0000-0000/02/11-1-4 IRANIAN JOURNAL OF PHARMACOLOGY & THERAPEUTICS Copyright © 2002 by Razi Institute for Drug Research (RIDR) IJPT 1:1-4, 2002 Toxicity of Peganum harmala: Review and a Case Report MASSOUD MAHMOUDIAN, HOSSEIN JALILPOUR and PIROOZ SALEHIAN Razi Institute for Drug Research (M.M.), Department of Pathology (H.J.), Emergency Ward of Firooz-Abadi Hospital (P.S.), Iran University of Medical Sciences, Tehran. Iran. Received May 6, 2002; Revised May 29, 2002; Accepted June 5, 2002 This paper is available online at http://ijpt.iums.ac.ir ABSTRACT Peganum harmala L. is a plant, which grows in semi-arid rangeland. The plant is used traditionally as an emmenagogue and an abortifacient agent in the Middle East and North Africa. All parts of plant are thought to be toxic and sever intoxication occurs in domestic animals. Digestive and nervous syndromes have been observed in animals that consume sub-lethal amount of the plant. The toxicated animal ap- pears in a narcotic state interrupted by occasional short period of excitement. Abortion is frequent in ani- mals that digest this plant in a dry year. While this plant has traditionally been used in Middle East, it shows toxic effects in human. A case of human overdose with P. harmala seeds is reported in this paper. Symptoms experienced by our patient found to be similar to what has been reported for domestic ani- mals. Keywords: abortion, human toxicity, animal toxicity, hallucination Plants and plant extracts have been used since the steppe areas and sandy soils. The plant is widely dis- dawn of civilization by mankind. The use of ethno- tributed in the Central Asia, North Africa and Middle botanical preparations for various reasons, justified or East and has been introduced in America and Australia. not, is still continued by various cultures all around the This plant is known as “Espand” in Iran, “Harmel” in world. Considering structural and biological diversity of North Africa and “African Rue”, “Mexican Rue” or terrestrial plants, they offer a unique renewable resource “Turkish Rue” in United States. It has alternately spaced for the discovery of potential new drugs and modern thong-like leaves, which have a strong deterrent odor medicine has developed a rational strategy for drug dis- when rumpled. Opposite to the leaves are solitary white covery which involves the study of plants and plant ma- flowers with green veins. terials based on their ethnobotanical usage [1]. How- The flowering period is March to April. The fruits ever, modern textbooks usually pay less attention to are globose capsules with 3 chambers containing many them and average medical practitioner is not aware of angular blackish seeds [2]. The plant is not usually their usage and toxicity, especially those remedies that grazed. Its bitter taste repels animals. However, when are used by cultures other than his own. Considering pasture is sparse, donkeys and other domestic animal current state of tourism and immigration there is no cul- may be attracted to and graze intermittently on this tural boundary in the world and any medical practitioner plant. All species are susceptible to poisoning from this may visit a patient who has used a drug, which he has plant, but dromedaries (camels) are the most often af- no knowledge of. The present article is a review of tox- fected [3]. icity and pharmacological properties of Peganum har- ACTIVE CONSTITUENTS mala L., which is used traditionally as an emmenagogue and an abortifacient agent in the Middle East and North The pharmacologically active compounds of P. Africa. harmala are several alkaloids, which are found espe- cially in the seeds and the roots. These include β- carbolines such as: harmine, harmaline (identical with BOTANICAL DESCRIPTION harmidine), harmalol and harman (Fig. 1) and quina- Peganum harmala L. (Zygophyllaceae) is a peren- zoline derivatives: vasicine and vasicinone. The alka- nial herbaceous, glabrous plant, which may grow to 30- loidal content of the unripe seeds is less than the ripe 100 cm. Its normal habitat is semi-arid rangeland, ones [4]. IJPT | Autumn 2002 | vol. 1 | no. 1 | 1-4 2 | IJPT | Autumn 2002 | vol. 1 | no. 1 Mahmoudian et al. Harmaline (harmidine). C13H15ON2 - First isolated by Harmine (banisterine). C13H12ON2 - It is present in P. Göbel [5] from the seeds and roots of P. harmala, this is harmala and in some species of Banisteia, viz., B. the major alkaloid of this plant. It crystallizes in color- caapi, Spruce., B. lutea and B. metallicolor. The alka- less or pale yellow prisms and is optically inactive. This loid is optically inactive and forms colorless rhombic compound is slightly soluble in water, alcohol and ether, prisms from methanol. It is slightly soluble in water, quite soluble in hot alcohol and dilute acids. Its hydro- alcohol or ether. Solutions of its salts show a deep blue chloride dihydrate, which crystallizes as yellow needles, fluorescence. Pharmacologically, harmine resembles is moderately soluble in water and alcohol. Harmaline is harmaline in its actions but is less toxic. The hydrochlo- almost twice as toxic as harmine and in moderate doses ride has been found to be highly active against Myco- causes tremors and clonic convulsions but with no in- bacterium tuberculosis [7]. crease in spinal reflex excitability [6]. Lethal doses Harmalol. C12H12ON2 - Which occurs in P. harmala bring about convulsions, which are soon followed by crystallizes from water as the trihydrate. It is freely motor paralysis due to the marked depressive action soluble in hot water, acetone or chloroform but only upon the central nervous system. Respiration is para- sparingly soluble in benzene. The alkaloid is unstable lyzed and a decrease in body temperature occurs. The when exposed to air. Its methyl ether is harmaline [7]. perfused heart is arrested in diastolic phase and the con- Harman. C12H10N2 - This related β-carboline alkaloid, tractions of smooth muscle are diminished with the ex- which is first isolated from the bark of Arariba rubra, ception of the uterus, which may be made to contract indigenous to Brazil; however its existence in P. har- more powerfully. Over a wide range of doses there is a mala is not reported. This alkaloid is crystallized from reduction in blood pressure due to a pronounced weak- several organic solvents as colorless prisms. It is readily ening of the heart muscle. soluble in methanol, alcohol, acetone, chloroform, or ether but only moderately so in hot water. It dissolves in mineral acids and exhibits a blue-violet fluorescence [7]. Vasicine (peganine). C H ON - This quinazoline N 13 15 2 N alkaloid was first isolated from the leaves of Adhatoda H CH vasica Nees by Hooper and subsequently discovered in 3 P. harmala under the name of Peganine. The base is Harmane optically inactive although the isolation of (-)-form from the fresh leaves of A. vasica and flowers and stems of P. harmala has been reported. The salts are readily ob- tained as crystals. The crude drug from A. vasica is used in India as a remedy for asthma and the pure alkaloid acts as a bronchodilator [8]. N Vasicinone. C11H10O2N2 - A further alkaloid present in H3CO N Adhatoda vasica Nees and P. harmala. The base forms H 22 CH3 colorless crystals from 95% alcohol. It has [α] -100° (c = 0.5 in CHCl3) and the UV spectrum has absorption Harmine maxima at 227, 272, 302 and 315 nm. The alkaloid yields crystalline salts with mineral acids. It is an active bronchodilator [8]. ANIMAL TOXICITY N All parts of plant are thought to be toxic. Intrave- H3CO N nous injection of harmine and harmaline (9 mg/kg) into H CH3 cattle have shown toxic effects such as accelerated Harmaline breathing and pulse and clonic muscular spasms [9]. The toxic doses of various alkaloids in different species are shown in the Table 1 [6]. All domesticated animals are susceptible to poisoning from P. harmala, camels especially young animals are the most affected in dry seasons [3]. There are reports of sever intoxication in N cattle [10], donkeys [11], sheep and horses [12]. Diges- HO N tive and nervous syndromes have been reported in ani- H CH3 mals that consume a sub-lethal amount of the plant [13]. The animal initially becomes prostrate and then ano- Harmalol rexia, hyper-salivation, vomiting and diarrhea occur. Usually, the nervous syndromes are predominant: the Fig. 1. Chemical structure of β-carboline alkaloids. first signs are excitability followed by muscular trem- bling and stiffness, an uneasy staggering gait, and accel- Toxicity of Peganum harmala ijpt.iums.ac.ir | 3 erated breathing. Standing is impossible and the animal served and the patient was taken to hospital. The signs goes into recumbency. The animal appears in a narcotic of P. harmala overdose comprised of hallucinations and state interrupted by occasional short periods of excite- neuro-sensorial syndromes, bradycardia and GI distur- ment. After a few hours, dyspnea and mydriasis are bances such as nausea and vomiting. noted. Frequent urination and subnormal temperature Para-clinical tests showed that the function of liver has also been reported in cattle [10]. Abortion fre- and kidney to be normal and the patient had a normal quently occurs. The course of the nervous syndrome is hematological picture. She was discharged from hospi- usually short and death follows within 30-36 hours after tal few hours later after signs of intoxication had disap- the onset of signs of CNS intoxication. The chronic in- peared. toxication of cattle is characterized by anorexia, rest- lessness, weakness of the hind limbs and knocking of the fetlock joint. CASE REPORT In postmortem examination of animal, no distinctive A 35 years old male patient, who was under treat- lesion is observed.