Hydroxylation and N-demethylation of N,N-dimethyltryptamine

Szara, Stephen; Axelrod, Julius

doi:10.1007/bf02158111

Cited by 68 publications

(12 citation statements)

References 6 publications

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“…Studies are in progress to determine whether the time course of hyperactivity produced by 5-MeO-DMT and an MAO inhibitor is temporally correlated with bufotenine brain levels. Many tryptamine derivatives are metabolized by 6-hydroxylation (Szara and Axelrod 1959; Kopin et al 1961; Szara 1961; Szara et al 1962), and thus it is also possible that 6-hydroxy-5-methoxy-DMT may contribute to the hyperactivity produced by 5-MeO-DMT and an MAO A inhibitor. However, 6-hydroxy-5-methoxy-DMT has yet to be conclusively identified as a metabolite of 5-MeO-DMT in rats (Agurell et al 1969).…”

Section: Discussionmentioning

confidence: 99%

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

2012

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RATIONALE Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral Pattern Monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAOA inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. OBJECTIVES The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO. RESULTS Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. CONCLUSIONS The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations.

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Section: Discussionmentioning

confidence: 99%

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

2012

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“…It is of interest to note that DMT-NO does not appear to be a substrate for MAO (Fish et al, 1955;Sitaram et al, 1987c). NMT has also been identified as a minor metabolite of DMT (Szara and Axelrod, 1959;Kaplan et al, 1974;Barker et al, 1980;Sitaram and McLeod, 1990) as has 2-MTHBC and traces of tryptamine and 1,2,3,4-tetrahydrob-carboline (THBC; Barker et al, 1980). NMT is also a substrate for MAO and is subject to be metabolized to IAA.…”

Section: Major Constituents and Metabolites Of Ayahuasca In Urinementioning

confidence: 97%

Methodology for and the determination of the major constituents and metabolites of the Amazonian botanical medicine ayahuasca in human urine

McIlhenny

Riba

Barbanoj

et al. 2010

Biomedical Chromatography

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Ayahuasca, also known as caapi or yage among various South American groups, holds a highly esteemed and millennia-old position in these cultures' medical and religious pharmacopeia. There is now an increasing interest in the potential for modern medical applications of ayahuasca, as well as concerns regarding its increasing potential for abuse. Toxicological and clinical research to address these issues will require information regarding its metabolism and clearance. Thus, a rapid, sensitive and specific method for characterization and quantitation of the major constituents and of the metabolites of ayahuasca in urine is needed. The present research provides a protocol for conducting such analyses. The characteristics of the method, conducted by sample dilution and using HPLC-electrospray ionization (ESI)-selected reaction monitoring (SRM)-tandem mass spectrometry, are presented. The application of the analytical protocol to urine samples collected from three individuals that were administered ayahuasca has also been demonstrated. The data show that the major metabolite of the hallucinogenic component of ayahuasca, N,N-dimethyltryptamine (DMT), is the corresponding N-oxide, the first time this metabolite has been described in in vivo studies in humans. Further, very little DMT was detected in urine, despite the inhibition of monoamine oxidase afforded by the presence of the harmala alkaloids in ayahuasca. The major harmala alkaloid excreted was tetrahydroharmine. Other excretion products and metabolites were also identified and quantified. The method described would be suitable for use in further toxicological and clinical research on ayahuasca.

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“…We found DMT-NO to be a major metabolite accounting for 20% of all tryptamine derivatives measured in urine and 10% of the administered DMT dose. Studies of DMT metabolism in vitro have identified DMT-NO as a major NADH dependent metabolite using mouse liver homogenates, [20] liver microsomal fractions from rabbits, [37] as well as rat brain homogenates. Studies with pure tryptamines and tryptamine derivatives, including DMT, 5-MeO-DMT, and 5-OH-DMT, have found oxidative deamination by MAO-A to be a major metabolic route in brain, liver and kidney in vitro, producing the corresponding indoleacetic acid.…”

Section: Time Interval Totalmentioning

confidence: 99%

“…Studies with pure tryptamines and tryptamine derivatives, including DMT, 5-MeO-DMT, and 5-OH-DMT, have found oxidative deamination by MAO-A to be a major metabolic route in brain, liver and kidney in vitro, producing the corresponding indoleacetic acid. [21,37] N-oxidation has also been identified as an important metabolic pathway of DMT in vivo, [31] while N-demethylation seems to function as a minor degradation route. In another study, [ 14 C]-IAA was identified as the major metabolite representing up to 23% of the radioactivity in the blood of rabbits 60 min after i.v.…”

Section: Time Interval Totalmentioning

confidence: 99%

Metabolism and disposition of N,N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca

Riba

McIlhenny

Valle

et al. 2012

Drug Testing and Analysis

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Ayahuasca is an Amazonian psychotropic plant tea obtained from Banisteriopsis caapi, which contains β-carboline alkaloids, chiefly harmine, harmaline and tetrahydroharmine. The tea usually incorporates the leaves of Psychotria viridis or Diplopterys cabrerana, which are rich in N,N-dimethyltryptamine (DMT), a psychedelic 5-HT(2A/1A/2C) agonist. The β-carbolines reversibly inhibit monoamine-oxidase (MAO), effectively preventing oxidative deamination of the orally labile DMT and allowing its absorption and access to the central nervous system. Despite increased use of the tea worldwide, the metabolism and excretion of DMT and the β-carbolines has not been studied systematically in humans following ingestion of ayahuasca. In the present work, we used an analytical method involving high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry(MS/MS) to characterize the metabolism and disposition of ayahuasca alkaloids in humans. Twenty-four-hour urine samples were obtained from 10 healthy male volunteers following administration of an oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight). Results showed that less than 1% of the administered DMT dose was excreted unchanged. Around 50% was recovered as indole-3-acetic acid but also as DMT-N-oxide (10%) and other MAO-independent compounds. Recovery of DMT plus metabolites reached 68%. Harmol, harmalol, and tetrahydroharmol conjugates were abundant in urine. However, recoveries of each harmala alkaloid plus its O-demethylated metabolite varied greatly between 9 and 65%. The present results show the existence in humans of alternative metabolic routes for DMT other than biotransformation by MAO. Also that O-demethylation plus conjugation is an important but probably not the only metabolic route for the harmala alkaloids in humans.

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Hydroxylation and N-demethylation of N,N-dimethyltryptamine

Cited by 68 publications

References 6 publications

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

Methodology for and the determination of the major constituents and metabolites of the Amazonian botanical medicine ayahuasca in human urine

Metabolism and disposition of N,N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca

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