Background and Objective <p>Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recovery of oral mescaline hydrochloride.</p> Methods <p>Data from 105 single-dose administrations (100–800 mg) in 49 participants from two phase I trials were analyzed with compartmental pharmacokinetics and pharmacokinetic-pharmacodynamic modeling. A one-compartment model with first-order absorption, elimination, and a lag time was used to describe mescaline plasma concentrations. Acute subjective effects, assessed by visual analog scales (range 0–100%), were modeled using a sigmoid <i>E</i>_max model linked to plasma concentrations via a first-order rate constant (k_e0).</p> Results <p>Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0&#xa0;h (geometric mean) and a half-life of 3.5&#xa0;h across all doses. Mean model-predicted onset of “any drug effect” occurred around 1 hour post-dose. Maximum predicted effect intensity and duration increased with dose, from 13% and 2.8&#xa0;h at 100 mg to 89% and 15&#xa0;h at 800 mg. Over all conditions, 53% of the dose was excreted into urine unchanged, and 31% was excreted as the main metabolite 3,4,5-trimethoxyphenylacetic acid over 24–30&#xa0;h.</p> Conclusions <p>These findings provide the first detailed pharmacokinetic-pharmacodynamic characterization of mescaline in humans and indicate an oral bioavailability of at least 53%, limited by first-pass metabolism to 3,4,5-trimethoxyphenylacetic acid, followed by predominant renal elimination of both analytes.</p> Clinical Trial Registration <p>ClinicalTrials.gov identifier: NCT04227756 and NCT04849013.</p>