Harmine

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Harmine
Harmine structure.svg
Harmine 3d structure.png
Names
Preferred IUPAC name
7-Methoxy-1-methyl-9H-pyrido[3,4-b]indole
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.485 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C13H12N2O/c1-8-13-11(5-6-14-8)10-4-3-9(16-2)7-12(10)15-13/h3-7,15H,1-2H3 Yes check.svgY
    Key: BXNJHAXVSOCGBA-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C13H12N2O/c1-8-13-11(5-6-14-8)10-4-3-9(16-2)7-12(10)15-13/h3-7,15H,1-2H3
    Key: BXNJHAXVSOCGBA-UHFFFAOYAR
  • COc1ccc2c(c1)[nH]c3c(C)nccc23
Properties
C13H12N2O
Molar mass 212.25 g/mol
Density 1.326 g/cm3
Melting point 321 °C (610 °F; 594 K) (·HCl); 262 °C (·HCl·2H2O) [1]
insoluble [2]
Solubility in Dimethyl sulfoxide 100mM [2]
Solubility in Ethanol 1 mg/mL [2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Harmine is a beta-carboline and a harmala alkaloid. It occurs in a number of different plants, most notably the Syrian rue and Banisteriopsis caapi . [3] 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. [4] Harmine is also known as banisterin, banisterine, telopathin, telepathine, leucoharmine [5] and yagin, yageine. [3] [6]

Contents

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. [7] 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. [8] 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. [7] 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 Harmine Biosynthesis.png
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. [7] 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. [8]

Uses

Monoamine oxidase inhibitor

Harmine is a RIMA, as it reversibly inhibits monoamine oxidase A (MAO-A), but not MAO-B. [4] Oral or intravenous harmine doses ranging from 30 to 300 mg may cause agitation, bradycardia or tachycardia, blurred vision, hypotension, paresthesias. Serum or plasma harmine concentrations may be measured as a confirmation of diagnosis. The plasma elimination half-life of harmine is on the order of 1–3 hours. [9]

Medically significant amounts of harmine occur in the plants Syrian rue and Banisteriopsis caapi . These plants also contain notable amounts of harmaline, [3] which is also a RIMA. [4] 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. [10] Syrian rue or synthetic harmine is sometimes used to substitute B. caapi in the oral use of DMT. [11]

Other

Harmaline and harmine fluoresce under ultraviolet light. These three extractions indicate that the middle one has a higher concentration of the two compounds. Harmaline Harmine.jpg
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. 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. [12] Harmine was used as an antiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications. [13]

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. [14] 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.

Adverse effects

Harmine has been found to be relatively toxic [15] to humans where symptoms arise at 3mg/kg. These symptoms include behavioral changes such as sleep, tremors, gastrointestinal issues, nausea and vomiting.[ citation needed ]

Natural sources

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. [16]

The harmine-containing plants include tobacco, Peganum harmala , two species of passiflora, and numerous others. Lemon balm (Melissa officinalis) contains harmine. [17]

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. [18]

The family Zygophyllaceae, which P. harmala belongs to, contains at least two other harmine-bearing plants: Peganum nigellastrum and Zygophyllum fabago .

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. [19] [13] The pharmacology of harmine was not studied in detail until 1895. [13] The structures of harmine and harmaline were determined in 1927 by Richard Helmuth Fredrick Manske and colleagues. [20] [21]

In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknown hallucinogenic ingredient in ayahuasca brew. [3] [13] "Telepathine" comes from "telepathy", as Zerda-Bayón believed that ayahuasca induced telepathic visions. [3] [22] 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". [3] This was solely to honor Zerda-Bayón, as Fischer-Cárdenas found that telepathine had only mild non-hallucinogenic effects in humans. [23] In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine from B. caapi, but named it "yajéine", [13] which in some texts is written as "yageine". [3] 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. [24] [13] In 1928, Louis Lewin isolated harmine from B. caapi, and named it "banisterine", [25] but this supposedly novel compound was soon also shown to be harmine. [13]

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. [26]

Australia

Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015). [27] 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. [27]

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. [27]

Related Research Articles

<span class="mw-page-title-main">Ayahuasca</span> South American psychoactive brew

Ayahuasca is a South American psychoactive brew, traditionally used by Indigenous cultures and folk healers in Amazon and Orinoco basins for spiritual ceremonies, divination, and healing a variety of psychosomatic complaints. Originally restricted to areas of Peru, Brazil, Colombia and Ecuador, in the middle of 20th century it became widespread in Brazil in context of appearance of syncretic religions that uses ayahuasca as a sacrament, like Santo Daime, União do Vegetal and Barquinha, which blend elements of Amazonian Shamanism, Christianity, Kardecist Spiritism, and African-Brazilian religions such as Umbanda, Candomblé and Tambor de Mina, later expanding to several countries across all continents, notably the United States and Western Europe, and, more incipiently, in Eastern Europe, South Africa, Australia, and Japan.

<i>N</i>,<i>N</i>-Dimethyltryptamine Chemical compound

N,N-Dimethyltryptamine is a substituted tryptamine that occurs in many plants and animals, including humans, and which is both a derivative and a structural analog of tryptamine. DMT is used as a psychedelic drug and prepared by various cultures for ritual purposes as an entheogen.

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<i>Banisteriopsis caapi</i> Species of plant

Banisteriopsis caapi, also known as, caapi, soul vine, or yagé (yage), is a South American liana of the family Malpighiaceae. It is commonly used as an ingredient of ayahuasca, a decoction with a long history of its entheogenic use and its status as a "plant teacher" among the Indigenous peoples of the Amazon rainforest.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

β-Carboline Chemical compound also known as norharmane

β-Carboline (9H-pyrido[3,4-b]indole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines primarily influence brain functions but can also exhibit antioxidant effects. Synthetically designed β-carboline derivatives have recently been shown to have neuroprotective, cognitive enhancing and anti-cancer properties.

<span class="mw-page-title-main">Harmala alkaloid</span> Group of chemical compounds

Harmala alkaloids are several alkaloids that increase effects of reward system neurotransmitter dopamine by acting as monoamine oxidase inhibitors (MAOIs). These alkaloids are found in the seeds of Peganum harmala, as well as leaves of tobacco and coffee beans. The alkaloids include harmine, harmaline, harmalol, and their derivatives, which have similar chemical structures, hence the name "harmala alkaloids". These alkaloids are of interest for their use in Amazonian shamanism, where they are derived from other plants. Harmine, once known as telepathine and banisterine, is a naturally occurring beta-carboline alkaloid that is structurally related to harmaline, and also found in the vine Banisteriopsis caapi. Tetrahydroharmine is also found in B. caapi and P. harmala. Dr. Alexander Shulgin has suggested that harmine may be a breakdown product of harmaline. Harmine and harmaline are reversible inhibitors of monoamine oxidase A (RIMAs). They can stimulate the central nervous system by inhibiting the metabolism of monoamine compounds such as serotonin and norepinephrine.

<i>Peganum harmala</i> Species of plant

Peganum harmala, commonly called wild rue, Syrian rue, African rue, esfand or espand, or harmel, is a perennial, herbaceous plant, with a woody underground rootstock, of the family Nitrariaceae, usually growing in saline soils in temperate desert and Mediterranean regions. Its common English-language name came about because of a resemblance to rue. Because eating it would sicken or kill livestock, it is considered a noxious weed in a number of countries. It has become an invasive species in some regions of the western United States. The plant is popular in Middle Eastern and north African folk medicine. The alkaloids contained in the plant, including the seeds, are monoamine oxidase inhibitors.

<span class="mw-page-title-main">Harmaline</span> Chemical compound

Harmaline is a fluorescent indole alkaloid from the group of harmala alkaloids and beta-carbolines. It is the partly hydrogenated form of harmine.

<span class="mw-page-title-main">Tetrahydroharmine</span> Chemical compound

Tetrahydroharmine (THH) is a fluorescent indole alkaloid that occurs in the tropical liana species Banisteriopsis caapi.

Pharmahuasca is a pharmaceutical version of the entheogenic brew ayahuasca. Traditional ayahuasca is made by brewing the MAOI-containing Banisteriopsis caapi vine with a DMT-containing plant, such as Psychotria viridis. Pharmahuasca refers to a similar combination that uses a pharmaceutical MAOI instead of a plant.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

<span class="mw-page-title-main">Tetrahydroharmol</span> Chemical compound

Tetrahydroharmol is a bioactive beta-carboline harmala alkaloid. It acts as a reversible inhibitor of monoamine oxidase A.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Tryptoline</span> Chemical compound

Tryptoline, also known as tetrahydro-β-carboline and tetrahydronorharmane, is a natural organic derivative of beta-carboline. It is an alkaloid chemically related to tryptamines. Derivatives of tryptoline have a variety of pharmacological properties and are known collectively as tryptolines.

<span class="mw-page-title-main">Pinoline</span> Chemical compound

Pinoline is a methoxylated tryptoline (5-methoxytryptoline) long claimed to be produced in the pineal gland during the metabolism of melatonin, however its pineal occurrence remains controversial. Its IUPAC name is 6-methoxy-1,2,3,4-tetrahydro-β-carboline, usually abbreviated as 6-MeO-THBC, and its more common name is a combination of "pineal beta-carboline". The biological activity of this molecule is of interest as a potential free radical scavenger, also known as an antioxidant, and as a monoamine oxidase A inhibitor.

<span class="mw-page-title-main">Harmane</span> Chemical compound

Harmane (harman) is a heterocyclic amine found in a variety of foods including coffee, sauces, and cooked meat. It is also present in tobacco smoke.

<span class="mw-page-title-main">Harmol</span> Chemical compound

Harmol is a chemical compound classified as a β-carboline. It is readily formed in vivo in humans by O-demethylation of harmine.

<span class="mw-page-title-main">Changa (drug)</span> DMT-infused smoking blend

Changa is a blend of N,N-Dimethyltryptamine (DMT) mixed with a monoamine oxidase inhibitor (MAOI). The addition of MAOIs extends the DMT experience in duration and intensity when compared with smoking DMT freebase alone. Typically, extracts from DMT-containing plants are combined with a blend of different MAOI-containing herbs, such as the ayahuasca vine, and/or leaf or harmala alkaloids from Peganum harmala to create a mix that is 25 to 50% DMT.

References

  1. ↑ The Merck Index (1996). 12th edition
  2. 1 2 3 "Harmine - CAS 442-51-3". scbio.de. Santa Cruz Biotechnology, Inc. Retrieved 27 October 2015.
  3. 1 2 3 4 5 6 7 Djamshidian A, et al. (2015). "Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson's Disease?". Movement Disorders Clinical Practice. 3 (1): 19–26. doi:10.1002/mdc3.12242. PMC   6353393 . PMID   30713897.
  4. 1 2 3 Frecska E, Bokor P, Winkelman M (2016). "The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization". Frontiers in Pharmacology. 7: 35. doi: 10.3389/fphar.2016.00035 . PMC   4773875 . PMID   26973523.
  5. ↑ Allen JR, Holmstedt BR (1980). "The simple β-carboline alkaloids". Phytochemistry. 19 (8): 1573–1582. doi:10.1016/S0031-9422(00)83773-5.
  6. ↑ "SciFinderⁿ Login". sso.cas.org. Retrieved 2021-11-12.
  7. 1 2 3 Berlin Jochen; Rugenhagen Christiane; Greidziak Norbert; Kuzovkina Inna; Witte Ludger; Wray Victor (1993). "Biosynthesis of Serotonin and Beta-carboline Alkaloids in Hairy Root Cultures of Peganum Harmala". Phytochemistry. 33 (3): 593–97. doi:10.1016/0031-9422(93)85453-x.
  8. 1 2 Nettleship Lesley; Slaytor Michael (1974). "Limitations of Feeding Experiments in Studying Alkaloid Biosynthesis in Peganum Harmala Callus Cultures". Phytochemistry. 13 (4): 735–42. doi:10.1016/s0031-9422(00)91406-7.
  9. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 727-728.
  10. ↑ Jonathan H, et al. (2019). "Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness". Current Neuropharmacology. 17 (2): 108–128. doi:10.2174/1570159X16666180125095902. PMC   6343205 . PMID   29366418.
  11. ↑ Simão AY, et al. (2019). "Toxicological Aspects and Determination of the Main Components of Ayahuasca: A Critical Review". Medicines. 6 (4): 106. doi: 10.3390/medicines6040106 . PMC   6963515 . PMID   31635364.
  12. ↑ Nathalie Ginovart; Jeffrey H. Meyer; Anahita Boovariwala; Doug Hussey; Eugenii A. Rabiner; Sylvain Houle; Alan A. Wilson (2006). "Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain". Journal of Cerebral Blood Flow & Metabolism . 26 (3): 330–344. doi: 10.1038/sj.jcbfm.9600197 . PMID   16079787.
  13. 1 2 3 4 5 6 7 Foley, Paul Bernard (2001). "V. Encephalitis lethargica: New strategies in the therapy of parkinsonism". Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism (PhD thesis). Bavarian Julius Maximilian University. pp. 166–180. Retrieved 2020-11-22.
  14. ↑ Wang, P. (2015). "Induction of human pancreatic beta cell replication by inhibitors of dual specificity tyrosine regulated kinase". Nature Medicine. 21 (4): 383–388. doi:10.1038/nm.3820. PMC   4690535 . PMID   25751815.
  15. ↑ Marwat, Sarfaraz Khan; Rehman, Fazal ur (1 January 2011). "Chapter 70 - Medicinal and Pharmacological Potential of Harmala (Peganum harmala L.) Seeds". Nuts and Seeds in Health and Disease Prevention. Academic Press. pp. 585–599. doi:10.1016/B978-0-12-375688-6.10070-2. ISBN   9780123756886.
  16. ↑ Shulgin, Alexander; Shulgin, Ann (1997). TiHKAL: The Continuation. Transform Press. ISBN   0-9630096-9-9. Pages 713–714
  17. ↑ Natalie Harrington (2012). "Harmala Alkaloids as Bee Signaling Chemicals". Journal of Student Research. 1 (1): 23–32. doi: 10.47611/jsr.v1i1.30 .
  18. ↑ Callaway J. C.; Brito G. S.; Neves E. S. (2005). "Phytochemical analyses of Banisteriopsis caapi and Psychotria viridis". Journal of Psychoactive Drugs . 37 (2): 145–150. doi:10.1080/02791072.2005.10399795. PMID   16149327. S2CID   30736017.
  19. ↑ "Bestandtheile der Samen von Peganum Harmala". Justus Liebigs Annalen der Chemie. 64 (3): 360–369. 1848. doi:10.1002/jlac.18480640353.
  20. ↑ Manske RH, Perkin, WH, Robinson R (1927). "Harmine and harmaline. Part IX. A synthesis of harmaline". Journal of the Chemical Society: 1–14. doi:10.1039/JR9270000001.
  21. ↑ 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.
  22. ↑ Baldo, Benjamin (1920). "Telepathy and Telepathine" (PDF). American Druggist. 68 (4): 15. Archived (PDF) from the original on 2020-10-23.
  23. ↑ Fischer-Cárdenas, Guillermo (1923). "V. Encephalitis lethargica: New strategies in the therapy of parkinsonism" (PDF). Estudio sobre el principio activo del Yagé (PhD). Universidad Nacional. Retrieved 2020-11-22.
  24. ↑ Elger, F. (1928). "Über das Vorkommen von Harmin in einer südamerikanischen Liane (Yagé)". Helvetica Chimica Acta. 11 (1): 162–166. doi:10.1002/hlca.19280110113.
  25. ↑ Schultes, RE (1982). "The beta-carboline Hallucinogens of South America". Journal of Psychoactive Drugs. 14 (3): 205–220. doi:10.1080/02791072.1982.10471930. PMID   6754896.
  26. ↑ EP 1634881,Wu, Jialin; Chen, Qi& Cao, Rihuiet al.,"Harmine derivatives, intermediates used in their preparations, preparation processes and use thereof",published 2006-03-15, assigned to Xinjiang Huashidan Pharmaceutical Research Co.
  27. 1 2 3 Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534
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