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Harmine
Pharmaceutical compound From Wikipedia, the free encyclopedia
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Harmine, also known as banisterine or telepathine among other synonyms,[a] is a β-carboline and a harmala alkaloid.[5] It occurs in a number of different plants, most notably Peganum harmala and Banisteriopsis caapi.[4] Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a reversible inhibitor of monoamine oxidase A (RIMA). Harmine does not inhibit MAO-B.[6]
The biosynthesis of harmine likely begins with L-tryptophan, which is decarboxylated to tryptamine—an intermediate also used in serotonin synthesis—before undergoing a series of reactions to form harmine, with feeding experiments supporting tryptamine’s role as an intermediate rather than a primary precursor. It is essential for enabling the oral activity of DMT in ayahuasca and is also used as a fluorescent pH indicator and in PET imaging to study MAO-A-related brain disorders.
Pharmaceutical-grade harmine hydrochloride is safe and well-tolerated at oral doses below 2.7 mg/kg in healthy adults, with higher doses causing mild to moderate gastrointestinal and neurological side effects and limited psychoactive effects. It is found in various plants—including tobacco, Passiflora species, lemon balm, and several Banisteriopsis species—as well as in some butterflies of the Nymphalidae family. Harmine was first isolated and named by in 1848 from Peganum harmala seeds, later identified in Banisteriopsis caapi under various names, with its structure determined in 1927. Recent patents focus on creating harmine derivatives with reduced toxicity.
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Uses
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Hallucinogen
Harmine is a hallucinogen at reported doses of 25 to 75 mg subcutaneously, 150 to 200 mg intravenously, and 300 mg or more orally.[5][7] However, in other reports, hallucinogenic effects were minimal at doses of up to 960 mg orally and 750 mg sublingually.[5][7] Along with harmaline and tetrahydroharmine, it is one of the psychoactive constituents of Banisteriopsis caapi.[5][7] These other constituents, particularly harmaline, may be the more relevant hallucinogenic constituents of this plant.[5][7]
Monoamine oxidase inhibitor
Harmine is a reversible inhibitor of monoamine oxidase A (RIMA), a type of monoamine oxidase inhibitor (MAOI) as it reversibly inhibits monoamine oxidase A (MAO-A), but not monoamine oxidase B (MAO-B).[6] Doses of harmine that are active as a RIMA in combination with dimethyltryptamine (DMT) are in the range of 140 to 190 mg orally, whereas smaller doses in the range of 120 to 140 mg were ineffective.[7] However, its RIMA activity at the preceding effective doses was described as significant but modest.[7] Oral or intravenous harmine doses ranging from 30 to 300 mg may cause agitation, bradycardia or tachycardia, blurred vision, hypotension, and paresthesias.
Medically significant amounts of harmine occur in the plants Syrian rue and Banisteriopsis caapi. These plants also contain notable amounts of harmaline,[4] which is also a RIMA.[6] The psychoactive ayahuasca brew is made from B. caapi stem bark usually in combination with dimethyltryptamine (DMT) containing Psychotria viridis leaves. DMT is a psychedelic drug, but it is not orally active unless it is ingested with MAOIs. This makes harmine a vital component of the ayahuasca brew with regard to its ability to induce a psychedelic experience.[8] Syrian rue or synthetic harmine is sometimes used to substitute B. caapi in the oral use of DMT.[9]
Harmine was used or investigated as an antiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications.[10]
Other uses
Harmine is a useful fluorescent pH indicator. As the pH of its local environment increases, the fluorescence emission of harmine decreases.
Due to its MAO-A specific binding, carbon-11 labeled harmine can be used in positron emission tomography to study MAO-A dysregulation in several psychiatric and neurologic illnesses.[11]
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Effects
The effects of harmine include euphoria, hallucinogenic effects, confusion, drowsiness, sleepiness, perceptual disturbances, closed-eye visuals, vertigo, lightheadedness, ataxia, speech impairment, and unpleasantness.[5]
Adverse effects
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 | This section needs additional citations for verification. (November 2024) |
A 2024 Phase 1 clinical trial investigating pharmaceutical-grade harmine hydrochloride in healthy adults found that the maximum tolerated dose (MTD) is approximately 2.7 mg/kg body weight.[12]
Below this threshold, harmine is generally well-tolerated with minimal adverse effects. Above 2.7 mg/kg, common adverse effects include nausea and vomiting, which typically occur 60–90 minutes after ingestion. Other reported effects include drowsiness, dizziness, and impaired concentration. These effects are generally mild to moderate in severity and resolve within several hours.
No serious adverse cardiovascular effects were observed at any dose tested (up to 500 mg), though rare instances of transient hypotension occurred during episodes of vomiting. Unlike some traditional preparations containing harmine (such as Ayahuasca), pure harmine did not cause diarrhea in study participants.
The study found that adverse effects were more common in participants with lower body weight when given fixed doses, leading the researchers to conclude that 2.7 mg/kg represents a more useful threshold than fixed dosing.
Pharmacology
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Pharmacodynamics
The pharmacology of harmine has been studied.[21][19][15] It showed affinity (Ki) for the serotonin 5-HT2A receptor (Ki = 230–397 nM) and for the serotonin 5-HT2C receptor (Ki = 5,340 nM), but not for the serotonin 5-HT1A receptor, the dopamine D2 receptor, or the benzodiazepine site of the GABAA receptor (all Ki = >10,000 nM).[19][15][16] The drug showed among the highest affinity for the serotonin 5-HT2A receptor of any other β-carboline, with a few exceptions.[15][16] Its functional activity at the serotonin 5-HT2A receptor has not been studied, but harmine has been found to increase dopamine release in the nucleus accumbens in a serotonin 5-HT2A receptor-dependent manner as evidenced by reversal by ketanserin.[19][22] Harmine has been found to be antagonistic to serotonin in certain tissues similarly to LSD.[23]
Harmine has also shown affinity for the imidazoline I2 receptor (Ki = 10 nM).[19] It has been suggested that this action might be involved in or responsible for its hallucinogenic effects.[19] The drug is a potent inhibitor of DYRK1A (Ki or IC50 = 33–700 nM) and a very weak dopamine reuptake inhibitor (IC50 = 12,000 nM).[19] Conversely, it is not a dopamine transporter (DAT) substrate or dopamine releasing agent.[19] Harmine is a highly potent inhibitor of monoamine oxidase A (MAO-A) (Ki = 16.9 nM, IC50 = 2.0–380 nM).[19][24][21] It shows 10,000-fold selectivity for MAO-A over monoamine oxidase B (MAO-B).[19]
In contrast to harmaline and 6-methoxyharmalan, which fully substituted for the psychedelic drug DOM in rodent drug discrimination tests, but similarly to harmane, harmine failed to significantly substitute for DOM and produced behavioral disruption at higher doses.[25]
Pharmacokinetics
The pharmacokinetics of harmine have been studied and described.[19][21] The plasma elimination half-life of harmine is on the order of 1 to 3 hours.[26]
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Chemistry
Harmine, also known as 7-methoxy-1-methyl-β-carboline, is a substituted β-carboline and cyclized tryptamine derivative. Analogues of harmine include harmaline and tetrahydroharmine, among others. A positional isomer of harmine is 6-methoxyharman and analogues of that isomer include 6-methoxyharmalan and 6-methoxytetrahydroharmine (6-MeO-THH).
Natural occurrence
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Harmine is found in a wide variety of different organisms, most of which are plants.
Alexander Shulgin lists about thirty different species known to contain harmine, including seven species of butterfly in the family Nymphalidae.[7]
The harmine-containing plants include tobacco, Peganum harmala, two species of passiflora, and numerous others. Lemon balm (Melissa officinalis) contains harmine.[27]
In addition to B. caapi, at least three members of the Malpighiaceae contain harmine, including two more Banisteriopsis species and the plant Callaeum antifebrile. Callaway, Brito and Neves (2005) found harmine levels of 0.31–8.43% in B. caapi samples.[28]
The family Zygophyllaceae, which P. harmala belongs to, contains at least two other harmine-bearing plants: Peganum nigellastrum and Zygophyllum fabago.
Biosynthesis
The coincident occurrence of β-carboline alkaloids and serotonin in Peganum harmala indicates the presence of two very similar, interrelated biosynthetic pathways, which makes it difficult to definitively identify whether free tryptamine or L-tryptophan is the precursor in the biosynthesis of harmine.[29] However, it is postulated that L-tryptophan is the most likely precursor, with tryptamine existing as an intermediate in the pathway.
The following figure shows the proposed biosynthetic scheme for harmine.[30] The Shikimate acid pathway yields the aromatic amino acid, L-tryptophan. Decarboxylation of L-tryptophan by aromatic L-amino acid decarboxylase (AADC) produces tryptamine (I), which contains a nucleophilic center at the C-2 carbon of the indole ring due to the adjacent nitrogen atom that enables the participation in a Mannich-type reaction. Rearrangements enable the formation of a Schiff base from tryptamine, which then reacts with pyruvate in II to form a β-carboline carboxylic acid. The β-carboline carboxylic acid subsequently undergoes decarboxylation to produce 1-methyl β-carboline III. Hydroxylation followed by methylation in IV yields harmaline. The order of O-methylation and hydroxylation have been shown to be inconsequential to the formation of the harmaline intermediate.[29] In the last step V, the oxidation of harmaline is accompanied by the loss of water and effectively generates harmine.
The difficulty distinguishing between L-tryptophan and free tryptamine as the precursor of harmine biosynthesis originates from the presence of the serotonin biosynthetic pathway, which closely resembles that of harmine, yet necessitates the availability of free tryptamine as its precursor.[29] As such, it is unclear if the decarboxylation of L-tryptophan, or the incorporation of pyruvate into the basic tryptamine structure is the first step of harmine biosynthesis. However, feeding experiments involving the feeding of one of tryptamine to hairy root cultures of P. harmala showed that the feeding of tryptamine yielded a great increase in serotonin levels with little to no effect on β-carboline levels, confirming that tryptamine is the precursor for serotonin, and indicating that it is likely only an intermediate in the biosynthesis of harmine; otherwise, comparable increases in harmine levels would have been observed.[30]
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History
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J. Fritzsche was the first to isolate and name harmine. He isolated it from the husks of Peganum harmala seeds in 1848. The related harmaline was already isolated and named by Fr. Göbel in 1837 from the same plant.[31][10] The pharmacology of harmine was not studied in detail until 1895.[10] The structures of harmine and harmaline were determined in 1927 by Richard Helmuth Fredrick Manske and colleagues.[32][33]
In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknown hallucinogenic ingredient in ayahuasca brew.[4][10] "Telepathine" comes from "telepathy", as Zerda-Bayón believed that ayahuasca induced telepathic visions.[4][34] In 1923, the Colombian chemist, Guillermo Fischer-Cárdenas was the first to isolate harmine from Banisteriopsis caapi, which is an important herbal component of ayahuasca brew. He called the isolated harmine "telepathine".[4] This was solely to honor Zerda-Bayón, as Fischer-Cárdenas found that telepathine had only mild non-hallucinogenic effects in humans.[35] In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine from B. caapi, but named it "yajéine",[10] which in some texts is written as "yageine".[4] In 1927, F. Elger, who was a chemist working at Hoffmann-La Roche, isolated harmine from B. caapi. With the assistance of Professor Robert Robinson in Manchester, Elger showed that harmine (which was already isolated in 1848) was identical with telepathine and yajéine.[36][10] In 1928, Louis Lewin isolated harmine from B. caapi, and named it "banisterine",[37] but this supposedly novel compound was soon also shown to be harmine.[10] Lewin, in 1928, was the first to describe the subjective effects of harmine in the literature.[5]
Harmine was first patented by Jialin Wu and others who invented ways to produce new harmine derivatives with enhanced antitumor activity and lower toxicity to human nervous cells.[38]
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Society and culture
Legal status
Australia
Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015).[39] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[39]
Exceptions are made when in herbs, or preparations, for therapeutic use such as: (a) containing 0.1 per cent or less of harmala alkaloids; or (b) in divided preparations containing 2 mg or less of harmala alkaloids per recommended daily dose.[39]
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Research
Pancreatic islet cell proliferation
Harmine is currently the only known drug that induces proliferation (rapid mitosis and subsequent mass growth) of pancreatic alpha (α) and beta (β) cells in adult humans.[40] These islet sub-cells are normally resistant to growth stimulation in the adult stage of a human's life, as the cell mass plateaus at around age 10 and remains virtually unchanged.
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External links
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