However, β-carbolines with substituents in position 3 reduce the effect ofbenzodiazepine onGABA-A receptors and can therefore haveconvulsive,anxiogenic and memory enhancing effects.[26] Moreover, 3-hydroxymethyl-beta-carboline blocks the sleep-promoting effect offlurazepam in rodents and – by itself – can decrease sleep in a dose-dependent manner.[27] Another derivative, methyl-β-carboline-3-carboxylate, stimulates learning and memory at lowdoses but can promote anxiety and convulsions at high doses.[26] With modification in position 9 similar positive effects have been observed for learning and memory without promotion of anxiety or convulsion.[23]
β-carboline derivatives also enhance the production of theantibiotic reveromycin A in soil-dwellingStreptomyces species.[28][29] Specifically, expression ofbiosyntheticgenes is facilitated by binding of the β-carboline to a largeATP-binding regulator of theLuxR family.
Since β-carbolines also interact with variouscancer-related molecules such asDNA,enzymes (GPX4,kinases, etc.) andproteins (ABCG2/BRCP1, etc.), they are also discussed as potential anticancer agents.[3]
The extract of thelianaBanisteriopsis caapi has been used by the tribes of theAmazon as anentheogen and was described as ahallucinogen in the middle of the 19th century.[38] In early 20th century, European pharmacists identifiedharmine as the active substance.[39] This discovery stimulated the interest to further investigate its potential as a medicine. For example,Louis Lewin, a prominent pharmacologist, demonstrated a dramatic benefit in neurological impairments after injections ofB. caapi in patients withpostencephalitic Parkinsonism.[38] By 1930, it was generally agreed thathypokinesia,drooling, mood, and sometimes rigidity improved by treatment with harmine. Altogether, 25 studies had been published in the 1920s and 1930s about patients withParkinson's disease and postencephalitic Parkinsonism. The pharmacological effects of harmine have been attributed mainly to its centralmonoamine oxidase (MAO) inhibitory properties.In-vivo and rodent studies have shown that extracts ofBanisteriopsis caapi and alsoPeganum harmala lead tostriataldopamine release.[40][41][42] Furthermore, harmine supports the survival of dopaminergic neurons inMPTP-treated mice.[43] Since harmine alsoantagonizesN-methyl-d-aspartate(NMDA) receptors,[44] some researchers speculatively attributed the rapid improvement in patients with Parkinson's disease to these antiglutamatergic effects.[38] However, the advent of syntheticanticholinergic drugs at that time led to the total abandonment of harmine.[38]
β-Carbolines belong to the group ofindole alkaloids and consist ofa pyridine ring that is fused to anindole skeleton.[45] The structure of β-carboline is similar to that oftryptamine, with theethylamine chain re-connected to theindole ring via an extracarbon atom, to produce a three-ringed structure. The biosynthesis of β-carbolines is believed to follow this route from analogous tryptamines.[46] Different levels ofsaturation are possible in the third ring which is indicated here in thestructural formula by coloring the optionally double bonds red and blue:
The fullyaromatic β-carbolines also occur in many foodstuffs, however in lower concentrations. The highest amounts have been detected in brewed coffee, raisins, well-done fish and meats.[54] Smoking is another source of fully aromatic β-carbolines, with levels up to thousands of μg per smoker each day.[55]
^Francik R, Kazek G, Cegła M, Stepniewski M (March 2011). "Antioxidant activity of beta-carboline derivatives".Acta Poloniae Pharmaceutica.68 (2):185–189.PMID21485291.
^abcdefShulgin 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.
^abcdefJacob P, Shulgin AT (1994)."Structure-activity relationships of the classic hallucinogens and their analogs"(PDF).NIDA Res Monogr.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.
^abCao R, Peng W, Wang Z, Xu A (2007). "beta-Carboline alkaloids: biochemical and pharmacological functions".Curr Med Chem.14 (4):479–500.doi:10.2174/092986707779940998.PMID17305548.
^abcdNichols DE, Glennon RA (1984)."Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.).Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142.ISBN978-0-89004-990-7.OCLC10324237.Harmaline (80) appears to be about twice as active as its fully saturated counterpart harmine (152). Naranjo (151,152) determined that harmaline was effective at intravenous doses of 1 mg/kg and at total oral doses of 300 to 400 mg. In a limited study, tetrahydroharmine (81) was found to be approximately one-third as active as harmaline, with an oral dose of 300 mg producing an effect similar to that of 100 mg harmaline (152). Repositioning of the 7-methoxy group of harmaline to the 6-position gives 6-methoxyharmalan (85). This compound was active at oral doses of approximately 100 mg (1.5 mg/kg). Reduction to the tetrahydro counterpart, 6-methoxytetrahydroharman (86), resulted in a compound with about one-third the potency of the parent 6-methoxyharmalan (152).
^abcBrimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds".Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144.ISBN978-0-85608-011-1.OCLC2176880.OL4850660M.6-Methoxyharmalan (4.32) produces marked subjective changes in man at oral doses of 1.5 mg./kg., being about 1.5 times as active as the isomeric harmaline (4.30). Intravenous doses of 1 mg./kg. are effective almost immediately but subjective changes appear about one hour following oral administration. 6-Methoxytetrahydroharman (4.34) was also psychoactive, eliciting mild subjective changes at 1.5 mg./kg. (p.o.), but being only three times as potent as harmaline. 1,2,3,4-Tetrahydroharmaline (4.31) was tested in only one subject, where it appeared to be about one-third as potent as harmaline in doses of 300 mg. (p.o.). Some of the responses to harmala alkaloids reported by Naranjo are nausea, dizziness, and general malaise, together with pareaesthesias of the hands, feet, and face, followed by numbness. Distortions of body image and of objects in the environment, so common with LSD or mescaline were not present and there was no enhancement of colour. However, there was abundant closed-eye imagery, hypersensitive hearing, and the superposition of imaginary scenes simultaneously with an undistorted perception of surrounding objects.
^abcdeHelsley S, Rabin RA, Winter JC (2001). "Drug discrimination studies with ibogaine".The Alkaloids. Chemistry and Biology.56:63–77.doi:10.1016/s0099-9598(01)56008-3.PMID11705117.One group of hallucinogens that has received little attention is the betacarboline (or Harmala) alkaloids group. Interestingly, these agents bear a strong structural resemblance to ibogaine. Anecdotal reports suggest that the tremorigenic and subjective effects of agents, such as harmaline and harmine, are not unlike those of ibogaine (13). Several of these alkaloids were tested in ibogaine-trained rats (10). The results are shown in Figure 3. Full generalization was observed with 6-methoxyharmalan and harmaline, while partial generalization was seen with harmine, harmane, harmalol, and THBC (tetrahydro-beta-carboline). No generalization was seen to 6,7-dimethoxy-4- ethyl-β-carboline-3-carboxylate (DMCM) or norharmane. Unfortunately, the mechanism of action of the harmala alkaloids remains unknown. [...]
^abNaranjo C (1969)."Psycotherapeutic Possibilities of New Fantasy-Enhancing Drugs".Clinical Toxicology.2 (2):209–224.doi:10.3109/15563656908990930.ISSN0009-9309. Retrieved27 May 2025.I intend to speak here of two drugs, harmaline and ibogaine, which bear some resemblance to one another in chemical constitution and may be grouped together in terms of their effects. [...] I have reported elsewhere [3] that a study carried out at the University of Chile demonstrated that 10-methoxyharmalan, when administered to humans, elicited subjective effects quite similar to those of harmaline. [...]
^abFortunato JJ, Réus GZ, Kirsch TR, Stringari RB, Fries GR, Kapczinski F, et al. (October 2010). "Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus".Journal of Neural Transmission.117 (10):1131–1137.doi:10.1007/s00702-010-0451-2.PMID20686906.S2CID21595062.
^López-Muñoz F, Alamo C (2009-05-01). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today".Current Pharmaceutical Design.15 (14):1563–1586.doi:10.2174/138161209788168001.PMID19442174.
^abWernicke C, Hellmann J, Zieba B, Kuter K, Ossowska K, Frenzel M, et al. (January 2010). "9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease".Pharmacological Reports.62 (1):35–53.doi:10.1016/s1734-1140(10)70241-3.PMID20360614.S2CID16729205.
^Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G (March 2008). "9-Methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture".Neurochemistry International.52 (4–5):688–700.doi:10.1016/j.neuint.2007.08.018.PMID17913302.S2CID24226033.
^Polanski W, Reichmann H, Gille G (June 2011). "Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?".Expert Review of Neurotherapeutics.11 (6):845–860.doi:10.1586/ern.11.1.PMID21651332.S2CID24899640.
^abHelsley S, Rabin RA, Winter JC (March 1998). "The effects of beta-carbolines in rats trained with ibogaine as a discriminative stimulus".European Journal of Pharmacology.345 (2):139–143.doi:10.1016/s0014-2999(98)00002-8.PMID9600629.
^abcdefAlper KR (2001). Alper KR, Glick SD (eds.)."Ibogaine: A Review"(PDF).The Alkaloids. Chemistry and Biology.56. San Diego: Academic:1–38.doi:10.1016/S0099-9598(01)56005-8.ISBN978-0-12-469556-6.ISSN1099-4831.OCLC119074989.PMID11705103. Archived fromthe original(PDF) on 27 September 2007.A high degree of stimulus generalization is reported between ibogaine and some of the Harmala alkaloids, a group of hallucinogenic beta-carbolines that are structurally related to ibogaine (101,102). While the discriminative stimulus for both the Harmala alkaloids and ibogaine apparently involves the 5-HT2 receptor (84,85,103), it does not appear essential to generalization between ibogaine and harmaline, as generalization to the harmaline stimulus was unaffected by the addition of a 5-HT2 antagonist in ibogaine-trained animals (84).
^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.
^abcdHelsley S, Fiorella D, Rabin RA, Winter JC (February 1998). "Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus".Pharmacology, Biochemistry, and Behavior.59 (2):419–425.doi:10.1016/s0091-3057(97)00451-6.PMID9476990.
^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.
^Ona G, Reverte I, Rossi GN, Dos Santos RG, Hallak JE, Colomina MT, Bouso JC (December 2023). "Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview".J Psychopharmacol.37 (12):1190–1200.doi:10.1177/02698811231200882.PMID37937505.
^Foley P (2003). "Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism".Wurzburger Medizinhistorische Mitteilungen.22:215–234.PMID15641199.
^Schwarz MJ, Houghton PJ, Rose S, Jenner P, Lees AD (June 2003). "Activities of extract and constituents of Banisteriopsis caapi relevant to parkinsonism".Pharmacology, Biochemistry, and Behavior.75 (3):627–633.doi:10.1016/s0091-3057(03)00129-1.PMID12895680.S2CID28243440.
^Brierley DI, Davidson C (January 2013). "Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell".Journal of Psychopharmacology.27 (1):98–108.doi:10.1177/0269881112463125.PMID23076833.S2CID40115950.
^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.PMID9649961.
^Hemmateenejad B, Abbaspour A, Maghami H, Miri R, Panjehshahin MR (August 2006). "Partial least squares-based multivariate spectral calibration method for simultaneous determination of beta-carboline derivatives in Peganum harmala seed extracts".Analytica Chimica Acta.575 (2):290–299.Bibcode:2006AcAC..575..290H.doi:10.1016/j.aca.2006.05.093.PMID17723604.
^Herraiz T, González D, Ancín-Azpilicueta C, Arán VJ, Guillén H (March 2010). "beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)".Food and Chemical Toxicology.48 (3):839–845.doi:10.1016/j.fct.2009.12.019.hdl:10261/77694.PMID20036304.
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^Badre A, Boulanger A, Abou-Mansour E, Banaigs B, Combaut G, Francisco C (April 1994). "Eudistomin U and isoeudistomin U, new alkaloids from the Caribbean ascidian Lissoclinum fragile".Journal of Natural Products.57 (4):528–533.Bibcode:1994JNAtP..57..528B.doi:10.1021/np50106a016.PMID8021654.
^Davis RA, Carroll AR, Quinn RJ (July 1998). "Eudistomin V, a new beta-carboline from the Australian ascidian Pseudodistoma aureum".Journal of Natural Products.61 (7):959–960.Bibcode:1998JNAtP..61..959D.doi:10.1021/np9800452.PMID9677285.
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