Scientific Name(s): Peganum harmala L.
Common Name(s): African rue, Harmal shrub, Harmel, isband, Ozallalk, Steppenraute, Syrian rue, Wild rue
Peganum harmala L. is native to Central Asia and the Mediterranean coasts of Europe, Africa, and the Middle East. In the 1920s, the plant was imported into the United States where it is now considered a noxious weed. The plant's bitter taste allows it to thrive as it is avoided by grazing animals.
The plant is a highly branched perennial shrub that grows from 30 to 60 cm tall. It has narrow leaves arranged alternately on fleshy, bright green stiff stems. The flowers are solitary and are small, white (or pale yellow), and 5-petaled. The fruit capsule is about 6 to 10 mm across, and is green when unripe, turning orange-brown when mature. The capsule contains small black-brown triangular seeds.1, 2, 3
The plant was known to Dioscorides (ca. 40 to 90 AD), Galen (ca. 129 to 217 AD), and Avicenna (ca. 980 to 1037 AD) as a psychoactive drug, and the ancient Greeks used powdered seeds to treat recurring fevers and for tapeworm. In Turkey, the dried capsules have been used as a talisman against "evil-eye," and smoke from burning the dried seeds have been used to treat mental illnesses. In Iran, Iraq, Tajikistan, Afghanistan, Pakistan, and India, the plant has been used as an hallucinogen in ceremonies, and has found its way into modern-day recreational use. It has reportedly been used as an abortifacient. In the Middle East, red dye produced from the seeds has been used for carpets.2, 3, 4
All plant parts are used, although the roots and seeds contain more of the active alkaloids than the stems and leaves. The beta-carboline alkaloids are the most studied and the most pharmacologically active constituents. They include harmine, isoharmine, and harmaline, which are reversible inhibitors of monoamine oxidase A, harmalol, harman, harmalidine, ruine, and tetrahydroharmine. Also present are the quinazolidine alkaloids vasicine (peganine), vasicinone, vascinol, peganol, peganidine, and deoxypeganine. Flavonoids and steroidal compounds have also been described, as well as fatty acids, amino acids, carbohydrates, lipids, protein, and minerals. High-performance liquid chromatography, thin-layer chromatography, gas-liquid chromatography, nuclear magnetic resonance, and ultraviolet methods for the analysis of the various chemical constituents have been described.2, 3, 5, 6, 7, 8, 9, 10, 11
Uses and Pharmacology
In vitro studies have found extracts of P. harmala seeds to have modest activity against several bacteria including Staphylococcus aureus, Salmonella spp., Proteus vulgaris, and Bacillus subtilis, as well as against HIV, fungal strains including Candida albicans, and protozoans and insect larvae.2, 12, 13, 14, 15, 16, 17, 18, 19
In vivo studies in poultry showed efficacy against relevant bacterial and protozoa.15, 20 In sheep and cattle intramuscular extracts of P. harmala seeds have been effective in managing infections with the tick-borne parasite Theileria hirci.21, 22 Peganine administered orally to hamsters has shown activity against Leishmania.17, 23
Research reveals no clinical data regarding the use of Syrian rue for antimicrobial use in humans.
In vitro studies have largely focused on the vasorelaxant effects of the beta-carboline alkaloids on isolated rat aorta. Activity on endothelial and vascular smooth muscle tissue has been shown and is suggested to be related to calcium channel activity, inhibition of phosphodiesterase, and free radical scavenging.24, 25, 26 Similarly, in vitro vasorelaxant activity has been demonstrated for the quinazolidine alkaloid vasicinone.18 Antiplatelet activity has been shown in vitro via selective inhibition of aggregation, with no cytotoxic effect on platelet cells.27
Dose-dependent transient hypotension and longer-lasting bradycardia was demonstrated in rodents given harman.24
There are no clinical data regarding the use of Syrian rue for cardiovascular use. However, reported adverse events include bradycardia and hypotension.28
Activity of alkaloids extracted from the seeds of P. harmala has been shown to exert acetylcholinesterase and MAO inhibitory activity2, 5, 29 as well as effects on dopamine, 5-hydroxytryptophan, nicotinic, opioid, and muscarinic receptors in rodent and in vitro studies.30, 31, 32, 33 Beta carbolines have been found in the brain tissue of patients with Parkinson disease and are thought to have a role in the pathophysiology of CNS diseases.31, 32
Limited studies have been conducted. Decreased nociception has been demonstrated in mice and rats.33, 34 Harmane produced an amnesia-like state in mice with no effect on anxiety or locomotor behavior.31, 32 Total alkaloid seed extract, as well as isolated harmaline and harmine, produced a centrally mediated hypothermic effect in rats.30 In alcohol-preferring rats, desoxypeganine produced a dose-dependent reduction in ethanol preference and intake without affecting food or fluid intake.35
There are no clinical data on the use of Syrian rue for use in treating CNS ailments, although such applications have been proposed. The mechanisms elucidated in animal studies provide the basis for the traditional use of P. harmala as an antidepressant and for its recreational use.5
In vitro studies of seed extracts, isolated alkaloids, flavonoids, and sterols have shown cytotoxicity against several human cancer cell lines.3, 16, 36 Inhibition of topoisomerases and interference with DNA and RNA replication have been shown.37, 38, 39 Interference with dioxin-medicated induction of carcinogen-activating enzymes, transcription factors, and cytokines, as well as apoptosis and antiangiogenic activity, have been demonstrated in vitro.16, 40, 41, 42, 43
Antiangiogenic activity (decreased capillary formation) by harmine was demonstrated in mice in one experiment. A protective effect was found for a P. harmala extract against thiourea-induced cancer in rats. Reduced levels of thyroid and neuroendocrine cancer markers were found, as well as a protective effect for hepatotoxicity caused by thiourea.44
There are no clinical data regarding the use of Syrian rue for use in cancer.
In vitro studies failed to demonstrate increased insulin secreting activity from INS-1 cells exposed to extracts of the hulls of the seeds of P. harmala in a screening experiment.45
The ethanol extract of P. harmala seeds has been reported to exhibit hypoglycemic activity in mice. The same researchers isolated 4-hydroxypipecolic acid and demonstrated decreased fasting blood glucose levels and increased insulin sensitivity in rats fed the extract for 10 days. Decreased cholesterol and increased high-density lipoprotein were also reported.46
There are no clinical data regarding the use of Syrian rue for use in diabetes or metabolic syndrome.
Immune system effects
In vitro studies have shown some inhibitory activity by extracts of the seeds of P. harmala against neutrophils, mononuclear cells, and transcription factor NF-kappaB. However, activity was less than that of other plants studied.47, 48
A double-blind, randomized controlled trial (n=54) investigated the effect of topical P. harmala seed extract applied 3 times/day for 4 weeks on pain relief in adults with primary knee osteoarthritis. Although no difference was seen in stiffness, significant improvements in pain and function were observed with administration of P. harmala compared to placebo (P<0.01); reduction in pain was 3 times that of the control. No adverse effects were reported.54
Effects may vary.49 Small doses of seeds (25 to 50 mg) are mildly stimulating and may cause agitation or act as a depressant.49 Larger doses (300 to 750 mg) have hallucinogenic effects.49 Consumption of decoctions made from 100 to 150 g of seeds have resulted in toxic effects.2, 49 Harmaline and harmine alkaloids are metabolized in the liver and other extrahepatic tissues to the less potent metabolites harmalol and harmol.5
Pregnancy / Lactation
Documented adverse reactions. Avoid use. Harmala has been used traditionally as an emmenagogue and abortifacient.2, 55 Reductions in reproduction rates in laboratory rats fed methanol extracts of the plant have been demonstrated.50
Case reports of interactions are lacking. In vitro studies have demonstrated effects of P. harmala beta-carboline alkaloids on cytochrome P450 enzymes (ie, CYP1A2, 2C19, 3A4, 2B6, 2D6, 2E1), providing a potential basis for interactions with drugs dependent on this pathway.51, 56 Because harmala alkaloids (specifically harmine and harmaline) are reversible MAOIs, the use of Peganum products in combination with MAOIs and tyramine-containing foods is contraindicated.2, 3, 49, 52 Tetrahydroharmine inhibits serotonin deamination and may cause serotonin syndrome, although case reports are lacking.28, 49 Beta-carboline alkaloids have also been shown to strongly inhibit acetylcholinesterase and butyrylcholinesterase as well as interfere with opioid, dopamine, GABA, benzodiazepine, 5-HT, and imidazoline signaling pathways.56
P. harmala is considered a drug of potential abuse due to the sedative and hallucinogenic properties attributed to its effects as an MAOI, as well as to its ability to prevent the deactivation of the recreational hallucinogenic N,N-dimethyltriptamine (DMT) by MAO. Even though combined intake of DMT and Syrian rue is advocated on some internet sites, such use has resulted in MAO-related toxicity, but there are no reports of deaths to date.5, 52, 53
Histological studies in rats have shown liver degeneration and spongiform changes in the CNS. Elevated renal and liver function tests were reported in a case of intoxication from tea made from P. harmala seeds. Oral doses at 0.15% of an animal's body weight are estimated to be lethal.49 Chickens fed extracts of the seed of P. harmala for 6 weeks showed increases in liver weight, as well as decreased serum alkaline phosphatase, protein, albumin, and globulin.20 Reductions in reproduction rates in laboratory rats fed methanol extracts of the plant have been demonstrated.50
Human toxicity include symptoms of nausea and vomiting, visual and auditory hallucinations, confusion, agitation, confusion, vertigo, hyperthermia, headache, deep sleep, bradycardia and other cardiac effects, anuria, hyperuremia, locomotor ataxia, tremors, paralysis, and convulsions, and in one report, life-threatening respiratory depression and coma. Severe GI distress, vomiting blood, gastric ulceration, and convulsions have also been reported following consumption of a decoction made from 150 g seeds. Cardiovascular effects including bradycardia and low blood pressure were also reported in one case report of toxicity. Symptoms generally last a few hours, and supportive therapy is recommended.2, 28, 49, 56 Neurological toxic effects are most common (34.4%) compared to GI (31.9%) and cardiovascular (15.8%) effects. Recovery from neurotoxic motor deficit sequelae, such as cerebellar ataxia and peripheral polyneuropathy, can continue for months after clinical improvement of P. harmala intoxication.55
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