Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review

Abstract

The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov , and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed.

From Venerable Cultural Practices to Modern Psychological Solutions: Enter Entheogens into Mainstream Medicine

“…Beta-carbolines are believed to inhibit the action of monoamine oxidase (MAO), allowing DMT to be orally active. Ayahuasca has been associated with alterations in serotonin receptor activity, modulation of brain connectivity, and subjective experiences encompassing heightened introspection, emotional processing, and potential therapeutic effects on mood disorders (Frecska et al, 2016;White, Kennedy, Ruffell, Perkins, & Ruffell, 2024).…”

“…DMT acts on serotonin 5-HT2A and sigma-1 receptors, leading to psychedelic and clinically significant psychoactive effects. Harmine acts as an MAO inhibitor and increases the bioavailability of DMT, thus potentiating its pharmacological effects (Frecska et al, 2016;White et al, 2024).…”

“…Ayahuasca can modulate neuronal activity by activating the default mode network (DMN) and other cortical and subcortical regions. Ayahuasca's psychoactive effects include changes in mood, perception, and egodeath experiences (Frecska et al, 2016;White et al, 2024).…”

“…The dose of ayahuasca used in research can vary. According to specific reviews, the average ceremonial dose of DMT in ayahuasca preparations is about 27 mg, with an average ritual/ceremonial oral dose of ayahuasca being 100-150 mL for a 70 kg person (Frecska et al, 2016;White et al, 2024). However, clinical studies have administered an oral dose of ayahuasca of 2.2 mL/kg (De Morais Santos et al, 2023).…”

“…DMT, while having low toxicity and abuse potential, may lead to persistent psychotic symptoms with prolonged use. Adverse effects such as panic attacks, seizures, and psychotic symptoms have been reported (Frecska et al, 2016;White et al, 2024).…”