Syrian Rue

Generic name: Peganum Harmala L.
Brand names: African Rue, Harmal Shrub, Harmel, Isband, Ozallalk, Steppenraute, Syrian Rue, Wild Rue

Usage of Syrian Rue

Antidiabetic effects

Animal and in vitro data

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)

Antimicrobial/Antiviral activity

Animal and in vitro data

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)

Benign prostatic hyperplasia

Clinical data

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)

Cancer

Animal and in vitro data

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)

Cardiovascular effects

Animal and in vitro data

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)

CNS effects

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)

Animal and in vitro data

In rodent and in vitro studies, alkaloids extracted from the seeds of P. harmala exerted acetylcholinesterase and MAO inhibitory activity(Adhami 2011, Herraiz 2010, Marwat 2011) as well as effects on dopamine, 5-hydroxytryptophan, nicotinic, opioid, and muscarinic receptors.(Abdel-Fattah 1995, Farouk 2008, 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)

Immune system effects

In vitro data

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)

Osteoarthritis

Clinical data

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)

Syrian Rue side effects

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)

Before taking Syrian Rue

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)

How to use Syrian Rue

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)

Warnings

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)

What other drugs will affect Syrian Rue

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)

Anticholinergic agents: Acetylcholinesterase inhibitors may diminish the therapeutic effect of anticholinergic agents. Anticholinergic agents may diminish the therapeutic effect of acetylcholinesterase inhibitors. Monitor therapy.(Aricept September 2013, Bloxiverz May 2013, Enlon March 2010, Exelon September 2013, Mestinon July 2001, Razadyne June 2013)

Benoxinate: Acetylcholinesterase inhibitors may enhance the therapeutic effect of benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy.(Oxybuprocaine September 2015)

Beta-blockers: Acetylcholinesterase inhibitors may enhance the bradycardic effect of beta-blockers. Monitor therapy.(Arad 1992, Baraka 1984, Eldor 1987, Kayrak 2008, Paulison 2010, Seidl 1984, Sprague 1975, Wagner 1982)

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)

Corticosteroids (systemic): Corticosteroids (systemic) may enhance the adverse/toxic effect of acetylcholinesterase inhibitors. Increased muscular weakness may occur. Monitor therapy.(Aristospan February 2006, Barrons 1997, Decadron May 2004, Lai 2005, Pearson 2001, Sprung 1998)

Dipyridamole: Dipyridamole may diminish the therapeutic effect of acetylcholinesterase inhibitors. Monitor therapy.(Giniatullin 1998, Persantine June 2006, Pitchford 1992, Searl 2006, Vizi 1976)

Neuromuscular-blocking agents (nondepolarizing): Acetylcholinesterase inhibitors may diminish the neuromuscular-blocking effect of neuromuscular-blocking agents (nondepolarizing). Monitor therapy.(Baruaah 2008, Bell 1994, Dhonneur 1996, Fuchs-Buder 2013, Fuchs-Buder 2010, Jones 1988, Morita 1997, Nicolardot 2018, Ozbey 2022, Preault 2016, Ramirez 2005, Rautoma 1998, Russell 2009, Sacan 2007)

Serotonergic agents (high risk): Syrian rue may enhance the serotonergic effect of serotonergic agents (high risk). This could result in serotonin syndrome. Monitor therapy.(Boyer 2005, Brush 2004, Callaway 1998, Dunkley 2003, Frison 2008, Sklerov 2005, Sternbach 1991)

Serotonergic agents (moderate risk): Syrian rue may enhance the serotonergic effect of serotonergic agents (moderate risk). This could result in serotonin syndrome. No action needed.(Boyer 2005, Brush 2004, Callaway 1998, Dunkley 2003, Frison 2008, Sklerov 2005, Sternbach 1991)

Succinylcholine: Acetylcholinesterase inhibitors may increase the serum concentration of succinylcholine. Consider therapy modification.(Bishop 1983, Crowe 2003, Donepezil June 2021, Fleming 1996, Galantamine October 2021, Heath 1996, Kopeman 1978, Manoguerra 1981, McCoy 1995, Physostigmine June 2016, Ramirez 2005, Succinylcholine February 2022, Sunew 1978, Williams 1999)

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