Thebiosynthesis of harmine likely begins withL-tryptophan, which is decarboxylated totryptamine—an intermediate also used inserotonin 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 ofDMT inayahuasca and is also used as afluorescent pH indicator and in PET imaging to study MAO-A-related brain disorders.
Pharmaceutical-grade harminehydrochloride 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 neurologicalside effects and limitedpsychoactive effects. It is found in various plants—includingtobacco,Passiflora species,lemon balm, and severalBanisteriopsis species—as well as in somebutterflies of theNymphalidae family. Harmine was first isolated and named by in 1848 fromPeganum harmala seeds, later identified inBanisteriopsis caapi under various names, with its structure determined in 1927. Recent patents focus on creating harmine derivatives with reducedtoxicity.
Medically significant amounts of harmine occur in the plantsSyrian rue andBanisteriopsis caapi. These plants also contain notable amounts ofharmaline,[11] which is also a RIMA.[12] The psychoactiveayahuasca brew is made fromB. caapi stem bark usually in combination withdimethyltryptamine (DMT) containingPsychotria viridis leaves. DMT is apsychedelic 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 apsychedelic experience.[18] Syrian rue or synthetic harmine is sometimes used to substituteB. caapi in the oral use of DMT.[19]
Harmine was used or investigated as anantiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications.[20]
Harmaline and harminefluoresce underultraviolet light. These three extractions indicate that the middle one has a higher concentration of the two compounds.
Harmine is a useful fluorescent pH indicator. As the pH of its local environment increases, the fluorescence emission of harmine decreases.
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.[13]
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 2.7mg/kg represents a more useful threshold than fixed dosing.
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[22][23][24][25][26][27][28][29][30]
In contrast to harmaline and6-methoxyharmalan, which fully substituted for thepsychedelic drugDOM in rodentdrug discrimination tests, but similarly toharmane, harmine failed to significantly substitute for DOM and produced behavioral disruption at higher doses.[36]
In addition toB. caapi, at least three members of theMalpighiaceae contain harmine, including two moreBanisteriopsis species and the plantCallaeum antifebrile. Callaway, Brito and Neves (2005) found harmine levels of 0.31–8.43% inB. caapi samples.[38]
The coincident occurrence ofβ-carboline alkaloids andserotonin inPeganum harmala indicates the presence of two very similar, interrelated biosynthetic pathways, which makes it difficult to definitively identify whether freetryptamine or L-tryptophan is the precursor in the biosynthesis of harmine.[39] 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.[40] TheShikimate acid pathway yields the aromatic amino acid, L-tryptophan. Decarboxylation of L-tryptophan byaromatic L-amino acid decarboxylase (AADC) produces tryptamine (I), which contains anucleophilic center at the C-2 carbon of theindole ring due to the adjacent nitrogen atom that enables the participation in aMannich-type reaction. Rearrangements enable the formation of aSchiff base from tryptamine, which then reacts with pyruvate inII to form a β-carbolinecarboxylic acid. The β-carboline carboxylic acid subsequently undergoesdecarboxylation to produce 1-methyl β-carbolineIII.Hydroxylation followed bymethylation inIV yieldsharmaline. The order of O-methylation and hydroxylation have been shown to be inconsequential to the formation of the harmaline intermediate.[39] In the last stepV, the oxidation of harmaline is accompanied by the loss of water and effectively generates harmine.
Proposed biosynthesis of harmine from L-tryptophan
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.[39] 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 ofP. 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.[40]
J. Fritzsche was the first to isolate and name harmine. He isolated it from the husks ofPeganum harmala seeds in 1848. The relatedharmaline was already isolated and named by Fr. Göbel in 1837 from the same plant.[41][20] The pharmacology of harmine was not studied in detail until 1895.[20] The structures of harmine and harmaline were determined in 1927 by Richard Helmuth Fredrick Manske and colleagues.[42][43]
In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknownhallucinogenic ingredient inayahuasca brew.[11][20] "Telepathine" comes from "telepathy", as Zerda-Bayón believed that ayahuasca induced telepathic visions.[11][44] In 1923, the Colombian chemist, Guillermo Fischer-Cárdenas was the first to isolate harmine fromBanisteriopsis caapi, which is an important herbal component of ayahuasca brew. He called the isolated harmine "telepathine".[11] This was solely to honor Zerda-Bayón, as Fischer-Cárdenas found that telepathine had only mild non-hallucinogenic effects in humans.[45] In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine fromB. caapi, but named it "yajéine",[20] which in some texts is written as "yageine".[11] In 1927, F. Elger, who was a chemist working atHoffmann-La Roche, isolated harmine fromB. caapi. With the assistance of ProfessorRobert Robinson in Manchester, Elger showed that harmine (which was already isolated in 1848) was identical with telepathine and yajéine.[46][20] In 1928,Louis Lewin isolated harmine fromB. caapi, and named it "banisterine",[47] but this supposedly novel compound was soon also shown to be harmine.[20] Lewin, in 1928, was the first to describe the subjective effects of harmine in the literature.[10]
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.[48]
Harmine is the most common name of the compound.[49] It is also known by other names includingbanisterine,banisterin,telepathine,telopathin,leucoharmine,yagin, andyageine, among others.[49][50][11]
Harmala alkaloids are considered Schedule 9 prohibited substances under thePoisons Standard (October 2015).[51] 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.[51]
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.[51]
Harmine is currently the only knowndrug that induces proliferation (rapidmitosis and subsequent mass growth) of pancreaticalpha (α) andbeta (β) cells in adult humans.[52] Theseislet sub-cells are normally resistant to growth stimulation in theadult stage of a human's life, as the cell mass plateaus at around age 10 and remains virtually unchanged.
^abcdGlennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, et al. (August 2000). "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors".Drug and Alcohol Dependence.60 (2):121–132.doi:10.1016/s0376-8716(99)00148-9.hdl:11380/17721.PMID10940539.
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^Reniers J, Robert S, Frederick R, Masereel B, Vincent S, Wouters J (January 2011). "Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors".Bioorganic & Medicinal Chemistry.19 (1):134–144.doi:10.1016/j.bmc.2010.11.041.PMID21183355.
^abcdefghijkBrierley DI, Davidson C (December 2012). "Developments in harmine pharmacology--implications for ayahuasca use and drug-dependence treatment".Progress in Neuro-Psychopharmacology & Biological Psychiatry.39 (2):263–272.doi:10.1016/j.pnpbp.2012.06.001.PMID22691716.
^abDeecher DC, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME, Glick SD (February 1992). "Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies".Brain Research.571 (2):242–247.doi:10.1016/0006-8993(92)90661-r.PMID1377086.
^abcZhang L, Li D, Yu S (December 2020). "Pharmacological effects of harmine and its derivatives: a review".Archives of Pharmacal Research.43 (12):1259–1275.doi:10.1007/s12272-020-01283-6.PMID33206346.
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^Grella B, Teitler M, Smith C, Herrick-Davis K, Glennon RA (December 2003). "Binding of beta-carbolines at 5-HT(2) serotonin receptors".Bioorganic & Medicinal Chemistry Letters.13 (24):4421–4425.doi:10.1016/j.bmcl.2003.09.027.PMID14643338.[...] several β-carbolines, including harmaline (1) and its positional isomer 6-methoxyharmalan (4) substituted for the hallucinogenic (5-HT2A agonist) phenylalkylamine [DOM] in a drug discrimination task with rats trained to discriminate DOM from saline vehicle.10 However, neither harmaline (1; Ki=7790 nM) nor 6-methoxyharmalan (4; Ki=5600 nM) binds with high affinity at 5-HT2A receptors, and both were found to lack action as 5-HT2A agonists in a phosphoinositol (PI) hydrolysis assay.5,9 [...] At this time, it is not known if the actions of 1 and 4 in the PI hydrolysis assay reflect their low affinity, low efficacy, or whether the actions of the β-carbolines (in drug discrimination and/or other assays) is attributable to, or compromised by, their actions at other populations of receptors—particularly 5-HT receptors—or by possible interactions with the serotonin transporter.
^Glennon RA, Young R, Jacyno JM, Slusher M, Rosecrans JA (January 1983). "DOM-stimulus generalization to LSD and other hallucinogenic indolealkylamines".European Journal of Pharmacology.86 (3–4):453–459.doi:10.1016/0014-2999(83)90196-6.PMID6572591.
^abcBerlin J, Rugenhagen C, Greidziak N, Kuzovkina I, Witte, Wray V (1993). "Biosynthesis of Serotonin and Beta-carboline Alkaloids in Hairy Root Cultures of Peganum Harmala".Phytochemistry.33 (3):593–597.Bibcode:1993PChem..33..593B.doi:10.1016/0031-9422(93)85453-x.
^US, Lotsof, Howard S., "Method of treating chemical dependency using β-carboline alkaloids, derivatives and salts thereof", published 1997-01-07, assigned to NDA International Inc.
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