|Jmol interactive 3D||Image|
|Molar mass||212.25 g/mol|
|Melting point||321 °C (610 °F; 594 K) (·HCl); 262 °C (·HCl·2H2O)|
|Solubility in Dimethyl sulfoxide||100mM|
|Solubility in Ethanol||1 mg/mL|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Harmine, also known as telepathine, is a fluorescent harmala alkaloid belonging to the beta-carboline family of compounds. It occurs in a number of different plants, most notably the Middle Eastern plant harmal or Syrian rue (Peganum harmala) and the South American vine Banisteriopsis caapi (also known as "yage" or "ayahuasca"). Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a RIMA. Harmine selectively binds to MAO-A but does not inhibit the variant MAO-B.
Isolated from the plant Peganum Harmala, harmine is an indole alkaloid with the pyrido[3,4-b]indole ring structure that is characteristic of the β-carboline alkaloids. The β-carboline alkaloids include as harmine, harmaline, harman and harmalol. These molecules are heterocyclic amines, biosynthesized through the combination of five- and six-membered ring structures that are derived from an amino acid- either L-tryptophan or tryptamine- which facilitates the formation of an indole ring system.
The coincident occurrence of β-carboline alkaloids and serotonin in P. 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 to the biosynthesis of harmine. 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. 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. 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. 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.
Monoamines include neurotransmitters (serotonin, dopamine), hormones (melatonin, epinephrine, norepinephrine) and psychedelic drugs (psilocybin, DMT and mescaline). By slowing the breakdown of neurotransmitters, monoamine oxidase inhibitors (MAOIs) can help to replenish the body's supply of these chemicals, and many MAOIs are used as antidepressants. Harmine has not been the subject of much clinical research in the treatment of depression, which could be due in part to its restricted legal status in many countries, as well as the existence of synthetic MAOIs with fewer side effects.
P. harmala and B. caapi are both traditionally used for their psychoactive effects. B. caapi has a tradition of use in conjunction with plants containing the drug DMT. Traditionally, B. caapi is consumed as a drink, with or without the DMT-bearing plants (see Ayahuasca). Ordinarily, DMT is not active when taken orally, but users report very different effects when MAOIs are present in such beverages. Harmine and substances containing it have been used in conjunction with many other drugs by modern experimenters. Many hallucinogens appear to exhibit increased potency when used in this way.
Harmine is also a useful fluorescent pH indicator. As the pH of its local environment increases, the fluorescence emission of harmine decreases.
Effects on bone and cartilage
It was also shown to inhibit osteoclastogenesis (the formation of bone resorbing cells)
Harmine, and plants containing significant amounts of harmine and other harmala alkaloids are generally not considered safe treatments for depression within the medical community. This bias however is primarily built on previous decades of experience with pharmaceutical non-specific MAOIs that block both MAO-A and MAO-B. Inhibiting MAO-A or MAO-B (in high enough doses) while consuming foods rich in tyramine, e.g. cheese, can cause tyramine, ordinarily metabolized by these enzymes, to accumulate to dangerous levels. This can cause a potentially fatal hypertensive crisis. Because harmine reversibly and selectively inhibits MAO-A and does not degrade MAO-B, MAO-B remains free to metabolize tyramine in the digestive tract. Consequently, the harmala alkaloids (including harmine) are unlikely to elicit tyramine-mediated hypertensive crisis, and a special diet does not need to be so strictly adhered to. Nonetheless, due to the reduction of the levels of tyramine degrading compounds in the gut, it is still not advisable to eat excessively large amounts of tyramine-rich food products. The reversibility and MAO-A selectivity of harmala alkaloids do not, however, prevent potentially fatal interactions with common medications such as antihistamines, most antidepressants, many stimulants, common migraine medications, some herbs, decongestants, expectorants, and common cough and cold medications.
It has recently been shown in the Journal of Photochemistry and Photobiology B: Biology that beta-carboline MAO inhibitors, such as harmine, bind with DNA and also exhibit anti-tumor properties. Harmine has been shown to bind one hundred times more effectively than its close analogue harmaline. The consequences of this are currently not well understood.
Rapid discontinuation of MAO inhibitors can cause serious withdrawal syndrome.
Oral or intravenous harmine doses ranging from 30–300 mg have caused agitation, bradycardia or tachycardia, blurred vision, hypotension, paresthesias and hallucinations. Serum or plasma harmine concentrations may be measured as a confirmation of diagnosis. The plasma elimination half-life is on the order of 1–3 hours.
Harmine is found in a wide variety of different organisms, most of which are plants. Shulgin lists about thirty different species known to contain harmine, including seven species of butterfly in the Nymphalidae family. The harmine-containing plants listed include tobacco, Peganum harmala, two species of passion flower/passion fruit, and numerous others. Lemon balm (Melissa officinalis) contains harmine.
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.
Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015). 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.
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. 
- "Harmine - CAS 442-51-3". scbio.de. Santa Cruz Biotechnology, Inc. Retrieved 27 October 2015.
- The Merck Index (1996). 12th edition
- Abstract Gerardy J, "Effect of moclobemide on rat brain monoamine oxidase A and B: comparison with harmaline and clorgyline.", Department of Pharmacology, University of Liège, Sart Tilman, Belgium.
- Wernicke, Catrin, and Jochen Lehmann. "Beta-Carbolines: Occurrence, Biosynthesis, and Biodegredation." By Hans Rommelspacher.
- Berlin, Jochen, Christiane Rugenhagen, Norbert Greidziak, Inna Kuzovkina, Ludger Witte, and Victor Wray. "Biosynthesis of Serotonin and Beta-carboline Alkaloids in Hairy Root Cultures of Peganum Harmala." Phytochemistry 33.3 (1993): 593-97.
- Nettleship, Lesley, and Michael Slaytor. "Limitations of Feeding Experiments in Studying Alkaloid Biosynthesis in Peganum Harmala Callus Cultures."Phytochemistry 13.4 (1974): 735-42.
- Nathalie Ginovart, Jeffrey H. Meyer, Anahita Boovariwala, Doug Hussey, Eugenii A. Rabiner, Sylvain Houle and 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.
- Pal Bais, Harsh; Park, Sang-Wook; Stermitz, Frank R.; Halligan, Kathleen M.; Vivanco, Jorge M. (18 June 2002). "Exudation of fluorescent β-carbolines from Oxalis tuberosa L. roots" (PDF). Phytochemistry 61 (5): 539–543. doi:10.1016/S0031-9422(02)00235-2. Retrieved 2008-02-02.
- Li Y, Sattler R, Yang EJ, Nunes A, Ayukawa Y, Akhtar S, Ji G, Zhang PW, Rothstein JD. (18 June 2011). "Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression". Neuropharmacology 60 (7–8): 1168–75. doi:10.1016/j.neuropharm.2010.10.016. PMC 3220934. PMID 21034752.
- Jahaniani, F; Ebrahimi, SA; Rahbar-Roshandel, N; Mahmoudian, M (July 2005). "Xanthomicrol is the main cytotoxic component of Dracocephalum kotschyii and a potential anti-cancer agent". Phytochemistry 66 (13): 1581–92. doi:10.1016/j.phytochem.2005.04.035. PMID 15949825. Retrieved 2008-01-12.
- "Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling". Biochemical and Biophysical Research Communications 409: 260–265. doi:10.1016/j.bbrc.2011.05.001.
- Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T. Novel chondrogenic and chondroprotective effects of the natural compound harmine" Biochimie 2013; 95(2):374-81. http://www.sciencedirect.com/science/article/pii/S0300908412004324. doi:10.1016/j.biochi.2012.10.016
- "The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells". Bone 49: 264–274. doi:10.1016/j.bone.2011.04.003.
- Eric Yarnell, Kathy Abascal (April 2001). "Botanical Treatments for Depression". Alternative & Complementary Therapies 7 (3): 138–143. doi:10.1089/10762800151125056.
- McKenna, Callaway, & Grb. "Scientific Investigation of Ayahuasca", Scientific Investigation of Ayahuasca, retrieved 2007-06-03.
- [dead link]
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 727-728.
- Shulgin, Alexander and Shulgin, Ann (1997). TiHKAL: The Continuation. Transform Press. ISBN 0-9630096-9-9. Pages 713–714
- Natalie Harrington (2012). "Harmala Alkaloids as Bee Signaling Chemicals". Journal of Student Research 1 (1): 23–32.
- 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.
- Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534
- Harmine found in Oxalis tuberosa
- Harmine entry in TiHKAL • info
- Developments in harmine pharmacology — Implications for ayahuasca use and drug-dependence treatment Daniel I. Brierley, Colin Davidson. Progress in Neuro-Psychopharmacology & Biological Psychiatry 39 (2012) 263–272.