The document describes a study that investigated the toxic effects of venlafaxine (VEN) on rats. Rats received either a single high dose of VEN (350 mg/kg), or repeated doses of VEN (starting at 100 mg/kg and increasing by 50 mg/kg every 10 days) for 30 days. Both acute and chronic VEN exposure caused clinical signs of toxicity in rats including seizures, coma and death. Biochemical tests and histological examination found evidence of liver and kidney injury in rats exposed to VEN. The study suggests that both single high doses and repeated exposure to high doses of VEN can cause organ toxicity.

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Toxicological Assessment of Venlafaxine: Acute and Subchronic Toxicity
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2. Toxicological Assessment of Venlafaxine:
Acute and Subchronic Toxicity Study in Rats
Melad G. Paulis1
, Essam M. Hafez1
, Nashwa F. El-Tahawy2
,
and Mohmed K. M. Aly3
Abstract
Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most
popular options. Venlafaxine is a nontricyclic dual-acting serotonin–norepinephrine reuptake inhibitor. Although an increased
incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are
still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats
were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg
every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then
assayed: alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase, prothrombin time, partial thromboplastin
time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic
administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even
death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological exam-
ination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful
effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic
doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug
may be addictive.
Keywords
venlafaxine, selective serotonin reuptake inhibitors, toxicity, liver, renal, abuse potential, addiction
Introduction
Venlafaxine (VEN) is a nontricyclic phenylethylamine deriva-
tive antidepressant. The drug was first marketed in the United
States and the United Kingdom in 1994 for the management of
major depressive disorder.1
Venlafaxine is now one of the most
frequently prescribed antidepressants worldwide.2
It is also
indicated for neuropathic pain,3
anxiety,4
fibromyalgia,5
among other disorders.
The main pathway of VEN metabolism is its hepatic
biotransformation to O-desmethylvenlafaxine, N,O-desmethy-
lvenlafaxine, and to a lesser extent, N-desmethylvenlafaxine.
O-desmethylvenlafaxine is the most important active metabo-
lite.6
Venlafaxine and its metabolites are potent inhibitors of
various neuronal reuptake channels in the postsynaptic mem-
brane. Venlafaxine principally acts on the neurotransmitters:
serotonin, norepinephrine, and dopamine. In humans, seroto-
nin is affected by low-dose VEN (<150 mg/d). However,
increasing VEN doses affects both serotonin and norepinephr-
ine (>150 mg/d). Dopamine is altered by higher drug doses
(>300 mg/d).2
In 2014, VEN was described as a new psychoactive sub-
stance by the European Monitoring Center for Drugs and Drug
Addiction.7
Several reports noted the ability of VEN to cause
abuse, with amphetamine-like manifestations. A previous
study8
reported a case report of a patient who used more than
2 g/d for over 2 years. Another case of chronic ingestion of
VEN reported the use of about 2,250 mg/d.9
In an acute toxicity study, a survey was conducted between
2001 and 2011 and found that a dose of 64 mg/kg produced
moderate to severe toxic manifestations. Manifestations
included fever, tachycardia, tachypnea, hypertension, abdom-
inal pain, and seizures.10
A review of the literature reveals that many case reports
describing VEN toxicity are available.6,11-13
The reported
1
Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine,
Minia University, Menia, Egypt
2
Department of Histology and Cell Biology, Faculty of Medicine, Minia
University, Menia, Egypt
3
Psychiatry Department, Faculty of Medicine, Minia University, Menia, Egypt
Corresponding Author:
Melad G. Paulis, Forensic Medicine and Clinical Toxicology Department,
Faculty of Medicine, Minia University, Menia, Egypt.
Email: melad.boulis@mu.edu.eg
International Journal of Toxicology
1-8
ª The Author(s) 2018
Reprints and permission:
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DOI: 10.1177/1091581818777470
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3. toxicity included neurological effects,14
cardiovascular
effects,15
and rhabdomyolysis.16
Other toxic effects include
interstitial pneumonitis17
and prostatism.18
However, only a small number of controlled studies have
detailed poisoning with this drug.19
Although VEN exerts well-
known toxic effects on the nervous and cardiovascular systems,
the potential toxic effects of this drug on other major organ
systems must be investigated. Therefore, the aim of this study
is to investigate acute and subchronic toxicity of VEN in liver,
kidney, and gastric tissues.
Materials and Methods
All experimental procedures were conducted in the Forensic
Medicine and Clinical Toxicology Department, Faculty of
Medicine, Minia University. Adult female Westar rats were
obtained from the Faculty of Veterinary Medicine, Minia
University. Ethical approval for the study was granted based
on the adherence to the guide on the use and care of laboratory
animals accepted by the Committee of Minia University. Female
rats were chosen as their hepatocytes were more sensitive to
hepatotoxicants than that of males.20
Animals were housed in
stainless steel cages under standard laboratory conditions. Ani-
mals were fed standard rat pellets and water was provided ad
libitum. The animals were acclimated in the laboratory for 2
weeks before initiating the experiment. Venlafaxine (Effegad
ER, 75 mg; Hikma Pharma, Cairo, Egypt) was dissolved in
saline immediately prior to oral administration.
This study used 3 groups of rats weighing 200 (7) g (each
group consisted of 20 rats). The control group (group I)
received normal saline via gavage. The acute toxicity group
(group II) was administered a single dose of 350 mg/kg VEN.21
The third group (group III) was treated with 100 mg/kg/d and
the dose was increased by 50 mg/kg every 10 days for 30 days.
Francesconi et al documented that patients addicted to VEN
may use up to 10 to 15 times the therapeutic doses.2
We
selected doses that were 10 times the uppermost human ther-
apeutic dose (225 mg/d; the maximum therapeutic dose recom-
mended for major depression22
) as the maximum dose that will
be given to the animal. The dose conversion from human to
animals was performed using a previously developed formula
depending on the body surface area.23
The following formula
was used24
:
Animal dose ðmg=kgÞ ¼
Human Dose ðmg=kgÞ Â Human Km
Animal Km
;
where Km is a correlation factor that is calculated by dividing
the average body weight of the animal (kg) by its surface area
(m2
): human Km ¼ 37 and rat Km ¼ 6.24
The body weight of the rats was recorded at the start of the
experiment and then every 10 days thereafter. Rats were
observed twice daily for the occurrence of convulsions, coma,
or death throughout the study. A modified Glasgow Coma
Scale was used to assess coma in rats.25
Rats that died of acute
or chronic toxicity exposure to VEN were excluded from bio-
chemical or histological analysis.
Biochemical Analysis
Rats were euthanized by decapitation 24 hours after the
administration of the last drug dose. Blood was collected
(0.5 mL) via cardiac puncture. Blood samples were centri-
fuged for 10 minutes at 5,000 rpm. The separated serum sam-
ples were used to assess kidney and liver function. The levels
of the following enzymes were measured to evaluate liver
injury: aspartate aminotransferase (AST), alanine aminotrans-
ferase (ALT), alkaline phosphatase (ALP), and g-glutamyl
transferase (GGT). Renal function was assessed by measuring
serum creatinine (SC) and blood urea nitrogen (BUN) levels.
The assay used in the present study was an enzyme-linked
immunosorbent assay manufactured by Ranbaxy Diagnostics
Ltd (Hayes, United Kingdom). The prothrombin time (PT)
and partial thromboplastin time (PTT) were measured in sec-
onds. The PT, PTT, and serum albumin levels were assessed
using the available commercial kits (Quimica Clinica Apli-
cada s.a., Tarragona, Spain) following the manufacturer’s
notes.
Histological Studies
The right lobe of the liver, right kidney, and stomach were
excised and then fixed with a buffered 10% formalin solution
for 24 hours. Tissues were then embedded in paraffin, sec-
tioned and stained with hematoxylin and eosin for histological
examination under a light microscope.26
A simple scoring sys-
tem was used to evaluate histological changes of the examined
tissues. Changes were classified as follow: (—) none, (þ) slight
change, (þþ) moderate change, and (þþþ) severe change.
Statistical Analysis
All data are presented as the means (standard deviation) and
were compared using 1-way analysis of variance. As the data
of clinical and histopathological examination did not show
normal distribution, these changes were analyzed by Mann-
Whitney U test with Bonferroni correction. All P values
0.05 were considered statistically significant. All statistical
procedures were conducted using SPSS 22 software on a per-
sonal computer.
Table 1. Clinical Manifestations of Rats Exposed to Acute and
Subchronic VEN Toxicity.a
Acute toxicity (20 rats), % Chronic toxicity (20 rats), %
Seizures 12 (60)b
4 (20)b
Coma 13 (65)b
1 (5)
Death 9 (45)b
1 (5)
Abbreviation: VEN, venlafaxine.
a
Twenty adult female Wister rats were treated with VEN (350 mg/kg) orally
once in acute toxicity and another 20 rats were given with 100 mg/d and
increased by 50 mg/kg every 10 days for 30 days.
b
Significant compared to the control group receiving saline.
2 International Journal of Toxicology XX(X)

4. Results
Clinical Findings
Table 1 summarizes the clinical findings in rats with acute and
subchronic VEN exposure. It is noteworthy that seizures devel-
oped after 30 minutes of VEN administration in rats of the
acute toxicity group. Two rats developed convulsive twitches.
Myoclonic jerks were observed in another 2 rats. Three rats
developed myoclonic jerks that progressed to generalized
tonic–colonic seizers. Generalized tonic–clonic convulsions
were reported in 5 rats from the start. Seven rats that developed
generalized convulsions died. In the chronic toxicity group,
only 4 rats developed mild convulsive states. Symptoms ranged
from ear and facial twitches to convulsive twitches. Twitches
repeated 3 to 4 times in the past 10 days of the study. In acute
toxicity study group, death occurred in 9 rats (7 after general-
ized convulsions and 2 without preceding convulsions). Death
occurred within 2 hours after VEN administration. A signifi-
cant reduction in body weight was observed in rats chronically
treated with VEN (Table 2).
Biochemical Results
A single treatment with a high dose of VEN produced liver
injury in rats. Table 3 shows significant increases in AST, ALT,
ALP, and GGT levels in rats that were acutely and chronically
treated with VEN. The PT was significantly diminished in both
treatment groups. The liver function tests in the subchronic
group differed from the control group but did not show the
same extent of changes as the acute exposure group.
Regarding the renal functions, the exposure to acute dose of
VEN impaired kidney function. Significant elevations in the
BUN and SC levels were observed. Subchronic treatment with
VEN also altered the kidney function (Table 3).
Histological Results
The control group showed the normal architecture of the gastric
tissue (Figure 1A and B). In acute VEN toxicity, there were
limited changes in the gastric mucosa in the form of edema of
the gastric mucosa that widely separated the gastric glands
(Figure 1C and D). The subchronic administration of VEN for
30 days induced numerous superficial mucosal ulcers, degen-
erated and vacuolated cells of the gastric glands, and submu-
cosal inflammatory cell infiltration.
The histological examination of hepatic tissues showed the
normal hepatic architecture of the control group (Figure 2A).
Rats receiving a single LD50 dose of VEN showed a loss of
lobular architecture with markedly degenerated hepatic tissue
and inflammatory cell infiltration. Additionally, some degen-
erated areas showed interstitial hemorrhage; apoptotic hepato-
cytes with densely stained cytoplasm and pyknotic or
fragmented nuclei were also observed (Figure 2B and C). The
subchronic toxicity group showed less impairment of liver
function and pathology than the acute exposure group. Liver
sections from rats treated with VEN for 30 days showed dis-
tortion of the architecture, dilated blood sinusoids, and
Table 2. Changes in the Mean Body Weight (in g) of Rats Treated With 100 mg/d VEN Orally and Increased by 50 mg/kg Every 10 days for 30
Days.
Chronic toxicity group at
the start of treatment
Chronic toxicity group: 10 days
after the start of treatment
Chronic toxicity group: 20 days
after the start of treatment
Chronic toxicity group: 30 days
after the start of treatment
Weight, mean
(SD)
203 (9) 187 (11)a
180 (10)a
173 (9)a
Abbreviations: SD, standard deviation; VEN, venlafaxine.
a
Significant at P < 0.05 (compared to the starting weight).
Table 3. Effects of VEN Administration on Liver and Kidney Functions in Adult Female Rats.a
Control (20 rats) Acute toxicity (11 rats) Chronic toxicity (19 rats)
Aspartate aminotransferase (AST, U/L) 21.1 (4.7) 95 (10.21)b
76 (9.65)b
Alanine aminotransferase (ALT, U/L) 12.32 (5.1) 102 (12.64)b
124 (13.42)b
Alkaline phosphatase (ALP, U/L) 32.81 (6.23) 178 (11.20)b
134 (12.46)b
g-Glutamyl transferase (GGT, U/L) 19.29 (4.56) 60.32 (6.70)b
45.43 (7.34)
Prothrombin time (PT, seconds) 10.34 (1.02) 16.45 (3.51)b
17.34 (2.1)b
Partial thromboplastin time (PTT, seconds) 28.23 (3.2) 44.81 (4.5) 61.67 (5.4)b
Blood urea nitrogen (BUN, mg/dL) 12.1 (1.4) 20.9 (1.5)b
18.1 (3.4)b
Serum creatinine (SC, mg/dL) 1.2 (0.2) 2.6 (0.6)b
2.1 (0.22)b
Abbreviation: VEN, venlafaxine.
a
Twenty adult female Wister rats were treated with VEN (350 mg/kg) orally once in acute toxicity and another 20 rats were given with 100 mg/d and increased by
50 mg/kg every 10 days for 30 days. Data are expressed as mean (standard deviation [SD]).
b
Significant at P < 0.05.
Paulis et al 3

5. degenerated vacuolated cells surrounding the central vein and
portal tract (Figure 2D and E). Histological examination of the
renal sections showed the normal cortical architecture of the
kidney in the control group formed of renal corpuscles and
proximal and distal convoluted tubules (Figure 3A). Acute
toxicity group showed marked congestion of the glomeruli with
interstitial hemorrhage (Figure 3B). The subchronic treatment
with VEN for 30 days produced distortion of the cortical archi-
tecture, tubular degeneration, hyperplasia of some tubules; the
tubular epithelium was formed of multiple layers instead of the
normal single layer, and glomerular hyperplasia (Figure 3C).
Table 4 summarizes the histological changes in the liver, kid-
ney, and stomach using the scoring system.
Discussion
Antidepressants are the most commonly prescribed drugs for
psychiatric treatment, and VEN is one of the most popular
options. Kumar et al27
reported a sharp increase in antidepres-
sant toxicity.
Acute VEN treatment in rats produces a high incidence of
seizures in 60% of exposed rats. Seizures occur at a lower rate
after subchronic treatment (20%). As reported in previous stud-
ies,27,28
seizures are the most common severe complication of
VEN overdose, and the probability of seizures increases as the
dose increases.29
The convulsant effect of VEN is attributed to
its action on dopamine. At high doses, VEN inhibits dopamine
reuptake and increases its presynaptic levels, which induces
convulsions.30
A single LD50 dose of VEN (350 mg/kg) treatment induced
fatality in 45% of rats. Conversely, chronic exposure to high
doses induces death in 6% of exposed rats. Several reports
discussed VEN-associated mortality.31,32
In most circum-
stances, the cause of death is related to cardiovascular
complications.10,33
Figure 1. Photomicrographs of the gastric tissue. A and B, The
control group (group I) showing the normal architecture of the gastric
tissue. Notice the basophilic chief cells (long arrows) and the acido-
philic parietal cells (short arrows). C and D, Group II (venlafaxine
[VEN] acute toxicity) showing edema (*) of the gastric mucosa widely
separating the gastric glands (arrows). E, Group III (VEN subchronic
toxicity) showing numerous superficial mucosal ulcers (arrows). F,
Group III (VEN subchronic toxicity) showing degenerated and
vacuolated cells (long thin arrows) of the gastric glands with predo-
minate parietal cells (short thick arrows) and submucosal inflamma-
tory cell infiltration (circles). Hematoxylin and eosin (H&E): A, C, and
E Â100; B, D, and F Â400.
Figure 2. Photomicrographs of the liver tissues. A and B, The control
group showing the normal lobular architecture. Notice the hepato-
cytes with an acidophilic cytoplasm and rounded vesicular nuclei
arranged in plates (arrows) surrounding the central veins (CV) and
separated by blood sinusoids (S). C, Group II (venlafaxine [VEN]
acute toxicity) showing a loss of the lobular architecture with
markedly degenerated hepatic tissue (D) and inflammatory cell infil-
tration (arrows). D, Group II (VEN acute toxicity) demonstrating a
degenerating area that shows interstitial hemorrhage (H) and apop-
totic hepatocytes with densely stained cytoplasm and pyknotic
(arrows) or fragmented nuclei (double head arrow). E, Group III
(VEN subchronic toxicity) showing dilated blood sinusoids (s), scat-
tered degenerated vacuolated cells (arrows) surrounding the central
vein (CV) or portal tract (PT). Hematoxylin and eosin (H&E): A, C, D,
and E Â400; B Â100.
4 International Journal of Toxicology XX(X)

6. Subchronic administration of high doses of VEN signifi-
cantly decreased the body weight of the treated rats throughout
the experimental period. These results are consistent with find-
ings from previous studies using therapeutic34,35
and toxic
doses.8
According to another study, VEN has no effect on body
weight, in contrast to other antidepressants that led to weight
gain. The authors attributed weight gain to the improved mood
and appetite caused by antidepressants.36
Ratsexposed toa singlehighly toxic doseofVEN(350mg/kg)
or subchronically exposed to an increased dose from 100 to
200 mg/kg daily for 30 days showed significant biochemical
and pathological changes in the liver. To our knowledge, our
study is the first controlled study of the toxic effect of VEN on
the hepatic tissue in laboratory animals. The literature review
identified several published case reports of VEN-induced hepa-
totoxicity in humans.37-40
Most of the reported cases were
exposed to therapeutic doses. In clinical trials, VEN elevated
liver enzymes in 0.4% of the 3,000 patients receiving therapeu-
tic doses.41
The liver damage was attributed to idiosyncratic
reactions (dose independent and erratic), which may only occur
following the administration of lower therapeutic doses. In the
present study, toxic doses of VEN exerted cytotoxic effects on
liver cells. One research group42
reported a case study of a
patient exposed to a toxic dose of VEN. Both the biochemical
and pathological changes were similar to our findings. In a
study on isolated hepatocytes, VEN produced a cytotoxic effect
on liver cells. Moreover, VEN induces oxidative stress in liver
tissues. The mitochondria and lysosomes are the main sites of
VEN-induced cellular injury.43
Few reports have examined the effects of antidepressants
on renal function. A study44
reported acute renal failure fol-
lowing the ingestion of 15 g of VEN. The authors did not
determine whether the renal failure was due to the direct
effect of VEN on the kidney or if it was secondary to circu-
latory failure. Acute exposure to a toxic dose of VEN impairs
kidney function, as evidenced by the elevated BUN and SC
levels. These changes were accompanied by pathological
changes in the renal cortex in the form of congested glomeruli
with interstitial hemorrhage and a disturbed architecture of
the renal tubules. Subchronic exposure to toxic doses pro-
duces glomerular degeneration and hyperplasia. The BUN
and SC levels were higher than normal levels but lower than
the levels in the acute exposure group. Recent data have con-
firmed VEN-induced increases in reactive oxygen species–
mediated apoptosis and cellular degeneration of nervous
tissues after exposure to therapeutic doses.45,46
Exposure to
high, toxic doses of VEN may extend this oxidative stress to
other tissues such as the liver, kidney, and stomach. Another
report confirmed that antidepressants, including VEN, exert
cytotoxic effects on cancer cells.47
Several studies described the association of gastrointest-
inal bleeding with antidepressants.48-51
In the study by
Opatrny et al,48
VEN had the highest risk of inducing gastro-
intestinal bleeding among antidepressants. The authors attrib-
uted the increased gastrointestinal bleeding risk to the trend
toward increased bleeding observed following the use of anti-
depressants,52
without any reference to the local effect of
VEN on the gastrointestinal mucosa. Based on the results of
the present study, VEN exerted a local detrimental effect on
the gastric mucosa. The effect of the subchronic treatment
was more evident than the effect of the acute treatment. This
result may help explain the cause of the increased gastroin-
testinal bleeding in VEN users.
One limitation of this study is the highly variable toxic VEN
dose. A literature review reported an acute toxic dose of 1,500
to 7,500 mg (10 mg/kg in humans).10
Other studies19
used
intravenous injections of acute toxic doses of 40 to 50 mg/kg
in pigs. This dose is similar to the LD50 of female rats (350 mg/
kg). Several reports evaluating chronic VEN intake found that
variable doses were ingested by abusers. For example, some
subjects reported taking 2,100 mg/d,53
2,100 to 3,750 mg/d ,54
1,950 to 2,100 mg/d,8
3,600 to 4,050 mg/d,55
1,500 mg/d,56
and
2,250 to 3,375 mg/d for variable peroids.9
Francesconi et al
summarized that VEN abusers might use 3 to 5 and up to 10 to
15 times the recommended therapeutic doses.2
Although VEN is widely used as an antidepressant and a
growing incidence of acute toxicity and addiction has been
reported, controlled studies examining its effects on different
organs are still lacking. To our knowledge, the present report
describes the first animal study examining the effects of acute
and chronic VEN exposure to toxic doses. Venlafaxine induces
harmful effects on the liver, kidney, and stomach. Thus, stra-
tegies that increase awareness of these effects among
Figure 3. Photomicrographs of the renal cortex. A, The control
group showing the normal architecture of the renal cortical tissue.
Notice the renal corpuscles (G), proximal convoluted tubules (p), and
distal convoluted tubules (d). B, Group II (venlafaxine [VEN] acute
toxicity) showing a markedly congested glomerulus (G) and interstitial
hemorrhages (arrows). C, Group III (VEN subchronic toxicity)
showing tubular distortion (thick arrows), hyperplasia of some
tubules, multiple epithelial layers (thin arrows), and glomerular
hyperplasia (star). Hematoxylin and eosin (H&E): A-C Â400.
Paulis et al 5

7. physicians and the public are needed, particularly due to the
possibility of abuse of this drug. Further work may address the
reversibility of these toxic effects after VEN exposure stops.
Author Contribution
Melad G. Paulis contributed to conception and design, contributed to
acquisition and analysis, drafted the manuscript, and critically revised
the manuscript. Essam Hafez contributed to conception and design
and critically revised the manuscript. Nashwa F. El-Tahawy contrib-
uted to conception, contributed to interpretation, drafted the manu-
script, and critically revised the manuscript. Mohmed K Aly
contributed to design, contributed to acquisition and analysis, drafted
the manuscript, and critically revised the manuscript. All authors gave
final approval and agree to be accountable for all aspects of work
ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Melad G. Paulis http://orcid.org/0000-0001-6742-6987
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Table 4. Semiquantitative Scoring System for Histopathological Changes of the Rats’ Livers, Kidneys, and Stomach (Mean [SD]).a,b
Histological changes Control group Acute toxicity group Chronic toxicity group
Liver
Lost architecture — (00 [0.47]) þþþc
(3.0 [0.41]) þþþc
(3.0 [0.51])
Inflammationd
þ (1.0 [0.28]) þþþc
(3.0 [0.43]) þþc
(2.0 [0.23])
Degeneration — (00 [0.55]) þþþc
(3.0 [0.01]) þþc
(2.0 [0.21])
Kidney
Lost architecture — (00 [0.32]) þþc
(2.0 [0.11]) þþþc
(3.0 [0.13])
Inflammatione
— (00 [0.33]) þþþc
(3.0 [0.42]) þ (1.0 [0.50])
Degeneration — (00 [0.65]) þþc
(2.0 [0.43]) þþc
(2.0 [0.12])
Hyperplasia — (00 [0.54]) — (00.0 [0.41]) þþþc
(3.0 [0.32])
Stomach
Edema — (00 [0.32]) þþþc
(3.0 [0.22]) þþc
(2.0 [0.42])
Superficial ulcer — (00 [0.12]) þ (1.0 [0.42]) þþc
(2.0 [0.22])
Inflammation þ (1.0 [0.26]) þ (1.0 [0.52]) þþc
(2.0 [0.33])
Degeneration — (00 [0.39]) þþc
(2.0 [0.22]) þþc
(2.0 [0.54])
Abbreviations: SD, standard deviation; VEN, venlafaxine.
a
Scoring key: — indicates none, þ indicates slight change, þþ indicates moderate change, and þþþ indicates severe change.
b
Control group: 20 rats received normal saline via gavage. Acute toxicity group included rats that received 350 mg/kg VEN once via gavage (11 rats that survive 24
hours after VEN ingestion). Chronic toxicity group received 100 mg/kg/d increased by 50 mg/kg every 10 days for 30 days (19 rats were examined).
c
Significant at P < 0.05 in comparing with control group.
d
Liver inflammation includes infiltration by inflammatory cells and dilated sinusoids.
e
Inflammation includes congested glomeruli and hemorrhage.
6 International Journal of Toxicology XX(X)

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8 International Journal of Toxicology XX(X)
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