Unsolicited Review

Human and Experimental Toxicology

1–12
Toxicity effects of Nerium oleander, ª The Author(s) 2020
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basic and clinical evidence: DOI: 10.1177/0960327120901571
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A comprehensive review

T Farkhondeh1 , M Kianmehr2, T Kazemi1,

S Samarghandian3 and MR Khazdair1

Abstract
Introduction: Nerium oleander is a plant that is frequently grown in gardens and public areas. N. oleander is
distributed originally in subtropical Asia but is now growing in many parts of the world, such as the United
States, Australia, China, and Middle East countries. Pharmacological effects of plant including antinociceptive,
anti-inflammatory, and anticancer activity were reported, but the potential toxic effects of all parts of the shrub
either fresh or dried on animal and human body were documented.
Method: The data of this review article were obtained from Medline/Pubmed, Scopusand Google Scholar
databases in English until September 2019. To include all publications in this field, keywords such as N. oleander
and toxicity were used.
Results: The poisoning effects of plant or their active alkaloids induced infiltration of cells with hemorrhage
and sever negative changes in the lung, induce lesions, and infiltration of inflammatory cells into the portal
spaces with scattered necrosis of hepatocytes in the liver, cardiac toxicity of the plant in the heart were
included, induced varying degrees of hemorrhage, myocardial degeneration, and necrosis. It also induced
arrhythmia, sinus bradycardia, and prolonged P-R interval in electrocardiographic records.
Conclusions: The toxic effects of N. oleander are mostly related to its inhibitory effects on the Naþ-Kþ
ATPase pump in the cellular membrane. However, the exact molecular mechanism involved in the toxicity of
N. oleander is not clear.

Keywords
Nerium oleander, toxicity, organs

Introduction antinociceptive activity in variable degrees against

p-benzoquinone-induced abdominal contractions. In
Nerium oleander is an ornamental shrub that is grown
as an attractive plant frequently in gardens and public addition, ethanolic extracts of dried and fresh flowers
city areas. N. oleander have linear and leathery leaves revealed potent anti-inflammatory effects against
with various colors from dark green to grey-green carrageenan-induced hind paw edema in mice
with separate light yellowish veins. The flowers of model.2 The ethanol extracts from Oleander flowers
N. oleander are funnel-shaped and fragrant, with
white to pink to deep red colors. Its fruit is a narrow 1
Cardiovascular Diseases Research Center, Birjand University
sheath containing many silky-haired seeds (Figure 1). of Medical Sciences, Birjand, Iran
This plant distributed originally in the subtropical 2
Esfarayen Faculty of Medical Sciences, Esfarayen, Iran
3
Asia and Mediterranean region but is now growing Department of Basic Medical Sciences, Neyshabur University
in many parts of the world, including the United of Medical Sciences, Neyshabur, Iran
States, Australia, China, and Middle East countries.1
Corresponding author:
N. oleander has several pharmacological activities. MR Khazdair, Cardiovascular Diseases Research Center, Birjand
Ethanolic and aqueous extracts from dried and fresh University of Medical Sciences, Birjand, Iran.
flowers and leaves of the plant showed significant Emails: khazdairMR@Bums.ac.ir; m.khazdair@yahoo.com
2 Human and Experimental Toxicology XX(X)

Figure 1. Nerium oleander (white, pink, and red colors flowers).

against four important plants pathogenic fungi N. oleander constituents

showed anti-mycotic activity using agar dilution A pentacyclic triterpene, oleanderocioic acid, two fla-
bioassay. 3 The methanolic extract of the fresh vonoid glycosides, such as quercetin and kaempferol,
leaves of N. oleander showed depressant effect in as well as cardenolide and oleandigoside were iso-
central nervous system of mice.4 Although several lated from the leaves of N. oleander.9 b-sitosterol and
pharmacological activities of N. oleander were oleanolic acid were isolated as the active components
reported, it has several toxicity effects on human from flowers of the plant.10
and animal body.
N. oleander is well-known for its toxicity, it has
potential toxic effects after ingestion, all parts of Toxic properties of N. oleander
the plant contain several toxic compounds, such as The toxicity of N. oleander has been found for years.
oleandrin, oleandrigenin, and other cardiac glyco- All parts of the plant especially seeds and roots contain
sides. N. oleander with red flowers in the flowering cardiac glycosides.11 The structure of cardiac glyco-
stage produces more cardiac glycosides than shrub sides is similar to digitoxin of the foxglove plant.11
with white flowers. 5 Several toxic exposure of Several studies have indicated that N. oleander may
humans and different domestic animals to N. olean- act as insecticides, pesticides, rodenticides, and antimi-
der in the different geographic regions were crobial agents.11 Consumption of five N. oleander
occurs.6 Generally, animal poisoning occurs due leaves can cause lethal poisoning.11 However, it was
to consumption of N. oleander toxic shrub by hun- reported that one N. oleander leaf had severe toxic
gry animals or due to unplanned contamination of effects in children. Controversially, ingestion of three
food with this plant.7 leaves of N. oleander with a 7 years old child caused
The lethal doses of N. oleander leaves were recog- moderate poisoning with no complication. Mild toxi-
nized, which differ among animal species, such as city was observed in an adult woman following con-
sheep and rats (250 and 4000 mg/kg body weight sumption of five leaves of N. Oleander, without severe
(b.w.), respectively).6,8 Therefore, the aim of this symptoms. Thus, determination of the fatal dose for
study was to show the toxicity effects of N. oleander N. oleander toxicity has not fully understood and more
on the animal and human body. studies should be done to found the lethal doses of the
plant. The severity of N. oleander toxicity is related to
Method several factors including the concentration of toxin in
ingested part of the plant, age, and health condition of
The data of this review article were obtained from the subject who consumed the plant.11
published articles, books, and conference papers in
English until September 2019 from Medline/Pubmed,
Scopus, Embase, and Google Scholar databases. To Toxic mechanism of N. oleander
include all publications in this field, keywords such as Cardiac glycosides component in N. oleander inhibits
N. oleander and toxicity were used. the “Naþ-Kþ ATPase pump” in the membrane of
Farkhondeh et al. 3

cardiomyocytes, resulting in an increase in intracellu- the lung of sheep.17 Administration of N. oleander

lar Naþ concentration. Additionally, this increase leaves (110 mg/kg, b.w.) induced varying degrees of
changes the shift of Naþ-Ca2þ channels, resulting in congestion or hemorrhage in the lungs of sheep.18 The
an elevation in intracellular Ca2þ and contraction results of the above studies indicated that leaves or
force and also cardiac automaticity. 12 “Na þ-K þ flowers of N. oleander have toxic effects in the lung
ATPase pump” inhibition changes the shift of Kþ, tissue of exposed animal, such as induced congestion
resulting in increased level of Kþ.12 Hyperkalemia in blood vessels, disruption of bronchus mucosal,
indicates the severity of toxicity in acute cardiac gly- induced inflammatory cells and neutrophils in the
cosides poisoning.12 bronchoalveolar, and induced congestion or hemor-
rhage in the lung tissue. The toxic effect of N. olean-
der on the lung tissue of animal models was
Toxic effects of N. oleander on lungs summarized in Table 1.
Intramuscularly (IM) administration of N. oleander
leaves extract (10 mL/kg) in both hind limbs of rats Toxic effects of N. oleander on liver
showed mononuclear cell infiltrates in the lung tissue
The results of Prussian blue iron-stained sections
section, most frequently around the blood vessel 3,
after 3, 6, and 12 h of N. oleander leaves extract
12, and 24 h after administration. Dilation and even
(10 mL/kg, IM) administration showed extensive
collapse in some alveoli were observed in alveolar
iron accumulation but in section after 12 h of admin-
tissue 24 h after administration. Massive infiltration
istration, mild deposition in sinusoidal space was
along with hemorrhage and extravasation of blood
also observed particularly. Distinct bluish granules
cells and severe negative changes were also observed
(ferritin) within hepatocytes 6 and 12 h after onset of
in the study group. Alveoli, alveolar sacs, and broncus
acute phase response were observed.13 The extracts
were observed in section of the control lung tissue.13
of N. oleander flowers (33 mg/kg, b.w.) induced
The aqueous decoction of leaves extract of N. olean-
hydropic degenerations in the liver tissue. In addi-
der leaves extract (10 mL/kg) induced histopatholo-
tion, mononuclear cell infiltration in the portal
gical changes in the Wistar rats lung tissues including
spaces with scattered necrosis of hepatocytes was
alterations in the pulmonary tissue with disruption of
induced by plant flower extract. Congestion and
bronchus mucosal folds. Also, alveolar cells with
hemorrhage in some cases were also observed.15
extreme widening of lumen of the bronchiole and
Dried leaves of N. oleander (110 mg/kg, b.w.)
vascular lesions have been observed. Inflammatory
induced lesions in the liver that caused fatty
cells, especially neutrophils, were frequently found
change and infiltration of inflammatory cells
in the bronchoalveolar region. In addition, lung sec-
into the portal spaces with scattered necrosis of
tions of the control group showed normal histological
hepatocytes in female goats and male sheep.6,17
architecture and numerous clear alveoli with thin
In addition, mild bile duct hyperplasia was
interalveolar septa and alveolar sacs.14
observed in two goats.17
The aqueous extracts of N. oleander flowers (11,
N. oleander leaves (110 mg/kg, b.w.) induced
22, and 33 mg/kg, b.w.) induced severe congestion in
varying degrees of hemorrhage, degeneration and
blood vessels and edema around the esophagus in
focal necrosis of hepatocytes, necrosis of hepato-
albino male mice, especially at the high dose of
cytes, fatty degeneration, and infiltration of mono-
extract.15 The aqueous leaves extract of N. oleander
nuclear inflammatory cells in liver. 18 Table 2
(10 mg/kg, b.w.) on healthy male New Zealand rab-
indicates the toxic effect of N. oleander on the liver
bits for 4-week treatment showed pathological
tissue of animal models.
changes, such as interstitial pneumonia, alveolar
space hemorrhage, disappearance of pulmonary
alveolus, thickening of the lung matrix, and alveolar Toxic effects of N. oleander on heart
septa, while in control group, there were no signifi- Oral administration of 100 mg of N. oleander ethano-
cant abnormalities observed in the lung tissue.16 lic extract showed diffuse mild interfascicular edema
Orally administration of N. oleander leaves at lethal with congested vessels and many fragmentations of
dose (110 mg/kg, b.w.) to native female goats induced myofibrils in degenerated myocytes 14 days after
interstitial hemorrhage in the lung 1 h after receiving treatment in heart muscles. In addition, 200 mg of
the oleander and also caused congestion and edema in N. oleander ethanolic extract showed moderate
4 Human and Experimental Toxicology XX(X)

Table 1. Toxic effects of N. oleander on lungs.

Dose/duration of
Experimental injection/exposure
Plant model route Findings References
N. oleander leaves Rat 10 mL/kg/3, 12, and
Mononuclear infiltration in the lung, Abbasi et al.13
extract 24 h/IM especially around the blood vessel
After 24 h, massive cellular infiltration,
hemorrhage, and extravasation of
blood cells
Alveoli, alveolar sacs, and abronchus
N. oleander leaves Rat (Wistar) 10 mL/kg/6 h/IM Histopathological changes in the lung Abbasi et al.14
extract tissues
Alterations in the pulmonary
architecture
Impairment of bronchus mucosal folds
Extreme flattened bronchiole lumen
Vascular lesions
Increased inflammatory cells in the
bronchoalveolar
N. oleander flowers Mice (male, 11, 22, and 33 mg/kg/ Induced severe congestion in blood Majeed19
extract albino) 4 days/IM vessels and edema around the
esophagus, especially at the high dose
of the extract
N. oleander leaves Rabbit (male, 10 mg/kg/4 weeks/oral Induced pathological changes, such Taheri et al.16
extract New Zealand) as interstitial pneumonia, alveolar
hemorrhage, disappearance of the
pulmonary alveolus, and stiffness
of the lung
N. oleander leaves Sheep (female, 110 mg/kg/1 h/oral Induced interstitial hemorrhage in the Aslani et al.6,17
extract goat) lung 1 h after receiving the oleander
Caused congestion and edema in the
lung
N. oleander leaves Sheep (male) 110 mg/kg/41, 56, Induced varying degrees of congestion Ozmaie et al.18
extract and 80 h/oral or hemorrhage in the lungs
N. oleander: Nerium oleander; IM: intramuscular.

interfascicular edema with dilated congested vessels addition, intra-sarcoplasmic vacuoles with myocyto-
and few degenerated myocytes with focal striation lysis were also observed in the heart samples in
loss and focal vacuolar degeneration in the heart mus- treated animals compared to the control group.16
cles; 30 days treatments animals with 100 mg of N. oleander flowers aqueous extracts (22 and 33
N. oleander showed focal mild interfascicular edema mg/kg, b.w.) showed congestion and hemorrhage,
with congested vessels and very few degenerated especially in the myocardium regions. In addition,
myocytes in the heart muscles, while 200 mg of varying degrees of coagulative necrosis of cardiac
N. oleander showed focal marked interfascicular muscle cells that were associated with the infiltration
edema with congested vessels and moderately degen- of mononuclear inflammatory cells in heart sections
erated myocytes with vacuolation of the muscle.20 were observed.15
Oral administration of aqueous leaf extract of N. oleander (110 mg/kg, b.w.) induced congestion
N. oleander for 28 days induced pathomorphological and severe hemorrhage especially in the subendocar-
changes in the heart in male rabbits. Mild granular dial regions in the hearts of goats. Additionally, vary-
degeneration of myocytes, coagulative necrosis, frag- ing degrees of coagulative necrosis of cardiac muscle
mentation in the cardiac muscle, and loss of striations cells associated with infiltration of inflammatory cells
were observed in heart by photomicrograph. In were also observed. The mononuclear inflammatory
Farkhondeh et al. 5

Table 2. Toxic effects of N. oleander on liver.

Dose/duration of
Experimental injection/exposure
Plant model route Findings References
N. oleander leaves Rat 10 mL/kg/3, 6, Induced extensive iron accumulation and Abbasi et al.13
extract and 12 h/IM deposition especially in sinusoidal space
after 12 h
Distinct bluish granules (ferritin) in liver
cells after onset of acute-phase response
N. oleander flowers Mice (male 11, 22, and 33 mg/kg/ Induced hydropic degenerations in the liver Majeed19
extract albino) 4 days/IM tissue
Infiltration of mononuclear cell in the portal
spaces with scattered hepatocytes
necrosis
Congestion and hemorrhage
N. oleander leaves Sheep (female, 110 mg/kg/1 h/oral Induced fatty change lesions in the liver Aslani et al.6,17
extract goat) Infiltration of inflammatory cells into the
portal spaces with scattered necrosis
of hepatocytes
Observed mild bile duct hyperplasia in two
goats
N. oleander leaves Sheep (male) 110 mg/kg/41, 56, Induced varying degrees of hemorrhage, Ozmaie et al.18
extract and 80 h/oral degeneration and focal necrosis of
hepatocytes, necrosis of hepatocytes,
fatty degeneration, and infiltration of
mononuclear inflammatory cells in liver
N. oleander: Nerium oleander; IM: intramuscular.

cell infiltration into the endoneurium of nerve fasci- electromechanical function in the heart by sodium
cles and hemorrhages in the left ventricular endocard (Naþ) and potassium (Kþ) pump inhibition, mito-
was observed.17 chondrial swelling, and the sarcoplasmic Ca 2þ
Administration of N. oleander leaves (110 mg/kg, ATPase impairment. A non-blinded, placebo-
b.w.) induced varying degrees of hemorrhage, myo- controlled study was designed to investigate the pro-
cardial degeneration, and necrosis in the heart of tective effect of digoxin-specific Fab fragments
sheep.18 An earlier study conducted by Aslani et al.6 (dsFab) against cardiotoxicity induced by N. Olean-
on the cardiotoxicity impact of N. Oleander der in dogs. N. Oleander leaves (30 mg/kg, intrave-
(110 mg/kg, orally, single dose) in male sheep indi- nous (IV)) caused dysrhythmias during 27 min of
cated that sinus bradycardia was seen as the first starting the administration. However, dsFab reversed
symptom in electrocardiogram (ECG) 0.5 h after to normal condition during the first minutes of injec-
receiving this plant.6 Then, the sinus arrhythmia was tion.22 Fattahi et al. indicated that N. oleander (100
observed. The second cardiac effect was moderate mg/kg, orally) caused ventricular fibrillation in sheep,
and consists of blockage of arterial/ventricular (AV) leading to death in two animals. However, pretreat-
valve, sinus tachycardia, ST-segment depression, AV ment with garlic extract improved arrhythmia in five
dissociation, ventricular tachycardia, and fibrillation.6 sheep.23 Khordadmehr et al. investigated cardiac toxi-
Histopathological examination indicated degenera- city of N. oleander (10, 12.5, 15, and 20 mg/kg,
tion and necrosis in the myocardium.6 Botelho et al. orally) in Wistar rats and Balb/c mice.24 Creatine
investigated the cardiotoxic effect of N. oleander kinase (CK) and troponin levels increased in mice and
hydroalcoholic extract (150 and 300 mg/kg) in guinea rat received N. oleander. Hyperemia, hemorrhage,
pigs.21 It was found that N. oleander caused death due and myofibroblasts were seen in the cardiac tissue
to severe cardiac arrhythmias in some animals. In of animals. Table 3 indicates the toxic effect of
vitro studies indicated that N. oleander disturbed N. oleander on the heart tissue of animal models.
6 Human and Experimental Toxicology XX(X)

Table 3. Toxic effects of N. oleander on heart.

Dose/duration of
Experimental injection/exposure
Plant model route Findings References
N. oleander leaves Mice (male) 100 and 200 mg of Induced diffuse moderate interfascicular edema Abdou et al.20
extract dried extract/kg/ and congested vessels
14 and 30 days/ Myofibrils fragmentations in degenerated
oral myocytes (100 mg, 14 days)
Moderate interfascicular edema with dilated
congested vessels and few degenerated
myocytes, focal vacuolar degeneration
(200 mg, 14 days)
Focal moderate interfascicular edema,
moderate congested vessels, and small
number of degenerated myocytes (100 mg,
30 days)
Focal sever interfascicular edema, dilated
congested vessels, moderate degenerated
myocytes, and muscle vacuolation (200 mg,
30 days)
N. oleander leaves Rabbit (male, 10 mg/kg/4 weeks/ Induced pathomorphological changes in the Taheri et al.16
extract New Zealand) oral cardiac cell
Moderate granular degeneration of
myocytes, coagulative necrosis, cardiac
muscle fragmentation, and loss of
striations
Induced intra-sarcoplasmic vacuoles,
myocytolysis in the cardiac cells
N. oleander Mice (male 11, 22, and 33 mg/kg/ Induced congestion and hemorrhage Majeed19
flowers extract albino) 4 days/IM especially in the myocardium regions
Induced coagulative necrosis in the heart
muscle cells
Induced inflammatory cells infiltration
N. oleander leaves Sheep (female, 110 mg/kg/1 h/oral Induced congestion and severe hemorrhage, Aslani et al.17
extract goat) particularly in the subendocardial in the
hearts
Induced coagulative necrosis of cardiac muscle
cells and inflammatory cells infiltration
Induced mononuclear cell infiltration into the
endoneurium of nerve fascicles of conductive
system and hemorrhages in the left
ventricular endocard
N. oleander Sheep (male) 110 mg/kg/41, 56, Induced varying degrees of hemorrhage, Ozmaie et al.18
leaves extract and 80 h/oral myocardial degeneration, and necrosis
in the heart
N. oleander leaves Sheep (female, 110 mg/kg/1 h/oral Induced sinus bradycardia, sinus arrhythmia, Aslani et al.6
extract goat) blockage of AV valve, sinus tachycardia,
ST-segment depression, AV dissociation,
ventricular tachycardia, and fibrillation
Degeneration and necrosis in the myocardium
N. oleander leaves Pig (male, 150 and 300 mg/kg/ Induced death due to severe cardiac Botelho
extract guinea) 0, 45, 90, 135, and arrhythmias et al.21
180 min/oral Disturbed electromechanical function in the
heart by Naþ and Kþ pump inhibition,
mitochondrial swelling, and the
sarcoplasmic Ca2þ ATPase impairment
(continued)
Farkhondeh et al. 7

Table 3. (continued)
Dose/duration of
Experimental injection/exposure
Plant model route Findings References
N. oleander leaves Dog 30 and 60 mg/kg, IV/ Induced dysrhythmias during 27 min Clark et al.22
extract 15, 30, 60, 120 and of starting the administration
160 min/oral
N. oleander leaves Sheep 100 mg/kg/oral Induced ventricular fibrillation, leading Fattahi et al.23
extract to death in two animals
Improved arrhythmia pretreatment with
garlic extract in five sheep
N. oleander leaves Rat (Wistar) and 10, 12.5, 15, and Increased CK and troponin levels in mice Khordadmehr
and flowers mice (Balb/c) 20 mg/kg/1–4 and rat and Nazifi24
extract days/oral Hyperemia, hemorrhage, and myofibroblasts
in the cardiac tissue of animals
N. oleander: Nerium oleander; AV: arterial/ventricular; Naþ: sodium; Kþ: potassium; CK: creatine kinase.

Toxic effects of N. oleander on blood volume (PCV), mean platelet volume, MCH, and Hb,
parameters while significantly increased RBC distribution width,
MCH concentration (MCHC), plateletcrit, PLT, and
Oral administration of N. oleander alcoholic extract
WBC in treated female mice compared to the control
(100 and 200 mg of dried extract/kg) after 14 days group.27 The aqueous leaves extract of N. Oleander
significantly changed blood parameters including (10 mg/kg b.w.) once a day for 28 days significantly
increased mean corpuscular hemoglobin (MCH) and increased RBC and WBC counts and also mean Hb
decreased white blood cells (WBCs) at 200 mg of value in the treated rabbits compared to the control
extract and also significantly decreased lymphocytes group. However, the PLTs count was decreased sig-
(%) at two dose of extracts. In addition, after 30 days nificantly in the treatment group compared to the con-
of oral administration, mean corpuscular volume trol group. The percent of PCV value was noticeably
(MCV), WBCs, and platelet (PLT) count signifi- higher in treated rabbits, although it was not statisti-
cantly elevated at 200 mg of extract. The percent cally significant.16
of lymphocytes also significantly decreased at two Table 4 indicates the toxic effect of N. Oleander on
dose of extracts.20 the blood parameters of animal models.
The aqueous extracts from boiling air-dried leaves
of N. oleander in 0.9% NaCl solution (1:1, w/v) sig-
nificantly altered hematological parameters such as Serum biochemical parameters
red blood cells (RBCs), hemoglobin (Hb), hematocrit, The toxic impact of N. oleander extract (100 and
MCV, lymphocyte, neutrophil, monocyte, and eosino- 200 mg of dried extract/kg, orally, for 14 and 30 days)
phil count in the groups of N. Oleander oral intake for was evaluated in mice. The findings indicated that
3 and 7 days compared to the control group.25 interleukin 1 (IL-1), IL-6, tumor necrosis factor a
The aqueous leaves extract of N. Oleander and (TNF-a), CK, and CK-MB were significantly
flowers (25 mg/kg, b.w.) significantly increased increased at 200 mg of N. oleander ethanolic extract
WBCs, while decreased RBCs and Hb, after 2 and after 14 days of treatment, but C reactive protein
4 weeks treatments in mice compared with the con- (CRP) and lactate dehydrogenase (LDH) were signif-
trol group.26 icantly increased at 100 and 200 mg of N. oleander
Intraperitoneal administration alkaloid extract of ethanolic extract. In addition, after 30 days of treat-
N. Oleander leaves (20 mg/kg) per day for a period ments, IL-6, TNF-a, CRP, aminotransferase (ALT),
of 30 days significantly decreases b.w. after 10, 20, LDH, CK, and CK-MB levels were significantly
and 30 days of experience in treated female mice increased at 100 and 200 mg of plant extract, while
compared with control group. Alkaloid extract of IL-1 was only significantly increased at 200 mg
N. oleander also significantly decreased packed cell extract group compared to the control group.20
8 Human and Experimental Toxicology XX(X)

Table 4. Toxic effects of N. oleander on blood parameter.

Dose/duration of
Experimental injection/exposure
Plant model route Findings References
N. oleander leaves Mice (male) 100 and 200 mg of dried Increased MCH and decreased WBCs Abdou et al.20
extract extract/kg/14 and (at 200 mg of extract)
30 days/oral Decreased lymphocytes (at two-dose
of extracts)
Increased MCV, WBCs, and PLT (at 200 mg
of extract, after 30 days)
Decreased the percent of lymphocytes
(at two-dose of extracts)
N. oleander leaves Rat (Wistar) Dried extract in 0.9% Altered RBCs, Hb, HCT, MCV, lymphocyte, Akhtar et al.25
extract NaCl solution (1:1, neutrophil, monocyte, and eosinophil
w/v)/3 and 7 days/oral count in the groups of N. oleander
N. oleander leaves Mice 25 mg/kg/4 weeks/oral Increased WBCs Altaee26
and flowers Decreased RBCs and Hb
extract
N. oleander leaves Mice 20 mg/kg/30 days/IP Decreased body weight after 10, 20, and 30 Hussein27
extract days of experience in treated female mice
Decreased PCV, MPV, MCH, and Hb
Increased RDW, MCHC, PCT, PLT,
and WBC in treated female mice
N. oleander leaves Rabbit (male, 10 mg/kg/4 weeks/oral Increased RBC and WBC counts and also Taheri et al.16
extract New mean Hb value
Zealand) Decreased the PLT count
N. oleander: Nerium oleander; MCH: mean corpuscular hemoglobin; WBC: white blood cell; MCV: mean corpuscular volume;
PLT: platelet; RBC: red blood cell; Hb: hemoglobin; HCT: hematocrit; PCV: packed cell volume; MPV: mean platelet volume;
RDW: red blood cell distribution width; MCHC: mean corpuscular hemoglobin concentration; PCT: plateletcrit; IP: intraperitoneal.

The oral administration of aqueous extract of extracts compared to the control group, while there
N. Oleander leaves and flowers (25 mg/kg, b.w.) were no significant differences between summer and
significantly increased alanine aminotransferase, winter groups. Increased levels of Kþ were depended
aspartate aminotransferase (AST), glutamic- on the time of treatment (2 and 4 weeks).28
pyruvate transaminase (GPT), and glutamyl oxaloa- The serum levels of ALT significantly increased
cetic transaminase (GOT) after 2 and 4 weeks between the two summer and winter N. oleander
treatments in mice compared with the saline- leaf extracts compared to the control, while there
treated control group. 26 These changes were was no significant increase differences between
depended on the time of treatments. winter and summer groups. Additionally, serum
Serum calcium levels decreased but not signifi- levels of AST and alkaline phosphatase were not
cantly after 2 weeks oral administration of the significantly changed between the summer and
N. oleander summer and winter leaf extracts com- winter N. oleander leaf extracts compared to the
pared to control rabbits, while in 4 weeks after treat- control.28
ment showed winter leaf extracts group decreased Administration of aqueous leaves extract of
calcium levels significantly compared to the control N. oleander (10 mL/kg, IM) significantly enhanced
group. The winter extract group was more toxic than total iron content in the serum with maximum
the summer group that may be due to the presence of increase of 156.87% after 12 h and 100% rise was
different active ingredient of the plant. The time of observed after 3 h, in male Wistar rats compared to
treatment was similar between different treated control group. The serum ferritin was declined at 3
groups.28 and 24 h of injection with 29% and 23%, respec-
Serum K þ levels after 2 weeks significantly tively, which were not significant differences with
increase in summer and winter N. oleander leaf control group. Serum hepcidin concentration greatly
Farkhondeh et al. 9

Table 5. Serum biochemical parameter.

Experimental
Plant model Dose/duration of injection Findings References
N. oleander leaves Mice (male) 100 and 200 mg of dried Increased IL-1, IL-6, TNF-a, CK, and Abdou et al.20
extract extract/kg/14 and CK-MB (at 200 mg, 14 days)
30 days/oral Increased CRP and LDH (at 100 and
200 mg, 14 days)
Increased IL-6, TNF-a, CRP, ALT,
LDH, CK, and CK-MB levels (at 100
and 200 mg, 30 days)
Increased IL-1 (at 200 mg)
N. oleander leaves Mice 25 mg/kg/4 weeks/oral Increased ALT, AST, GPT, and GOT Altaee26
and flowers
extract
N. oleander leaves Rabbit 94.36 mg/kg for summer Decreased serum calcium levels Salih and
extract Increased serum Kþ levels
extract and 79.75 mg/kg Alkhayyat28
Increased the serum levels of ALT
for winter extract/2 and
4 weeks/oral between the two summer and
winter N. oleander leaf extracts
compared to the control
Not significantly changes in serum
levels of AST and ALP between the
two summer and winter N. oleander
leaf extracts compared to the
control
N. oleander leaves Rat (Wistar) 10 mL/kg/3, 12, and 24 h/IM Enhanced total iron content in the Abbasi et al.29
extract serum with maximum increase
156.87% after 12 h
Decreased the serum ferritin at 3 and
24 h of injection with 29% and 23%
Increased serum hepcidin
concentration which reached the
peak at 12 h compared with the
control group while decreased
9.53% value after 24 h
N. oleander leaves Sheep (male) 110 mg/kg/41, 56, Decreased serum glucose and urea Ozmaie et al.18
extract and 80 h/oral concentration
Increased serum activity of enzymes
such as ALT and AST
N. oleander: Nerium oleander; IL-1: interleukin 1; TNF-a: tumor necrosis factor a; CK: creatine kinase; CK-MB: creatine kinase MB;
CRP: C reactive protein; LDH: lactate dehydrogenase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GPT: glutamic-
pyruvate transaminase; GOT: glutamyl oxaloacetic transaminase; IM: intramuscular.

increased which reached a peak at 12 h compared

with the control group while decreased 9.53% value
Clinical toxicity of N. oleander
after 24 h.29 Human poisoning due to N. oleander may be caused
Administration of N. oleander leaves (110 mg/kg, by accidental or intentional consumption, consump-
b.w.) as lethal dose decreased serum glucose and urea tion for medicinal purpose, or criminal poisoning.
concentration. Serum activity of enzymes such as Oleander poisoning has been observed in some coun-
ALT and AST was increased in experimental group tries, including Europe, United States, Asia, and
compared to the control group.18 Africa and also in Australia.30 Few case report asso-
Table 5 indicates the toxic effect of N. oleander ciated with N. oleander poisoning has been observed.
on the serum biochemical parameters of animal In this context, a case of N. oleander poisoning was
models. reported by Osterloh et al.31 They reported a 96 years
10 Human and Experimental Toxicology XX(X)

old woman who died following consumption of Additionally, this plant has hepatotoxic, hematotoxic,
N. oleander. However, Driggers et al. reported a sur- and respiratory toxic effects. The lethal dose of this
vived 83 years old woman of N. oleander poisoning plant in the animal studies is not similar as some
who ingested for suicide.32 studies used dried leaves and others used green plant.
It was reported death of 58 years old Caucasian Additionally, the amount of toxic glycoside in the
woman due to consumption of N. oleander for self- plant varies according to the size of leaves, season,
poisoning. The pathological evaluation indicated and other environmental parameters in which that
petechiae, edema, and congestion in tongue, gastric, plant has grown. However, Osterloh et al.31 reported
and lung.33 PBI-05204, a N. Oleander extract com- the lethal dose of oleander leaf for their patient was
prising oleandrin, blocked the “a-3 subunit of Na/K approximately 4 g, but more studies should be done
ATPase, FGF-2 export, Akt and p70S6K,” leading to for calculating exact lethal dose. The toxic effects of
alleviating the activity of mTOR. Grade 1 atrioven- N. oleander are mostly related to its inhibitory effects
tricular block was observed in 10 subjects and supra- on the “Naþ-Kþ ATPase pump” in the cellular mem-
ventricular tachycardia (grade II) in one patient.34 brane. However, the exact molecular mechanism
N. oleander poisoning was reported in a 21 years old involved in the toxicity of N. oleander is not clear.
woman. She was admitted to hospital with vomiting, In recent years, digoxin-specific Fab antibody frag-
lightheadedness, and cardiac block. Electrocardio- ments are found as a suitable agent for dysrhythmias
gram indicated P wave reversion in inferior and PR and hyperkalemia in acute poisoning with N. olean-
interval prolongation, with varying degree AV der. Additionally, animal studies suggested that plant
blocks.35 Shumaik et al. presented a case report about with antioxidant activity could be suitable approach
self-poisoning with N. Oleander.36 The main symp- for ameliorating of cardiotoxicity induced by N.
toms were bradycardia and sinoatrial nodal arrest oleander. Overall, N. oleander is a toxic plant and
inpatient. “Digoxin-specific Fab antibody fragments should not be grown in gardens and public areas for
(Digibind®)” improved cardiac problems. It was also protection of children and animals.
reported that a man was criminally administrated
N. oleander roots extract for 8 weeks. The symptoms
such as nausea, diarrhea, abdominal pain, and
Limitation
confusion were similar to acute toxicity. His clinical Due to limited studies conducted on the N. oleander
symptoms were moderate at the beginning, but ele- poisoning and also a low number of animal and
vated later. “Sinus tachycardia” with “diffuse ST human that poisoned with this plant ingestion, the
depression” and inverted “T wave” were observed present study could not reveal all aspects related to
in ECG and also elevation in the levels of CK.37 N. oleander such as lethal doses for human with dif-
ferent age and various animal species. Therefore,
more experimental studies are needed to clear these.
Conclusion
N. oleander poisoning commonly occurred in animal Declaration of conflicting interests
and human; however, the fatal cases due to this plant The author(s) declared no potential conflicts of interest
toxicity were reported. Children are very susceptible in this article.
to the toxic effect of N. oleander. Accidental inges-
tion in children and use of the plant for suicide are two Funding
main causes of N. oleander poisoning in the world. The author(s) received no financial support for the
The important clinical characteristic of N. oleander research, authorship, and/or publication of this article.
consists of vomiting, nausea, abdominal pain, diar-
rhea, arrhythmias, and hyperkalemia. The important
ORCID iDs
toxic impact of oleander poisoning is cardiotoxicity
(ventricular arrhythmia, tachycardia, and bradycar- T Farkhondeh https://orcid.org/0000-0002-9579-8339
MR Khazdair https://orcid.org/0000-0001-9854-6121
dia). Electrocardiography indicates an elevated “PR
interval,” a reduced “QRS-T interval,” and “T wave
inversion.” Animal studies have also indicated that References
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