{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:12:00Z","timestamp":1785888720906,"version":"3.56.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004944","name":"Naresuan University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004944","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Food and Herb for Health and Beauty Project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ayahuasca is a traditional Amazonian brew composed of Psychotria viridis, containing N,N-dimethyltryptamine (DMT), and Banisteriopsis caapi, which includes harmala alkaloids such as harmine. Ayahuasca can produce potent psychoactive effects primarily due to DMT, whose metabolism is inhibited by harmine via monoamine oxidase-A enzymes. This inhibition increases DMT\u2019s systemic bioavailability, thereby allowing more DMT to reach the brain and intensify its psychedelic effects. Beyond its traditional psychoactive uses, ayahuasca has shown potential therapeutic benefits for mental health conditions such as depression, anxiety, and substance use disorders. To support better design of dosing regimens in both preclinical and clinical settings, we developed linked physiologically based pharmacokinetic (PBPK) models for DMT and harmine in rats and humans. The models account for multiple routes of administration (intraperitoneal, oral, intravenous, and buccal) and integrate harmine\u2019s inhibition of DMT metabolism in the liver and lungs. Key absorption and metabolism parameters were optimized using published time\u2013concentration data. The models reasonably predicted plasma concentrations of DMT and harmine across various dosing conditions. Simulation results offer insights into how the route of administration and co-administration with harmine influence exposure. The model also enables exploration of the dose metric driving the therapeutic effects, suggesting that plasma concentration above a threshold may be more relevant than peak levels. Overall, this PBPK model offers a mechanistic framework for guiding preclinical and clinical studies, supporting safer and more effective therapeutic use of ayahuasca and potentially other psychedelic compounds.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf118","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T11:48:38Z","timestamp":1755690518000},"page":"48-60","source":"Crossref","is-referenced-by-count":2,"title":["Development of a physiologically based pharmacokinetic model of N,N-dimethyltryptamine, harmine, and their interactions from ayahuasca in rats and humans"],"prefix":"10.1093","volume":"208","author":[{"given":"Naphat","family":"Wittayakarn","sequence":"first","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]},{"name":"Pharmacokinetic Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Mei","family":"Tan","sequence":"additional","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pattanachai","family":"Choomalaiwong","sequence":"additional","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]},{"name":"Pharmacokinetic Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Chen","sequence":"additional","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hoer","sequence":"additional","affiliation":[{"name":"Department of Organismic and Evolutionary Biology, Harvard University , Cambridge, MA 02138,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilubon","family":"Thaoboonruang","sequence":"additional","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]},{"name":"Pharmacokinetic Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manupat","family":"Lohitnavy","sequence":"additional","affiliation":[{"name":"Center of Excellence for Environmental Health & Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]},{"name":"Pharmacokinetic Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]},{"name":"Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University , Phitsanulok 65000,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"2025111015222276900_kfaf118-B1","doi-asserted-by":"crossref","first-page":"118329","DOI":"10.1016\/j.biopha.2025.118329","article-title":"Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects","volume":"189","author":"\u00c4bel\u00f6","year":"2025","journal-title":"Biomed Pharmacother"},{"key":"2025111015222276900_kfaf118-B2","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1016\/0006-2952(82)90062-4","article-title":"Comparison of the brain levels of N,N-dimethyltryptamine and alpha, alpha, beta, beta-tetradeutero-N-N-dimethyltryptamine following intraperitoneal injection. 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