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

Abstract

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.

Neuropharmacology of N,N-dimethyltryptamine

“…Only a small fraction of DMT made intracellularly is actually released into the blood. This process helps explain the inconsistent detection levels assessed in many studies discussed below (Karkkainen et al, 2005; Barker et al, 2012; see endogenous section). DMT production is increased under stress in rodent brain and adrenal gland (Christian et al, 1977; Beaton and Christian, 1977).…”

“…In human volunteers, 8.3% of the administered dose of DMT was recovered as IAA (Szara, 1956). Around 50% was recovered as IAA but also as DMT-NO (10%) and other MAO-independent compounds (Riba et al, 2012). Neither the Erspamer nor Szara study detected unchanged DMT in urine.…”

Application of ambient ionization high resolution mass spectrometry to determination of the botanical provenance of the constituents of psychoactive drug mixtures

“…A c c e p t e d M a n u s c r i p t M a n u s c r i p t 19 In-source CID analysis was also performed on B. caapi and P. harmala to confirm the presence of harmine and harmaline, the bioactive β-carbolines reported [16,18,24,[26][27][28] in these plants. Figure 4 shows the in-source CID spectra at 90 V of B. caapi and P. harmala …”

“…For this reason, the psychoactive effects of orally ingested DMT require concurrent consumption of an MAO inhibitor (MAOI). Plant-derived β-carboline alkaloids such as harmine, harmaline and tetrahydroharmine ( Figure 1) [16,18,24,[26][27][28] serve this purpose. Thus, Ayahuasca brews contain plant combinations that contribute both DMT and β-carbolines.…”

“…Thus, Ayahuasca brews contain plant combinations that contribute both DMT and β-carbolines. [23,25,[28][29][30] Banisteriopsis caapi (yage) and Peganum harmala (Syrian rue) are the two most common β- States, only marijuana, peyote and psilocybin mushrooms are specifically scheduled plant materials. [33,34] Because the presence of identification protocols is a necessary prerequisite to the legislation of mind-altering materials, the development of methods to accurately confirm the identity of plant-based drugs of abuse is of high concern, as highlighted in the 2009 National Academy of Science report on the status of forensic sciences in the United States.…”