Harmaline

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Wikipedia

Harmaline
Clinical data
Other names7-Methoxyharmalan; 7-MeO-harmalan; 7-OMe-harmalan; 3,4-Dihydroharmine; 3,4-Dihydro-7-methoxy-1-methyl-β-carboline; Harmadine
Routes of
administration		Oral
Legal status
Legal status
Identifiers
  • 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.594 Edit this at Wikidata
Chemical and physical data
FormulaC13H14N2O
Molar mass214.268 g·mol−1
3D model (JSmol)
Melting point232–234 °C (450–453 °F)
  • COc3ccc2c1CCN=C(C)c1[nH]c2c3
  • InChI=1S/C13H14N2O/c1-8-13-11(5-6-14-8)10-4-3-9(16-2)7-12(10)15-13/h3-4,7,15H,5-6H2,1-2H3 checkY
  • Key:RERZNCLIYCABFS-UHFFFAOYSA-N checkY
  (verify)

Harmaline, also known as 7-methoxyharmalan or as 3,4-dihydro-7-methoxy-1-methyl-β-carboline, is a harmala alkaloid and β-carboline which has hallucinogenic effects and monoamine oxidase inhibitor (MAOI) activity.[1][2][3] It is the partly hydrogenated form of harmine.[1][3]

Plants containing harmaline are combined in ayahuasca to inhibit monoamine oxidase, allowing orally consumed dimethyltryptamine (DMT) to become orally active and produce psychoactive effects. Harmala alkaloids, including harmaline, are psychoactive on their own in humans, with harmaline being particularly hallucinogenic, although other compounds such as harmine and tetrahydroharmine have also been reported to produce hallucinogenic effects as well.

Harmaline is present in Peganum harmala (Syrian rue). Syrian rue seeds contain about 3% harmala alkaloids by dry weight. Harmaline was first isolated from plants in 1841, its chemical structure identified in 1919, and it was first synthesized in 1927.

Use and effects

The harmala alkaloids are psychoactive in humans.[4] According to Alexander Shulgin, harmaline is the only harmala alkaloid that has a reputation of being hallucinogenic.[2][5] However, other harmala alkaloids and β-carbolines, like harmine, tetrahydroharmine (THH), 6-methoxyharmalan, and 6-methoxytetrahydroharman, have also been reported to be hallucinogenic.[6] Harmaline produces vivid dream-like visual effects and physical discomfort at oral doses of 300 to 400 mg, often leading users to seek solitude in a quiet, dark environment.[2][3] The hallucinogenic effects of harmaline and other β-carbolines are said to be qualitatively distinct from and unlike those of serotonergic psychedelics like LSD but similar to those of ibogaine.[7][8][9][10]

Harmaline-containing plants and tryptamine-containing plants are used in ayahuasca brews. The inhibitory effects on monoamine oxidase allows dimethyltryptamine (DMT), the psychoactively prominent chemical in the mixture, to bypass the extensive first-pass metabolism it undergoes upon ingestion, allowing a psychologically active quantity of the chemical to exist in the brain for a perceivable period of time.[11]

Interactions

Harmaline is a reversible inhibitor of MAO-A (RIMA)".[12] This means that the risk of a hypertensive crisis, a dangerous high blood pressure crisis from eating tyramine-rich foods such as cheese, is likely lower with harmaline than with irreversible MAOIs such as phenelzine. Since harmaline is a RIMA, it could, in theory, induce both serotonin syndrome and hypertensive crises in combination with tyramine, serotonergics, catecholaminergics drugs or prodrugs.

Pharmacology

Pharmacodynamics

Harmaline activities
TargetAffinity (Ki, nM)
5-HT1A>10,000 (rat/human)
5-HT1B>10,000
5-HT1D>10,000
5-HT1END
5-HT1FND
5-HT2A5,010–7,790 (Ki) (rat)
>20,000 (EC50Tooltip half-maximal effective concentration)
>10,000 (IC50Tooltip half-maximal inhibitory concentration)
5-HT2BND
5-HT2C9,430 (rat)
5-HT3>10,000
5-HT4ND
5-HT5A>10,000
5-HT61,480
5-HT75,500
α1A>10,000
α1B>10,000
α1DND
α2A2,540
α2B1,130
α2C810
β1, β2>10,000
β3ND
D1–D5>10,000 (human/rat)
H1–H4ND
M1–M5>10,000
I113,800
I222
σ15,447 (guinea pig)
σ219,816 (rat)
MOR>100,000 (bovine)
DOR>100,000 (bovine)
DOR>100,000 (bovine)
TAAR1Tooltip Trace amine-associated receptor 1ND
BDZ>10,000 (rat)
PCP>10,000 (rat)
SERTTooltip Serotonin transporter>10,000 (Ki)
NETTooltip Norepinephrine transporter3,260 (Ki)
DATTooltip Dopamine transporter>10,000 (Ki) (bovine)
MAO-ATooltip Monoamine oxidase A2.5–33 (IC50)
MAO-BTooltip Monoamine oxidase B100,000 (IC50)
DYRK1ATooltip Dual specificity tyrosine-phosphorylation-regulated kinase 1A4,600 (IC50)
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][6][17][18][19]

Harmaline shows weak but significant affinity for the serotonin 5-HT2A and 5-HT2C receptors in the low micromolar range.[6][16] However, harmaline and other β-carbolines do not activate the serotonin 5-HT2A receptor even at very high concentrations in vitro.[14] Harmaline shows high affinity for the imidazoline I2 receptor (Ki = 22 nM).[15] Unlike ibogaine and noribogaine, harmaline does not bind to the κ-opioid receptor or other opioid receptors.[19]

Harmaline and the psychedelic DOM partially substitute for each other in rodent drug discrimination tests.[20][6] Harmaline was much more effective in substituting for DOM than harman and harmine, which did not achieve significant generalization and produced behavioral disruption at higher doses.[20] On the other hand, harmaline and 6-methoxyharman were comparable in terms of DOM substitution.[20] Unlike serotonergic psychedelics, ibogaine and harmala alkaloids like harmaline do not cause pupil dilation or increase blood pressure in humans.[7]

Harmaline and ibogaine have both been found to produce neurotoxicity against Purkinje cells in the cerebellum in rats that is mediated by upstream olivocerebellar pathway activation.[21][22][23][24] This may explain long-lasting motor deficits induced by ibogaine in these rats.[25] However, this phenomenon involves high doses of ibogaine and has not been observed with ibogaine in primates or humans.[25][26][27] In any case, the rodent findings are notable in that they further suggest that harmaline and ibogaine share a common mechanism of action.[21]

Chemistry

Harmaline and harmine fluoresce under ultraviolet light. These three extractions indicate that the middle one has a higher concentration of the two compounds.

Harmaline, also known as 7-methoxyharmalan or 3,4-dihydro-7-methoxy-1-methyl-β-carboline, is a β-carboline and a cyclized tryptamine analogue of 6-methoxy-DMT.

It is fluorescent under ultraviolet light.

Natural occurrence

Various plants contain harmaline including Peganum harmala (Syrian rue) as well as the hallucinogenic beverage ayahuasca, which is traditionally brewed using Banisteriopsis caapi. Present at 3% by dry weight, the harmala alkaloids may be extracted from the Syrian rue seeds.[4]

History

Harmaline was first isolated from plants in 1841.[2] The chemical structure of harmaline was not correctly identified until 1919.[2] Harmaline was first synthesized in 1927.[2]

Society and culture

Australia

Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015).[28] 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.[28]

Canada

Harmaline and Harmalol are considered Schedule III controlled substances by the Controlled Drugs and Substances Act. Every person found to be in possession of a Schedule III drug is guilty of an indictable offence and liable to imprisonment for a term not exceeding three years; or for a first offence, guilty on summary conviction, to a fine not exceeding one thousand dollars or to imprisonment for a term not exceeding six months, or to both. Every person found to be trafficking a Schedule III drug is guilty of an indictable offence and liable to imprisonment for a term not exceeding ten years, or is guilty on summary conviction (first-time offenders) and liable to imprisonment for a term not exceeding eighteen months.[29]

See also

References

  1. 1 2 Brimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. OL 4850660M. Archived from the original on 2025-05-27. Retrieved 2025-06-17. [...] the apparent superiority of extracts of Banisteriopsis over the pure harmine prompted the suggestion (Hochstein and Paradies, 1957) that either harmaline or 1,2,3,4-tetrahydroharmine, or other as then unidentified constituents, were the psychoactive compounds. Naranjo (1967) has now confirmed their hallucinogenic activity in man together with that of 6-methoxyharmalan and 6-methoxytetrahydroharman. [...]
  2. 1 2 3 4 5 6 Shulgin AT (1977). "Profiles of Psychedelic Drugs: 4. Harmaline". Journal of Psychedelic Drugs. 9 (1): 79–80. doi:10.1080/02791072.1977.10472029. ISSN 0022-393X. Retrieved 11 April 2025. Close biosynthetic relatives of harmaline (harmine and tetrahydroharmine) are known components of plants of several other genera which have medical use but no reputation as hallucinogens [...] The effective dose range of harmaline in man is 70-100 mg i.v., or 300-400 mg orally. The initial effects are noted about one hour following oral administration and persist for about 6 hours [...] The indicators of physical toxicity are common and often severe. Paresthesias of hands, feet, or face are almost always present with the onset of effects, and are usually followed by the sensation of numbness. There can be isolated symptoms such as pressure in the head or chest, nausea and distressful vomiting, dizziness, and general malaise. Mydriasis and pressor effects are never seen. The anxiety and general discomfort encourages a withdrawal from social contact, and a quiet dark environment is preferred by most subjects. The modality most consistently affected by harmaline is the visual sense. There can be vivid images generated, often in the form of meaningful dream-like sequences, and frequently containing subject matter such as wild animals or jungle scenes. Other reported visual syntheses are limited to the generation of geometric patterns which are entertaining but not felt to be of any intrinsic significance.
  3. 1 2 3 "Erowid Online Books : "TIHKAL" - #13 HARMALINE". www.erowid.org. Retrieved 11 April 2025.
  4. 1 2 "Peganum Harmala pamphlet: Syrian Rue". Erowid.
  5. ↑ Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Res Monogr. 146: 74–91. PMID 8742795. Archived from the original (PDF) on August 5, 2023. An additional family of compounds should be mentioned here, the β-carbolines. [...] In nature, they usually are found in one of three degrees of hydrogenation: harmine, harmaline, and tetrahydroharmine. [...] Only harmaline, one of the principal components of Ayahuasca, has a reputation for being intrinsically an active hallucinogen. The aromatic analog, harmine, has little if any psychotropic activity.
  6. 1 2 3 4 Grella B, Dukat M, Young R, Teitler M, Herrick-Davis K, Gauthier CB, Glennon RA (April 1998). "Investigation of hallucinogenic and related beta-carbolines". Drug Alcohol Depend. 50 (2): 99–107. doi:10.1016/s0376-8716(97)00163-4. PMID 9649961.
  7. 1 2 Naranjo C (1973). "Ibogaine: Fantasy and Reality" (PDF). The Healing Journey: New Approaches to Consciousness. New York: Parthenon Books. pp. 174–228. ISBN 978-0-394-48826-4.
  8. ↑ Naranjo C (1969). "Psycotherapeutic Possibilities of New Fantasy-Enhancing Drugs". Clinical Toxicology. 2 (2): 209–224. doi:10.3109/15563656908990930. ISSN 0009-9309. Retrieved 27 May 2025.
  9. ↑ González J, Prieto JP, Rodríguez P, Cavelli M, Benedetto L, Mondino A, Pazos M, Seoane G, Carrera I, Scorza C, Torterolo P (2018). "Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile". Front Pharmacol. 9 374. doi:10.3389/fphar.2018.00374. PMC 5934978. PMID 29755349.
  10. ↑ Helsley S, Rabin RA, Winter J (2001). "Chapter 4 Drug discrimination studies with ibogaine". The Alkaloids: Chemistry and Biology (PDF). Vol. 56. Elsevier. pp. 63–77. doi:10.1016/s0099-9598(01)56008-3. ISBN 978-0-12-469556-6. PMID 11705117.
  11. ↑ Shen HW, Jiang XL, Winter JC, Yu AM (October 2010). "Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions". Current Drug Metabolism. 11 (8): 659–66. doi:10.2174/138920010794233495. PMC 3028383. PMID 20942780.
  12. ↑ Massaro EJ (2002). Handbook of Neurotoxicology. Totowa, NJ: Humana Press. p. 237. ISBN 978-0-89603-796-0.[permanent dead link]
  13. ↑ Liu T. "BindingDB BDBM50029799 7-Methoxy-1-methyl-2,9-dihydro-1H-beta-carboline::7-Methoxy-1-methyl-4,9-dihydro-3H-beta-carboline::7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole::CHEMBL2089157::CHEMBL340807::HARMALINE". BindingDB. Retrieved 18 June 2025.
  14. 1 2 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. PMID 14643338. [...] 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.
  15. 1 2 Husbands SM, Glennon RA, Gorgerat S, Gough R, Tyacke R, Crosby J, Nutt DJ, Lewis JW, Hudson AL (October 2001). "beta-carboline binding to imidazoline receptors". Drug Alcohol Depend. 64 (2): 203–208. doi:10.1016/s0376-8716(01)00123-5. PMID 11543990.
  16. 1 2 Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, Smith C, Egan C, Davis K, Mattson MV (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 Alcohol Depend. 60 (2): 121–132. doi:10.1016/s0376-8716(99)00148-9. hdl:11380/17721. PMID 10940539.
  17. ↑ Beato A, Gori A, Boucherle B, Peuchmaur M, Haudecoeur R (February 2021). "β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer's Disease Therapy". J Med Chem. 64 (3): 1392–1422. doi:10.1021/acs.jmedchem.0c01887. PMID 33528252.
  18. ↑ Bowen WD, Vilner BJ, Williams W, Bertha CM, Kuehne ME, Jacobson AE (June 1995). "Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity". Eur J Pharmacol. 279 (1): R1 – R3. doi:10.1016/0014-2999(95)00247-i. PMID 7556375.
  19. 1 2 Deecher 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 Res. 571 (2): 242–247. doi:10.1016/0006-8993(92)90661-r. PMID 1377086.
  20. 1 2 3 Glennon RA, Young R, Jacyno JM, Slusher M, Rosecrans JA (January 1983). "DOM-stimulus generalization to LSD and other hallucinogenic indolealkylamines". Eur J Pharmacol. 86 (3–4): 453–459. doi:10.1016/0014-2999(83)90196-6. PMID 6572591.
  21. 1 2 Zubaran C (2000). "Ibogaine and Noribogaine: Comparing Parent Compound to Metabolite". CNS Drug Reviews. 6 (3): 219–240. doi:10.1111/j.1527-3458.2000.tb00149.x. ISSN 1080-563X. As with ibogaine, harmaline also produces activation of the olivocerebellar pathway and degeneration of cerebellar Purkinje cells, suggesting that these related plant alkaloids have a similar mechanisms of action (70).
  22. ↑ Ali S, Tian X, Cunningham KA, Zhou J (September 2025). "Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics". J Med Chem. 68 (18): 18744–18751. doi:10.1021/acs.jmedchem.5c02510. PMID 40994282. (−)-Ibogaine 1 induces long-lasting hallucinations which are generally well tolerated,12,32 but its use is also associated with tremors as well as Purkinje cell death in rats at high doses.33
  23. ↑ O'Hearn E, Molliver ME (July 1993). "Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline". Neuroscience. 55 (2): 303–310. doi:10.1016/0306-4522(93)90500-f. PMID 8377927. S2CID 25273690.
  24. ↑ O'Hearn E, Molliver ME (November 1997). "The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity". J Neurosci. 17 (22): 8828–8841. doi:10.1523/JNEUROSCI.17-22-08828.1997. PMC 6573067. PMID 9348351.
  25. 1 2 Cherian K, Shinozuka K, Tabaac BJ, Arenas A, Beutler BD, Evans VD, Fasano C, Muir OS (2024). "Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine". Am J Ther. 31 (2): e133 – e140. doi:10.1097/MJT.0000000000001723. PMID 38518270. There has been mixed evidence of neurotoxicity in animal and human research on ibogaine.6 Initial research suggested that ibogaine, by stimulating the inferior olivary nucleus in the medulla oblongata,58 causes Purkinje cells in the rat cerebellum to degenerate,59 perhaps explaining long-term motor deficits in these rats. However, the dose used in this study (100–300 mg/kg) was much higher than the typical therapeutic dose of ibogaine (6–30 mg/kg).20 A lower dose of 40 mg/kg did not cause Purkinje cells to degenerate.60 In humans, there are no records of cerebellar or Purkinje cell damage after ibogaine use, even among fatalities.61
  26. ↑ Mash DC, Kovera CA, Buck BE, Norenberg MD, Shapshak P, Hearn WL, Sanchez-Ramos J (May 1998). "Medication development of ibogaine as a pharmacotherapy for drug dependence". Annals of the New York Academy of Sciences. 844 (1): 274–92. Bibcode:1998NYASA.844..274M. doi:10.1111/j.1749-6632.1998.tb08242.x. PMID 9668685. S2CID 22068338.
  27. ↑ Alper KR, Stajić M, Gill JR (March 2012). "Fatalities temporally associated with the ingestion of ibogaine". Journal of Forensic Sciences. 57 (2): 398–412. doi:10.1111/j.1556-4029.2011.02008.x. PMID 22268458. S2CID 6670557.
  28. 1 2 "Poisons Standard October 2015". Australian Government. 30 September 2015.
  29. ↑ "Controlled Drugs and Substances Act (S.C 1996, c.19)". Justice Laws Website. 19 September 2019. Retrieved 25 September 2019.