Background and Objective

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.

Methods

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 sigmoidE_max model linked to plasma concentrations via a first-order rate constant (k_e0).

Results

Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0 h (geometric mean) and a half-life of 3.5 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 h at 100 mg to 89% and 15 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 h.

Conclusions

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.

Clinical Trial Registration

ClinicalTrials.gov identifier:NCT04227756 andNCT04849013.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40262-025-01544-x.

Study Design

The present analysis included data from two different previously published studies that were conducted in healthy volunteers at the University Hospital Basel [4,21]. Overall, we analyzed data from 113 mescaline HCl administrations in 49 individuals.

In Study 1, 32 participants were included. Sixteen participants received 300 mg of mescaline HCl, and 16 participants received 500 mg of mescaline HCl. Study 1 compared the acute subjective effects of oral single doses of LSD (100 µg), psilocybin (20 mg), mescaline HCl (300 or 500 mg), and placebo in a randomized double-blind crossover design [21]. Because of weaker acute subjective effects at 300 mg of mescaline compared with LSD (100 µg) and psilocybin (20 mg) in the first 16 participants, the mescaline HCl dose was increased to 500 mg for the second 16 participants. Only data of the mescaline conditions were used for the present analysis.

Study 2 investigated acute subjective effects of different oral doses of mescaline HCl in 17 participants using a randomized double-blind crossover design [4]. Each participant received single doses of mescaline HCl (100, 200, 400, and 800 mg) and a combination of mescaline HCl (800 mg) with ketanserin (40 mg). One participant dropped out after experiencing distress during the first session (800 mg of mescaline HCl) and was excluded from within-subject comparisons [4] but was retained in the present analysis. The co-administration of mescaline HCl (800 mg) with ketanserin (40 mg) markedly reduced the acute subjective response to mescaline and mescaline-induced emesis compared with 800 mg of mescaline HCl alone. Frequent emesis after administration of the highest dose of mescaline HCl (800 mg) may have reduced the absorption of mescaline [4]. In the present analysis, we included the mescaline and ketanserin condition in the PK analysis but not in the PK-PD analysis.

The washout periods between sessions were at least 10 or 14 days for Studies 1 and 2, respectively [4,21]. All participants provided written informed consent and received compensation for their participation. Both studies were approved by the local ethics committee and registered at ClinicalTrials.gov (NCT04227756 andNCT04849013). The research was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. Approval for administering psychedelics to healthy participants was granted by the Swiss Federal Office for Public Health, Bern, Switzerland.

Participants

Physically and mentally healthy people, 25–65 years of age with a body mass index of 18–29 kg/m², were eligible for the studies. Key exclusion criteria were pregnancy, breastfeeding, a personal or first-degree relative history of major psychiatric disorders, chronic somatic illness, and/or the use of medications that might interfere with the studies. Complete inclusion and exclusion criteria are provided in the Electronic Supplementary Material (ESM).

Study Drug

Mescaline HCl was synthesized by ReseaChem GmbH, Burgdorf, Switzerland. In both studies, capsules that contained 100 mg of mescaline HCl and identical capsules that contained mannitol as placebo were produced according to Good Manufacturing Practice (Apotheke Dr. Hysek, Biel, Switzerland). The exact analytical contents of mescaline HCl in the dosing units, together with the corresponding calculated mescaline contents that were used as dosing inputs for all analyses, are provided in the ESM.

Study Procedures

After providing written informed consent, the eligibility of participants was assessed at a screening visit based on a medical history, physical examination, psychiatric assessment, electrocardiogram, vital parameters, and analyses of blood chemistry and hematology. The included participants attended four 25-h or six 31-h dosing sessions in Studies 1 and 2, respectively. Dosing sessions were conducted in a calm hospital room and began at 8 a.m. with baseline measurements and a standardized small breakfast. The study medication was administered at 9 a.m., after which outcome measures were repeatedly assessed for 24 or 30 h, respectively. The participants remained under constant supervision during the acute effect phase, and an investigator spent the night in the room next to the participants. After all sessions, an end-of-study visit was conducted to assess the overall study experience and the participants’ health status [4,21].

Blood and Urine Samples

Blood samples were drawn and collected into lithium heparin tubes 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 16, and 24 h after dosing for Study 1 and 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 14, 16, 20, 24, and 30 h after dosing for Study 2. Blood samples were immediately centrifuged, and plasma was stored at −80 °C until analysis. In Study 1, urine was collected over time intervals of 8 h (0–8, 8–16, and 16–24 hours). In Study 2, urine was collected cumulatively from 0 to 30 h after dosing. Urine samples were frozen and stored at −80 °C until analysis. Cases of incomplete urinary sampling because of strong psychedelic effects were excluded from the analysis. Concentrations of mescaline and its metabolites 3,4,5-trimethoxyphenylacetic acid (TMPAA) andN-acetylmescaline (NAM) were determined by a fully validated, high-performance liquid chromatography-tandem mass spectrometry method [27].

Acute Subjective Effects

Single-item visual analog scales (VASs), presented as 100-mm horizontal lines (0–100%) and marked from “not at all” on the left to “extremely” on the right, were repeatedly used to assess acute subjective effects over time. The VASs included “any drug effect,” “good drug effect,” “bad drug effect,” “nausea,” and “the boundaries between me and my surroundings seem to blur,” the latter measuring “ego dissolution” (i.e., loss of sense of self), a subjective effect that is characteristic of psychedelics [5,8,28–30]. In both studies, VASs were administered at the same timepoints as blood samples were drawn [4,21].

PK Analyses and PK-PD Modeling

All analyses were performed using Phoenix WinNonlin 8.4 (Certara, Princeton, NJ, USA) using the actual sampling times. Doses were adjusted to the analytically exact content of mescaline in the capsules. For urinary recovery, molar doses and concentrations were used. As vomiting could lead to incomplete absorption after oral drug administration, profiles were excluded if emesis occurred within 1 hour after dosing or up to 1 h after the observed peak plasma (C_max) concentration.

We first conducted non-compartmental analyses (NCAs) for mescaline, TMPAA, and NAM. Peak plasma concentration and time toC_max (t_max) were obtained directly from the observed data. The terminal elimination rate constant (ʎ_z) to calculate the half-life (t_1/2) was estimated by log-linear regression after semilogarithmic transformation of the data using at least three data points of the linear phase of the concentration–time curve. The area under the concentration–time curve from 0 to the last post-dosing timepoint was computed by employing the linear‑up log‑down method. The infinite area under the concentration–time curve (AUC_∞) was derived by extrapolating the area under the concentration–time curve from 0 to the last post-dosing timepoint using the constant ʎ_z. Because the two studies used different sampling timepoints, we report the AUC_∞ together with the percentage of extrapolation of the AUC_∞. Total (µmoL) and relative (% of dose) urinary recovery was calculated for mescaline and its metabolites. Renal clearance (L/h) was calculated as urinary recovery/AUC_∞.

Subsequently, we conducted sequential compartmental PK and PK-PD modeling of mescaline plasma concentrations and acute effects. Datasets were modeled individually for each participant and condition. All models were developed using the naïve pooled engine in Phoenix WinNonlin, which applies a quasi-Newton Broyden–Fletcher–Goldfarb–Shanno algorithm to minimize the −2 Log likelihood (−2LL) objective function. A stepwise approach was applied to evaluate model performance using visual fits of predicted versus measured concentrations/effects, the −2LL, Akaike information criteria (AIC), coefficients of variation of parameter estimates, parameter correlations, and residual error plots during the model fitting process. The addition of a parameter to the model was evaluated using likelihood ratio tests by comparing the difference −2LL values between nested models. Statistical significance was determined using the chi-squared distribution with degrees of freedom equal to the number of additional parameters in the more complex model. A drop of 3.84 in the −2LL value was considered statistically significant for the addition of one parameter, corresponding to ap-value of 0.05. We counted the number of profiles showing a significant improvement. Further, the mean, standard deviation (SD), and 95% confidence intervals (CIs) of the differences in −2LL and AIC across individual profiles were calculated. Plasma concentrations below the lower limit of quantification occurring before dose administration were manually set to zero. Post-dose below the lower limit of quantification values were handled using a censored likelihood approach equivalent to the M3 method [31], implemented in Phoenix WinNonlin.

For the PK model development, a one-compartment model with first-order absorption and first-order elimination was initially created after visual inspection of raw plasma concentrations of mescaline. The addition of a lag time (t_lag) to account for dissolution of the capsule after oral administration, and of a second compartment was evaluated as described above. The absorption rate constant (k_a),t_lag, apparent clearance (Cl/F), and apparent volume of distribution (V_d/F) were the primary estimated model parameters. Secondary parameters were derived as follows:k_e = (Cl/F)/(V_d/F),t_max = log (k_a/k_e)/(k_a–k_e) +t_lag,C_max = Dose/V_de^{–(ke(tmax-tlag))}, AUC = dose/(V_d/F)/k_e,t_1/2 = ln2/k_e. A multiplicative residual error model was used to account for proportional residual variability.

After fitting the PK model, a combined PK-PD model was developed. Individually estimated PK parameters were frozen for PK-PD modeling. For the PD modeling, the VAS item “any drug effect” was used as the primary outcome. A sigmoid maximum effect (E_max) model (EC₅₀,E_max) with anE_max of 100%, according to the range of VASs from 0 to 100% was selected. The addition of a steepness parameter (γ) and a first-order equilibrium rate constant (k_e0), connecting plasma concentration to a virtual effect compartment, was evaluated using the same stepwise process described above. An additive residual error model was used for the PD effects. The PK-PD model was developed primarily for the VAS item “any drug effect,” which reflects the overall effect strength. The same model structure was then applied to the VAS items “good drug effect” and “ego dissolution.” These measures include further emotional components of the experience that depend on a variety of other factors partly independent of the mescaline plasma concentration and are to be considered explorative. “Bad drug effect” and “nausea” showed a poor correlation with plasma concentrations and were not modeled. EC₅₀,k_e0, andγ were determined as primary model PD parameters. The secondary PD parameters area under the effect-time curve, maximal reached effects (E_max), time ofE_max (t_maxE), time of effect onset (t_onset), and effect duration were derived using an NCA on the model-predicted individual effect-time profiles at 10-min intervals. This NCA applied linear trapezoidal integration for calculation of the area under the effect-time curve and a threshold of 10% of the individualE_max for estimation oft_onset and effect duration. Primary and secondary model parameters were then summarized using standard statistics.

Participants

Characteristics of the participants who were included in the present study are shown in TableS1 of the ESM. Overall, 49 participants (25 female, 24 male) with a mean ± SD age of 30 ± 7 years were included in the present analysis. A total of 34 participants (69%) had prior experience with psychedelics (five ± four times).

Early vomiting occurred in eight participants (1 after 400 mg, 5 after 800 mg, and 2 after 800 mg plus ketanserin). After exclusion of these profiles, data from a total of 105 administrations remained in the final analysis.

Results from the NCA and Urinary Recovery

Urinary recovery data are provided in Table1. Over all conditions, 53% (geometric mean) of the administered dose was recovered as unchanged mescaline and 31% as TMPAA. In Study 1, the total and relative recovery of mescaline and TMPAA was nominally lower than in Study 2, where almost the complete dose was recovered. More than 50% of recovered mescaline, TMPAA, and NAM appeared in urine in the first 8 h after dose administration, with diminishing amounts at later time intervals (Table S4 of the ESM).

Both mescaline and TMPAA showed dose linearity between 100 and 800 mg (Fig.S1 and Table S2 of the ESM). Mescaline and TMPAA exhibited very similar concentration–time profiles, characterized by rapid absorption and comparableC_max,t_max, andt_1/2. This is further illustrated by individually plotting raw concentrations of both analytes (Fig. S3 of the ESM). Peak plasma concentration and AUC values of NAM were considerably lower and <10% compared with mescaline.

Model Building

A one-compartment model with first-order absorption and elimination was initially built to describe mescaline pharmacokinetics. The addition of a second compartment did not improve the visual fit, and while a significant drop in −2LL was observed in 40 out of 105 profiles, the two volumes of distribution were strongly correlated. We therefore discarded the second compartment. Adding a lag time parameter improved the visual fit aroundC_max in many profiles and led to a significant improvement in −2LL in 59 out of 105 profiles. Mean ± SD (95% CI) differences across profiles were 11 ± 12 (8.4–13) for −2LL and 8.7 ± 12 (6.4–11) for AIC, supporting the inclusion of the lag parameter in the final PK model.

For the PK-PD model, a simpleE_max model was initially evaluated, but it substantially underestimated peak effects and overestimated later responses. Adding a sigmoidicity parameter (y) greatly improved the visual fit and resulted in a significant drop in −2LL in 81 out of 91 profiles. Ak_e0 parameter was subsequently tested to account for a counterclockwise hysteresis observed in the concentration-effect data (Fig. S2 of the ESM). This addition further improved the visual fit, particularly at peak effect times, and led to a significant drop in −2LL in 74 out of 91 profiles. Mean ± SD (95% CI) differences across profiles were 30 ± 25 (20–35) for −2LL and 28 ± 25 (23–33) for AIC, favoring the inclusion ofk_e0 in the final PK-PD model.

Results from PK and PK-PD modeling

Figure1a presents the geometric mean of model-predicted mescaline concentrations over time, and Table2 summarizes the corresponding primary and secondary PK parameters. The interindividual variability of drug exposure is illustrated in overlayed individual predictions over time in Fig. S5 of the ESM. The PK model successfully captured concentration–time profiles of mescaline, and the results aligned well with the NCA (Table S2 of the ESM). Model diagnostic plots and curves of individual estimated versus observed concentrations that illustrate the visual fit are provided in Figs. S4 and S6 of the ESM, respectively.

Mean model-predicted subjective effect-time curves for single-item VAS ratings of “any drug effect,” “good drug effect,” and “ego dissolution” are illustrated in Fig.1b–d. Figure2 shows the interindividual variability of “any drug effect” by plotting individual predicted effect-time curves. Corresponding plots for “good drug effect” and “ego dissolution” are provided in Figs. S10 and S13 of the ESM. Diagnostic plots for all PK-PD models and individual curves of observed versus predicted effects over time are provided in Figs. S7–9, S11–12, and S14 of the ESM. Primary and secondary parameters of the PK-PD model are presented in Table3. In profiles where observed effects were consistently very low or remained at zero, the estimated EC₅₀ values were extreme outliers, often unreasonably high. To avoid skewing, profiles with estimated maximal effects <1% were excluded from the summary statistics for primary PD parameters. However, for the calculation of secondary PD parameters using an NCA of predicted effect-time profiles, these profiles were retained. Their low predicted effects over time were deemed valid as they predicted the zero effects and excluding them might have led to an overestimation of the effects. Again, a good alignment between acute drug effects that were predicted by the PK-PD model and those from the NCA (Table S3 of the ESM) was observed. Mean model-predicted “any drug effects” started around 1 hour after dosing, and maximal effects were reached between 1.9 (100 mg) and 4.2 h (500 mg). Maximal effect strength and effect duration for “any drug effect” increased with higher doses from 13% and 2.8 h (100 mg) to 89% and 15 h (800 mg), respectively.

Funding

Open access funding provided by University of Basel. This work was supported by the Swiss National Science Foundation (grant no. 32003B_185111 to MEL), University Hospital Basel, and Mind Medicine, Inc. The expertise and data associated with this work and owned by the University Hospital Basel were licensed by Mind Medicine, Inc. Mind Medicine, Inc., had no role in planning or conducting the present study or writing the present publication.

Conflicts of Interest/Competing Interests

Matthias E. Liechti is a consultant for Mind Medicine, Inc. Lorenz Mueller, Aaron Klaiber, Laura Ley, Anna M. Becker, Jan Thomann, Dino Luethi, and Yasmin Schmid have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

Both included trials were approved by the local ethics committee (Ethikkokmmission Nordwest- und Zentralschweiz, EKNZ) and registered at ClinicalTrials.gov (NCT04227756 andNCT04849013).

Consent to Participate

All participants provided written informed consent.

Consent for Publication

All participants provided written informed consent.

Availability of Data and Materials

The datasets presented in this article are not readily available because the data associated with this work are owned by the University Hospital Basel and were licensed by Mind Medicine Inc. Requests to access the datasets should be directed to Matthias E. Liechti,matthias.liechti@usb.ch.

Code Availability

Not applicable.

Authors’ Contributions

YS and MEL designed the studies. LM analyzed the data. LM and AK wrote the manuscript. AK, LL, and AB performed the research. JT and DL validated the analytical method and analyzed the PK samples. All authors revised and gave final approval for the manuscript.

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Supplementary Materials

Data Availability Statement

The datasets presented in this article are not readily available because the data associated with this work are owned by the University Hospital Basel and were licensed by Mind Medicine Inc. Requests to access the datasets should be directed to Matthias E. Liechti,matthias.liechti@usb.ch.