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| Other names | 6-Methoxyharmalane; 6-Methoxy-1-methyl-3,4-dihydro-β-carboline; 10-Methoxyharmalan; 6-MeO-harmalan; 6-OMe-harmalan |
| Routes of administration | Oral,intravenous injection[1] |
| Drug class | Serotonin receptor modulator;Monoamine oxidase inhibitor;Hallucinogen |
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| Pharmacokinetic data | |
| Onset of action | Oral: 1 hour[1] IVTooltip Intravenous injection: almost immediate[1] |
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| Chemical and physical data | |
| Formula | C13H14N2O |
| Molar mass | 214.268 g·mol−1 |
| 3D model (JSmol) | |
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6-Methoxyharmalan, or6-methoxyharmalane, also known as6-methoxy-1-methyl-3,4-dihydro-β-carboline, is anaturally occurringserotonin receptor modulator,monoamine oxidase inhibitor, andhallucinogen of theβ-carboline family related toharmaline (7-methoxyharmalan).[2][3][4] It is acyclized tryptamine andanalogue of5-MeO-DMT andmelatonin (N-acetyl-5-methoxytryptamine).[3][5] The compound has been isolated fromVirola species.[6][7]
6-Methoxyharmalan has been reported to be hallucinogenic in humans at a dose of 1.5 mg/kg (~100 mg)orally, with slightly (1.5-fold) greater potency thanharmaline.[8][1][9][3][4] Itsonset of action via oral administration is about 1 hour.[1] The drug also produces hallucinogenic effects at a dose of 1 mg/kgintravenously and with a near-immediate onset by this route.[1] Its hallucinogenic effects are described as similar to those of harmaline.[10] The hallucinogenic effects of β-carbolines like harmaline and 6-methoxyharmalan have been described as qualitatively distinct from those ofserotonergic psychedelics likemescaline.[1][4] On the other hand, they have been said to be similar to those ofibogaine.[11][10]
| Target | Affinity (Ki, nM) |
|---|---|
| 5-HT1A | >10,000 |
| 5-HT1B | >10,000 |
| 5-HT1D | >10,000 |
| 5-HT1E | ND |
| 5-HT1F | ND |
| 5-HT2A | 4,220–5,600 (Ki) (rat) >10,000 (EC50Tooltip half-maximal effective concentration) >10,000 (IC50Tooltip half-maximal inhibitory concentration) |
| 5-HT2B | ND |
| 5-HT2C | 924 (rat) |
| 5-HT3 | >10,000 |
| 5-HT4 | ND |
| 5-HT5A | >10,000 |
| 5-HT6 | 1,930 |
| 5-HT7 | 2,960 |
| α1A–α1D | ND |
| α2A–α2C | ND |
| β1,β3 | ND |
| D1–D5 | >10,000 (human/rat) |
| H1–H4 | ND |
| M1–M5 | >10,000 |
| I1,I2 | ND |
| σ1,σ2 | ND |
| TAAR1Tooltip Trace amine-associated receptor 1 | ND |
| BDZ | >10,000 (rat) |
| PCP | >10,000 (rat) |
| SERTTooltip Serotonin transporter | >10,000 (Ki) |
| NETTooltip Norepinephrine transporter | 4,100 (Ki) |
| DATTooltip Dopamine transporter | >10,000 (Ki) (bovine) |
| MAO-ATooltip Monoamine oxidase A | ND (IC50) |
| MAO-BTooltip Monoamine oxidase B | ND (IC50) |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[12][13][14][3][15] | |
6-Methoxyharmalan shows modestaffinity for theserotonin5-HT2A receptor (Ki = 4,220–5,600 nM) and for the serotonin5-HT2C receptor (Ki = 924 nM).[14][3] Its affinity for the serotonin 5-HT2A receptor is similar to that of harmaline.[14][3] Despite their appreciable affinities for the serotonin 5-HT2A receptor, neither 6-methoxyharmalan nor harmaline showed anyagonist orantagonist activity at the receptor at a concentration of 10,000 nM (and also at 20,000 nM in the case of harmaline).[14] On the other hand, 6-methoxyharmalan has been reported to be apotentserotonin antagonist in otherin-vitro systems, such as the isolated ratuterus and isolated guinea pigileum.[16] 6-Methoxyharmalan does not bind to the serotonin5-HT1A receptor or thedopamineD2 receptor.[14] However, it does also bind to the serotonin5-HT6 and5-HT7 receptors (Ki = 1,930 nM and 2,960 nM, respectively), but not to various otherserotonin receptors, theserotonin transporter (SERT), or a variety of othertargets.[13] The compound has also been reported to be a very weakglycine receptorantagonist (IC50Tooltip half-maximal inhibitory concentration = 82,000–101,000 nM).[17][18] Besides receptor and transporter interactions, 6-methoxyharmalan has been reported to be a potentmonoamine oxidase inhibitor (MAOI).[19][20]
Similarly to harmaline, but in contrast toharman andharmine, 6-methoxyharmalan substitutes for theserotonergic psychedelicDOM in rodentdrug discrimination tests.[2] In addition, 6-methoxyharmalan fully substitutes for the atypical hallucinogenibogaine in drug discrimination tests, whereas harmaline partially to fully substitutes for ibogaine in these tests.[11][21]
It is unclear whether the serotonin 5-HT2A receptor mediates the hallucinogenic effects of 6-methoxyharmalan and other β-carbolines or not.[13][14] While 6-methoxyharmalan and harmaline showed no serotonin 5-HT2A receptor agonistic activityin vitro, there could be limitations of theassay or they might haveactive metabolites that activate the receptor instead, among other possibilities.[14] Alternatively, the hallucinogenic effects of these compounds may not be mediated by serotonin 5-HT2A receptor activation.[13][14] This would be in accordance with their hallucinogenic effects being described as distinct from those of psychedelics likemescaline[1][4] but similar to those of thestructurally relatedibogaine.[22][23] Moreover, the relativelyselective serotonin 5-HT2A receptor antagonistpirenperone did not affect harmaline's substitution of ibogaine in rodent drug discrimination tests.[22][23]
6-Methoxyharmalan was first described by at least the early 1960s.[19][16] Its hallucinogenic effects were first described byClaudio Naranjo in 1967.[3][4] Melatonin can easily undergocyclization into 6-methoxyharmalan under physiological conditionsin vitro[5] and 6-methoxyharmalan has been hypothesized to be a minormetabolite of melatoninin vivo.[19][1] 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 thepathophysiology ofpsychiatric disorders.[19][16][24][25] However, all attempts to find 6-methoxyharmalan in living organisms were unsuccessful.[26]
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. [...] It is possible also that 6-methoxyharmalan could be derived from melatonin by dehydrative cyclization, and the compound has been tentatively proposed as a melatonin metabolite (Mcisaac and others, 1961). Both β-carbolines are hallucinogenic in man (Naranjo, 1967), [...]
6-Methoxyharmalan is reportedly hallucinogenic at oral doses of 1.5 mg/kg, and 6-methoxytetrahydroharman elicited mild psychoactive effects at 1.5 mg/kg and is said to be about one-third as potent as 6-methoxyharmalan (Naranjo, 1967); however, details were not provided and only scant information is available about these latter agents. [...] The DOM stimulus also generalizes to harmaline and 6-methoxyharmalan (Glennon et al., 1983). [...] We have also demonstrated that the DOM stimulus generalizes to harmaline (ED50= 6.19 mg/kg) and 6-methoxyharmalan (ED50=5.13 mg/kg; Glennon et al., 1983).
Finally, the hormone melatonin (60.15), associated with the pineal gland, can undergo facile cyclization to 60.16 in vitro under physiological conditions (47), and there is a single report (48) that it has central activity in man. However, attempts to identify it in body fluids or tissue extracts have failed.
The β-carbolines 6-methoxyharmalan and 6-methoxyharman, which have been suggested to possess some psychoactive effects, have also been isolated from V. elongata [19].
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).
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).
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. [...]
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. [...]
[...] 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.
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.
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].
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}}:|journal= ignored (help)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).
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.