A systematic review of the pharmacokinetics of classical serotonergic psychedelic compounds in healthy adult subjects

Classical psychedelics are serotonergic compounds with a long history of human use and a renewed role in modern clinical research. However, the pharmacokinetic properties of the main compounds remain incompletely characterised, and the existing literature has been fragmented across compound-specific reviews and a limited number of studies. The paper notes that understanding absorption, distribution, metabolism, and elimination is important because these features shape both subjective effects and practical considerations for clinical use. Hampsey and colleagues therefore set out to provide a systematic review of the pharmacokinetics of the main classical serotonergic psychedelics in healthy adults. Their aim was to synthesise available blood-based pharmacokinetic data for LSD, psilocybin/psilocin, DMT, mescaline, and 5-MeO-DMT, and to compare compounds and routes of administration where the evidence allowed. The review was framed as timely given the increasing number of clinical trials and the prospect of regulatory decisions for some psychedelics.

The researchers conducted a PRISMA-guided systematic review, which was also pre-registered on PROSPERO. They searched Embase, Medline, Global Health, and APA PsycINFO, and also used Google Scholar and reference lists of included papers. The search covered studies up to 1 October 2023, followed by supplementary searches from 1 October 2023 to 1 September 2025. There were no restrictions on publication region, language, or format. Eligible reports were prospective trials in healthy adults over 18 years of age that administered a single classical psychedelic substance and reported at least one blood pharmacokinetic parameter. The substances included LSD, N,N-DMT, 5-MeO-DMT, psilocybin, and mescaline. The review excluded studies with coadministered compounds, participants with psychiatric conditions, medical illnesses, or substance misuse, reports not available in English, and studies reporting only urinary or saliva measurements. The screening process used Rayyan, with duplicates removed in a staged fashion and eligibility assessed in two stages by pairs of independent, blinded raters. Data extraction was also performed independently by paired reviewers using a predefined proforma, with disagreements resolved by a third rater. The researchers extracted standard pharmacokinetic outcomes, including C max (maximum concentration), T max (time to peak concentration), half-life, clearance, volume of distribution, and AUC (area under the concentration-time curve). Missing data were not imputed. If dose was reported as mg/kg, it was converted to mg using an assumed 70 kg body weight, and other measures were standardised to common units where possible. For the quantitative presentation, the researchers used Python-based tools for data handling and visualisation. Confidence intervals for the dose-proportionality analyses were generated using bootstrapping with 1000 iterations, and regression lines with confidence bands were overlaid on scatterplots. The extracted text does not clearly describe a formal risk-of-bias tool or a full meta-analytic pooling model beyond these descriptive and regression-based summaries.

The review included 32 eligible trials. LSD was the most studied compound, followed by DMT, which was represented in both intravenous and oral forms. Psilocybin was also frequently studied. Mescaline appeared in only two eligible studies, and 5-MeO-DMT was represented by two trials, one inhaled and one intranasal. IV LSD and IV psilocybin were each reported in a single trial arm. For oral LSD, the review identified 431 administrations across 23 trial arms. Sample sizes ranged from 3 to 39 participants, with 59.5% male participants overall. Doses ranged from 0.005 to 0.200 mg. C max ranged from 0.151 to 4.30 ng/mL, T max from 0.5 to 2.0 hours, and half-life from 2.5 to 8.25 hours. AUC and clearance values showed wide ranges, and the authors noted substantial interindividual variability. For oral psilocybin, which was discussed in terms of psilocin exposure, there were 220 administrations across 12 trial arms. Sample sizes ranged from 6 to 32, with 65.0% male participants. Doses ranged from 11.9 to 46.9 mg. Psilocin C max ranged from 8.2 to 37.6 ng/mL, T max from 1.3 to 3.7 hours, and half-life from 1.8 to 3 hours. Compared with LSD, psilocin showed more rapid elimination, although variability in peak concentrations remained marked. IV DMT was administered 254 times across 16 trial arms, with sample sizes ranging from 5 to 27 and 55.4% male participants. Session durations were much shorter than for oral psychedelics, ranging from 2 to 10 hours. The review notes that IV dosing could be delivered as a continuous infusion, a bolus, or both. The results text does not provide one consolidated set of numerical ranges for all IV DMT parameters in the same way as for the oral compounds, but it states that peak plasma concentrations increased proportionally with infusion rate and that the elimination half-life was short. Oral DMT was reported 63 times across 5 trial arms. Sample sizes ranged from 8 to 15 and 77.4% of analysed participants were male. Doses ranged from 35.5 to 217 mg. C max ranged from 4.50 to 17.4 ng/mL, T max from 1.14 to 1.79 hours, and half-life from 0.52 to 4.32 hours. Clearance and volume of distribution were very large and variable, reflecting the complexities of oral bioavailability. Mescaline was reported in only two studies, with 96 administrations across 6 trial arms. Each arm had 16 participants, sex was balanced at 50%, and mean age was 31.7 years. Doses ranged from 100 to 800 mg. Mescaline C max ranged from 298 to 1721 ng/mL, T max from 1.6 to 2.3 hours, and half-life from 3.5 to 3.7 hours. The authors highlighted the very limited size of this evidence base. Two studies examined 5-MeO-DMT. One inhalation study included 22 participants in a 4-arm escalating dose design, and one intranasal study included 31 participants in a 7-arm escalating dose design. For intranasal 5-MeO-DMT, doses ranged from 1 to 12 mg, C max from 5.90 to 32.3 ng/mL, T max from 0.07 to 0.25 hours, and half-life from 0.25 to 0.44 hours. The inhalation study reported only C max, which ranged from 0.20 to 0.97 ng/mL. Overall, the available data suggested very rapid onset and elimination. For the single IV LSD tartrate arm, 0.080 mg slow infusion produced a median C max of 5.94 ng/mL at 0.16 hours, with a half-life of 3.8 hours and clearance of 4.7 L/hour. For the single IV psilocybin arm, 1.00 mg bolus dosing produced psilocin C max of 12.9 ng/mL at 0.03 hours, with a half-life of 1.24 hours and clearance of 187.6 L/hour. These were small, experimental samples rather than established clinical regimens. Across compounds, the authors report that LSD showed consistent absorption patterns but substantial interindividual variability in most pharmacokinetic parameters. Psilocybin/psilocin was characterised by faster elimination than LSD, with extensive tissue distribution. IV DMT showed a short half-life and a dose-response relationship between infusion rate and peak concentration. Oral DMT differed substantially from IV DMT and was described as especially variable because oral absorption depends on monoamine oxidase inhibition. Mescaline had slower peak effects and a longer session duration than LSD or psilocin, while 5-MeO-DMT showed very rapid peak concentrations and elimination.

The authors interpret the findings as showing meaningful differences in absorption, distribution, and elimination across the main classical psychedelics, with important implications for both research and clinical use. They describe LSD as having a broadly consistent absorption profile but high interindividual variability, which they suggest may partly reflect pharmacogenetic differences in metabolic capacity. They also note that psilocybin/psilocin appears to clear more rapidly than LSD, DMT has a much shorter half-life than LSD, and mescaline and 5-MeO-DMT each have distinct kinetic profiles that may influence the duration and intensity of their effects. Relative to earlier research, the authors state that their review provides a more comprehensive synthesis than previous narrative or compound-specific reviews. They highlight that oral DMT is difficult to characterise accurately because its bioavailability depends on monoamine oxidase inhibition and because coadministration frequently induces emesis, which complicates pharmacokinetic estimation. They also point out that mescaline remains the least studied of the classical psychedelics in contemporary clinical research, despite its historical importance. The authors acknowledge several limitations. The evidence base was small for some compounds, especially mescaline and 5-MeO-DMT, and some formulations were represented by only a single trial arm. The studies were mostly small, with variable sample sizes, dose ranges, and session durations. The extracted text also indicates that not all studies reported the full set of pharmacokinetic parameters, particularly for some DMT and inhaled 5-MeO-DMT data. The authors further note that the high variability observed across compounds and participants limits generalisability. In terms of implications, the authors suggest that understanding these pharmacokinetic differences may be useful as psychedelics move towards licensing decisions and broader clinical implementation. They imply that route of administration and compound selection may need to be considered carefully in both trial design and future therapeutic use. They also indicate that larger studies, including planned patient trials for 5-MeO-DMT, will be needed to clarify the pharmacokinetics and practical significance of several compounds.

The authors conclude that their systematic review provides an up-to-date and comprehensive synthesis of pharmacokinetic data for the main classical serotonergic psychedelics in healthy adults. They state that the comparisons across compounds and routes of administration may help readers judge whether, and how, these drugs could have clinical applicability as the field moves towards regulatory decisions.