lee et al., 2013).
Ketamine is also known to alter neuromodulation of
various neurotransmitter systems. It reduces cholinergic
neurotransmission by acting as a non-competitive and voltage-
dependent inhibitor of nicotinic acetylcholine ion channel
receptors, particularly in β1 subunit-containing receptors
(Yamakura et al., 2000). It appears to reduce acetylcholine
release in the medial pontine reticular formation (mPRF),
which may in part explain its ability to alter arousal and
breathing (Lydic and Baghdoyan, 2002). Unique to most
other anesthetics, ketamine produces stimulatory effects on
noradrenergic neurons in the medial prefrontal cortex (mPFC;
Kubota et al., 1999), and more recently, it has also been shown to
raise ACh levels in the PFC during anesthetic dosing (Pal et al.,
2015). Despite increased cholinergic tone in the PFC, however,
high-frequency gamma activity and cortical coherence were both
suppressed, suggesting that ketamine-induced unconsciousness
is characterized by dissociation of cholinergic tone and cortical
activation, possibly mediated by suppression of the NMDA
receptors on both pyramidal and inhibitory neurons. Thus, with
preserved activation of subcortical arousal nuclei and increased
cholinergic tone, ketamine-induced loss of consciousness may
occur via higher-level mechanisms, as evidenced by fragmented
cortical coherence and attention of high-frequency gamma
activity (Pal et al., 2015). Disrupted cortical communication and
information transfer may in fact be a common mechanism of
loss of consciousness across diverse pharmacological classes of
anesthetics (Lee et al., 2013), as will be discussed further below.
Network Connectivity
Despite the differences of ketamine’s actions at the molecular
and systems neuroscience levels, there appears to be a
common network-level effect that might explain the common
functional outcome of lost responsiveness induced by ketamine
and the primarily GABAergic anesthetics. Ketamine has
been found to functionally disrupt corticocortical connectivity
with anesthetic dosing, and this pattern seems to follow
a frontal-to-posterior direction (Figure 3;Lee et al., 2013;
Blain-Moraes et al., 2014; Schroeder et al., 2016). This
frontal-to-posterior disrupted cortical connectivity has been
proposed as a mechanism of general anesthesia, having
been demonstrated across a broad range of anesthetic drug
classes during loss of consciousness (Lee et al., 2013).
Previous electroencephalographic studies have used indirect,
surrogate measures of information transfer—such as transfer
entropy and phase lag index—to demonstrate disrupted
connectivity during anesthetic-induced loss of consciousness
(Lee et al., 2013; Blain-Moraes et al., 2014). Bonhomme
et al. (2016) presented functional MRI data from human
volunteers whereby ketamine disrupted cortical connectivity
between frontal and posterior cortices, while auditory and
visual network integrity was maintained. A recent study
used intracranial recordings to demonstrate direct, structural
interruption of corticocortical sensory information transfer
during ketamine-induced anesthesia in macaque monkeys
FIGURE 3 | Measures of directed connectivity after induction with
Ketamine, adapted from Blain-Moraes et al. (2014).Graphical depiction
of dominant feedback connectivity in the waking state that is neutralized after
ketamine induction. Please see original article (Blain-Moraes et al., 2014) for
additional information.
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Li and Vlisides Ketamine Update
(Schroeder et al., 2016). During anesthesia, somatosensory
information transfer was maintained through thalamocortical
pathways, though corticocortical information transfer was
inhibited. This study showed direct evidence of inhibited
information transfer along structurally connected cortical
pathways. Thus, collectively, there is accumulating evidence
that ketamine disrupts corticocortical information transfer
in the frontal-to-posterior direction while preserving sensory
network function during anesthesia. These findings contribute
to a higher-order, network-level understanding of the neural
correlates of consciousness and also shed further insight into the
‘‘dissociative’’ anesthetic nature of ketamine.
Subanesthetic ketamine administration has recently
been shown to alter functional connectivity patterns as
well, with possible mechanistic implications for depression.
Wong et al. (2016) found that subanesthetic ketamine
administration disrupted functional connectivity between
the subgenual anterior cingulate cortex, which is involved
with the modulation of mood (Davey et al., 2012), and a
network cluster involving the thalamus, hippocampus and
the retrosplenial cortex. Using a ketamine infusion dose often
used for the treatment of depression, Muthukumaraswamy
et al. (2015) demonstrated reduced functional connectivity
in frontoparietal networks concomitant with an increase
in blissful feelings. Thus, modulation of brain connectivity
patterns might also provide a network-level mechanism for
ketamine’s effects on depression. As patients in these studies
were not reported to lose consciousness, there may be a
dose-dependent component to the disruption of functional
connectivity.
CLINICAL USES IN MEDICINE
Ketamine has enjoyed expanded clinical relevance since its early
development and is now being actively used or explored in a
number of clinical fields (Table 3).
Anesthesia
Ketamine’s rapid onset, safety, and hemodynamic stability have
made it a useful anesthetic induction agent, especially in certain
patient populations or settings where its characteristics are
particularly advantageous.
Hemodynamic Instability
Ketamine’s effects of sympathetic activation may make it
beneficial for use in hemodynamically unstable patients (e.g.,
traumatic injury, septic shock). In septic patients requiring
emergency intubation, ketamine may also be a safer alternative
to etomidate, which may cause adrenal insufficiency and is
associated with higher in-hospital morbidity in such patient
populations (Jabre et al., 2009). However, caution should still
be observed, as the cardiac depressant effects may hasten
cardiovascular compromise in catecholamine-depleted states
(Waxman et al., 1980; Dewhirst et al., 2013).
Pediatrics
The ability to administer ketamine intramuscularly has made
it advantageous for patients in which IV administration may
be difficult, including neonates, infants and young children.
Together with the ease of administration, efficacy and safety
profile in children, ketamine has become one of the most
commonly used drugs for procedural sedation and analgesia for
children in emergency departments (ED; Haley-Andrews, 2006;
Bhargava and Young, 2007). However, anecdotal observations
suggest a higher risk of airway complications with ketamine
in infants less than 3 months of age (Green and Johnson,
1990; Green et al., 2011), likely due to infant-specific differences
in airway reactivity and anatomy rather than ketamine itself.
Furthermore, although emergence reactions in children and
teenagers are rare and typically mild, risk factors for recovery
agitation have emerged. Two clinically pertinent risk factors
are: (1) low IM ketamine dosing (<3.0 mg/kg), which may
not provide suitable analgesia but still increases agitation; and
(2) unusually high IV ketamine dosing (>2.5 mg/kg), which
increases the risk of airway complications and emesis (Green
et al., 2009). Finally, the use of ketamine as an opioid-sparing
agent in children has recently been challenged by a large
meta-analysis (Michelet et al., 2016), though this may have
been from lack of power given the studies available. Further
investigation into ketamine’s effects in children is certainly
warranted.
Traumatic Brain Injury (TBI)
Despite historic concerns that ketamine may cause harmful
increases in ICP, recent reports have challenged this with
evidence that ketamine can be safely and effectively used in
TABLE 3 | Summary of clinical uses for ketamine.
Anesthesia Analgesia and sedation Psychiatry and neuroscience
Advantageous settings:
•Hemodynamic instability
•Pediatric patients
•Uncooperative patients
•Traumatic brain injury
•Bronchospasm
•Battlefield/Mass casualty
Acute settings:
•Procedures
•Burns
•ED Agitation/Pain
•Post-operative
pain
Chronic settings:
•Cancer pain
•CRPS
•Phantom limb pain
•Fibromyalgia
•Ischemic pain
•Migraines
Emerging use:
•Depression
•Suicidal ideation
•PTSD
Modeling:
•Schizophrenia
•Consciousness
ED, emergency department; CPRS, complex regional pain syndrome; PTSD, post-traumatic stress disorder. Please see text (“Clinical Uses in Medicine” Section) for
associated references.
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Li and Vlisides Ketamine Update
patients with head injuries or risk of intracranial hypertension
(Bourgoin et al., 2003, 2005; Wang et al., 2014). In fact,
ketamine may have beneficial effects, including protection
against seizures, cerebral ischemia or secondary brain injury
related to hypotension (Albanèse et al., 1997; Bar-Joseph et al.,
2009).
Bronchospasm
Ketamine’s bronchodilating properties make it an attractive
anesthetic induction agent for patients with active
bronchospasm. Of note, however, ketamine may predispose
patients to laryngospasm through its stimulation of copious
secretions, but the incidence of this appears to be relatively rare
(Green et al., 2010).
Trauma Medicine
Upon being marketed as a human anesthetic in the 1970s,
ketamine quickly became a popular battlefield anesthetic and
continues to be used in military conflict (Mercer, 2009). Its
pharmacological properties and ease of administration allow it
to be a safe and effective option for anesthetic use in pre-hospital
settings, including mass casualty events (Ashkenazi et al., 2005).
Moreover, ketamine’s emerging role in affective disorders may
have the potential to protect patients in these settings from
developing stress-induced disorders (Brachman et al., 2016).
Analgesia and Sedation
Unlike most other agents, ketamine offers the important
advantage of being able to provide both profound analgesia and
adequate sedation without significantly compromising airway
reflexes or respiratory function (Corssen and Domino, 1966).
It is thus often used in acute clinical settings, though there is a
growing interest in its role as a chronic therapeutic agent as well.
Acute Setting
Procedural sedation
Ketamine is frequently used in the ED for procedural sedation.
IM administration has made it an especially popular choice
for sedation in children who may otherwise be uncooperative.
Although not as frequently used in adults for this purpose
due to an increased likelihood of emergence delirium (1–2% in
children vs. 10–20% in adults; Strayer and Nelson, 2008), this
can effectively be reduced with benzodiazepine administration
(Dundee and Lilburn, 1978; Perumal et al., 2015) or with the
co-administration of propofol (Willman and Andolfatto, 2007;
Andolfatto and Willman, 2010).
Burn medicine
Historically, ketamine has played a prominent role in burn
care protocols, providing effective analgesia and sedation for
burn patients who must undergo debridements, grafts, and
repeated dressing changes (Demling et al., 1978; Hondorp, 1987;
Canpolat et al., 2012; Kundra et al., 2013) without compromising
the airway or respiratory function. Furthermore, the ability to
administer ketamine intramuscularly and even orally provides
an additional advantage in burn patients who have extensive
scarring that might make IV administration challenging.
Acute agitation
Ketamine is also used to treat acutely agitated and violent patients
in the ED. Even among agitated patients who are intoxicated,
ketamine does not appear to have any major adverse effects on
physiological stability (Hopper et al., 2015). However, additional
pharmacological treatment is often required in these patients,
suggesting that ketamine may be useful only for initial control
of severe agitation in this setting (Hopper et al., 2015).
Acute pain
More recently, low-dose ketamine infusions have been advocated
to provide pain relief in the ED. Administering a 15 mg bolus
of IV ketamine followed immediately by a continuous infusion
at 20 mg/h for 1 h may significantly improve pain scores
while maintaining stable vital signs and high patient satisfaction
(Ahern et al., 2015).
Postoperative pain
The use of ketamine infusions has been shown to be an opiate-
sparing technique in managing post-operative pain following a
variety of surgeries, including abdominal (Guillou et al., 2003;
Webb et al., 2007; Zakine et al., 2008; Kaur et al., 2015), thoracic
(Michelet et al., 2007; Nesher et al., 2008, 2009; Chazan et al.,
2010), orthopedic (Adam et al., 2005; Kollender et al., 2008;
Cha et al., 2012; Akhavanakbari et al., 2014), spinal (Kim et al.,
2013) and gynecological (Sen et al., 2009; Suppa et al., 2012).
However, others have not observed ketamine to have significant
clinical benefits or opioid-sparing effects in postoperative pain
management (Jensen et al., 2008; Sveticic et al., 2008; Reza
et al., 2010; Yeom et al., 2012). These discrepant results may be
explained by variation in dosing strategies, patient profiles and
other co-administered analgesics.
Chronic Setting
Cancer pain
Ketamine’s potentiation of opioid analgesia and opioid-sparing
effect may be useful in cancer patients who otherwise require a
high-dose of opioids, although as stated above, there is currently
conflicting evidence surrounding ketamine’s effects on opioid
requirements. While ketamine’s use as an adjunct analgesic has
been demonstrated by randomized control trials (Yang et al.,
1996; Mercadante et al., 2000) and smaller studies and case
reports (Fine, 1999; Tarumi et al., 2000; Kannan et al., 2002;
Amin et al., 2014), the evidence remains inconclusive, as others
have not found any net clinical benefit by using ketamine as a
part of the analgesic regimen in cancer pain (Hardy et al., 2012;
Salas et al., 2012). As above with postoperative pain, inconsistent
findings may result from variations in study design.
Non-cancer pain
Ketamine is increasingly used as an adjunct in treating chronic
pain states and appears to provide analgesia through its
direct NMDA-receptor antagonism as well as modulation of
descending inhibitory paths of pain often implicated in chronic
pain states (Niesters et al., 2013). For example, ketamine has
been used as an analgesic in patients with complex regional
pain syndrome (CPRS: Correll et al., 2004; Finch et al., 2009;
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Li and Vlisides Ketamine Update
Schwartzman et al., 2009; Sigtermans et al., 2009). IV and
oral ketamine have also been reported to alleviate symptoms
of phantom limb pain (Shanthanna et al., 2010; Mitra and
Kazal, 2015), though one case report demonstrated exacerbation
of pain after IV ketamine, possibly due to ketamine-induced
hallucinations (Sakai and Sumikawa, 2014). Ketamine can also
attenuate key mechanisms in fibromyalgia patients, such as
muscle and referred pain (Graven-Nielsen et al., 2000); however,
these infusions may only provide short-term analgesic relief
(Noppers et al., 2011). Ketamine is also an effective analgesic in a
variety of chronic pain cases, such as ischemic pain (Liman et al.,
2015), migraine with aura (Afridi et al., 2013), breakthrough pain
in chronic pain states (Carr et al., 2004), and in patients with
developed opioid tolerance or previous opiate abuse (Chazan
et al., 2008; Dahi-Taleghani et al., 2014).
Psychiatric Uses
Depression
There has been surging interest in the use of ketamine as a
potential therapeutic agent for affective disorders, particularly
depression. Even a single-dose of ketamine may cause rapid
antidepressant effects in otherwise treatment-resistant cases
of bipolar (DiazGranados et al., 2010b; Ibrahim et al., 2011;
Kantrowitz et al., 2015) and major depression (Zarate et al.,
2006; Murrough et al., 2013). Remarkably, this also includes the
acute reduction of suicidal ideation (DiazGranados et al., 2010a;
Larkin and Beautrais, 2011; Zigman and Blier, 2013; Murrough
et al., 2015). Recent neuroimaging studies support potential
anti-anhedonic and anti-depressant effects, demonstrating its
ability to alter glucose metabolism in regions implicated in mood
disorders (Lally et al., 2014, 2015; Nugent et al., 2014). Repeated
ketamine doses may improve depressive symptoms comparable
to—and perhaps even more rapidly than—electroconvulsive
therapy (ECT; Ghasemi et al., 2014), and it may even be
successful in treating ECT-resistant depression (Ibrahim et al.,
2011). Despite its observed promising antidepressant effects,
however, more rigorous investigation is needed to establish
its clinical use as an antidepressant. The current evidence
is limited by bias, small sample sizes, and limited data on
important cofounding variables. In fact, a recent Cochrane
Review determined that the efficacy of ketamine as an
antidepressant may be limited beyond 1 week (McCloud et al.,
2015).
Post-Traumatic Stress Disorder (PTSD)
One of the newer applications of ketamine is its role as
a potential treatment for Post-Traumatic Stress Disorder
(PTSD), although studies examining this remain limited (Feder
et al., 2014; Donoghue et al., 2015). For instance, Feder et al.
(2014) found that ketamine may reduce symptom severity
of PTSD more rapidly than midazolam; however, they did
not exclude previously depressed patients, and the observed
results may have been due—in part—to ketamine’s known
antidepressive effects. A case reported by Donoghue et al.
(2015) describing ketamine-induced remission of PTSD
and disruptive symptoms in a child similarly provides
inconclusive evidence for effects of ketamine specific to
PTSD. While it is postulated that ketamine may be useful in
preventing the development of PTSD through the induction
of stress resilience (Brachman et al., 2016), more research
is clearly needed to better define ketamine’s effects on
PTSD.
Models of Schizophrenia
Since its discovery, ketamine has been observed to produce
symptoms similar to those of schizophrenia. As a result,
researchers have used these drugs extensively as models to study
schizophrenia. While it now appears that overlaps in symptoms
and even receptor effects are insufficient to explain the complex
neuropathology of schizophrenia, ketamine and has undoubtedly
facilitated and stimulated research efforts into understanding
schizophrenia (Domino and Luby, 2012).
CONCLUSIONS AND FUTURE
DIRECTIONS
When the first clinical use of ketamine was reported in
1966 in Anesthesia and Analgesia, it quickly became a popular
induction agent among anesthesiologists. Now, 50 years later,
ketamine is increasingly being used beyond the operating room,
demonstrating clinical utility in the fields of emergency medicine,
critical care medicine, pain medicine and psychiatry.
The growing interest of ketamine in a range of settings
and patient populations may reflect an impressive benefit-
to-risk ratio. Unique compared to other anesthetic agents,
ketamine produces potent anesthesia, sedation and analgesia
while maintaining cardiopulmonary stability and airway
patency. Ketamine offers flexible options for administration,
and the adverse psychological effects are often transient
and either prevented by or alleviated with premedication
or combined use with other agents. Nonetheless, the
psychoactive effects often remain the limiting factor for its
expanded clinical use, and just as ketamine was originally
developed to reduce the emergence delirium that prevented
phencyclidine’s use in humans, researchers have now moved
towards developing shorter acting analogs of ketamine
to further reduce the psychogenic effects (Harvey et al.,
2015).
Scientifically, investigators have taken advantage of
ketamine’s complex molecular and neurophysiological
mechanisms of action to gain further insights into the neural
correlates of consciousness. Ketamine appears to inhibit
information transfer in cortical networks (Bonhomme et al.,
2016; Schroeder et al., 2016), which may be a shared mechanism
by which diverse anesthetics induce unconsciousness (Lee
et al., 2013). Perturbations in cortical network connectivity
also correlate with pathological brain states, such as depression
(Muthukumaraswamy et al., 2015; Nugent et al., 2016), and
ketamine-induced alterations in connectivity patterns may
subserve its antidepressant effects (Muthukumaraswamy
et al., 2015; Nugent et al., 2016). Indeed, ketamine is being
used as a tool for probing the mind to further inform our
neurobiological framework of consciousness and altered brain
Frontiers in Human Neuroscience | www.frontiersin.org 9November 2016 | Volume 10 | Article 612
Li and Vlisides Ketamine Update
states, and lines of investigation are actively ongoing (Mashour,
2016).
Over the past 50 years, countless patients have benefited
greatly from ketamine. We anticipate many more exciting
discoveries in the next 50 years of investigating its clinical
applications and mechanisms of modulating the mind.
AUTHOR CONTRIBUTIONS
Both authors contributed to the writing of the manuscript,
approved the final version to be published, and are accountable
for manuscript accuracy and integrity. LL: conception, design
and drafting of the initial manuscript. PEV: critical manuscript
review and revision of all final content.
FUNDING
PEV is supported by the National Institutes of Health, Bethesda,
MD, USA, Grant T32GM103730. Funding also provided by the
Department of Anesthesiology, University of Michigan Medical
School.
ACKNOWLEDGMENTS
The authors would like to acknowledge support from the
Department of Anesthesiology at the University of Michigan
Medical School. Additionally, the authors would like to thank
Dr. George Mashour for expert consultation throughout the
manuscript writing process.
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