A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

The researchers randomised 48 healthy participants into six single-ascending-dose cohorts. Dose assignments in the extracted Methods text were: 0.34 mg (n = 4), 1 mg (n = 6), 3.3 mg (n = 6), 10 mg (n = 6), 15 mg (n = 6) and 20 mg (n = 6). In total, 34 participants received GM-2505 and 14 received placebo. Two participants in the placebo group were excluded from pharmacodynamic (PD) analyses because they did not complete all measurements. The extraction refers to participant demographics in a Table and to a CONSORT diagram in a supplement, but those items are not reproduced here. The trial is described in the extracted text as a single-ascending-dose, randomised study with placebo participants. The Methods text in the extraction does not clearly report some procedural details (for example, specific inclusion/exclusion criteria, the route of administration, or whether the study was blinded), and these details appear to be reported elsewhere in the full paper or supplements. Pharmacokinetic (PK) endpoints were obtained by non-compartmental analysis of plasma concentration–time data using the PKNCA package in R. Repeatedly measured PD outcomes were analysed using mixed-model analyses of covariance with fixed effects for treatment, time and treatment-by-time interaction, participant as a random effect, and baseline as a covariate. Least-square mean estimates over time by treatment were presented with 95% confidence intervals. Treatment effects were assessed as contrasts between placebo and each GM-2505 dose. The trial was exploratory and not prospectively powered for formal hypothesis testing; reported P-values (α = 0.05) are described as nominal and no corrections for multiple comparisons were made. Variables were log-transformed when appropriate. All PD calculations except electroencephalography (EEG) were performed in SAS. EEG was evaluated in a post-hoc analysis using a linear mixed-effects model (MATLAB fitlme) with fixed effects for dose, time and their interaction and random intercepts for subjects; each dose was contrasted with placebo at each time point.

The extracted Results text focuses on how safety, PK and PD data were summarised and analysed rather than presenting detailed numerical outcome data. Categorical outcomes (for example, adverse events) were summarised as counts and percentages. Continuous measures (for example, ECG, blood pressure and PK parameters) were summarised using descriptive statistics including means, change from baseline (CFB), standard deviation and coefficients of variation. PK endpoints were derived by the non-compartmental approach noted above. Repeated PD measures were analysed with the mixed-model ANCOVA framework; least-square mean estimates with 95% confidence intervals were generated and treatment contrasts versus placebo were reported. The authors note that the trial was exploratory, P-values are nominal, and no multiplicity correction was applied. EEG analyses were performed post hoc with a linear mixed-effects model testing dose effects at each time point against placebo. The extracted Results section does not include the specific numerical findings, frequencies of adverse events, PK parameter values (beyond the analytic approach), or PD effect sizes. The extraction refers to summary tables and supplementary material (for participant characteristics and a CONSORT diagram) that are not included in the provided text, so the precise results are not reproducible from this extraction alone.

The extracted Conclusion reports preclinical in vitro and in vivo pharmacology for GM-2505 and refers to supporting methods in a supplemental section. According to the extracted text, GM-2505 acted as a potent agonist at 5-HT2A and 5-HT2C receptors in Ca2+ flux assays. The extracted EC50 values and maximal activation percentages reported in the text are: 5-HT2A — 17 nM, 82% activation; 5-HT2C — 9.5 nM, 85% activation. By contrast, GM-2505 showed minimal agonist activity at 5-HT2B (reported as >10,000 with 0.8% activation) and a high EC50 at 5-HT1A (reported as 16,918 nM with 83% activation). The extraction contains an unclear parenthetical remark about units (μM versus nM) and possible transcription artefacts; the precise units for the >10,000 figure are not clearly reported in the extracted text. In a rat synaptosome assay, GM-2505 reportedly increased serotonin (5-HT) release with an EC50 of 12.9 nM; the extraction compares this to DMT in the same assay (EC50 84.7 nM). In C57BL/6 mice, GM-2505 produced a dose-dependent head-twitch response (HTR) with an ED50 of 0.3 mg/kg subcutaneously (95% CI: 0.21–0.41). The extracted Conclusion indicates these in vitro and in vivo findings support the compound's engagement of 5-HT2A/2C-related pharmacology, and that detailed methodology is provided in the supplemental material, but does not include additional interpretation or clinical data in the provided text.