Harmaline

DEA NFLIS-Drug Category -> Stimulants

Pharmaceuticals -> Listed in ZINC15

Slightly soluble in water, alcohol, ether; quite soluble in hot alcohol, dilute acids

Soluble in chloroform, pyridine

30.6 [ug/mL] (The mean of the results at pH 7.4)

229-231 °C

250 - 251 °C

146.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

148.98 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 33.3% (1 of 3) of reports.

Warning

H302 (33.3%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P270, P301+P317, P308+P316, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/CASE REPORTS/ Peganum harmala, commonly called "Syrian rue," is native to countries around the Mediterranean sea and western United States. Known for its sedative effects when consumed by farm animals, its seeds have stimulant and hallucinogenic effects at low doses (3-4 g when eaten) in humans. Its active ingredients harmaline and harmine have monoamine oxidase inhibitor properties. A 41-year-old female prepared a hot drink by boiling approximately 100 g of P. harmala seeds in water (10-20 times the recommended dose for "calming one's nerves"). Upon presentation to the emergency department, she was unconscious and had hypertension, tachycardia, and tachypnea. Hepatic and renal function markers were grossly elevated. After intubation, she improved with supportive care over the course of five days. Her level of consciousness, renal and hepatic markers gradually returned to normal. Poisoning with high doses of Peganum harmala can be life-threatening, although patients usually recover with supportive therapy alone.

/LABORATORY ANIMALS: Neurotoxicity/ Both harmaline and physostigmine are known to produce whole-body tremors in rodents, yet there is little quantitative information on the differential frequency characteristics of these tremors or on other possible motor effects of these drugs. In addition, the degree to which tolerance develops to their tremorogenic effects is uncertain. OBJECTIVES: The purpose of this work was to use a new kind of instrument (the force-plate actometer) to describe quantitatively the frequency characteristics of tremor induced by the two drugs and simultaneously to measure locomotor activity effects. Another aim was to detect any tolerance effects on the tremor or locomotor measurements. Sprague-Dawley rats in four separate groups received harmaline (0, 4.0, 8.0, and 16.0 mg/kg) while another four groups received physostigmine (0, 0.10, 0.25, and 0.50 mg/kg). Dosing continued for 4 consecutive days. Each day, every rat's whole-body tremor and locomotor activity were recorded for 30 min. Fourier analysis of the force-plate recordings was used to quantify tremor and characterize its frequency components. Harmaline induced a dose-related tremor that peaked in the 10 Hz region of the spectrum, while the dose related-tremor of physostigmine was demonstrably of a broader-band frequency composition. While harmaline tremor exhibited pronounced tolerance, physostigmine tremor remained substantial across the 4 days of dosing. Both drugs suppressed locomotor activity, and there was no tolerance on this measure for either drug. In regard to tremor, harmaline and physostigmine induced quantitatively different kinds of tremor, and these differences probably reflect the drugs' different sites of action in the brain (harmaline: inferior olive; physostigmine: basal ganglia). For harmaline, tolerance to the tremorogenic effect was concurrent with a lack of tolerance to locomotor suppression, and this finding suggested the presence of a strong motor effect of harmaline that continued to be expressed despite the absence of tremor.

/LABORATORY ANIMALS: Neurotoxicity/ beta-Carboline alkaloids are found in several medicinal plants and display a variety of actions on the central nervous, muscular and cardiovascular systems. The aim of the present study was to evaluate the effects of systemic administration of beta-carboline alkaloids on object recognition in mice. Adult Swiss mice received an intra-peritoneal injection (ip) of alkaloids (1.0, 2.5 or 5.0 mg/kg) 30 min before training in an object recognition task. The fully aromatic beta-carbolines, harmine and harmol, induced an enhancement of short-term memory (STM) at all doses tested when compared to controls. Harmaline, a dihydro beta-carboline and inverse agonist of the MK-801 binding site on the N-methyl-d-aspartate (NMDA) receptor, also induced an enhancement of both short-term memory (STM) and long-term memory (LTM). These results demonstrate that systemic administration of beta-carboline alkaloids can improve object recognition memory in mice.

/LABORATORY ANIMALS: Neurotoxicity/ A behavioral preparation especially sensitive to low-dose drug effects on fine motor behavior in rats was used to assess the tremorogenic effects of harmaline, an indole alkaloid and beta-carboline derivative. Rats that were trained to press downward on a force transducer for water reinforcement were initially administered harmaline (0.5 and 1.0 mg/kg) in an acute dosing regime. Immediately following the day of initial acute exposure to 1 mg/kg, 3 consecutive days at this dose ensued, providing for a 4-day, repeated-dosing analysis. Harmaline did not significantly suppress task engagement during either acute or repeated dosing. Acute administration of harmaline dose-dependently increased power in the high-frequency (10-25 Hz) band of the power spectrum (tremor) without affecting overall forelimb force output. Upon continued administration, tremor remained significantly elevated above vehicle values. Harmaline also slowed the rats' licking frequency, an effect that did not diminish with repeated dosing. Harmaline increased the durations of individual responses during acute dosing and continued to exert this effect with repeated dosing. The effects reported in the present study may represent low-dose harmaline-induced alterations in the olivo-cerebellar system.

/LABORATORY ANIMALS: Neurotoxicity/ Harmaline's effects on reflex and classically conditioned eyelid responses and on tremor picked up by a coil attached to the back were measured in alert cats. Harmaline at a dose of 10 mg/kg produced skeletal muscle tremogenic effects that lasted 4h. Back movements presented a tremor-like displacement with a frequency peak at 10 Hz, but lid responses oscillated as in controls, at 20 Hz during both reflex and conditioned eyelid movements, with no increase in oscillation amplitude or frequency. The learning curves of harmaline-injected animals remained as in controls, but eyelid conditioned responses showed longer latencies, and smaller amplitude and peak velocity. Reflex and already-learned eyelid responses were not modified by harmaline. These results imply that neuronal control systems for skeletal-motor and facial responses are differentially affected by harmaline.

For more Non-Human Toxicity Excerpts (Complete) data for HARMALINE (13 total), please visit the HSDB record page.

Treatment: For patients with a "bad trip" or panic reaction, provide gentile reassurance and relaxation techniques in a quiet environment. Treat agitation or severe anxiety states with diazepam or midazolam. Butyrophenones such as haloperidol are useful despite a small theoretic risk of lowering the seizure threshold. Treat seizures, hyperthermia, rhabdomyolysis, hypertension, and cardiac arrhythmias if they occur. /LSD and other hallucinogens/

Specific drugs and antidotes. There is no specific antidote. Sedating doses of diazepam may alleviate anxiety, and hypnotic doses can induce sleep for the duration of the "trip". /LSD and other hallucinogens/

Decontamination. Most of these drugs are taken orally in small doses, and decontamination procedures care relatively ineffective and likely to aggravate psychological distress. Consider the use of activated charcoal ... only after recent (within 30-60 minutes) large ingestions. /LSD and other hallucinogens/

Enhanced elimination. These procedures are not useful. Although urinary acidification may increase the urine concentration of some agents, it does not significantly enhance total-body elimination and may aggravate myoglobinuric renal failure. /LSD and other hallucinogens/

For more Antidote and Emergency Treatment (Complete) data for HARMALINE (7 total), please visit the HSDB record page.

Three psychological active principles from the seeds of Peganum harmala L., harmine, harmaline and harmalol, showed vasorelaxant activities in isolated rat thoracic aorta preparations precontracted by phenylephrine or KCl with rank order of relaxation potency of harmine > harmaline > harmalol. The vasorelaxant effects of harmine and harmaline (but not harmalol) were attenuated by endothelium removal or pretreatment with a nitric oxide (NO) synthase Nomega-nitro-L-arginine methyl ester. In cultured rat aortic endothelial cells, harmine and harmaline (but not harmalol) increased NO release, which was dependent on the presence of external Ca2+. In endothelium-denuded preparations, pretreatment of harmine, harmaline or harmalol (3-30 microM) inhibited phenylephrine-induced contractions in a non-competitive manner. Receptor binding assays indicated that all 3 compounds interacted with cardiac alpha1-adrenoceptors with comparable affinities (Ki value around 31 - 36 microM), but only harmine weakly interacted with the cardiac 1,4-dihydropyridine binding site of L-type Ca2+ channels (Ki value of 408 microM). Therefore, the present results suggested that the vasorelaxant effects of harmine and harmaline are attributed to their actions on the endothelial cells to release NO and on the vascular smooth muscles to inhibit the contractions induced by the activation of receptor-linked and voltage-dependent Ca2+ channels. The vasorelaxant effect of harmalol was not endothelium-dependent.

The psychotropic beta-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K(cat) (min(-1)) and Ku (uM) values for harmaline were: CYP1A1, 10.8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.

Harmaline has known human metabolites that include Harmalol.

A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here.

A chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. (From Gilman, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p414)

Harmaline, a known type A monoamine oxidase (MAO) inhibitor in adult brain of various species was found to elevate whole brain levels of dopamine and serotonin (5-HT) in rat fetuses of mothers injected 2-4 hr before Caesarean delivery. Similar stimulatory effects were observed for the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG), however, no significant effect was obtained for norepinephrine. The dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) were decreased with the same treatment. These results imply that harmaline or one of its metabolites may cross the placental barrier to affect the fetal brain system not merely as a type A MAO inhibitor (i.e., relatively 5-HT-specific), but possibly also as a stimulatory agent for aldehyde reductase or catechol-O-methyltransferase (COMT) or alternately as an agent inhibiting the conjugation, efflux, or turnover of biogenic amine metabolites such as MHPG.

Central nervous system stimulant

Prohibited noxious weed ... /introduced in the US/. /Peganum harmala L./