6-Methoxyharmalan, or 6-methoxyharmalane, also known as 6-methoxy-1-methyl-3,4-dihydro-β-carboline, is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

, and

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

of the β-carboline family related to

harmaline Harmaline, also known as 7-methoxyharmalan or as 3,4-dihydro-7-methoxy-1-methyl-β-carboline, is a fluorescent indole alkaloid from the group of harmala alkaloids and β-carbolines. It is the partly hydrogenated form of harmine. It is a rever ...

(7-methoxyharmalan). It is a cyclized tryptamine and analogue of

5-MeO-DMT 5-MeO-DMT (5-methoxy-''N'',''N''-dimethyltryptamine), also known as ''O''-methylbufotenin or mebufotenin (), is a naturally occurring psychedelic of the tryptamine family. It is found in a wide variety of plant species, and is also secreted by ...

and

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

(''N''-acetyl-5-methoxytryptamine). The compound has been isolated from '' Virola'' species.

Use and effects

6-Methoxyharmalan has been reported to be hallucinogenic in humans at a dose of 1.5mg/kg (~100mg) orally, with slightly (1.5-fold) greater potency than

. Its

onset of action Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other meth ...

via oral administration is about 1hour. The drug also produces hallucinogenic effects at a dose of 1mg/kg

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

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 psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s like

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

. On the other hand, they have been said to be similar to those of

ibogaine Ibogaine is a psychoactive indole alkaloid derived from plants such as '' Tabernanthe iboga'', characterized by hallucinogenic and oneirogenic effects. Traditionally used by Central African foragers, it has undergone controversial research ...

Pharmacology

6-Methoxyharmalan shows modest

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A receptor (K_i = 4,220–5,600nM) and for the serotonin 5-HT_2C receptor (K_i = 924nM). 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 An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. On the other hand, 6-methoxyharmalan has been reported to be a potent

serotonin antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A receptor are sometimes used ...

in other '' in-vitro'' systems, such as the isolated rat

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

and isolated guinea pig

ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...

. 6-Methoxyharmalan does not bind to the serotonin 5-HT_1A receptor or the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₂ receptor. However, it does also bind to the serotonin 5-HT₆ and 5-HT₇ receptors (K_i = 1,930nM and 2,960nM, respectively), but not to various other

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s, the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT), or a variety of other

target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...

s. The compound has also been reported to be a very weak

glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochem ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Besides receptor and transporter interactions, 6-methoxyharmalan has been reported to be a potent

(MAOI). Similarly to harmaline, but in contrast to harman and harmine, 6-methoxyharmalan substitutes for the

DOM in rodent drug discrimination tests. In addition, 6-methoxyharmalan fully substitutes for the atypical hallucinogen

in drug discrimination tests, whereas harmaline partially to fully substitutes for ibogaine in these tests. 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 An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity ...

or they might have

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

s 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

but similar to those of the structurally related

. Moreover, the relatively selective serotonin 5-HT_2A receptor antagonist pirenperone did not affect harmaline's substitution of ibogaine in rodent drug discrimination tests.

History

6-Methoxyharmalan was first described by at least the early 1960s. Its hallucinogenic effects were first described by Claudio Naranjo in 1967. Melatonin can easily undergo

cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...

into 6-methoxyharmalan under physiological conditions ''in vitro'' and 6-methoxyharmalan has been hypothesized to be a minor

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of melatonin ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

''. 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 Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s. However, all attempts to find 6-methoxyharmalan in living organisms were unsuccessful.

References

External links

6-Methoxyharmalan - Isomer Design
{{DEFAULTSORT:Methoxyharmalan, 6- Beta-Carbolines Hallucinogens 5-Methoxytryptamines N-Monoalkyltryptamines Monoamine oxidase inhibitors Serotonin receptor modulators

Use and effects

Pharmacology

History

See also

References

External links