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Pharmacokinetics of the three main alkaloids present in the South American psychoactive beverage Ayahuasca after oral administration to healthy volunteers

Valle M, Riba J, Yritia M, Barbanoj MJ.

Institut de Recerca del HSCSP. Hospital de la Santa Creu i Sant Pau. 08025 Barcelona, Spain

Ayahuasca is a South American psychotropic plant tea used since pre- Columbian times in the Upper Amazon and Orinoco River Basins. This tea is obtained from Banisteriopsis caapi and Psychotria viridis and combines monoamine-oxidase- inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine) with N,N-dimethyltryptamine (DMT), a hallucinogenic agent showing 5-HT2A/2C agonist activity. Important individual differences have been observed under laboratory conditions in the subjective effect profile reported by volunteers after oral administration of ayahuasca. The objective of the present work was to characterize the pharmacokinetics of DMT (main psychoactive compound), harmaline and tetrahydroharmine after oral dosing with ayahuasca.

Methods: Two oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg) were administered to 18 healthy volunteers according to a double blind, crossover design. Plasma concentrations of DMT, harmaline and tetrahydroharmine were determined at different times by means of validated GC (DMT) and HPLC techniques. Pharmacokinetic analyses were carried out with NONMEM (version V), using first-order or first-order conditional estimation methods. Absorption was modeled as zero- or first-order processes, and sometimes as a combination of both processes with different lag times. Different linear and non-linear models (saturable, time-dependent) were investigated in order to describe drug elimination. To describe the distribution of the alkaloids, different compartmental models were employed.

Results: DMT: A one-compartment model with first-order absorption and elimination processes from the central compartment best described the time course of DMT plasma concentrations. The estimated volume of distribution from the central compartment (V/F) and its relative standard error (%) were 3210 L (20), with an associated interindividual variability (IIV (CV (%)) of 82 (37). The total estimated plasma clearance (Cl/F) was 1300 L/h (13), with a IIV of 34 (33). Absorption was described as a dose-dependent process: ka=4.57 h-1 (70) for the low dose, and ka=1.78 h-1 (23) for the high dose; the associated IIV was 63 (70). The estimated lag time was 0.6 h (14) with an IIV of 22 (39). Harmaline: A one-compartment model with zero-order absorption and first-order elimination processes from the central compartment best fitted the time course of harmaline plasma concentrations. The estimated V/F was 1290 L (17), with an IIV of 48 (34). Estimated Cl/F was 658 L/h (22), with a higher IIV, 78 (58). The duration of the absorption for the low dose was estimated to be 1.48 h (7.5), after a lag time of 0.257 h (44). For the high dose, the duration of this process was longer, 2.59 (7.1) without lag time. Tetrahydroharmine: A one-compartment model with first-order absorption and elimination processes from the central compartment best described the time course of tetrahydroharmine plasma concentrations. The estimated V/F was 375L (30), with an IIV of 95(40). Cl/F was dose-dependent: 462 L/h (23) for the low dose and 335 L/h (20) for the high dose, with a high IIV, 91 (69). The estimated absorption ka was 0.189 h-1 (18) after a lag time of 0.696 h (14).