Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics

Ayahuasca, a South American psychedelic beverage combining DMT with MAO-inhibiting beta-carboline alkaloids, produces significant subjective perceptual and mood effects peaking 1.5 to 2 hours after oral administration. In a double-blind placebo-controlled trial with 18 experienced psychedelic users, doses of 0.6 and 0.85 mg DMT/kg increased diastolic blood pressure by 9 mm Hg at the high dose, while systolic pressure and heart rate rose modestly but not significantly. Peak DMT blood concentrations (Cmax) were 12.14 ng/ml and 17.44 ng/ml for low and high doses, respectively, coinciding with subjective effect peaks. Urinary normetanephrine increased, but deaminated monoamine metabolites did not decrease, and harmine plasma levels were negligible, suggesting harmine acts primarily in the gastrointestinal tract and liver to prevent DMT breakdown and allow its entry into the brain.

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Abstract

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 beta-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.