6-Methoxyharmalan

6-Methoxyharmalan, or 6-methoxyharmalane, also known as 6-methoxy-1-methyl-3,4-dihydro-β-carboline, is a naturally occurring serotonin receptor modulator, monoamine oxidase inhibitor, and hallucinogen of the β-carboline family related to harmaline (7-methoxyharmalan).^[2][3][4] It is a cyclized tryptamine and analogue of 5-MeO-DMT and melatonin (N-acetyl-5-methoxytryptamine).^[3][5] The compound has been isolated from Virola species.^[6][7]

6-Methoxyharmalan

Clinical data
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
ATC code	None
Pharmacokinetic data
Onset of action	Oral: 1 hour[1] IVTooltip Intravenous injection: almost immediate[1]
Identifiers
IUPAC name 6-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole
CAS Number	3589-73-9
PubChem CID	417052
ChemSpider	10522291
UNII	43F45VJV8C
ChEBI	CHEBI:92962
ChEMBL	ChEMBL338115
CompTox Dashboard (EPA)	DTXSID80957306
Chemical and physical data
Formula	C13H14N2O
Molar mass	214.268 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=NCCC2=C1NC3=C2C=C(C=C3)OC
InChI InChI=1S/C13H14N2O/c1-8-13-10(5-6-14-8)11-7-9(16-2)3-4-12(11)15-13/h3-4,7,15H,5-6H2,1-2H3 Key:HMBHRMFLDKKSCT-UHFFFAOYSA-N

Use and effects

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 than harmaline.^{[8][1][9][3][4]} Its onset of action via oral administration is about 1 hour.^[1] The drug also produces hallucinogenic effects at a dose of 1 mg/kg intravenously 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 of serotonergic psychedelics like mescaline.^[1][4] On the other hand, they have been said to be similar to those of ibogaine.^[11][10]

Pharmacology

6-Methoxyharmalan activities

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 modest affinity for the serotonin 5-HT_2A receptor (K_i = 4,220–5,600 nM) and for the serotonin 5-HT_2C receptor (K_i = 924 nM).^[14][3] Its affinity for the serotonin 5-HT_2A receptor is similar to that of harmaline.^[14][3] 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 nM (and also at 20,000 nM in the case of harmaline).^[14] 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.^[16] 6-Methoxyharmalan does not bind to the serotonin 5-HT_1A receptor or the dopamine D₂ receptor.^[14] However, it does also bind to the serotonin 5-HT₆ and 5-HT₇ receptors (K_i = 1,930 nM and 2,960 nM, respectively), but not to various other serotonin receptors, the serotonin transporter (SERT), or a variety of other targets.^[13] The compound has also been reported to be a very weak glycine receptor antagonist (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 potent monoamine oxidase inhibitor (MAOI).^[19][20]

Similarly to harmaline, but in contrast to harman and harmine, 6-methoxyharmalan substitutes for the serotonergic psychedelic DOM in rodent drug discrimination tests.^[2] 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.^[11][21]

It is unclear whether the serotonin 5-HT_2A 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-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.^[14] Alternatively, the hallucinogenic effects of these compounds may not be mediated by serotonin 5-HT_2A receptor activation.^[13][14] This would be in accordance with their hallucinogenic effects being described as distinct from those of psychedelics like mescaline^[1][4] but similar to those of the structurally related ibogaine.^[22][23] Moreover, the relatively selective serotonin 5-HT_2A receptor antagonist pirenperone did not affect harmaline's substitution of ibogaine in rodent drug discrimination tests.^[22][23]

History

6-Methoxyharmalan was first described by at least the early 1960s.^[19][16] Its hallucinogenic effects were first described by Claudio Naranjo in 1967.^[3][4] Melatonin can easily undergo cyclization into 6-methoxyharmalan under physiological conditions in vitro^[5] and 6-methoxyharmalan has been hypothesized to be a minor metabolite of melatonin in 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 the pathophysiology of psychiatric disorders.^{[19][16][24][25]} However, all attempts to find 6-methoxyharmalan in living organisms were unsuccessful.^[26]

See also

• Substituted β-carboline
• 6-MeO-THH (6-methoxy-1,2,3,4-tetrahydroharman)
• Pinoline (6-methoxy-1,2,3,4-tetrahydronorharman)
• 5-Methoxyharmalan
• Harmaline (7-methoxyharmalan)