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

DMT (N,N-dimethyltryptamine) is a tryptamine structurally related to serotonin that acts as a 5-hydroxytryptamine 2A (5-HT2A) receptor agonist and, when administered parenterally, produces rapid, intense but short-lived alterations of perception and self-experience together with autonomic activation. Ayahuasca is a botanical preparation that combines DMT-containing Psychotria viridis (or Diplopterys cabrerana) with Banisteriopsis caapi, a vine rich in β-carboline alkaloids (harmine, harmaline, tetrahydroharmine) that inhibit monoamine oxidase (MAO). It is widely hypothesised that inhibition of MAO by the β-carbolines prevents first-pass metabolism of orally ingested DMT and thereby permits DMT to reach the systemic circulation and the central nervous system; β-carbolines might also contribute centrally by inhibiting MAO in the brain or weakly blocking serotonin reuptake, but the site and extent of their action in humans remained unclear prior to this work. Riba and colleagues therefore set out to characterise the human pharmacology of ayahuasca in a controlled experimental setting. The study aimed to measure subjective and cardiovascular effects, urinary monoamine metabolite excretion as an in vivo index of MAO inhibition, and the pharmacokinetics of DMT and the principal β-carbolines after oral administration of encapsulated freeze-dried ayahuasca in healthy volunteers experienced with psychedelics.

Design and participants: The investigation used a within-subject, placebo-controlled crossover design. Eighteen healthy volunteers (15 male, 3 female) with prior psychedelic experience (minimum five prior uses) were recruited. Exclusion criteria included current or past psychiatric disorder, family history of Axis-I disorder in first-degree relatives, substance dependence, and high trait anxiety. Mean age was 25.7 years and mean weight 66.47 kg. The study complied with ethical standards and participants provided written informed consent. Interventions and dosing: A 9.6-litre batch of Brazilian ayahuasca was freeze-dried and assayed. One gram of the lyophilised material contained 8.33 mg DMT, 14.13 mg harmine, 0.96 mg harmaline, and 11.36 mg tetrahydroharmine (THH). Two active dose levels were prepared on a mg/kg basis: a low dose delivering 0.6 mg DMT/kg and a high dose delivering 0.85 mg DMT/kg (corresponding proportional amounts of harmine, harmaline, and THH). The lyophilisate was encapsulated in varying capsule sizes and placebo capsules (lactose) were used to maintain blinding and equal capsule number across sessions. Experimental procedure and sample collection: Each volunteer attended four experimental sessions at least one week apart. All participants received a single-blind placebo on the first day for familiarisation; the remaining three sessions (placebo, low dose, high dose with one random repetition) were administered in a double-blind balanced order. Subjects fasted overnight, had an indwelling venous cannula, and took capsules at ~10:00 with 250 ml water. They remained seated in a quiet, dimly lit room; a meal was provided at 4 h and discharge occurred approximately 9 h after dosing. Blood samples for plasma alkaloid assays were drawn at baseline and at 30, 60, 90, 120, 150 min, and 3, 4, 6, 8, and 24 h. Urine was collected in 0–8 h, 8–16 h and 16–24 h fractions and acidified for preservation. Outcome measures and bioanalysis: Subjective effects were assessed with visual analogue scales (VAS; 100 mm lines for items such as "any effect", "liking", "visions", "high"), the Hallucinogen Rating Scale (HRS; six domains) administered at 4 h, and the short-form Addiction Research Center Inventory (ARCI) administered at baseline and 4 h. Cardiovascular measures (systolic and diastolic blood pressure, heart rate) were taken at baseline and repeatedly up to 240 min. Urinary monoamine metabolites (vanillylmandelic acid, homovanillic acid, 5‑HIAA, metanephrine, normetanephrine) were quantified by HPLC with coulometric detection; limits of quantification were reported for each analyte. Plasma DMT was measured by gas chromatography with nitrogen-phosphorus detection; β-carbolines and their O-demethylated metabolites (harmol, harmalol) were measured by HPLC with fluorescence detection. Limits of quantification and assay precision (intraday and interday coefficients of variation <13.4%) were provided. Pharmacokinetic and statistical analysis: Pharmacokinetic parameters (Cmax, Tmax, AUC0–8h extrapolated to infinity, terminal half-life, clearance CL/F, apparent volume Vz/F) were obtained using noncompartmental methods (WinNonlin). For subjective and cardiovascular measures, peak effects, time to peak and AUCs were derived. Repeated-measures one-way ANOVA (drug as factor) evaluated dose effects, with Tukey post hoc tests when significant. Two-way repeated measures ANOVA (drug × time) explored temporal profiles. Pharmacokinetic comparisons used paired t tests (or Wilcoxon for Tmax). Significance threshold was p<0.05.

Subjective effects: Ayahuasca produced clear psychedelic and stimulatory subjective effects. Both active doses increased scores on five of six HRS domains at 4 h; Volition was significantly altered only at the high dose. The ARCI showed dose-dependent increases on the A (stimulant-like), MBG (euphoria), and LSD (somatic-dysphoric) scales. All seven VAS items exhibited significant drug effects for peak values and AUC, with drug-by-time interactions. Effects typically appeared between 30 and 45 min, rose steeply around 60 min, reached maximal values between 90 and 120 min, and had returned to baseline by 360 min. The largest VAS effects were on any effect, liking, and high; the smallest change was on the drunken item. Cardiovascular effects: Cardiovascular activation was moderate. Statistically significant differences from placebo were observed only for diastolic blood pressure (DBP) for both peak values and 0–4 h AUC. The largest DBP difference versus placebo was approximately 9–10 mm Hg (noted at ~75 min). Systolic blood pressure (SBP) and heart rate (HR) showed modest, nonsignificant increases (SBP maximal differences with placebo about 4–6 mm Hg at 75 min; HR increased by about 4–5 beats/min at 60 min). A small number of individuals reached conventional hypertensive thresholds at isolated time points: two volunteers had SBP ≥140 mm Hg and two had DBP >90 mm Hg at specific post-dose times; one volunteer had HR >100 beats/min after the high dose. Urine monoamine metabolites: Urine collections were complete for 15 of 18 participants. A significant drug effect was found only for normetanephrine (an O-methylated metabolite of norepinephrine), which increased after ayahuasca. Contrary to the expectation for systemic MAO inhibition, deaminated metabolites (VMA, HVA, 5‑HIAA) did not show the anticipated decreases and were nonsignificantly increased. No drug-by-time interactions were detected for metabolites over the three collection intervals. Pharmacokinetics: Pharmacokinetic analyses were performed on 15 participants; three were excluded because of vomiting and one additional subject was excluded from a specific metabolite analysis due to atypical plasma profiles. DMT plasma concentrations rose steeply with a median Tmax of 1.5 h after both low and high doses, coinciding with peak subjective effects. Reported Cmax values for DMT were 12.14 ng/ml (low dose) and 17.44 ng/ml (high dose) and Tmax matched the timing of maximal VAS responses. Harmaline and THH peaked later than DMT, with Tmax values increasing with dose. Harmine was largely undetectable in plasma (measurable only at a few time points in 4 of 18 volunteers), whereas its O-demethylated metabolite harmol was measurable and showed dose-dependent plasma increases with Tmax around 1.5–2 h. Harmalol (from harmaline) was also quantifiable, with Tmax at ~2.5–2.75 h. Normalised AUC (AUC/dose) for DMT differed significantly between doses, suggesting a non-proportional increase in systemic exposure at the higher dose; Vz/F and CL/F for DMT decreased with dose (the Vz/F decrease reached statistical significance and CL/F showed a trend). No significant differences were found between DMT Tmax and the Tmax for the seven VAS items.

Riba and colleagues interpret their findings as demonstrating that orally dosed, encapsulated freeze-dried ayahuasca produces distinct psychedelic subjective effects together with modest cardiovascular activation in healthy, experienced users. The qualitative and quantitative pattern of subjective change—activation, euphoria, perceptual alterations, cognitive and affective changes—places ayahuasca within the psychedelic class while also showing stimulant-like features on some measures; the temporal profile was intermediate between the very short-lived effects of intravenous DMT and the longer duration of mescaline or LSD. Pharmacokinetic data showed that DMT reached measurable systemic concentrations with peak levels and timing that paralleled subjective effects, supporting a link between circulating DMT and psychoactivity. However, circulating harmine was negligible in most participants while O‑demethylated metabolites (harmol, harmalol) were present, a pattern the authors suggest reflects extensive first-pass metabolism of harmine and/or limited harmine absorption. Because urinary monoamine metabolites did not show the clear reduction in MAO-dependent deaminated metabolites expected with systemic MAO-A inhibition, the investigators conclude that MAO inhibition by ayahuasca alkaloids was predominantly peripheral (gastrointestinal and/or hepatic). Such peripheral inhibition would be sufficient to prevent first-pass degradation of DMT and allow it to reach the CNS, but may have been insufficient in magnitude or duration to produce the classic systemic MAO inhibitor urinary metabolite profile within the collection windows used. The authors note several points that may account for interstudy differences and interpretative limits: lower Cmax values compared with some prior reports might reflect decreased bioavailability from the lyophilised preparation or lower β-carboline content leading to less MAO inhibition; absence of harmine in plasma argues for extensive first-pass O-demethylation (consistent with detectable harmol) catalysed by cytochrome P450 isoenzymes; and urinary metabolite measurements cannot localise the site of MAO inhibition because metabolites have both central and peripheral origins. They also acknowledge that the degree and duration of MAO inhibition required to alter urinary deaminated metabolite excretion may not have been achieved or captured within the 8‑h urine collection periods. In sum, the investigators conclude that oral ayahuasca yields measurable systemic DMT and reproducible psychedelic effects despite negligible circulating harmine, consistent with a primarily peripheral β-carboline–DMT interaction that prevents first-pass DMT degradation and permits central psychoactivity.