Original Article

Human and Experimental Toxicology

31(9) 877–886
Long-term ketamine and ketamine ª The Author(s) 2012
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plus alcohol treatments produced DOI: 10.1177/0960327112436404
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damages in liver and kidney

MSM Wai1, WM Chan1, AQ Zhang2, Y Wu3 and DT Yew1

Abstract
Ketamine is one of the common recreational drugs used in rave parties and it is frequently taken with alcohol.
In spite of this, the potential toxicity of ketamine in liver and kidney has not been fully documented. In this
study, ICR mice were treated for periods of 6, 16 and 28 weeks with 30 mg/kg ketamine injected daily intra-
peritoneally, and together with alcohol (0.5 ml of 10% alcohol for each mouse) during the last 4 weeks of the
treatment periods. Our experimental results showed significant damage in liver, including fatty degeneration of
liver cells, fibrosis and increase in liver glutamic oxaloacetic transaminase, proliferative cell nuclear antigen and
lactate dehydrogenase after 16 weeks of treatment with ketamine. Hydropic degenerations of the kidney
tubules were observed as early as 6 weeks of treatment. Long-term ketamine administration (28 weeks) led
to atresia of glomeruli in the kidney. Proteinuria was confirmed in the 67% of the ketamine-treated animals
after 28 weeks of treatment. It was apparent that ketamine when taken chronically (16 weeks of treatment
and thereafter) affected both liver and kidney definitively. The damages in both liver and kidney of these mice
were more severe when the animals were treated with both ketamine and alcohol.

Keywords
toxicology, ketamine, alcohol, liver, kidney, side effects

Introduction and alteration in hyperphosphorylated tau formation

Ketamine was discovered in 1960s. It was used as an
anaesthetic for both human and animals.1 Several
decades later, ketamine lost its favour largely because
of its association with psychic emergence reactions
such as hallucination.1 In the last two decades, it was
used mainly (a) in paediatric surgery; (b) in surgery of
high-risk patients; (c) in veterinary surgery; (d) for
pain relief and analgesia; and (e) for opioid sparring
effects in abusers.1 Clinical usage of ketamine as
anaesthetic and for pain relief might be justified, as
harmful effects were minimal if not frequently
applied.2,3
Unfortunately, in the last 10 years, ketamine has
been used as an abusive agent by the younger gener-
ation in some Asian countries, with a high percentage
of addiction for long term.4 This trend has in fact
begun to spread to America and Europe.5–7 Data from
animal models had demonstrated adverse effects in
the central nervous system due to the long-term keta-
mine treatment; these included neuronal apoptosis
as well as down regulation of sensory8,9 and cerebel-
lar activities.10
Organs other than those of the nervous system
might also be affected. For example, long-term keta-
mine treatment led to inflammation, muscular atrophy
and eventually fibrosis of the urinary bladder11,12 and
decreased motility of sperm in rodents.12 However,
ketamine effect on liver and kidney has never been
1
Brain Research Centre, School of Biomedical Sciences, The
Chinese University of Hong Kong, Hong Kong, China
2
Department of Anatomy, Capital Medical University, Beijing,
China
3
Institute of Hepatobiliary Surgery, Chinese PLA General
Hospital, Beijing, China
Corresponding author:
David T Yew, Brain Research Centre, School of Biomedical
Sciences, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong, China
Email: david-yew@cuhk.edu.hk

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878
studied. Abusers of ketamine usually consumed
ketamine and alcohol together in ‘rave parties’, and
damages attributable to ketamine alone or combined
with alcohol were unclear. It was reported recently
that ketamine and alcohol might potentiate each oth-
er’s action and increase apoptosis in the cerebellum
of treated mouse.10 This report is a new study on
damages inflicted on the liver and kidney by treat-
ment with ketamine alone or ketamine combined
with alcohol.
Methods
Animal studies
Approval for this study had been obtained from the
Animal Experimentation Ethics Committee of the
Chinese University of Hong Kong and the HKSAR
Government (License number: (10-17) in DH/
HA&P/8/2/1 Pt.10). A total of 90 one-month-old male
ICR mice of 30 g each were used. The animals were
randomly allotted into 3 study groups based on the
treatment periods of 6, 16 and 28 weeks. Apart from
the control, each study group was further divided into
two subgroups. One treatment subgroup was treated
with ketamine alone and the other with ketamine
together with alcohol. Daily intraperitoneal (i.p.)
injection of 30 mg/kg ketamine was given to all
experimental group mice. The rationale for the dosage
was documented in a previous article.12 For the com-
bined ketamine and ethanol treatment subgroup,
0.5 ml of 10% ethanol was given orally to each mouse
every day during the last 4 weeks of the study period.
The amount of alcohol administered was based on the
fact that (a) wine normally contained 12% of alcohol
and (b) an average human of 50 kg weight would con-
sume 500 ml of wine per day. This meant that theore-
tically an individual of 50 g weight should use 0.5 ml
alcohol. Since mouse had a much higher metabolic
rate than human,12 we used 0.5 ml for a 30 g mice.
Saline was injected i.p. to the controls of the different
study periods. In this experiment, alcohol was only
given for 4 weeks as the preliminary result indicated
that alcohol–ketamine interaction had drastic effects
on organs as early as 2 weeks after combinational
usage. These data also indicated that longer-term
combinational treatment could lead to a much higher
mortality. Thus, for this first study, we decided on a 4-
week treatment. We might work on ketamine–alcohol
interaction for longer terms in future study. Upon
completion of treatments, all animals were killed by
cervical dislocation and urine samples were collected
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Human and Experimental Toxicology 31(9)
directly from the urinary bladder. Livers and kidneys
were removed and processed as described below.
Histological studies
The kidneys from mice of different subgroups were
divided into midsagittal halves together with the
excised livers and were fixed in 4% paraformalde-
hyde, dehydrated in alcohol, cleared in xylene,
embedded in paraffin and sectioned at 5 mm thickness.
After sectioning, they were deparaffinized, rehy-
drated and immersed in Mayer’s haematoxylin for
5 min. After washing with water, the sections were
dipped in 0.1% acid water and then immersed in
Scott’s tap water for 1 min to develop a blue colour.
They were then immersed in 1% eosin for 5–10 min
to develop a red colour. The sections were then run
through in ascending alcohol series, cleared in xylene
and mounted in Permount.
Sirius red study on the liver. Slides of livers from
control and experimental groups were stained with
Sirius red (Merck Chemicals, Darmstadt, Germany)
for 1 h and further washed in 2 changes of acidified
water to visualize collagen fibres of connective tissue.
After this, the slides were further dehydrated in 3
changes of 100% ethanol, cleared in xylene and
mounted in Permount.
Immunostaining for lactate dehydrogenase. Kidney
and liver sections were first dewaxed, rehydrated and
permeabilized for 10 min with 1 phosphate-buffered
saline (PBS) supplemented with 0.1% Triton-X and
0.05% Tween 20, followed by three rinses for 5 min
each in 1 PBS. The endogenous peroxidase activity
was blocked by 3% hydrogen peroxidase in methanol
for 45 min. After 3 more rinses in 1 PBS, nonspecific
binding was suppressed with 1.5% normal blocking
serum for 30 min. The sections were then incubated
with primary antibodies lactate dehydrogenase-A
(LDH-A (N-14) 1:200; Santa Cruz Biotechnology1,
Inc., Germany; sc-27230) overnight at 4 C. On the fol-
lowing day, sections were rinsed thrice with 1 PBS
before incubation with respective diluted biotinylated
anti-goat secondary antibodies (1:500; Zymed1
Laboratories, Inc., USA; 61-1640) for 2 h and then
rinsed again. Subsequently, the sections were incu-
bated with diluted streptavidin-horseradish peroxidase
(HRP)-conjugated solution (1:500; InvitrogenTM,
USA, 43-4323) for 2 hours and rinsed again. The pos-
itive staining was then visualized by 0.05% 3,30 diami-
nobenzidine tetrahydrochloride in 1 PBS containing
Wai MSM et al. 879

0.01% hydrogen peroxide (H2O2). Then all sections

were dehydrated, cleared and mounted with Permount.

Immunostaining for proliferative cell nuclear antigen.

Similar to the steps described for immunostaining of
LDH, kidney and liver sections were first dewaxed,
rehydrated and permeabilized with 1 PBS, supple-
mented with 0.1% Triton-X and 0.05% Tween 20 for
10 min, followed by 3 rinses in 1 PBS (5 min each),
and subsequent immersion in methanol with 3%
hydrogen peroxidase for 45 min to block endogenous
peroxidase activity. After rinsing with 1 PBS for 3
times and treatment with 1.5% normal blocking serum
for 30 min to suppress nonspecific binding, the sec-
tions were incubated with diluted primary antibodies
against proliferative cell nuclear antigen (PCNA;
1:1000; Abcam1, USA; AB2916) overnight at 4 C.
On the following day, after rinsing thrice with 1
PBS, the sections were incubated with respective
diluted biotinylated anti-mouse secondary antibodies
(1:1000; Zymed1 Laboratories, Inc.; 62-6540) for
2 h and then rinsed again. Subsequently, the sections
were incubated with diluted streptavidin-HRP-
conjugated solution (1:1000; Invitrogen, 43-4323) for
2 h and rinsed again. The positive staining was then
visualized by 0.05% 3,30 -diaminobenzidine tetrahy-
drochloride in 1 PBS containing 0.01% H2O2. The
sections were dehydrated, cleared and mounted with
Permount. The stained slides were then examined
under microscope with magnification at 100, and
the densities of PCNA-positive nuclei of different
subgroups were also compared.
Glutamic oxaloacetic transaminase test for liver
function. Glutamic oxaloacetic transaminase (GOT),
an enzyme found in large amount in the liver, cata-
lyzes the reversible reaction of amino acids. It was
used as an indicator for liver functions of the mice.
The GOT kit (C010, Nanjing Jiancheng Bioengineer-
ing Institute, China) was used for assay. Ten milli-
grams of liver sampled from different subgroups
were weighed and prepared for 1% diluted tissue solu-
tions with 0.75% saline. The diluted solutions were
then centrifuged at 3500 r/min. One hundred microli-
tres of supernatant was removed and added in 500 ml
of substrate solution and incubated at 37 C in a water
bath for 30 min as instructed in the manual. Corre-
sponding references were also prepared. At the end
of the transamination reaction, pyruvate reacted with
newly added dinitrophenylhydrazine (DNPN) to form
the hydrazone complex. The mixture was further
Figure 1. Microscopic study showing fatty degeneration in
liver cells (arrow). Note also very active nucleoli in the
nuclei of these cells (400).
incubated at 37 C in a water bath for 20 min. Five
millilitres of 0.4 mol/L sodium hydroxide solution was
added to provide an alkaline medium for the formation
of a colour complex, the intensity of which was
detected at 505 nm by spectrophotometer (Shimadzu
Corporation, Japan). The activity of the enzyme in each
sample was then quantified and standardized against
the protein contents in the sample.
Protein assay paper test. To detect the presence
of protein in urine, screening test strips for rapid
determination of protein (Medi-Test Combi 3A1,
Germany) were used. The test strip was dipped into
2 ml of fresh urine for approximately 1 s. The test
strip was then compared with the reference colour
scale after 30 s.
Results
Microscopic study of liver from the 6-week ketamine-
treated mice exhibited fatty degeneration of liver
cells. Many of these liver cells had active nuclei
with prominent nucleoli (Figure 1). By 16 weeks of
ketamine treatment, some fibrosis was observed at
the tips of liver lobes in ketamine-treated animals
(Figure 2(a)); while in the control, the corresponding
areas of the livers were relatively clear (Figure 2(b)).
By 28 weeks of ketamine treatment, fibrosis spread
into the parenchyma of the liver in the ketamine-
treated mouse (Figure 2(c)) and the extent of fibrosis

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880 Human and Experimental Toxicology 31(9)

Figure 2. (a) Fibrosis (arrows) was apparent in the 16-week ketamine-treated liver, particularly around the tips of lobules.
Sirius red staining was used for collagen fibres (50). (b) Control liver of equivalent region showed no fibrosis (50). (c)
Ketamine-treated liver in mouse after 28 weeks of treatment showed fibrosis extended into the liver parenchyma (arrow;
200). (d) Ketamine plus alcohol-treated liver of 28 weeks (alcohol treatment in the last 4 weeks) in the mouse showing
extensive fibrosis (arrow; 400). (e) Control liver with no fibrosis (400).

was more abundant in the livers of animals in the
subgroup treated with ketamine plus alcohol, and with
large bundles of collagen fibre reaching the centres of
lobules (Figure 2(d)). Very few collagen fibres were
observed in the parenchyma of the liver of the control
(Figure 2(e)). Immunocytochemistry of PCNA (indi-
cating proliferative nuclei) in the control liver
had very few positive sites (Figure 3(a)), but in the
28-week ketamine-treated and ketamine-plus-alcohol-
treatedsubgroups, the proliferative nuclei (PCNA-pos-
itive) were observed throughout the liver (Figure 3(b)).
A semi-quantitative histogram depicting the densities
of PCNA-positive nuclei (n ¼ 30 fields of 1500 mm2
sizes from each group with magnification at 100) was
illustrated in Figure 3(c). It was clear from this figure
that ketamine plus alcohol treatment induced more

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Wai MSM et al. 881

Figure 3. (a) Control liver shows no significant proliferative cell nuclear antigen (PCNA)-positive proliferating nuclei
(100). (b) Increase in number of PCNA-positive proliferating nuclei (arrow) was observed throughout the livers of the
16-week and 28-week ketamine-treated animals, in this case, the 28-week ketamine-treated mouse liver (200). (c) A
histogram showing the number of proliferative nuclei in the liver of 28-week control, ketamine- and ketamine-plus-
alcohol-treated subgroups (*p < 0.001).

Figure 4. Quantitative analysis of liver enzyme (glutamic-oxaloacetic transaminase: GOT) in the control, ketamine- and
ketamine-plus-alcohol-treated mice after 28 weeks of treatment (*p ¼ 0.048; **p < 0.001; ***p ¼ 0.001).

proliferation of nuclei in the liver than ketamine
treatment alone. The elevation of liver enzyme GOT
was also recorded, with the highest level in the keta-
mine-plus-alcohol-treated subgroup (Figure 4).
Immunohistochemical studies of the liver in addi-
tion reflected an increase in LDH activity in animals
after 6 weeks of ketamine treatment (Figure 5(a))
when compared with the control (Figure 5(b)). LDH
activity in the treated group was spotty and mostly
in scattered droplets (Figure 5(a)). The most intense
activity of LDH was observed in livers from the
28-week ketamine treatment combined with 4-week

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882 Human and Experimental Toxicology 31(9)

Figure 5. (a) Lactate dehydrogenase (LDH) immunohistochemistry in the liver of the 6-week ketamine-treated mouse
showing spotty activities in some cells (100). (b) No activity of LDH was observed in the control mouse (100). (c)
Immunohistochemistry of lactic acid dehydrogenase in the liver of 28-week ketamine-plus-alcohol-treated (4 weeks) mice.
Note high activity inside whole cells (arrow) surrounded by fibrous tissue (T; 100). (d) Immunohistochemistry of lactic
acid dehydrogenase in the liver of 28-week ketamine-treated mouse (arrow). Though many cells had activities, the activity
was not as high as those in Figure c and were spotty in the cells (100).

alcohol subgroup (Figure 5(c)), compared with those
treated with ketamine alone (Figure 5(d)). In the cases
of ketamine–alcohol interaction, LDH activity was
seen inside the whole cytoplasm of cells (Figure
5(c)), while those of ketamine-treated mice were still
spotty and scattered droplet-like (Figure 5(d)). An
estimation of the number of LDH-positive cells
showed that liver after 6 weeks of ketamine treat-
ment had an average of 100 positive cells per
1500 mm2, 130/1500 mm2 after 28 weeks of ketamine
treatment, while in the control, it was 5/1500 mm2. In
the liver of combined ketamine plus alcohol treat-
ment group, there were about 160 LDH-positive
cells per 1500 mm2.
With regard to the kidney, histological changes in
the 6- and 16-week ketamine-treated animals demon-
strated hydropic degenerations in many of the kidney
tubules (Figure 6(a)). By 28 weeks of ketamine
treatment, atresia of glomeruli in the kidney
was observed in both ketamine-treated and ketamine
plus alcohol-treated animals (Figure 6(b)). A rough
estimate showed that the ketamine subgroup had
glomerular atresia of less than 10%, while in the keta-
mine-plus-alcohol-treated subgroup, it was as much
as 20%. Empty space originally occupied by glomer-
ulus was seen in the kidneys from the ketamine-plus-
alcohol-treated subgroup (Figure 6(c)).
Immunocytochemistry of PCNA (proliferating
nuclei) showed positive sites in a few of the kidney
tubules of the control. Some tubules of the 28-week
ketamine-treated mice and most of the tubules from the
ketamine-plus-alcohol-treated subgroup (Figures 7(a, b
and c)) had the highest number of PCNA-positive sites,
followed by the ketamine-treated and then the control.
Figure 7(d) showed the semiquantitation of PCNA
nuclei per field in the kidney (n ¼ 30 per group, size

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Wai MSM et al. 883

Figure 6. (a) Hydropic degeneration of kidney tubules (arrow) in the 16-week ketamine-treated mouse (400). (b) Atresia
of glomerulus in the 28-week ketamine-treated mouse (400). (c) Degenerated glomerulus with space (arrow) in the kidney
of the 28-week ketamine-plus-alcohol-treated mouse (400).

of the field was 1500 mm2 and magnification of
observation was 100) of the three groups.
Proteinuria was observed in 0% of urine samples
from the control, 15% in ketamine-treated and
27% in ketamine-plus-alcohol-treated animals in the
6-week treatment period groups. After 16 weeks of
treatment, proteinuria was detected in 0% of the con-
trol, 40% of the ketamine-treated and 60% in the keta-
mine-plus-alcohol-treated subgroups. By 28 weeks of
treatment, proteinuria was present in 67% of the
ketamine-treated animals and 70% of the animals
with combined ketamine–alcohol treatment while that
of the control remained at 0%.
Discussion
Our results showed definitive pathological and
biochemical changes in both the liver and the kidney
after long-term ketamine treatment and damages
could be aggravated when ketamine was admini-
strated together with alcohol. Preliminary studies in
our laboratory showed that when GOT levels in a
28-week ketamine-treated liver were compared with
those treated with alcohol alone for 28 weeks, they
were equivalent (135 + 18 karmen units versus
137 + 15 karmen units), while the GOT level in the
liver upon combined treatment of ketamine and alco-
hol (for only 4 weeks) were higher (185 + 22 karmen
units). Damages of cells in both organs led to cell
death and fibrosis as well as physiological derange-
ments. Our liver studies indicated very high activity
of LDH after both ketamine and ketamine plus alco-
hol treatment. Since increase in LDH has been linked
to necrosis,13,14 the mode of cell death was probably
by necrosis. Our previous study reported necrotic
cells were also in the kidney.15 This could explain our
observation of the absence of apoptosis (unpublished
data) by the TUNEL technique on the liver cells after
ketamine or ketamine plus alcohol treatment. This
result appeared to have differed from our past report
that ketamine induced apoptosis in the prefrontal cor-
tices, hippocampi of monkey and mice and that

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884 Human and Experimental Toxicology 31(9)

Figure 7. (a) Proliferative cell nuclear antigen (PCNA)-positive sites (arrows) in control mouse kidney (200). (b)
Increase of PCNA-positive sites in the kidney of mouse after 28 weeks of ketamine treatment (arrows; 200). (c) Further
increase in PCNA-positive sites (arrows) in the kidney of mouse that had 28 weeks of ketamine plus alcohol (4 weeks)
treatment (200). (d) Histogram of PCNA-positive sites in kidney of control, ketamine-treated and ketamine-plus-
alcohol-treated (4 weeks) mice after receiving 28 weeks of ketamine treatment (*p < 0.001).

hypertau-positive cells were present in the prefrontal
cortices of the monkey and mice.8,10 In fact, the mode
of ketamine- and ketamine-plus-alcohol-induced cell
death in the internal organs could differ from organ
to organ.
One of our present findings that ketamine up regu-
lates liver enzyme levels agrees with results from
studies on the human.16 Our long-treatment study fur-
ther indicated that liver damage caused by ketamine
(alone or with alcohol) led to cirrhosis. Chan et al.17
observed expression of multiple forms of P450 rat liver
microsomes after 4 days of ketamine treatment at
1080 mg/kg. When ketamine was given in combination
with cocaine or tetrachloromethane, increased oxidative
metabolism or even mortality was documented.17,18 On
the other hand, acute injection of high dose of ketamine
(70 mg/kg) could afford hepatoprotection mediated by
up regulation of haeme-oxygenase 1 and its end
product was carbon monoxide19,20 and down regula-
tion of inducible nitric oxide synthase.21 There was,
however, difference between short duration treat-
ment and long duration treatment.22
Increase in toxicity upon ketamine–alcohol cotreat-
ment could be detected after only a short period of
treatment such as 4 weeks of alcohol in our study. As
we have presently demonstrated, the extent of damage
could be quite alarming when compared with ketamine
treatment alone. This increased toxicity affects not
only the liver and kidney but also the central nervous
system, including peripheral sensory sites.23 Working
on rodents, we observed an exponential increase in
apoptosis and down regulation of blood oxygen images
of functional magnetic resonance imaging activities in
the cerebellum after combined ketamine and alcohol
treatment when compared with those that received
ketamine alone. It could be due to the fact that both
ketamine and alcohol acted on the N-methyl-D-aspar-
tate (NMDA) receptors24,25 which could account for
a much greater extent of damage than a mere additive
effect. Apart from the NMDA receptors, ketamine
could act on other receptors like GABA, glutamate and
NO as well.25,26 Finally ketamine by itself could cause
severe damages as one of its metabolites, hydroqui-
none, would directly fragment the DNA of cells.25
The aim of this study was to evaluate whether long-
term treatment of ketamine could lead to damages in
liver and kidney, in addition to other organs like the
brain and bladder reported earlier.8–12,15 The results
clearly revealed cirrhosis of liver as well as glomeru-
lar damage and tubular necrosis in the kidney.
Acknowledgements
We are grateful to Prof. Chow PH for her English
corrections.

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Wai MSM et al.
Funding
This work was supported by the Beat Drugs Fund Associ-
ation, Hong Kong Government (Project Ref. No.: BDF
100052).
Declaration of conflicting interests
The authors declared no conflicts of interest.
References
1. Annetta MG, Iemma D, Garisto C, Tafani C and
Proietti R. Ketamine: new indications for an old drug.
Curr Drug Targets 2005; 6: 789–794.
2. Bhutta AT. Ketamine: a controversial drug for neo-
nates. Semin Perinatol 2007; 31: 303–308.
3. Persson J. Wherefore ketamine? Curr Opin Anaesthe-
siol 2010; 23: 455–460.
4. Report TIB, Narcotics Division, Security Bureau, Hong
Kong Government, http://www.nd.gov.hk/
5. Hopcroft SA, Cottrell AM, Mason K, Abrams P and
Oxley JD. Ureteric intestinal metaplasia in association
with chronic recreational ketamine abuse. J Clin
Pathol 2011; 64: 551–552.
6. Meyer MR and Maurer HH. Absorption, distri-
bution, metabolism and excretion pharmacogenomics
of drugs of abuse. Pharmacogenomics 2011; 12:
215–233.
7. Wilkins LK, Girard TA and Cheyne JA. Ketamine as a
primary predictor of out-of-body experiences associ-
ated with multiple substance use. Conscious Cogn
2011; 20: 943–950.
8. Sun L, Lam WP, Wong YW, Lam LH, Tang HC, Wai
MS, et al. Permanent deficits in brain functions caused
by long-term ketamine treatment in mice. Hum Exp
Toxicol 2010; 30: 1287–1296.
9. Yeung LY, Wai MS, Fan M, Mak YT, Lam WP, Li Z,
et al. Hyperphosphorylated tau in the brains of mice
and monkeys with long-term administration of keta-
mine. Toxicol Lett 2010; 193: 189–193.
10. Chan WM, Xu J, Fan M, Tsui YM, Wai SM, Lam WP,
et al.. Downregulation in the human and mice cerebella
after ketamine versus ketamine plus ethanol treatment.
Microsc Res Tech. Epub ahead of print 1 August 2011.
DOI: 10.1002/jemt.21052.
11. Yeung LY, Rudd JA, Lam WP, Mak YT and Yew
DT. Mice are prone to kidney pathology after pro-
longed ketamine addiction. Toxicol Lett 2009; 191:
275–278.
12. Tan S, Chan WM, Wai MS, Hui LK, Hui VW,
James AE, et al. Ketamine effects on the urogenital
Downloaded from het.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 24, 2015
885
system-changes in the urinary bladder and sperm
motility. Microsc Res Tech 2011; 74: 1192–1198.
13. Trouton TG, Allen JD, Young IS, Trimble ER and
Adgey AA. Altered cardiac oxygen extraction, lactate
production and coronary blood flow after large dose
transthoracic DC countershocks. Pacing Clin Electro-
physiol 1993; 16: 1304–1309.
14. Zhao R, Fang SH, Lin KN, Huang XQ, Lu YB, Zhang
WP, et al. Pranlukast attenuates hydrogen peroxide-
induced necrosis in endothelial cells by inhibiting
oxygen reactive species-mediated collapse of mito-
chondrial membrane potential. J Cardiovasc Pharma-
col 2011; 57: 479–488.
15. Wai MS, Jiang YL, Chan WM, Tsui YM, Tang HC,
Lam WP, et al. Long term ketamine and ketamine plus
alcohol toxicity—what can we learn from animal
models? Mini Rev Med Chem. 2011 (Submitted for
publication).
16. Madej JA and Stańczyk JF. Effect of ketamine anaesthe-
sia on enzyme activity in organs of dogs and cats.
Anaesth Resuscitation Intensive Ther 1975; 3: 297–303.
17. Chan WH, Sun WZ and Ueng TH. Induction of rat
hepatic cytochrome P-450 by ketamine and its toxico-
logical implications. J Toxicol Environ Health 2005;
68: 1581–1597.
18. Rofael HZ. Effect of ketamine pretreatment on
cocaine-mediated hepatotoxicity in rats. Toxicol Lett
2004; 152: 213–222.
19. Helmer KS, Cui Y, Dewan A and Mercer DW.
Ketamine/xylazine attenuates LPS-induced iNOS
expression in various rat tissues. J Surg Res 2003;
112: 70–78.
20. Suliburk JW, Ward JL, Helmer KS, Adams SD,
Zuckerbraun BS and Mercer DW. Ketamine-induced
hepatoprotection: the role of heme oxygenase-1. Am
J Physiol Gastrointest Liver Physiol 2009; 296:
G1360–G1369.
21. Suliburk JW, Gonzalez EA, Kennison SD, Helmer KS
and Mercer DW. Differential effects of anesthetics on
endotoxin-induced liver injury. J Trauma 2005; 58:
711–717.
22. Sear JW. Ketamine hepato-toxicity in chronic pain
management: another example of unexpected toxicity
or a predicted result from previous clinical and
pre-clinical data? Pain 2011; 152: 1946–1947.
23. Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim
RB, Aarts L, et al. Effect of ketamine on endogenous
pain modulation in healthy volunteers. Pain 2011;
152: 656–663.
24. Zou X, Patterson TA, Sadovova N, Twaddle NC,
Doerge DR, Zhang X, et al. Potential neurotoxicity
886 Human and Experimental Toxicology 31(9)

of ketamine in the developing rat brain. Toxicol Sci
2009; 108: 149–158.
25. Alfonso-Loeches S and Guerri C. Molecular and beha-
vioral aspects of the actions of alcohol on the adult and
developing brain. Crit Rev Clin Lab Sci 2011; 48: 19–47.
26. Sorce S, Schiavone S, Tucci P, Colaianna M, Jaquet V,
Cuomo V, et al. The NADPH oxidase NOX2 controls
glutamate release: a novel mechanism involved in
psychosis-like ketamine responses. J Neurosci 2010;
30: 11317–11325.

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