Plants containing harmaline are combined inayahuasca to inhibitmonoamine oxidase, allowing orally consumeddimethyltryptamine (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 asharmine andtetrahydroharmine have also been reported to produce hallucinogenic effects as well.
Harmaline is present inPeganum 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.
The harmala alkaloids are psychoactive in humans.[5] According toAlexander Shulgin, harmaline is the only harmala alkaloid that has a reputation of beinghallucinogenic.[2][6] However, other harmala alkaloids and β-carbolines, like harmine,tetrahydroharmine (THH),6-methoxyharmalan, and6-methoxytetrahydroharman, have also been reported to be hallucinogenic.[7] Harmaline produces vividdream-likevisual effects andphysical discomfort at doses of 150 to 400mg orally or 70 to 100mgintravenously, often leading users to seeksolitude in a quiet, dark environment.[2][1] The hallucinogenic effects of harmaline and other β-carbolines are said to be qualitatively distinct from and unlike those ofserotonergic psychedelics likeLSD but similar to those ofibogaine.[8][9][10][11] Taken orally, theonset of harmaline is 1 to 2hours, peak effects occur after around 2hours, and itsduration is 5 to 8hours.[1][2] Conversely, its onset byintravenous injection is within seconds and its duration is much shorter by this route than with oral administration.[2]
Harmaline-containing plants and tryptamine-containing plants are used inayahuasca brews. The inhibitory effects onmonoamine oxidase A (MAO-A) allowsdimethyltryptamine (DMT), the psychoactively prominent chemical in the mixture, to bypass the extensivefirst-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.[13]
Besides DMT, harmaline has also been used to inhibit the metabolism of and thereby potentiate5-MeO-DMT, which like DMT is otherwise orally inactive and has a very shortduration.[1]
Harmaline is a reversibleinhibitor ofMAO-A (RIMA)".[14] This means that the risk of a hypertensive crisis, a dangerous high blood pressure crisis from eatingtyramine-rich foods such as cheese, is likely lower with harmaline than with irreversible MAOIs such asphenelzine. Since harmaline is a RIMA, it could, in theory, induce bothserotonin syndrome andhypertensive crises in combination with tyramine, serotonergics, catecholaminergics drugs or prodrugs.
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[15][16][17][18][7][19][20][21]
Harmaline and ibogaine have both been found to produceneurotoxicity againstPurkinje cells in thecerebellum in rats that is mediated by upstreamolivocerebellar pathway activation.[23][24][25][26] This may explain long-lastingmotor deficits induced by ibogaine in these rats.[27] However, this phenomenon involves high doses of ibogaine and has not been observed with ibogaine in primates or humans.[27][28][29] In any case, the rodent findings are notable in that they further suggest that harmaline and ibogaine share a commonmechanism of action.[23]
Harmaline andharminefluoresce underultraviolet light. These three extractions indicate that the middle one has a higher concentration of the two compounds.
Various plants contain harmaline includingPeganum harmala (Syrian rue) as well as the hallucinogenic beverageayahuasca, which is traditionally brewed usingBanisteriopsis caapi.Present at 3% by dry weight, the harmala alkaloids may be extracted from theSyrian rue seeds.[5]
Harmala alkaloids are considered Schedule 9 prohibited substances under thePoisons Standard (October 2015).[30] 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.[30]
Harmaline and Harmalol are considered Schedule III controlled substances by theControlled 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.[31]
^abcdefghijklmnShulgin AT (1977)."Profiles of Psychedelic Drugs: 4. Harmaline".Journal of Psychedelic Drugs.9 (1):79–80.doi:10.1080/02791072.1977.10472029.ISSN0022-393X. Retrieved11 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.
^abBrimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds".Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144.ISBN978-0-85608-011-1.OCLC2176880.OL4850660M. Archived fromthe original on 2025-05-27. Retrieved2025-06-17.[...] 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. [...]
^Jacob P, Shulgin AT (1994)."Structure-activity relationships of the classic hallucinogens and their analogs"(PDF).NIDA Research Monograph.146:74–91.PMID8742795. Archived fromthe 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.
^abcdGrella 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.
^abGrella 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.
^abHusbands 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.
^abGlennon 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.
^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".European Journal of Pharmacology.279 (1):R1 –R3.doi:10.1016/0014-2999(95)00247-i.PMID7556375.
^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.
^abcGlennon 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.
^Ali S, Tian X, Cunningham KA, Zhou J (September 2025). "Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics".Journal of Medicinal Chemistry.68 (18):18744–18751.doi:10.1021/acs.jmedchem.5c02510.PMID40994282.(−)-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
^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.PMID8377927.S2CID25273690.
^abCherian K, Shinozuka K, Tabaac BJ, Arenas A, Beutler BD, Evans VD, et al. (2024)."Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine".American Journal of Therapeutics.31 (2):e133 –e140.doi:10.1097/MJT.0000000000001723.PMID38518270.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
