Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids

Gable frames the paper as a risk-focused review of ceremonial oral dimethyltryptamine (DMT) combined with b‑carboline monoamine oxidase inhibitors (commonly known as ayahuasca or hoasca). Earlier literature and legal debate motivated the review: a US Supreme Court case over the sacramental use of hoasca highlighted limited systematic evidence about acute systemic toxicity, psychological hazards and dependence potential. The introduction emphasises that ‘‘risk’’ is treated probabilistically and that, because published data on orally administered DMT are sparse, many alleged effects remain only plausibly associated rather than causally established. The paper sets out to assemble and evaluate available scientific and technical information on acute toxicity, cardiovascular effects, psychological adverse reactions and dependence/abuse potential of ayahuasca/hoasca. Gable takes a broad view of potential hazards, including pharmacological properties of the two principal constituents (DMT and harmala alkaloids), customary patterns of preparation and ceremonial use, and supplementary information obtained from participant observation and legal documentation, with the aim of estimating relative safety margins and identifying circumstances that increase risk.

Gable conducted a systematic literature search of English‑language serial publications from 1969 to 2005 using six databases: Biosis Previews, Digital Dissertations, Google, PsychAbstracts, PubMed and Toxline, with occasional follow‑up via the Science Citation Index. Six primary search terms were used—'ayahuasca', 'hoasca', 'dimethyltryptamine', 'harmine', 'harmaline' and 'tetrahydroharmine'—and these were cross‑searched with toxicity‑related descriptors such as 'overdose', 'lethal dose', 'toxicity' and 'abuse potential'. The search was supplemented by consultation of books, monographs and special journal issues to broaden the evidence base beyond database returns. The review also incorporated limited primary field observation and documentary sources: Gable met with 16 people around an ayahuasca ceremony in 2003 and examined a detailed legal evidentiary document made available in 2005. Items located during the search were considered potentially relevant if they met at least two of four prespecified criteria: quantitative dosing or toxicity data for DMT/MAOIs, indication of the individual's health status, mention of concomitant substances, and a technical or scholarly data source. Where available, animal LD50 data, human pharmacodynamic observations and case reports were used to estimate safety margins; when extrapolations from animal data were necessary, the author made and stated conservative assumptions to convert to human equivalents.

The search yielded relatively few directly relevant English‑language studies: fewer than 100 scholarly articles focused specifically on ayahuasca/hoasca and roughly 200 citations for the individual alkaloid descriptors, but after cross‑indexing with 'toxicity' fewer than 25 non‑redundant items met the screening criteria. Including scholarly books, monographs and reports, about 140 documents were filed for review. Composition and dosage: DMT content in Psychotria viridis leaves was reported between 0.1% and 0.66% dry weight, with notable within‑plant diurnal variation reported in one sample (about 3–9.5 mg/g dry weight). B. caapi b‑carbolines were reported between 0.05% and 1.95% dry weight. Assayed ayahuasca brews produced average DMT doses ranging from about 8.8 mg to 42 mg; the author cites an average ceremonial DMT dose near 27 mg. Substantial inter‑batch variation is expected because of plant chemistry and preparation methods; ceremonial practices (testing potency by the ritual leader and offering variable cup sizes) provide some informal dose control. Pharmacology and time‑course: smoked, injected or insufflated DMT produces very rapid, short‑lived peak cognitive effects (3–10 minutes, returning toward baseline within 30 minutes). Orally administered DMT with MAOI shows initial somatic effects after ~20 minutes, cognitive peaks between 60 and 120 minutes, and return toward normal over about 4 hours; at customary ceremonial doses oral DMT effects are generally less intense than parenteral administration. Acute lethality: rodent LD50s for DMT are reported as 47 mg/kg intraperitoneally and 32 mg/kg intravenously in mice. For related tryptamines and for b‑carboline extracts, LD50 reports are sparse but include an oral LD50 of ~2 g/kg for an aqueous extract of Peganum harmala seed in rats. Because direct human LD50 data are unavailable, the author applies conservative scaling assumptions—assuming humans are 20 times more sensitive than rodents and an intravenous:oral bioavailability conversion of 1:5—and estimates an oral median lethal dose of about 560 mg DMT for a 70 kg person. Comparing this to an average ceremonial dose of ~27 mg yields a calculated safety margin of approximately 20; Gable emphasises these calculations rest on several precautionary assumptions. Cardiovascular effects and serotonin risk: intravenous DMT (0.4 mg/kg) produced rapid increases in heart rate and blood pressure in human studies (eg, mean heart rate +26 beats per minute, systolic +35 mmHg). Oral ayahuasca doses (reported 0.48–1.0 mg/kg total alkaloid exposure in some studies) produced more modest, delayed increases that peaked around 90–120 minutes and were approximately one‑third of the acute changes seen with intravenous DMT. Interindividual variation in haemodynamic responses was large. The harmala b‑carbolines are reversible MAO inhibitors; MAO blockade can potentiate serotonergic accumulation and, when combined with other serotonergic agents (for example SSRIs, certain analgesics, MDMA or various herbal products), may precipitate serotonin syndrome with symptoms ranging from tremor and autonomic instability to hyperthermia and, rarely, death. Adverse events and fatalities: the review identified a small number of severe toxic reactions involving tryptamine and/or b‑carbolines, but many of these cases involved non‑traditional preparations, high doses (for example ingestion of large quantities of Peganum harmala seeds), or combinations with other pharmacologically active agents (including nicotine administered atypically). No deaths attributable to traditional ayahuasca/hoasca brews were identified in the material surveyed. The author notes that emesis provoked by ayahuasca may reduce the likelihood of massive overdose, and that atypical metabolism or compromised health increase individual risk. Psychological effects and dysfunction: ayahuasca reliably produces dose‑dependent visionary experiences, altered time and self‑perception, and variable emotional responses ranging from wellbeing to terror. Experimental data cited from controlled dosing showed dose‑related increases in measures of affect and altered perceptual states; ceremonial reports and qualitative interviews describe profound personal reflections and life changes in some users. The UDV reported 13–24 incidents over 5 years in which ayahuasca may have contributed to psychotic episodes out of an estimated 25 000 servings—an incidence under 1%—and most reported episodes were transient and resolved spontaneously. The literature contains hypotheses linking endogenous DMT and psychosis, but Gable notes these remain speculative with conflicting evidence. Dependence and abuse potential: no convincing evidence of physiological dependence or a clear abstinence syndrome following DMT cessation was found. Animal studies show variable tolerance; small human studies reported little or no tolerance across short repeated dosing schedules. Reports indicate weak reinforcing properties for tryptamine hallucinogens in animal self‑administration paradigms. The UDV reports that 15–20% of first‑time participants later became church members, a figure comparable to membership uptake in some religious contexts; this is presented as not prima facie evidence of compulsive drug‑seeking. Overall, the pharmacological and epidemiological signals reviewed suggest limited abuse and dependence potential compared with classical drugs of abuse.

Gable concludes that evidence on acute adverse health effects of ayahuasca is limited but indicates relatively low acute systemic toxicity when ingested within customary ceremonial dosages. By the author's conservative extrapolation, the calculated safety margin for ayahuasca is on the order of 20 times the customary dose, a figure comparable to substances such as codeine, mescaline and methadone; prior estimates have varied depending on the scaling assumptions used. The principal acute hazard emphasised is serotonergic interaction risk—particularly when ayahuasca is combined with other serotonergic medicines or recreational drugs—rather than intrinsic cardiotoxicity or routine fatal overdose from traditional brews. The discussion highlights important uncertainties and caveats: the scarcity of direct human and animal studies of oral DMT/b‑carboline decoctions constrains causal inference, and many poisoning reports involve atypical preparations or concurrent substances. Gable acknowledges that the review did not address possible chronic health effects. Practical implications noted by the author include the importance of social and ritual context (which may modulate risk and dose control), the dangers of Internet‑based do‑it‑yourself preparations and non‑traditional combinations, and the low apparent potential for widespread recreational abuse given the unpredictable, sometimes aversive, acute effects and common somatic symptoms such as nausea and diarrhoea. Finally, Gable observes that some reported experiences described in ceremonial settings—spiritual or transcendent states—lie outside toxicology's customary remit but may nonetheless merit rigorous scientific study; the author cautions that policy and legal decisions must be made with imperfect evidence and calls attention to the need for further research to clarify chronic effects, interaction risks and the epidemiology of adverse psychological outcomes.