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Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics

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The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug’s pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting β-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

Ayahuasca, also known by the names Daime, Yajé, Natema, and Vegetal, is a psychotropic plant tea used by shamans throughout the Amazon Basin in traditional medicine, rites of passage, and magico-religious practices (Schultes and Hofmann, 1982; Dobkin de Rios, 1984). This ancient pattern of use has given way to a more widespread and frequent consumption by members of a number of modern Brazilian-based syncretic religious groups, mainly the Santo Daime and the Uniao do Vegetal, which have incorporated the use of the beverage in their rituals (Dobkin de Rios, 1996). In recent years, groups of followers of these Brazilian religions have become established in the United States and in several European countries, including Germany, Great Britain, Holland, France, and Spain (Anonymous, 2000). As a larger number of people have come into contact with ayahuasca, the tea has begun to attract the attention of biomedical researchers (Callaway et al., 1999; Riba et al., 2001b).

Ayahuasca is obtained by infusing the pounded stems of the malpighiaceous vine Banisteriopsis caapi either alone or, more frequently, in combination with the leaves of Psychotria viridis (rubiaceae) in Brazil, Peru, and Ecuador or Diplopterys cabrerana (malpighiaceae), used mainly in Ecuador and Colombia (Schultes and Hofmann, 1980; McKenna et al., 1984). P. viridis and D. cabrerana are rich in the psychedelic indole N,N-dimethyltryptamine (DMT; Rivier and Lindgren, 1972; Schultes and Hofmann, 1980), whereas B. caapi contains substantial amounts of β-carboline alkaloids, mainly harmine and tetrahydroharmine (THH), and to a lesser extent harmaline and traces of harmol and harmalol (Rivier and Lindgren, 1972; McKenna et al., 1984).

DMT is structurally related to the neurotransmitter serotonin and, like better-characterized psychedelics such as LSD and mescaline, binds to 5-hydroxytryptamine 2A receptors in the central nervous system (CNS), where it acts as an agonist (Pierce and Peroutka, 1989; Smith et al., 1998). Studies in humans have shown that when administered parenterally, DMT provokes dramatic modifications in perception, the sense of self and reality that can be very intense but relatively short in duration (Strassman et al., 1994). The drug also exerts marked autonomic effects elevating blood pressure, heart rate, and rectal temperature, and causes mydriasis (Strassman and Qualls, 1994). Unlike the vast majority of known psychedelic phenethylamines, tryptamines, and ergolines, DMT is orally inactive (Ott, 1999), apparently due to metabolism by monoamine oxidase (MAO; Suzuki et al., 1981). Interestingly, harmine and harmaline, and, to a lesser extent, THH, are potent MAO inhibitors (Buckholtz and Boggan, 1977; McKenna et al., 1984). In 1968, Agurell and coworkers (cited in Ott, 1999, p. 172) postulated that the interaction between β-carbolines and DMT in ayahuasca “might result in specific pharmacological effects”. It is now a widely accepted hypothesis that following ayahuasca ingestion, MAO inhibition brought about by harmine, given that it is more potent than THH and is present in the tea in larger amounts than harmaline (McKenna et al., 1984), prevents the enzymatic degradation of DMT, allowing its absorption. It has also been speculated that β-carbolines may contribute to the overall central effects of ayahuasca by blocking brain MAO and weakly inhibiting serotonin reuptake, which combined would lead to enhanced neurotransmitter levels and modulate the effects of DMT (Callaway et al., 1999).

In the present paper we report a double-blind placebo-controlled crossover clinical trial conducted with ayahuasca, in which subjective and cardiovascular effects, and alkaloid pharmacokinetics were assessed in a group of healthy volunteers experienced in psychedelic drug use. Additionally, urine monoamine metabolites were studied to measure in vivo the MAO-inhibitory effects of ayahuasca. In this respect, the neurotransmitters norepinephrine, epinephrine, and dopamine are physiologically degraded by MAO and catechol-O-methyltransferase (COMT) to produce deaminated and methylated metabolites, respectively. Serotonin, on the other hand, is exclusively metabolized by MAO to produce a deaminated compound. In vivo and in vitro studies have shown that when MAO is pharmacologically inhibited, the levels of MAO-dependent deaminated metabolites decrease and those of COMT-dependent methylated metabolites increase. In humans, MAO inhibitors decrease, after acute administration, the urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), the deaminated metabolites of norepinephrine/epinephrine, dopamine, and serotonin, respectively, while increasing that of metanephrine and normetanephrine, the methylated metabolites of epinephrine and norepinephrine, respectively (Pletscher, 1966; Koulu et al., 1989). Monoamine metabolites have both a CNS and a non-CNS origin, and their assessment in urine does not give information regarding the organ in which MAO was inhibited. Nevertheless, this approach can identify dose-response relationships after drug administration and allows for the study of the time course of MAO inhibition.

Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003). Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. Journal of Pharmacology and Experimental Therapeutics, 306(1), 73-83. 10.1124/jpet.103.049882
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