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TOPIC
JTCM
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Volume 35
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Online Submissions: http://ww w.journaltcm.com J Tradit Chin Med 2015 February 15; 35(1): 104-109
info@journaltcm.com ISSN 0255-2922
© 2015 JTCM. All rights reserved.
REVIEW
Medicinal properties of Peganum harmala L. in traditional Iranian
medicine and modern phytotherapy: a review
Mina Cheraghi Niroumand, Mohammad Hosein Farzaei, Gholamreza Amin
aa
Mina Cheraghi Niroumand, Department of Traditional
Pharmacy, Faculty of Traditional Medicine, Tehran University
of Medical Sciences, Tehran 1417653761, Iran
Mohammad Hosein Farzaei, Faculty of Pharmacy, Kerman-
shah University of Medical Sciences, Kermanshah
6734667149, Iran; Department of Traditional Pharmacy, Fac-
ulty of Traditional Medicine, Tehran University of Medical Sci-
ences, Tehran 1417653761, I ran
Gholamreza Amin, Department of Pharmacognosy, School
of Pharmacy and Medicinal Plants Research Center, Tehran
University of Medical Sciences, Tehran 1417653761, Iran
Correspondence to: Dr. Gholamreza Amin, Department
of Pharmacognosy, School of Pharmacy and Medicinal
Plants Research Center, Tehran University of Medical Scienc-
es, Tehran 1417653761, Iran. gh_amin@yahoo.com
Telephone: +98-21-66482609
Accepted: February 16, 2014
Abstract
OBJECTIVE: To review the pharmacological activi-
ties of Peganum harmala L. (P. harmala, Nitrariace-
ae) in traditional Iranian medicine (TIM) and mod-
ern phytotherapy.
METHODS: Opinions of TIM and modern phyto-
therapy about safety and acceptable dosage of this
plant are discussed. Various medical properties of P.
harmala were collected from important TIM refer-
ences and added to scientific reports derived from
modern medical databases like PubMed, Scirus, Sci-
enceDirect and Scopus.
RESULTS: The main medicinal part of the plant is
the seed. In TIM resources, this plant possesses vari-
ous Pharmacological activities such as carminative,
galactagogue, diuretic, emmenagogue, antithrom-
botic and analgesic. In modern phytotherapy, P. har-
mala demonstrated numerous medicinal effects in-
cluding cardiovascular, neurologic, antimicrobial,
insecticidal, antineoplasmic, antiproliferative, gas-
trointestinal and antidiabetic effects. Adverse
events such as neuro-sensorial symptoms, visual
hallucination, bradycardia, hypotension, agitation,
tremors, ataxia, abortion and vomiting cause peo-
ple to use this plant cautiously. P. harmala is con-
traindicated during pregnancy, due to its abortive
and mutagenic activities. Because of increasing
the expression of CYP1A2, 2C19, and 3A4 and inhi-
bition of monoamine oxidase, the pharmacokinet-
ic parameters of drugs which are mainly metabo-
lized by these enzymes may be affected by P. har-
mala.
CONCLUSION: The medicinal properties declared
for this plant in TIM are compared with those
showed in modern phytotherapy. Some of the TIM
properties were confirmed in modern phytothera-
py like emetic and analgesic activities and some
have not been evaluated in modern phytotherapy
such as its therapeutic effects on paralysis, epilepsy
and numbness. Finally, the current review provides
the evidence for other researchers to use TIM prop-
erties of P. harmala as an efficacious natural drug.
Further preclinical and clinical studies for adequate
evaluating safety and therapeutic efficacy are rec-
ommended.
© 2015 JTCM. All rights reserved.
Key words: Peganum harmala; Pharmacological
phenomena; Medicine, traditional; Phytotherapy;
Review
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INTRODUCTION
Peganum harmala L. (P. harmala) commonly known as
Syrian Rue is a widely used medicinal plant from the
family Nitrariaceae.1The names used in Traditional Ira-
nian Medicine (TIM) for this plant are "Esfand", "Es-
pand"and "Harmal".2,3 Its habitat is semi-arid condi-
tions including those which obtain in Iran, steppe areas
and sandy soils.4The primary origin of P. harmala is
central Asia but nowadays it grows in Australia, north
of Africa and southwest of America.5
It is a highly branched perennial, herbaceous, glabrous
plant which grows from 30 to 60 cm tall with short
creeping roots. It possesses narrow leaves arranged alter-
nately on fleshy, bright green stiff stems. The flowers
are solitary, small, pale yellow or white, and 5-petaled.
The fruits are capsules with 3 chambers and about 6 to
10 mm across. The unripe fruits are green and turning
orange-brown when mature. The capsules contain
more than 50 small black-brown triangular seeds.6,7
The main medicinal part of the plant is the seed in
both TIM and modern phytotherapy.2,3,6 Pharmacologi-
cally active compounds of P. harmala are several alka-
loids, β-carbolines (such as harmine, harmaline, har-
man and harmalol) and the quinazoline derivatives vasi-
cine and vasicinone.8
The ideology of TIM is based on quadratic elements.
These elements are air, fire, water, and soil with particu-
lar qualities. For example, air is hot and moist, fire is
hot and dry, water is cold and moist, and soil is cold
and dry. Believers of this doctrine suppose that the en-
tire world is made of quadratic elements and the differ-
ences and diversities among objects originate from dif-
ferent ratios of these four elements used in their struc-
tures. This definite quality has been known as tempera-
ment (Midzaj).9,10 Theory of temperament also existed
in many other traditional medical ideologies, including
Unani (Greek), Arabic, Roman, Indian, European, and
Traditional Chinese Medicine.11 Based on this theory, P.
harmala is thought to have hot and dry nature.2,3,12,13
The goal of this study is to systematically review the
pharmacological activities of P. harmala in TIM and
modern phytotherapy. Opinions of TIM and modern
phytotherapy about safety and acceptable dosage of
this plant are discussed.
METHODS
Various medical properties of P. harmala were collected
from important TIM references including the twenti-
eth book of Al-Havi, the second volum of Canon, the
Tohfe- al-omenin and the Makhzan-al-Advia.2,3,12,13 The
data added to scientific reports are derived from mod-
ern medical literatures. For this purpose, databases in-
cluding Scopus, PubMed, Web of Science, and Google
Scholar were searched for studies focusing on the bio-
logical and pharmacological activities, herb/drug inter-
action and toxicity of P. harmala . Data were collected
from 1966 to 2014 (up to June). The search terms
were: "Syrian Rue" or "Peganum harmala" or "P. har-
mala". There was no language restriction. Results from
primary search were screened by two independent in-
vestigators. The reference list from retrieved studies
was also reviewed for additional applicable articles. All
published articles as well as abstracts presented at meet-
ings were evaluated. In vitro,in vivo and human studies
were separated and the data from each were discussed
in our paper.
RESULTS
Pharmacologic properties
View of TIM: the seeds have been known to be intoxi-
cating, emetic,2,3,12,13 carminative, anthelmintic, aphrodi-
siac, galactagogue, diuretic, emmenagogue, antithrom-
botic, phlegmatic purgative,2,3,13 and strengthening the
vision.2,3 They are useful for epilepsy, psychosis, loss of
memory, chronic headache, kidney stone, dropsy, jaun-
dice, colic and sciatica.2,3 Aqueous extract of the seeds
is useful for blood purification.2,3,12 A mixture of the
seeds with flax seeds and honey has been used for the
treatment of dyspnea.2,3 The decoction has been used
for numbness, lung and liver diseases.2,3 The poultice
from seeds is beneficial for paralysis, numbness, joints
pain, coxalgia and back pain.2,3 The incense of seeds is
used for toothache and repelling mosquitos.2,3 The
most popular traditional use of P. harmala seeds is its
use as a disinfectant. For this purpose, seeds are
smoked by straight heat.14 Its smoke has also been used
as a talisman against "evil-eye".15
View of modern phytotherapy: numerous pharmaco-
logical studies reported a wide range of cardiovascular
effects from P. harmala including reducing systemic ar-
terial blood pressure and total peripheral vascular resis-
tance, bradycardia, elevating cardiac contractile force,
pulse pressure and peak aortic flow,16 as well as vasore-
laxant17 activities. It also exhibited angiogenic inhibito-
ry effects.4The aqueous extract of the seeds of P. harma-
la has antispasmodic, anticholinergic, antihistaminic
and antiadrenergic effects.18
P. harmala and its active alkaloids possess a wide range
of pharmacological effects on the nervous system in-
cluding psychoactive,19 analgesia,20 hallucination, excita-
tion,21 anti-depressant,20 neuroprotective,22 and strong
inhibition of monoamine oxidase (MAO).23 Its analge-
sic effect acts both centrally and peripherally.20,24 It has
been proven that the alkaloids possess good anti-parkin-
sonism effects via inhibition of MAO-B.25,26 In an in vi-
tro study desoxypeganine, one of the P. harmala alka-
loids, lessened ethanol consumption in female Alko al-
cohol rats dose-dependently, with no effect on food
and fluid consumption.27
Various studies have revealed antiparasidal,28 antifungal,
antibacterial,29 insecticidal30-32 and antileishmanial8,33 ef-
fects from P. harmala alkaloids. Different species of bac-
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teria have been shown to be susceptible to the P. harma-
la alkaloids; such as Proteus vulgaris and Bacillus subtil-
is.4,29 In one study, P. harmala demonstrated inhibitory
effects on the growth of Candida albicans, Aspergillus
flavus, Aspergillus fumigates and Aspergillus niger.4,34 P.
harmala also exhibited larvicidal effect on Plodia inter-
punctella,30 insecticidal activity against Tribolium casta-
neum,31 as well as strong growth inhibitory activity on
the malaria parasite Plasmodium falciparum.32
Various investigations reported cytotoxicity activity on
tumor cells from P. harmala in vitro and in vivo.35-40 It ex-
hibited anti-proliferative effect on leukemic cell lines,36
inhibitory action on the metastasis of melanoma cells,
inducing apoptosis in melanoma cells,37 tumor angio-
genesis inhibition38 and binding to RNA of tumor
cells.39
Anti-inflammatory activity of P. harmala and its alka-
loids has been proven in various studies. P. harmala per-
forms anti-inflammatory and immune modulatory ef-
fects via suppressing pro-inflammatory mediators such
as prostaglandin E2, tumor necrosis factor alpha and
nuclear factor-Kappa B.4,40
P. harmala also exhibited gastrointestinal activities in-
cluding alleviating colic syndrome, through blocking
different types of intestinal calcium channels, antispas-
modic and anticholinergic,42,43 noticeable nauseant and
emetic effects44,45 as well as hypoglycemic function.46
Toxicity
The adverse effects of P. harmala in TIM are headache,
dizziness and nausea.2,3 It is used cautiously in patients
with hot temperament. The most important character-
istics of these people are feeling hot more than normal
in a hot condition, getting warm easily in a cold condi-
tion, having enough energy, inability to stand hunger
easily, preferring cold drinks, suffering from sore eye
and headaches, a sudden hot feeling in a normal condi-
tion and having blood hypertension.11 It should be
used by these people with juice of sour fruits or oxymel
(a syrup made from honey and vinegar) which prevents
adverse events.2,3
In modern phytotherapy, the abortive effect of P. har-
mala has been reported by Shapira et al 41 Several cases
of human and animal intoxications that are induced by
P. harmala have been reported in literature.4In an in vi-
tro study, intrapretoneal administration of P. harmala
extract at a dose of 50 mg/kg resulted in symptoms
such as: abdominal writhing, body tremors and slight
decrease in locomotor activity while oral administra-
tion demonstrated no toxicity.24 The same symptoms al-
so have been reported in human cases subsequent to in-
gestions of P. harmala seed extract or its infusion in-
cluding neuro-sensorial symptoms, visual hallucina-
tion, slight elevation of body temperature, cardio-vascu-
lar disorder (i.e. bradycardia and low blood pressure),
ataxia, diffuse tremors, psychomotor agitation and
vomiting.4,47,48 High-doses of P. harmala extract can be
toxic and can lead to liver degeneration, paralysis, spon-
giform alterations in the central nervous system,49 eu-
phoria, hypothermia, convulsions as well as bradycar-
dia.47,48,50 Nevertheless, it has been confirmed that thera-
peutic doses are safe in rodents.51 MAO inhibition ac-
tivity of P. harmala constituents are the main reason for
toxicological effects subsequent to ingestion of the
plant.52 In addition, the intercalation of P. harmala alka-
loids into DNA causes its mutagenic activity that can
result in genotoxic effects.4,53
Drug interaction and dosage
P. harmala interacts with various drugs metabolism due
to its significant function on the expression of cyto-
chrome P450s (CYP). The seeds increase the expres-
sion of CYP1A2, 2C19, and 3A4 dose-dependently,
while reduce the expression of CYP2B6, 2D6 and
2E1.54 It also possesses strong inhibitory action on
monoamine oxidase.23 It has been proven that beta-car-
bolines from P. harmala interact with a wide range of
signaling pathways including opioid, dopamine, gam-
ma-Aminobutyric acid, benzodiazepine, 5-hydroxytryp-
tamine and imidazoline.4
Based on TIM texts, the therapeutic dose of seeds is ap-
proximately between 4 -9 grams.2,3 There is no certain
dosage for this plant in modern phytotherapy. Effects
can vary; low doses of seeds (25 to 50 mg) are mildly
stimulating and may cause agitation or depression
whereas higher doses (300 to 750 mg) have hallucino-
genic effects.55
DISCUSSION
Traditional medicines of nations as the main source of
complementary and alternative medicine have recently
made some hopes in management of various human
diseases. Medicinal plants play a pivotal role in thera-
peutic approach of traditional medicines. A wide range
of safe and available medicinal plants have been used
for alleviating the symptomatologies associated with
many diseases in TIM.56-58 P. harmala is a widely used
medicinal plant with various pharmacological effects in-
cluding cardiovascular, neurologic, antimicrobial, anti-
cancer, gastrointestinal and antidiabetic activities.
Some of pharmacologic properties documented for this
plant in TIM have been confirmed by different studies
in modern phytotherapy. Among these properties,
emetic activity of the seeds is very popular in TIM.
The other confirmed pharmacologic properties of P.
harmala mentioned in TIM include analgesic (for the
management of sciatica, joints pain, coxalgia, chronic
headache and toothache), intoxicating, abortive, disin-
fectant (antibacterial and antifungal activities), anthel-
mintic, insect repellant, carminative and its beneficial
effect in colic disorder (due to calcium channels block-
ing, antispasmodic and anticholinergic mechanisms).
Anti-inflammatory and suppressing pro-inflammatory
mediators indicate its antithrombotic function in TIM.
Also potential effects of P. harmala in the management
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of kidney stone may be due to its antispasmodic and
anticholinergic activities. In contrast, various medicinal
indications mentioned in TIM resources have not been
evaluated in modern phytotherapy including its thera-
peutic activity on paralysis, epilepsy, numbness, loss of
memory, vision performance, dropsy, jaundice, dys-
pnea, as well as its carminative, and purgative proper-
ties. It is mandatory to perform experimental investiga-
tion in order to evaluate the therapeutic activity of this
plant on mentioned diseases.
There is a wide range of therapeutic dosages in modern
phytotherapy from 25 to 750 mg, while therapeutic
dosage in TIM ranges from 4 to 9 g. The higher thera-
peutic dose in TIM may be due to using the seed of P.
harmala with its correctives. Moreover, TIM is a holis-
tic therapeutic system, and the nature of the patient is
considered before treatment. With regard to TIM liter-
ature, the most adverse events of this plant are ob-
served in people with a hot nature, and it is preferred
not to administer this plant for them, whereas in mod-
ern medicine the nature of patients is not considered
for treatment.
Since serious adverse events have been reported follow-
ing ingestion of specific amounts of P. harmala seeds, it
is recommended that high dose administration of this
plant be avoided till adequate studies confirm safety
and quality. P. harmala is abortifacient; thus, it is con-
traindicated during pregnancy. Because of inhibition of
cytochrome P450 3A4 (CYP3A4), the pharmacokinet-
ic parameters of drugs that mainly metabolized with
this isoenzyme may be affected by P. harmala. Consid-
ering TIM recommendation such as using P. harmala
with its correctives can lead to producing a safer and
more tolerable product from this plant.
Finally, the current review provides the evidence for
other researchers to use TIM properties of P. harmala
as an efficacious natural drug and its safety and accept-
able dosage were discussed. Further preclinical and clin-
ical studies for adequate evaluation of the safety and
therapeutic efficacy of P. harmala are recommended.
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