P. harmala has been traditionally used as a hallucinogen in ceremonies and has found its way into modern-day recreational use. In vitro and animal experiments suggest antimicrobial, vasorelaxant, CNS, and antidiabetic effects; however, limited clinical studies exist to recommend use for any indication.
Clinical trial data are lacking to support specific dosing recommendations. Concerns regarding toxicity exist.
Harmala alkaloids (specifically harmine and harmaline) are reversible monoamine oxidase inhibitors (MAOIs); concomitant use with MAOI agents and tyramine-containing foods is contraindicated.
Avoid use. Adverse reactions have been documented.
Constituents of P. harmala have been shown to interact with several CYP-450 enzymes as well as monoamine oxidase (MAO), acetylcholinesterase, opioid, dopamine, gamma-aminobutyric acid (GABA), and other enzymes and signaling pathways that are important in drug metabolism. See Drug Interactions section.
Case reports of toxicity include nausea and vomiting, visual and auditory hallucinations, confusion, agitation, locomotor ataxia, tremors and convulsions, and life-threatening respiratory depression and coma. Severe GI distress, vomiting blood, gastric ulceration, and convulsions have also been reported, as well as bradycardia and low blood pressure. Symptoms are generally of short duration (a few hours), and supportive therapy is recommended.
Information is limited. Elevated renal and liver function tests have been reported. Symptoms of intoxication include neurological, GI, and cardiovascular effects.
P. 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.
P. harmala is a highly branched perennial shrub that grows 30 to 60 cm in height. 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.(Dube 2011, Marwat 2011, USDA 2022)
P. harmala was known to Dioscorides (ca. AD 40 to 90), Galen (ca. AD 129 to 217), and Avicenna (ca. AD 980 to 1037) as a psychoactive drug, and the ancient Greeks used powdered seeds to treat recurring fevers as well as tapeworm. In Turkey, the dried capsules have been used as a talisman against "evil-eye," and smoke from burning the dried seeds has been used to treat mental illnesses. In Iran, Iraq, Tajikistan, Afghanistan, Pakistan, and India, P. harmala has been used as a hallucinogen in ceremonies and has found its way into modern-day recreational use. P. harmala has reportedly traditionally been used as an emmenagogue and abortifacient in the Middle East, India, and North Africa. In the Middle East, red dye produced from the seeds has been used for carpets.(Dube 2011, Duke 2003, Marwat 2011)
All plant parts are used, although the roots and seeds contain more active alkaloids than the stems and leaves. The beta-carboline alkaloids are the most studied and the most pharmacologically active constituents and include harman, harmine, tetrahydroharmine, harmalol, harmol, and harmaline, which are reversible and competitive inhibitors of MAO-A. 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 analysis of the various chemical constituents have been described.(Dube 2011, Herraiz 2010, Kartal 2003, Khan 2009, Marwat 2011, Pulpati 2008, Sharifi-Rad 2021)
In vitro studies failed to demonstrate increased insulin-secreting activity from INS-1 cells exposed to extracts of P. harmala seed hulls.(Hussain 2004)
The ethanol extract of P. harmala seeds has been reported to exhibit hypoglycemic activity in mice. 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 HDL were also reported.(Singh 2012)
In in vitro studies, extracts of P. harmala seeds showed 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.(Ali 2011, Arshad 2008, Astulla 2008, Hashem 2011, Khaliq 2009, Ma 2013, Marwat 2011, Nenaah 2010, Rehman 2009, Zeng 2010) Drug-resistant Pseudomonas aeruginosa persister cells were susceptible to P. harmala, with minimum inhibitory concentrations of 3 mcg/mL and 1 mcg/mL for 2 isolates and minimum bactericidal concentrations of 10 mcg/mL and 30 mcg/mL.(Jalili 2022) Activity against the SARS-CoV-2 virus was explored using molecular docking analysis, with no conclusions able to be drawn.(Tuzun 2021)
In vivo studies in poultry showed efficacy against relevant bacteria and protozoa.(Arshad 2008, Arshad 2008) In sheep and cattle, intramuscular extracts of P. harmala seeds have been effective in managing infections with the tick-borne parasite Theileria hirci.(Derakhshanfar 2008, Mirzaei 2007) Peganine administered orally to hamsters has shown activity against Leishmania.(Khaliq 2009, Misra 2008)
A clinical study (N=90) evaluated treatment with P. harmala seed (oral capsules containing 1 g of P. harmala) with and without tamsulosin or tamsulosin alone in men with benign prostatic hyperplasia with lower urinary tract symptoms. All study groups reportedly showed an improvement in International Prostate Standard Survey scores; however, there was no significant difference between groups, and methodological limitations exist.(Sharifi-Rad 2021, Shirani-Boroujeni 2016)
In vitro studies of P. harmala seed extracts, isolated alkaloids, flavonoids, and sterols have shown cytotoxicity against several human cancer cell lines.(Dube 2011, Li 2007, Zeng 2010) Inhibition of topoisomerases and interference with DNA and RNA replication have been shown.(Nafisi 2010, Nafisi 2010, Sobhani 2002) 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.(El Gendy 2010, Hamsa 2010, Lamchouri 2000, Zaker 2007, Zeng 2010)
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 observed, as well as a protective effect for hepatotoxicity caused by thiourea.(Hamden 2008) Ongoing research focuses on the role of harmine and related alkaloids as potential agents in the treatment of cancer.(Jalali 2021)
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.(Berrougui 2006, Shi 2000, Shi 2001) Similarly, in vitro vasorelaxant activity has been demonstrated for the quinazolidine alkaloid vasicinone.(Astulla 2008) Antiplatelet activity has been shown in vitro via selective inhibition of aggregation, with no cytotoxic effect on platelet cells.(Im 2009)
In an in vivo study evaluating cardiovascular effects of harman isolated from P. harmala, dose-dependent transient hypotension and longer-lasting bradycardia were observed in rodents administered harman.(Shi 2000)
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.(Nasehi 2010, Nasehi 2012)
Decreased nociception has been demonstrated in mice and rats given P. harmala alkaloid extract.(Farouk 2008, Monsef 2004) Harmane produced an amnesia-like state in mice, with no effect on anxiety or locomotor behavior.(Nasehi 2010, Nasehi 2012) Total alkaloid seed extract, as well as isolated harmaline and harmine, produced a centrally mediated hypothermic effect in rats.(Abdel-Fattah 1995) In alcohol-preferring rats, desoxypeganine produced a dose-dependent reduction in ethanol preference and intake without affecting food or fluid intake.(Doetkotte 2005)
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.(Bremner 2009, Koko 2008)
A double-blind, randomized controlled trial (N=54) investigated the effect of topical P. harmala seed extract (applied 3 times per day for 4 weeks) on pain relief in adults with primary knee osteoarthritis. Although no difference was observed regarding stiffness, significant improvements in pain and function were observed with administration of P. harmala compared with placebo (P<0.01); reduction in pain was 3 times that of the control. No adverse effects were reported.(Abolhassanzadeh 2015)
Clinical trial data are lacking to provide dosing recommendations. Concerns regarding toxicity exist.
The pharmacokinetics of harmine have been described by a 2-compartment open model in dogs, with low bioavailability described.(Zhang 2020) Harmaline and harmine alkaloids are metabolized in the liver and other extrahepatic tissues to the less potent metabolites harmalol and harmol.(Herraiz 2010)
Avoid use. Adverse reactions have been documented. Harmala has been used traditionally as an emmenagogue and abortifacient.(Berdai 2014, Ghizlane 2021, Marwat 2011) Reductions in reproduction rates in laboratory rats fed methanol extracts of P. harmala have been demonstrated.(Shapira 1989)
In vitro studies have demonstrated effects of P. harmala beta-carboline alkaloids on CYP-450 enzymes (ie, CYP1A2, CYP2C19, CYP3A4, CYP2B6, CYP2D6, CYP2E1), providing a potential basis for interactions with drugs dependent on this pathway.(Li 2017, Zhao 2011) 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.(Dube 2011, Haroz 2005, Marwat 2011, Yuruktumen 2008) Tetrahydroharmine inhibits serotonin deamination and may cause serotonin syndrome.(Frison 2008, Yuruktumen 2008) A case report exists of toxicity in an older adult following consumption of approximately 100 g of P. harmala seeds brewed for 5 minutes and consumed as a single dose; the patient was being treated with rasagiline for Parkinson disease; potentiation of this concomitant MAO-B inhibitor use by the P. harmala alkaloids was considered the cause of the serotonergic syndrome. Other similar case reports exist.(Durmaz Çelik 2021)
Beta-carboline alkaloids have also been shown to strongly inhibit acetylcholinesterase and butyrylcholinesterase and to interfere with opioid, dopamine, GABA, benzodiazepine, 5- hydroxytryptamine, and imidazoline signaling pathways.(Li 2017)
Amifampridine: Acetylcholinesterase inhibitors may enhance the therapeutic effect of amifampridine. Amifampridine side effects may also be increased. Amifampridine may enhance the therapeutic effect of acetylcholinesterase inhibitors. Acetylcholinesterase inhibitor side effects may also be increased. Monitor therapy.(Firdapse November 2018, Firdapse June 2017)
Benoxinate: Acetylcholinesterase inhibitors may enhance the therapeutic effect of benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy.(Oxybuprocaine September 2015)
Cholinergic agonists: Acetylcholinesterase inhibitors may enhance the adverse/toxic effect of cholinergic agonists. Specifically, cholinergic effects may be enhanced or increased. Monitor therapy.(Aricept December 2018, Exelon December 2018, Razadyne March 2020)
P. harmala is considered a drug of potential abuse due to the sedative and hallucinogenic properties attributed to its MAO inhibitory effects, as well as 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; however, there have been no reports of deaths.(Halpern 2005, Haroz 2005, Herraiz 2010) Reported adverse events include bradycardia and hypotension.(Frison 2008)
Small doses of seeds (25 to 50 mg) are mildly stimulating and may cause agitation or act as a depressant. Larger doses (300 to 750 mg) have hallucinogenic effects.(Yuruktumen 2008) Consumption of decoctions made from 100 to 150 g of seeds has resulted in toxic effects.(Marwat 2011, Yuruktumen 2008)
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.(Yuruktumen 2008) 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.(Arshad 2008) Reductions in reproduction rates in laboratory rats fed methanol extracts of P. harmala have been demonstrated.(Shapira 1989)
Human toxicity includes symptoms of nausea and vomiting, visual and auditory hallucinations, confusion, agitation, vertigo, hyperthermia, headache, deep sleep, bradycardia and other cardiac effects, anuria, hyperuremia, locomotor ataxia, tremors, paralysis, and convulsions, as well as one report of 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 of P. harmala 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.(Frison 2008, Li 2017, Marwat 2011, Yuruktumen 2008) Neurological toxic effects are most common (34.4%) followed by 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.(Berdai 2014) Although uncommon, fatality following consumption of "a handful of seeds" of P. harmala in order to induce an abortion has been reported in the literature.(Ghizlane 2021)
This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.
This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.
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