Harmaline

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = verified | verifiedrevid = 443852550 | image = Harmalin.svg | image_class = skin-invert-image | width = 250px | image2 = Harmaline-from-xtal-Mercury-3D-bs.png | image_class2 = bg-transparent | width2 = 250px

<!-- Clinical data --> | tradename = | Drugs.com = | pregnancy_US = | dependency_liability = | routes_of_administration = Oral, intravenous<ref name="TiHKAL1997" /><ref name="Shulgin_1977" /> | class = Hallucinogen; Oneirogen; Monoamine oxidase inhibitor; Reversible inhibitor of MAO-A | ATC_prefix = None | ATC_suffix = | ATC_supplemental =

<!-- Legal status --> | legal_AU = S9 | legal_CA = Schedule III | legal_UK = | legal_US =

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | onset = Oral: 1–2 hours<ref name="TiHKAL1997" /><ref name="Shulgin_1977" /><br />{{Abbrlink|IV|Intravenous injection}}: Seconds<ref name="Shulgin_1977" /> | elimination_half-life = 2 hours<ref name="BritodaCosta_2020" /> | duration_of_action = Oral: 5–8 hours<ref name="TiHKAL1997" /><ref name="Shulgin_1977" /><br />{{Abbr|IV|Intravenous injection}}: "Much shorter" (than oral)<ref name="Shulgin_1977" /> | excretion =

<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 304-21-2 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 28172 | PubChem = 5280951 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 10211258 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = CN58I4TOET | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C06536 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 340807 | synonyms = 7-Methoxyharmalan; 7-MeO-harmalan; 7-OMe-harmalan; 7-Methoxy-3,4-dihydroharman; 3,4-Dihydroharmine; 3,4-Dihydro-7-methoxy-1-methyl-β-carboline; Harmadine

<!-- Chemical data --> | IUPAC_name = 7-methoxy-1-methyl-4,9-dihydro-3''H''-pyrido[3,4-''b'']indole | C=13 | H=14 | N=2 | O=1 | SMILES = COc3ccc2c1CCN=C(C)c1[nH]c2c3 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RERZNCLIYCABFS-UHFFFAOYSA-N

<!-- Physical data --> | density = | melting_point = 232 | melting_high = 234 | boiling_point = }}

'''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.<ref name="Brimblecombe_1975">{{cite book | vauthors = Brimblecombe RW, Pinder RM | chapter = Indolealkylamines and Related Compounds | title = Hallucinogenic Agents | location = Bristol | pages = 98–144 | date = 1975 | publisher = Wright-Scientechnica | isbn = 978-0-85608-011-1 | oclc = 2176880 | ol = OL4850660M | url = https://bitnest.netfirms.com/external/Books/978-0-85608-011-1 | quote = [...] 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. [...] | archive-date = 2025-05-27 | access-date = 2025-06-17 | archive-url = https://web.archive.org/web/20250527204106/https://bitnest.netfirms.com/external/Books/978-0-85608-011-1 }}</ref><ref name="Shulgin_1977">{{cite journal | vauthors = Shulgin AT | title = Profiles of Psychedelic Drugs: 4. Harmaline | journal = Journal of Psychedelic Drugs | volume = 9 | issue = 1 | pages = 79–80 | date = 1977 | doi = 10.1080/02791072.1977.10472029 | issn = 0022-393X | url = https://www.tandfonline.com/doi/full/10.1080/02791072.1977.10472029 | access-date = 11 April 2025 | quote = 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. | url-access = subscription }}</ref><ref name="TiHKAL1997">{{cite web | title = Erowid Online Books: "TIHKAL" - #13 HARMALINE | website = www.erowid.org | url = http://www.erowid.org/library/books_online/tihkal/tihkal13.shtml | access-date = 11 April 2025 }}</ref> It is the partly hydrogenated form of harmine.<ref name="Brimblecombe_1975" /><ref name="TiHKAL1997" />

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== ===As a hallucinogen=== The harmala alkaloids are psychoactive in humans.<ref name="erowid" /> According to Alexander Shulgin, harmaline is the only harmala alkaloid that has a reputation of being hallucinogenic.<ref name="Shulgin_1977" /><ref name="Jacob_1994">{{cite journal | vauthors = Jacob P, Shulgin AT | title = Structure-activity relationships of the classic hallucinogens and their analogs | journal = NIDA Research Monograph | volume = 146 | pages = 74–91 | date = 1994 | pmid = 8742795 | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | quote = 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. | archive-url = https://web.archive.org/web/20230805004551/https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | archive-date = August 5, 2023 }}</ref> However, other harmala alkaloids and β-carbolines, like harmine, tetrahydroharmine (THH), 6-methoxyharmalan, and 6-methoxytetrahydroharman, have also been reported to be hallucinogenic.<ref name="Grella_1998" /> Harmaline produces vivid dream-like visual effects and physical discomfort at doses of 150 to 400{{nbsp}}mg orally or 70 to 100{{nbsp}}mg intravenously, often leading users to seek solitude in a quiet, dark environment.<ref name="Shulgin_1977" /><ref name="TiHKAL1997" /> 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.<ref name="Naranjo_1973" /><ref name="Naranjo_1969">{{cite journal | vauthors = Naranjo C | title = Psycotherapeutic Possibilities of New Fantasy-Enhancing Drugs | journal = Clinical Toxicology | volume = 2 | issue = 2 | pages = 209–224 | date = 1969 | doi = 10.3109/15563656908990930 | issn = 0009-9309 | url = http://www.tandfonline.com/doi/full/10.3109/15563656908990930 | access-date = 27 May 2025 | url-access = subscription }}</ref><ref name="Gonzalez_2018">{{cite journal | vauthors = González J, Prieto JP, Rodríguez P, Cavelli M, Benedetto L, Mondino A, Pazos M, Seoane G, Carrera I, Scorza C, Torterolo P | title = Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile | journal = Frontiers in Pharmacology | volume = 9 | date = 2018 | pmid = 29755349 | pmc = 5934978 | doi = 10.3389/fphar.2018.00374 | doi-access = free | article-number = 374 }}</ref><ref name="Helsley_2001">{{cite book | vauthors = Helsley S, Rabin RA, Winter J | chapter = Chapter 4 Drug discrimination studies with ibogaine | title = The Alkaloids: Chemistry and Biology | volume = 56 | pages = 63–77 | date = 2001 | pmid = 11705117 | doi = 10.1016/s0099-9598(01)56008-3 | publisher = Elsevier | isbn = 978-0-12-469556-6 | url = https://www.iceers.org/Documents_ICEERS_site/Scientific_Papers/ibogaine/Ibogaine%20Proceedings/ch04_Discrimination_Helsley.pdf }}</ref> Taken orally, the onset of harmaline is 1 to 2{{nbsp}}hours, peak effects occur after around 2{{nbsp}}hours, and its duration is 5 to 8{{nbsp}}hours.<ref name="TiHKAL1997" /><ref name="Shulgin_1977" /> Conversely, its onset by intravenous injection is within seconds and its duration is much shorter by this route than with oral administration.<ref name="Shulgin_1977" />

===As an MAOI=== Harmaline is a monoamine oxidase inhibitor (MAOI), or more specifically a reversible inhibitor of monoamine oxidase A (RIMA).<ref name="Cesura_1992">{{cite book | vauthors = Cesura AM, Pletscher A | chapter = The new generation of monoamine oxidase inhibitors | title = Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques | pages = 171–297 | date = 1992 | doi = 10.1007/978-3-0348-7141-9_3 | publisher = Birkhäuser Basel | pmid = 1609114 | publication-place = Basel | isbn = 978-3-0348-7143-3 | chapter-url = http://link.springer.com/10.1007/978-3-0348-7141-9_3 | access-date = 10 November 2025 }}</ref><ref name="TiHKAL1997" /> The effective doses for this activity are 70 to 150{{nbsp}}mg orally.<ref name="TiHKAL1997" />

Harmaline-containing plants and tryptamine-containing plants are used in ayahuasca brews. The inhibitory effects on monoamine oxidase A (MAO-A) 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.<ref name="Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.">{{cite journal | vauthors = Shen HW, Jiang XL, Winter JC, Yu AM | title = Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions | journal = Current Drug Metabolism | volume = 11 | issue = 8 | pages = 659–666 | date = October 2010 | pmid = 20942780 | pmc = 3028383 | doi = 10.2174/138920010794233495 }}</ref>

Besides DMT, harmaline has also been used to inhibit the metabolism of and thereby potentiate 5-MeO-DMT, which like DMT is otherwise orally inactive and has a very short duration.<ref name="TiHKAL1997" />

== Interactions ==

Harmaline is a reversible inhibitor of MAO-A (RIMA)".<ref>{{cite book | vauthors = Massaro EJ | title = Handbook of Neurotoxicology | location = Totowa, NJ | page = 237 | year = 2002 | publisher = Humana Press | isbn = 978-0-89603-796-0 | url = https://books.google.com/books?id=2c2K-epbCDQC&q=harmaline+antidepressant&pg=PA237 }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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=== {| class="wikitable floatleft" style="font-size:small;" |+ {{Nowrap|Harmaline activities}} |- ! Target !! Affinity (K_i, nM) |- | 5-HT_1A || >10,000 (rat/human) |- | 5-HT_1B || >10,000 |- | 5-HT_1D || >10,000 |- | 5-HT_1E || {{Abbr|ND|No data}} |- | 5-HT_1F || {{Abbr|ND|No data}} |- | 5-HT_2A || 5,010–7,790 (K_i) (rat)<br />>20,000–100,000 ({{Abbrlink|EC₅₀|half-maximal effective concentration}})<br />>10,000 ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}}) |- | 5-HT_2B || {{Abbr|ND|No data}} |- | 5-HT_2C || 9,430 (rat) |- | 5-HT₃ || >10,000 |- | 5-HT₄ || {{Abbr|ND|No data}} |- | 5-HT_5A || >10,000 |- | 5-HT₆ || 1,480 |- | 5-HT₇ || 5,500 |- | α_1A || >10,000 |- | α_1B || >10,000 |- | α_1D || {{Abbr|ND|No data}} |- | α_2A || 2,540 |- | α_2B || 1,130 |- | α_2C || 810 |- | β₁, β₂ || >10,000 |- | β₃ || {{Abbr|ND|No data}} |- | D₁–D₅ || >10,000 (human/rat) |- | H₁–H₄ || {{Abbr|ND|No data}} |- | M₁–M₅ || >10,000 |- | I₁ || 13,800 |- | I₂ || 22 |- | σ || 510–3,850 (mouse) |- | σ₁ || 5,447 (guinea pig) |- | σ₂ || 19,816 (rat) |- | MOR || >100,000 (bovine) |- | DOR || >100,000 (bovine) |- | DOR || >100,000 (bovine) |- | {{Abbrlink|TAAR1|Trace amine-associated receptor 1}} || {{Abbr|ND|No data}} |- | {{Abbr|BDZ|Benzodiazepine (BDZ) site of the GABAA receptor}} || >10,000 (rat) |- | {{Abbr|PCP|Phencyclidine (PCP) site of the NMDA receptor}} || >10,000 (rat) |- | {{Abbrlink|SERT|Serotonin transporter}} || >10,000 (K_i)<br />15,000 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) (mouse) |- | {{Abbrlink|NET|Norepinephrine transporter}} || 3,260 (K_i) |- | {{Abbrlink|DAT|Dopamine transporter}} || >10,000 (K_i) (bovine) |- | {{Abbrlink|MAO-A|Monoamine oxidase A}} || 2.5–33 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- | {{Abbrlink|MAO-B|Monoamine oxidase B}} || 100,000 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- | {{Abbrlink|DYRK1A|Dual specificity tyrosine-phosphorylation-regulated kinase 1A}} || 4,600 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="BindingDB">{{cite web | vauthors = Liu T | title = 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 | website = BindingDB | url = https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50029799 | access-date = 18 June 2025 }}</ref><ref name="Grella_2003" /><ref name="Husbands_2001">{{cite journal | vauthors = Husbands SM, Glennon RA, Gorgerat S, Gough R, Tyacke R, Crosby J, Nutt DJ, Lewis JW, Hudson AL | title = beta-carboline binding to imidazoline receptors | journal = Drug and Alcohol Dependence | volume = 64 | issue = 2 | pages = 203–208 | date = October 2001 | pmid = 11543990 | doi = 10.1016/s0376-8716(01)00123-5 }}</ref><ref name="Glennon_2000" /><ref name="Grella_1998" /><ref name="Beato_2021">{{cite journal | vauthors = Beato A, Gori A, Boucherle B, Peuchmaur M, Haudecoeur R | title = β-Carboline as a Privileged Scaffold for Multitarget Strategies in Alzheimer's Disease Therapy | journal = Journal of Medicinal Chemistry | volume = 64 | issue = 3 | pages = 1392–1422 | date = February 2021 | pmid = 33528252 | doi = 10.1021/acs.jmedchem.0c01887 | url = https://hal.science/hal-04020932 }}</ref><ref name="ItzhakStein1990">{{cite journal | vauthors = Itzhak Y, Stein I | title = Sigma binding sites in the brain; an emerging concept for multiple sites and their relevance for psychiatric disorders | journal = Life Sci | volume = 47 | issue = 13 | pages = 1073–1081 | date = 1990 | pmid = 2172677 | doi = 10.1016/0024-3205(90)90165-n | url = | doi-access = free }}</ref><ref name="Bowen_1995">{{cite journal | vauthors = Bowen WD, Vilner BJ, Williams W, Bertha CM, Kuehne ME, Jacobson AE | title = Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity | journal = European Journal of Pharmacology | volume = 279 | issue = 1 | pages = R1–R3 | date = June 1995 | pmid = 7556375 | doi = 10.1016/0014-2999(95)00247-i }}</ref><ref name="Deecher_1992" /><ref name="Rolquin2022">{{cite thesis | vauthors = Rolquin JD | degree = Master of Science | date = 3 May 2022 | title = Examining Ayahuasca Constituents at 5-HT2A Receptors in Search of Antidepressant Action | publisher = Virginia Commonwealth University | via = VCU Scholars Compass | url = https://scholarscompass.vcu.edu/etd/6884/ | access-date = 7 April 2026 }}</ref><ref name="BuckholtzBoggan1977">{{cite journal | vauthors = Buckholtz NS, Boggan WO | title = Inhibition by beta-carbolines of monoamine uptake into a synaptosomal preparation: structure-activity relationships | journal = Life Sci | volume = 20 | issue = 12 | pages = 2093–2099 | date = June 1977 | pmid = 18641 | doi = 10.1016/0024-3205(77)90190-4 | url = }}</ref><ref name="RabinReginaDoat2002">{{cite journal | vauthors = Rabin RA, Regina M, Doat M, Winter JC | title = 5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens | journal = Pharmacol Biochem Behav | volume = 72 | issue = 1-2 | pages = 29–37 | date = May 2002 | pmid = 11900766 | doi = 10.1016/s0091-3057(01)00720-1 | url = | quote = The β-carbolines, harmaline and harmane, also did not alter [5-HT2A] phosphoinositide hydrolysis. [...] Table 1 Comparison of in vitro (phosphoinositide hydrolysis) and in vivo (LSD or DOM appropriate responding) efficacy of indoleamine, phenethylamine and β-carboline hallucinogens [...] Concentrations of up to 100 μM of the β-carbolines, harmaline and harmane, did not alter the generation of inositol phosphates in the PC12-5-HT2A cells (Table 1).}}</ref> |}

Harmaline shows weak but significant affinity for the serotonin 5-HT_2A and 5-HT_2C receptors in the low micromolar range.<ref name="Grella_1998">{{cite journal | vauthors = Grella B, Dukat M, Young R, Teitler M, Herrick-Davis K, Gauthier CB, Glennon RA | title = Investigation of hallucinogenic and related beta-carbolines | journal = Drug and Alcohol Dependence | volume = 50 | issue = 2 | pages = 99–107 | date = April 1998 | pmid = 9649961 | doi = 10.1016/s0376-8716(97)00163-4 }}</ref><ref name="Glennon_2000">{{cite journal | vauthors = Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, Smith C, Egan C, Davis K, Mattson MV | title = Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors | journal = Drug and Alcohol Dependence | volume = 60 | issue = 2 | pages = 121–132 | date = August 2000 | pmid = 10940539 | doi = 10.1016/s0376-8716(99)00148-9 | hdl-access = free | hdl = 11380/17721 }}</ref> However, in contrast to serotonergic psychedelics, harmaline and other β-carbolines do not activate the serotonin 5-HT_2A receptor even at very high concentrations ''in vitro'' (20,000–100,000{{nbsp}}nM).<ref name="Grella_2003">{{cite journal | vauthors = Grella B, Teitler M, Smith C, Herrick-Davis K, Glennon RA | title = Binding of beta-carbolines at 5-HT(2) serotonin receptors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 24 | pages = 4421–4425 | date = December 2003 | pmid = 14643338 | doi = 10.1016/j.bmcl.2003.09.027 | quote = [...] 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. }}</ref><ref name="RabinReginaDoat2002" /><ref name="Rolquin2022" /> Harmaline shows high affinity for the imidazoline I₂ receptor (K_i = 22{{nbsp}}nM).<ref name="Husbands_2001" /> Unlike ibogaine and noribogaine, harmaline does not bind to the κ-opioid receptor or other opioid receptors.<ref name="Deecher_1992">{{cite journal | vauthors = Deecher DC, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME, Glick SD | title = Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies | journal = Brain Research | volume = 571 | issue = 2 | pages = 242–247 | date = February 1992 | pmid = 1377086 | doi = 10.1016/0006-8993(92)90661-r }}</ref>

Harmaline and the psychedelic DOM partially substitute for each other in rodent drug discrimination tests.<ref name="Glennon_1983">{{cite journal | vauthors = Glennon RA, Young R, Jacyno JM, Slusher M, Rosecrans JA | title = DOM-stimulus generalization to LSD and other hallucinogenic indolealkylamines | journal = European Journal of Pharmacology | volume = 86 | issue = 3–4 | pages = 453–459 | date = January 1983 | pmid = 6572591 | doi = 10.1016/0014-2999(83)90196-6 }}</ref><ref name="Grella_1998" /> 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.<ref name="Glennon_1983" /> On the other hand, harmaline and 6-methoxyharman were comparable in terms of DOM substitution.<ref name="Glennon_1983" /> Unlike serotonergic psychedelics, ibogaine and harmala alkaloids like harmaline do not cause pupil dilation or increase blood pressure in humans.<ref name="Shulgin_1977" /><ref name="Naranjo_1973">{{cite book | vauthors = Naranjo C | chapter = Ibogaine: Fantasy and Reality | title = The Healing Journey: New Approaches to Consciousness | location = New York | pages = 174–228 | date = 1973 | publisher = Parthenon Books | isbn = 978-0-394-48826-4 | chapter-url = https://www.claudionaranjo.net/pdf_files/psychedelics/healing_journey_ch_5_ibogaine_english.pdf }}</ref>

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.<ref name="Zubaran_2000">{{cite journal | vauthors = Zubaran C | title = Ibogaine and Noribogaine: Comparing Parent Compound to Metabolite | journal = CNS Drug Reviews | volume = 6 | issue = 3 | pages = 219–240 | date = 2000 | doi = 10.1111/j.1527-3458.2000.tb00149.x | issn = 1080-563X | doi-access = free | quote = 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). }}</ref><ref name="Ali_2025">{{cite journal | vauthors = Ali S, Tian X, Cunningham KA, Zhou J | title = Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics | journal = Journal of Medicinal Chemistry | volume = 68 | issue = 18 | pages = 18744–18751 | date = September 2025 | pmid = 40994282 | doi = 10.1021/acs.jmedchem.5c02510 | quote = (−)-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 }}</ref><ref name="O'HearnMolliver1993">{{cite journal | vauthors = O'Hearn E, Molliver ME | title = Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline | journal = Neuroscience | volume = 55 | issue = 2 | pages = 303–310 | date = July 1993 | pmid = 8377927 | doi = 10.1016/0306-4522(93)90500-f | s2cid = 25273690 }}</ref><ref name="O'HearnMolliver1997">{{cite journal | vauthors = O'Hearn E, Molliver ME | title = The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity | journal = The Journal of Neuroscience | volume = 17 | issue = 22 | pages = 8828–8841 | date = November 1997 | pmid = 9348351 | pmc = 6573067 | doi = 10.1523/JNEUROSCI.17-22-08828.1997 }}</ref> This may explain long-lasting motor deficits induced by ibogaine in these rats.<ref name="Cherian_2024" /> However, this phenomenon involves high doses of ibogaine and has not been observed with ibogaine in primates or humans.<ref name="Cherian_2024">{{cite journal | vauthors = Cherian K, Shinozuka K, Tabaac BJ, Arenas A, Beutler BD, Evans VD, Fasano C, Muir OS | title = Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine | journal = American Journal of Therapeutics | volume = 31 | issue = 2 | pages = e133–e140 | date = 2024 | pmid = 38518270 | doi = 10.1097/MJT.0000000000001723 | quote = 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 | doi-access = free }}</ref><ref name="Mash_1998">{{cite journal | vauthors = Mash DC, Kovera CA, Buck BE, Norenberg MD, Shapshak P, Hearn WL, Sanchez-Ramos J | title = Medication development of ibogaine as a pharmacotherapy for drug dependence | journal = Annals of the New York Academy of Sciences | volume = 844 | issue = 1 | pages = 274–292 | date = May 1998 | pmid = 9668685 | doi = 10.1111/j.1749-6632.1998.tb08242.x | s2cid = 22068338 | bibcode = 1998NYASA.844..274M }}</ref><ref name="Alper_2012">{{cite journal | vauthors = Alper KR, Stajić M, Gill JR | title = Fatalities temporally associated with the ingestion of ibogaine | journal = Journal of Forensic Sciences | volume = 57 | issue = 2 | pages = 398–412 | date = March 2012 | pmid = 22268458 | doi = 10.1111/j.1556-4029.2011.02008.x | s2cid = 6670557 }}</ref> In any case, the rodent findings are notable in that they further suggest that harmaline and ibogaine share a common mechanism of action.<ref name="Zubaran_2000" /> Harmaline-induced tremors in rodents have been linked to upregulation of the serotonin transporter (SERT) in the cerebellum and consequent reduced serotonin levels in this area and increased Purkinje cell excitability.<ref name="WangZhouLin2025">{{cite journal | vauthors = Wang L, Zhou Z, Lin S, Li Y, Zhang S, Xu TL, Song XL, Wu Y | title = Transcriptomics and Proteomics Identify Serotonin Transporter as a Promising Therapeutic Target for Essential Tremor | journal = Mol Cell Proteomics | volume = 24 | issue = 12 | article-number = 101442 | date = December 2025 | pmid = 41192557 | pmc = 12741371 | doi = 10.1016/j.mcpro.2025.101442 | url = }}</ref>

===Pharmacokinetics=== The elimination half-life of harmaline has been reported to be about 2{{nbsp}}hours.<ref name="BritodaCosta_2020">{{cite journal | vauthors = Brito-da-Costa AM, Dias-da-Silva D, Gomes NG, Dinis-Oliveira RJ, Madureira-Carvalho Á | title = Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids ''N'',''N''-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact | journal = Pharmaceuticals | volume = 13 | issue = 11 | page = 334 | date = October 2020 | pmid = 33114119 | pmc = 7690791 | doi = 10.3390/ph13110334 | doi-access = free }}</ref>

==Chemistry== [[Image:Harmaline Harmine.jpg|thumb|right|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.

===Properties=== It is fluorescent under ultraviolet light.

===Synthesis=== The chemical synthesis of harmaline has been described.<ref name="TiHKAL1997" />

===Analogues=== Analogues of harmaline include harmine, tetrahydroharmine, harmalol, 5-methoxyharmalan, 6-methoxyharmalan, and ibogamine, among others.<ref name="TiHKAL1997" />

==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.<ref name="erowid">{{ cite web | title = Peganum Harmala pamphlet: Syrian Rue | url = http://www.erowid.org/plants/syrian_rue/syrian_rue_info9.shtml | publisher = Erowid }}</ref>

==History== Harmaline was first isolated from plants in 1841.<ref name="Shulgin_1977" /> The chemical structure of harmaline was not correctly identified until either 1919<ref name="Shulgin_1977" /> or 1927.<ref name="PSR-Manske">{{cite web | vauthors = Shulman E | date = 8 February 2021 | title = Richard Manske | website = Psychedelic Science Review | url = https://psychedelicreview.com/person/richard-manske/ | access-date = 9 March 2026 }}</ref><ref name="Manske1927">{{cite journal | vauthors = Manske RH, Perkin WH, Robinson R | date = 1927 | title = I.—Harmine and harmaline. Part IX. A synthesis of harmaline | journal = J. Chem. Soc. | volume = 0 | issue = 0 | pages = 1–14 | doi = 10.1039/JR9270000001 | issn = 0368-1769 }}</ref> Harmaline was first synthesized by Richard Manske in 1927.<ref name="Shulgin_1977" /><ref name="PSR-Manske" /><ref name="Manske1927" />

==Society and culture== ===Legal status=== {{Globalize|date=January 2016}}

====Australia==== Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015).<ref name="Poisons Standard">{{cite web | title = Poisons Standard October 2015 | date = 30 September 2015 | url = https://www.comlaw.gov.au/Details/F2015L01534 | publisher = Australian Government }}</ref> 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.<ref name="Poisons Standard" />

====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.<ref>{{cite web | title = Controlled Drugs and Substances Act (S.C 1996, c.19) | date = 19 September 2019 | url = https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-2.html | website = Justice Laws Website | access-date = 25 September 2019 }}</ref>

== See also == * Substituted β-carboline * Harmala alkaloid

== References == {{Reflist}}

== External links == * [https://isomerdesign.com/pihkal/explore/5013 Harmaline - Isomer Design] * [https://psychonautwiki.org/wiki/Harmaline Harmaline - PsychonautWiki] * [https://www.erowid.org/chemicals/harmala/harmala.shtml Harmala Alkaloids - Erowid] * [http://www.erowid.org/library/books_online/tihkal/tihkal13.shtml Harmaline - TiHKAL - Erowid] * [https://isomerdesign.com/pihkal/read/tk/13 Harmaline - TiHKAL - Isomer Design]

{{Hallucinogens}} {{Serotonin receptor modulators}} {{Imidazoline receptor modulators}} {{Acetylcholine metabolism and transport modulators}} {{Monoamine metabolism modulators}} {{Tryptamines}}

Category:Acetylcholinesterase inhibitors Category:Antidepressants Category:Beta-Carbolines Category:Entheogens Category:N-Monoalkyltryptamines Category:Monoamine oxidase inhibitors Category:Oneirogens Category:Phenol ethers Category:Reversible inhibitors of MAO-A Category:Psychedelic-assisted therapy Category:Serotonin receptor modulators Category:TiHKAL Category:Tryptamine alkaloids