Application of Physiologically Based Pharmacokinetics (PBPK) in the prediction of drug interactions between DMT and harmine in ayahuasca and synthetic drugs: assessment of a neglected risk

• Grant number: 23/15903-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2024
• End date: January 31, 2027
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Tania Marcourakis
• Grantee: Gabriella de Souza Gomes Ribeiro
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/09664-0 - Physiologically Based Pharmacokinetics (PBPK) modeling of ayahuasca and the effects of N,N-dimethyltryptamine (DMT) and harmine on cocaine-induced neurotoxicity, AP.R
• Associated scholarship(s): 25/13731-0 - PREDICTION OF N,N-DIMETHYLTRYPTAMINE (DMT) AND HARMINE TRANSFER INTO BREAST MILK: ASSESSMENT OF NEONATAL EXPOSURE POTENTIAL USING IN VITRO MODELS, BE.EP.DR

Abstract

Ayahuasca is a psychedelic beverage traditionally used in rituals and therapies by indigenous groups in the Amazon, composed of N,N-dimethyltryptamine (DMT) and ¿-carbolines, such as harmine (HRM). The ¿-carbolines are reversible inhibitors of monoamine oxidase A (MAO-A), allowing DMT to be absorbed and distributed to the central nervous system. Fluoxetine (FL), prescribed for the treatment of depression, is biotransformed into its active metabolite norfluoxetine (NFL) predominantly by the CYP2D6 and 2C9 enzymes. Additionally, paroxetine (PR) is also currently one of the most prescribed SSRIs in clinical practice and, like FL, has CYP2D6 as an important enzyme for its metabolism. Theoretically, the concomitant use of FL and PR with ayahuasca could lead to serotonin syndrome, as FL and PR are strong inhibitors of CYP2D6, an enzyme also involved in the metabolism of HRM and DMT. This study aims to develop a PBPK model to analyze the pharmacokinetics (PK) of ayahuasca alkaloids as well as the kinetic disposition of FL and PR to subsequently predict the interaction between HRM and DMT, as well as the interactions between HRM, DMT, and SSRIs. The models will be constructed using PK-Sim® V11 software, based on in vitro parameters and clinical data observed in volunteers after oral and IV administration of ayahuasca, FL, and PR. The validation of the PBPK models will be conducted using observed PK data from clinical studies on ayahuasca, FL, and PR, visually inspecting plasma concentration versus time graphs and comparing observed and predicted PK parameters. The mean fold error (MFE) is considered satisfactory when the predicted parameters are within two times the corresponding observed value. Interaction scenarios of FL-HRM, FL-DMT, PR-HRM, and PR-DMT will be simulated to analyze the extent of drug interaction between HRM and DMT after simultaneous administration with FL and PR. Since DMT and HRM have CYP2D6 as a metabolizing enzyme, and FL and PR have a high inhibition index for this enzyme, our intention is to determine the risk of serotonin syndrome. This approach will not only allow for a deeper understanding of the pharmacokinetic processes of these compounds in the human body but will also pave the way for predicting previously unexplored scenarios, such as the effect of genetic polymorphisms of the CYP enzymes involved in the metabolism of these substances on the plasma and brain concentrations of DMT and HRM. This innovative practice will contribute to our scientific understanding of the effects of ayahuasca, as well as the identification of significant implications in the health field.