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.
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
Harmaline and harmine fluoresce under ultraviolet 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.[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 2.7mg/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:[13][14][15][16][17][18][19][20]
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 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.
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.[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]
History
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]
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]
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.
^ 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.
^ abcGrella B, Dukat M, Young R, Teitler M, Herrick-Davis K, Gauthier CB, et al. (April 1998). "Investigation of hallucinogenic and related beta-carbolines". Drug and Alcohol Dependence. 50 (2): 99–107. doi:10.1016/s0376-8716(97)00163-4. PMID9649961.
^Husbands SM, Glennon RA, Gorgerat S, Gough R, Tyacke R, Crosby J, et al. (October 2001). "beta-carboline binding to imidazoline receptors". Drug and Alcohol Dependence. 64 (2): 203–208. doi:10.1016/s0376-8716(01)00123-5. PMID11543990.
^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.
^ 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.
^Brierley DI, Davidson C (January 2013). "Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell". Journal of Psychopharmacology. 27 (1). Oxford, England: 98–108. doi:10.1177/0269881112463125. PMID23076833.
^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.
^Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 727–728.
^ 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 5591738, 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.
^EP 1634881, Wu J, Chen R, Cao F, Yu Z, Wang W, Peng, "Harmine derivatives, intermediates used in their preparations, preparation processes and use thereof", published 2006-03-15, assigned to Xinjiang Huashidan Pharmaceutical Research Co.
