6-Methoxyharmalan

6-Methoxyharmalan has been reported to be hallucinogenic in humans at a dose of 1.5{{nbsp}}mg/kg (~100{{nbsp}}mg) orally, with slightly (1.5-fold) greater potency than harmaline.{{cite book | vauthors = Nichols DE, Glennon RA | veditors = Jacobs BL | chapter = Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens | title = Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives | location = New York | pages = 95–142 | date = 1984 | publisher = Raven Press | isbn = 978-0-89004-990-7 | oclc = 10324237 | url = https://books.google.com/books?id=EdpsAAAAMAAJ&pg=PA95 | chapter-url = https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95 | quote = 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). }}{{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 = 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. }}{{cite book | vauthors = Shulgin AT | veditors = Gordon M | chapter = Psychotomimetic Agents | title = Psychopharmacological Agents: Use, Misuse and Abuse | volume = 4 | pages = 59–146 | date = 1976 | doi = 10.1016/b978-0-12-290559-9.50011-9 | series = Medicinal Chemistry: A Series of Monographs | isbn = 978-0-12-290559-9 | publisher = Academic Press | chapter-url = https://bitnest.netfirms.com/external/10.1016/B978-0-12-290559-9.50011-9 | quote = In the analogous 6-methoxyharman series, Naranjo has reported the analog of harmaline, 6-methoxyharmalan (XL VI) to be orally active with threshold effects noted at oral levels of 1.5 mg/kg. The same levels of the tetrahydro counterpart, 6-methoxytetrahydroharman (XL VII) led to "mild effects." It is uncertain if the totally aromatic analog, 6-methoxyharman, was evaluated. The psychic changes associated with the most thoroughly studied member of this series, harmaline, have been discussed at length (Naranjo, 1969) and compared with several other pharmacologically related psychotomimetic drugs (Naranjo, 1973). }} Its onset of action via oral administration is about 1{{nbsp}}hour. The drug also produces hallucinogenic effects at a dose of 1{{nbsp}}mg/kg intravenously and with a near-immediate onset by this route. Its hallucinogenic effects are described as similar to those of harmaline. The hallucinogenic effects of β-carbolines like harmaline and 6-methoxyharmalan have been described as qualitatively distinct from those of serotonergic psychedelics like mescaline. On the other hand, they have been said to be similar to those of ibogaine.{{cite journal | last=Naranjo | first=Claudio | title=Psycotherapeutic Possibilities of New Fantasy-Enhancing Drugs | journal=Clinical Toxicology | volume=2 | issue=2 | date=1969 | issn=0009-9309 | doi=10.3109/15563656908990930 | pages=209–224 | url=http://www.tandfonline.com/doi/full/10.3109/15563656908990930 | access-date=27 May 2025 | quote=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. [...]}}

6-Methoxyharmalan shows modest affinity for the serotonin 5-HT_2A receptor (K_i = 4,220–5,600{{nbsp}}nM) and for the serotonin 5-HT_2C receptor (K_i = 924{{nbsp}}nM).{{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 = 11380/17721 | url = https://psilosybiini.info/paperit/Binding%20of%20%DF-carbolines%20and%20related%20agents%20at%20serotonin%20(5-HT2%20and%205-HT1A),%20dopamine%20(D2)%20and%20benzodiazepine%20receptors%20(Glennon%20et%20al.,%202000).pdf }} Its affinity for the serotonin 5-HT_2A receptor is similar to that of harmaline. Despite their appreciable affinities for the serotonin 5-HT_2A receptor, neither 6-methoxyharmalan nor harmaline showed any agonist or antagonist activity at the receptor at a concentration of 10,000{{nbsp}}nM (and also at 20,000{{nbsp}}nM in the case of harmaline). On the other hand, 6-methoxyharmalan has been reported to be a potent serotonin antagonist in other in-vitro systems, such as the isolated rat uterus and isolated guinea pig ileum. 6-Methoxyharmalan does not bind to the serotonin 5-HT_1A receptor or the dopamine D₂ receptor. However, it does also bind to the serotonin 5-HT₆ and 5-HT₇ receptors (K_i = 1,930{{nbsp}}nM and 2,960{{nbsp}}nM, respectively), but not to various other serotonin receptors, the serotonin transporter (SERT), or a variety of other targets.{{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. }} The compound has also been reported to be a glycine receptor antagonist.{{cite journal | vauthors = Hamill J, Hallak J, Dursun SM, Baker G | title = Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness | journal = Current Neuropharmacology | volume = 17 | issue = 2 | pages = 108–128 | date = 2019 | pmid = 29366418 | pmc = 6343205 | doi = 10.2174/1570159X16666180125095902 | quote = Another study showed that 4 beta-carbolines (1,2,3,4-tetrahydronorharmane, norharmane, harmane, and 6-methoxyharmalan) act as competitive antagonists at the glycine receptor ligand binding site, leading to inhibition at the glycine receptor [111]. }} Besides receptor and transporter interactions, 6-methoxyharmalan has been reported to be a potent monoamine oxidase inhibitor (MAOI).{{cite thesis | vauthors = McKenna DJ | title = Monoamine oxidase inhibitors in Amazonian hallucinogenic plants : ethnobotanical, phytochemical, and pharmacological investigations | date = 1984 | doi = 10.14288/1.0096656 | degree = Ph.D. | publisher = University Of British Columbia | url = https://open.library.ubc.ca/media/download/pdf/831/1.0096656/1 | archive-url = https://web.archive.org/web/20200221103437/https://open.library.ubc.ca/media/download/pdf/831/1.0096656/1 | archive-date = 21 February 2020 }}

Similarly to harmaline, but in contrast to harman and harmine, 6-methoxyharmalan substitutes for the serotonergic psychedelic DOM in rodent drug discrimination tests. In addition, 6-methoxyharmalan fully substitutes for the atypical hallucinogen ibogaine in drug discrimination tests, whereas harmaline partially to fully substitutes for ibogaine in these tests.{{cite journal | vauthors = Helsley S, Rabin RA, Winter JC | title = Drug discrimination studies with ibogaine | journal = The Alkaloids. Chemistry and Biology | volume = 56 | pages = 63–77 | date = 2001 | pmid = 11705117 | doi = 10.1016/s0099-9598(01)56008-3 | quote = 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. [...] }}{{cite journal | vauthors = Helsley S, Rabin RA, Winter JC | title = The effects of beta-carbolines in rats trained with ibogaine as a discriminative stimulus | journal = European Journal of Pharmacology | volume = 345 | issue = 2 | pages = 139–143 | date = March 1998 | pmid = 9600629 | doi = 10.1016/s0014-2999(98)00002-8 }}

It is unclear whether the serotonin 5-HT_2A receptor mediates the hallucinogenic effects of 6-methoxyharmalan and other β-carbolines or not. While 6-methoxyharmalan and harmaline showed no serotonin 5-HT_2A receptor agonistic activity in vitro, there could be limitations of the assay or they might have active metabolites that activate the receptor instead, among other possibilities. Alternatively, the hallucinogenic effects of these compounds may not be mediated by serotonin 5-HT_2A receptor activation. This would be in accordance with their hallucinogenic effects being described as distinct from those of psychedelics like mescaline but similar to those of the structurally related ibogaine. Moreover, the relatively selective serotonin 5-HT_2A receptor antagonist pirenperone did not affect harmaline's substitution of ibogaine in rodent drug discrimination tests.{{cite journal | vauthors = Alper KR | veditors = Alper KR, Glick SD | title = Ibogaine: A Review | journal = The Alkaloids. Chemistry and Biology | location = San Diego | volume = 56 | pages = 1–38 | year = 2001 | pmid = 11705103 | doi = 10.1016/S0099-9598(01)56005-8 | publisher = Academic | isbn = 978-0-12-469556-6 | issn = 1099-4831 | oclc = 119074989 | url = http://ibogaine.org/ch01.pdf | url-status = dead | archive-url = https://web.archive.org/web/20070927225940/http://ibogaine.org/ch01.pdf | archive-date = 27 September 2007 | quote = 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). }}{{cite journal | vauthors = Helsley S, Fiorella D, Rabin RA, Winter JC | title = Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus | journal = Pharmacology, Biochemistry, and Behavior | volume = 59 | issue = 2 | pages = 419–425 | date = February 1998 | pmid = 9476990 | doi = 10.1016/s0091-3057(97)00451-6 }}

6-Methoxyharmalan was first described by at least the early 1960s.{{cite book | vauthors = Szmuszkovicz J, Heinzelman RV | chapter = Recent Studies in the Field of Indole Compounds | title = Progress in Drug Research / Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques | journal = Fortschritte der Arzneimittelforschung. Progress in Drug Research. Progres des Recherches Pharmaceutiques | pages = 75–150 | orig-date = 1963 | date = 2013 | volume = 5 | pmid = 14287134 | doi = 10.1007/978-3-0348-7050-4_2 | publisher = Birkhäuser Basel | publication-place = Basel | isbn = 978-3-0348-7052-8 | chapter-url = http://link.springer.com/10.1007/978-3-0348-7050-4_2 | access-date = 27 May 2025 | quote = Melatonin is formed from serotonin by N-acetylation followed by O-methylation [137, 204, 14, 15]. Its major metabolic pathway involves 6-hydroxylation to (X), followed by conjugation [119, 122]. A minor non-indolic metabolite is also produced, possibly by cyclodehydration of melatonin to form 3,4-dihydro-6-methoxy-l-methyl-9H-pyrido-[3,4-bJindole (XI) [122]. Depending on the numbering system used, this compound has been variously named '10-methoxyharmalan' [122], '6-methoxyharmalan' and '7-methoxyharmalan'. An interesting hypothesis concerning the cause of mental disease has been proposed by McIsAAC [134] who suggests that in certain cases of mental disease the normal metabolism of serotonin is blocked, causing formation of abnormally large amounts of melatonin and, hence, of its hypothetical metabolite (XI). The latter, a powerful monoamine oxidase inhibitor, would further inhibit the normal metabolism of serotonin and, by a chemical feedback mechanism, ultimately cause its own accumulation. Furthermore, (XI) was shown to be both a potent serotonin antagonist and a 'psychotomimetic agent', as evidenced by its effect on avoidance escape behavior in rats [136, 134]. }}{{cite book | vauthors = Hoffer A, Osmond H | chapter = Indole Hallucinogens Derived from Tryptophan | title = The Hallucinogens | pages = 443–516 (468) | date = 1967 | doi = 10.1016/b978-1-4832-3296-6.50008-2 | chapter-url = https://bitnest.netfirms.com/external/Books/TheHallucinogens#page=451 | publisher = Elsevier | isbn = 978-1-4832-3296-6 | lccn = 66030086 | oclc = 332437 | ol = OL35255701M | url = https://bitnest.netfirms.com/external/Books/TheHallucinogens | quote = Melatonin is converted to 10-methoxyharmalan by the loss of one molecule of water (Mclsaac et al., 1961). The sequence of change (Mclsaac, 1961a,b) was from melatonin to 10-methoxyharmalan which is similar to harmine or harmaline. Mclsaac suggested that due to a peculiarity in metabolism, some serotonin could be converted to 5-methoxytryptamine and to a harminelike alkaloid or from serotonin to acetyl serotonin, melatonin, and then a harminelike toxic substance. Once produced, this would block monoamine oxidase, decrease the destruction of serotonin by a common pathway, and so increase the production of more psychotogen. This chemical reverberating system would perpetuate the illness (Mclsaac, 1961a,b). [...] Woolley and Shaw (1957) reported harmaline was a serotonin antagonist. Using the isolated estrus rat uterus (Mclsaac et al., 1961) found that 0.2 µg of serotonin was completely blocked by 0.5 µg of LSD and 50 µg of harmine or harmaline added 5 minutes before. At higher levels they caused muscle contractions and later antagonism to serotonin was reduced. Methoxyharmalan was 25 times as active and 2 µg was as effective as 0.5 µg of LSD. Similar results were obtained on isolated guinea pig ileum. It seemed likely 10-methoxyharmalan and serotonin were competitive. The methoxyharmalan also antagonized the pressor effect of serotonin. }} Its hallucinogenic effects were first described by Claudio Naranjo in 1967. Melatonin can easily undergo cyclization into 6-methoxyharmalan under physiological conditions in vitro and 6-methoxyharmalan has been hypothesized to be a minor metabolite of melatonin in vivo. It was once suggested, by William McIsaac and colleagues in the early 1960s, that excessive production of 6-methoxyharmalan from melatonin might be involved in the pathophysiology of psychiatric disorders.{{cite journal | vauthors = McIsaac WM | title = A biochemical concept of mental disease | journal = Postgraduate Medicine | volume = 30 | pages = 111–118 | date = August 1961 | issue = 2 | pmid = 13774015 | doi = 10.1080/00325481.1961.11694351 }}{{cite journal | vauthors = McIsaac WM, Khairallah PA, Page IH | title = 10-Methoxyharmalan, a potent serotonin antagonist which affects conditioned behavior | journal = Science | location = New York, N.Y. | volume = 134 | issue = 3480 | pages = 674–675 | date = September 1961 | pmid = 13774014 | doi = 10.1126/science.134.3480.674 | bibcode = 1961Sci...134..674M }} However, all attempts to find 6-methoxyharmalan in living organisms were unsuccessful.{{cite journal | vauthors = Shulgin AT | title = Psychotomimetic Agents Related to the Catecholamines | journal = Journal of Psychedelic Drugs | volume = 2 | issue = 2 | pages = 14–19 | date = 1969 | doi = 10.1080/02791072.1969.10524409 | issn = 0022-393X | url = https://www.tandfonline.com/doi/full/10.1080/02791072.1969.10524409 | quote = More intriguing are the isomers of marmaline wherein the methoxyl group is relocated to the position entirely analogous to serotonin. This material is 6-methoxyharmalan (Vib; Figure 4), and its dehydro- and dihydro- counterparts (6-methoxyharman and 6-methoxytetrahydroharman) are all several times more potent than the 7-methoxy compounds. They have yet to be found in nature. They have, nonetheless, been generated in vitro by the cyclization of melatonin, and although such reactions are most appealing in the hypothesis of the in situ generation of an active psychotogen from a known pineal metabolite, all searches for this product in the intact living system have failed. }}

• Substituted β-carboline
• 6-MeO-THH (6-methoxy-1,2,3,4-tetrahydroharman)
• Pinoline (6-methoxy-1,2,3,4-tetrahydronorharman)

{{Reflist}}

• [https://isomerdesign.com/pihkal/explore/5409 6-Methoxyharmalan - Isomer Design]

{{Hallucinogens}}

{{Monoamine metabolism modulators}}

{{Serotonin receptor modulators}}

{{Tryptamines}}

{{DEFAULTSORT:Methoxyharmalan, 6-}}

Category:Beta-Carbolines

Category:Hallucinogens

Category:5-Methoxytryptamines

Category:N-Monoalkyltryptamines

Category:Monoamine oxidase inhibitors

Category:Serotonin receptor modulators