Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers

Ayahuasca is a traditional South American psychoactive brew that contains N,N-dimethyltryptamine (DMT) together with β-carboline alkaloids (harmine, harmaline, tetrahydroharmine) that inhibit monoamine oxidase (MAO), allowing orally ingested DMT to reach the systemic circulation. Use of the tea for magico-religious and therapeutic purposes in the Amazon basin has spread to parts of Europe and North America, raising public health interest in its somatic, psychological, and neurophysiological effects. Previous literature indicates that parenteral DMT produces intense, short-lived psychedelic experiences, but oral DMT is normally inactive unless co-administered with a MAO inhibitor, and systematic clinical data on standardised ayahuasca preparations are limited. Riba and colleagues set out to characterise the subjective effects and tolerability of three increasing oral doses of a freeze-dried ayahuasca preparation in healthy volunteers. The study aimed to document dose-related psychological effects using standardised scales and to monitor cardiovascular, somatic and laboratory measures, as part of a wider programme to clarify the pharmacology of ayahuasca in humans.

Six healthy male volunteers with prior ayahuasca experience were recruited in Barcelona and screened with a structured psychiatric interview (DSM-III-R), the trait-anxiety scale of the State-Trait Anxiety Inventory, physical examination, laboratory tests, ECG and urinalysis. Exclusion criteria included lifetime or current axis-I psychiatric disorders, alcohol or other substance dependence, and high trait anxiety. Mean age was 32.2 years (range 26–44); prior ayahuasca exposures varied between participants. The research protocol was approved by the local ethics committee and informed consent was obtained. A 9.6-litre batch of ayahuasca (Daime) was freeze-dried and analysed by HPLC. The freeze-dried material contained 8.33 mg DMT per gram and measurable amounts of harmine (14.13 mg/g), harmaline (0.96 mg/g) and tetrahydroharmine (11.36 mg/g), corresponding to approximately 0.53 mg DMT/ml in the original tea. Experimental oral doses were chosen as 0.5, 0.75 and 1.0 mg DMT/kg body weight, encapsulated as combinations of 00 gelatin capsules so each volunteer received 20 capsules per session; placebo capsules contained lactose. Capsules were stored at −20°C and administered with water under fasting conditions. The study employed a single-blind, placebo-controlled crossover design with four weekly experimental sessions given in an ascending sequence for safety: placebo first, then low (0.5 mg/kg), medium (0.75 mg/kg), and high (1.0 mg/kg) ayahuasca doses. Volunteers abstained from other substances before and during the study, underwent urine drug screening at each session, and remained seated in a dim, quiet room with an experimenter present. Capsules were given at about 09:00 and volunteers remained in the unit for five hours, with measurements taken at baseline and at predefined post-dose time points (the extracted text omits some specific intermediate timings). Blood samples for alkaloid pharmacokinetics were collected but those data are not reported in the extracted text. Psychological effects were assessed with 100-mm visual analogue scales (VAS) labelled for items such as "any effect", "good effects", "liking", "drunken", "stimulated" and "high", completed before dosing and at specified post-dose times including 240 minutes. Self-report questionnaires included Spanish adaptations of the Hallucinogen Rating Scale (HRS; six subscales: somaesthesia, affect, volition, cognition, perception, intensity) and the Addiction Research Center Inventory (ARCI; MBG, PCAG, LSD, BG, A scales) administered pre-dose and at 4 h post-dose. Cardiovascular tolerability was monitored by sphygmomanometer with systolic and diastolic blood pressure (SBP, DBP) and heart rate measured at baseline and at the same post-dose time points. Somatic-dysphoric effects were recorded via questionnaires and spontaneous verbal reports, and post-session laboratory testing included haematology and biochemistry. For analysis, cardiovascular variables and ARCI scores were transformed to differences from baseline or pre-administration as appropriate. The Friedman non-parametric test was used to assess overall treatment effects; when significant, post hoc Wilcoxon tests compared conditions. HRS scores and mean VAS/cardiovascular values across time points were also analysed with non-parametric tests. Statistical significance was set at P < 0.05.

Subjective effects showed clear dose dependence. Significant treatment effects were observed on all seven VAS items, on five of the six HRS subscales (somaesthesia, affect, cognition, perception, intensity; volition did not change significantly), and on three ARCI scales (A, MBG, LSD). The low dose (0.5 mg DMT/kg) was psychoactive in five of six volunteers and subthreshold in one, producing significant changes on most VAS items (except "high"), the HRS somaesthesia subscale, and the ARCI MBG scale. At the medium (0.75 mg/kg) and high (1.0 mg/kg) doses, all participants identified active effects; both doses differed from placebo on most VAS items and HRS subscales (again excluding volition). The medium dose increased ARCI MBG and A scores, while the high dose increased LSD, MBG and A scores. Some measures discriminated between low and high doses (five VAS items and HRS cognition); no variables distinguished medium from high doses. Time course data indicated that somatic sensations were first reported at about 15–30 minutes, psychological effects emerged around 30–60 minutes, peaked between 60 and 120 minutes, and generally resolved by approximately 240 minutes. Notably, "good effects" and "liking" VAS ratings remained elevated at 240 minutes, described by volunteers as a lingering sense of well-being after other effects subsided. Verbal reports documented dose-dependent visual imagery (from enhanced clarity to moving patterns and scenes with eyes open or closed), enhanced auditory perception, accelerated and personalised thought content, intensified emotions (both positive and negative), altered sense of self and time, and recollection of recent personal memories. Five of six volunteers maintained adequate interaction with the experimenter across doses; one volunteer experienced intense transient disorientation and anxiety at the medium dose and subsequently withdrew from the study. This participant had the least prior ayahuasca exposure (two prior occasions). Cardiovascular effects were modest. All three ayahuasca doses produced increases in SBP and DBP relative to placebo, but these changes were not statistically significant overall; a trend toward significance for SBP at the high dose was reported (P = 0.0503). Peak SBP differences versus placebo were 13.8 mm Hg (high), 13.4 mm Hg (medium) and 8.8 mm Hg (low), with maximal SBP around 90 minutes post-dose. Peak DBP differences were 10.4 mm Hg (high), 9.8 mm Hg (medium) and 8.6 mm Hg (low), maximising at about 60 minutes. Heart rate increases were small, with peak differences up to 9.2 beats/min (high dose) at ~45 minutes. No individual reached SBP ≥ 140 mm Hg or heart rate ≥ 100 beats/min; two volunteers had brief DBP readings of 91–93 mm Hg after medium and high doses lasting 15–30 minutes. Somatic-dysphoric effects most commonly comprised modified body sensations (burning in the stomach, tingling, altered temperature and skin sensitivity) and mild nausea. No clinically relevant changes were observed in haematological or biochemical laboratory tests after sessions. Spontaneous verbal reports and questionnaire responses are consistent with a mixed stimulatory and psychedelic profile of effects with generally positive overall appraisals by five of the six participants.

Riba and colleagues interpret their findings as showing that ayahuasca produces dose-dependent modifications of consciousness across perceptual, affective, cognitive and somatic domains, eliciting both stimulatory and psychedelic effects. The investigators note that no volunteer lost consciousness or contact with reality during the sessions and that most subjects rated the experience as pleasant, despite frequent somatic discomforts such as nausea. Comparisons with parenteral DMT indicated that ayahuasca has a slower onset and considerably longer duration of action, attributes the authors ascribing to the oral route plus reversible MAO inhibition by β-carbolines which both permit and prolong DMT's central effects. The paper suggests additional attenuation of perceptual intensity relative to intravenous DMT may arise from competition with elevated serotonin at receptor sites. Cardiovascular changes were milder and more delayed than reported for intravenous DMT and were of a magnitude the authors equate to low intravenous DMT doses (0.1–0.2 mg/kg). The greater prominence of somatic-dysphoric effects (body sensations, nausea) is discussed as plausibly related to the β-carbolines and to increased peripheral 5-HT. The authors place their psychometric findings in relation to prior studies: low-dose ayahuasca in this study resembled modest IV-DMT effects on somatic measures, whereas medium-dose HRS scores approximated those seen with 0.2 mg/kg IV DMT; even the high oral dose did not reproduce the overwhelming effects reported for the highest IV DMT doses in earlier work. Riba and colleagues acknowledge a possible ceiling or "saturation" effect across some subjective measures and propose that the ascending (non-randomised) dose order used for safety reasons may have produced an order effect that limited discrimination between medium and high doses. From a neuropharmacological perspective, the discussion reiterates the likely central role of serotonergic mechanisms—especially 5-HT2A and 5-HT1A receptor interactions—in mediating ayahuasca's subjective effects, and mentions secondary dopaminergic changes and functional imaging/electrophysiological data reported in other studies that the authors consider consistent with cortical excitatory actions underlying perceptual and auditory/visual enhancements. The investigators conclude that, in this small sample of experienced users, ayahuasca was generally well tolerated with moderate cardiovascular effects and no clinically relevant laboratory abnormalities, but they note the occurrence of one transiently severe dysphoric reaction in the least experienced participant. Finally, the authors recommend further research in larger samples using double-blind balanced designs, brain imaging and additional measures such as sensorimotor gating to clarify mechanisms and safety.