A phase 1, dose-ranging study to assess safety and psychoactive effects of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in healthy volunteers

The extracted text does not include a discrete Introduction or a full Methods section. However, the available material (abstract and results/conclusion text) indicates this was a Phase I, dose-ranging study in healthy volunteers (total n = 22) designed to assess safety, tolerability and dose-related psychoactive effects of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation. Participants received single inhaled doses of 2 mg (N = 4), 6 mg (N = 6), 12 mg (N = 4) and 18 mg (N = 4), and a separate group (N = 4) received an individualized dose escalation (IDE) regimen in which participants received successive inhalations until a peak experience was reached. The psychedelic experience was evaluated with a newly developed Peak Experience Scale (PES) and with validated questionnaires: the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness questionnaire (5D-ASC). Cognitive functioning, mood, and well‑being were assessed at baseline, approximately 2 hours after dosing, and at a 7‑day follow up. Vital signs were measured at baseline and at 1 and 3 hours post‑administration. Blood concentrations of 5-MeO-DMT were measured, although the extracted text notes limited pharmacokinetic detail. For statistical analysis, the researchers conducted ANOVAs and generalized linear model repeated‑measures ANOVAs. For measures of the psychedelic experience they used a single‑factor Dose ANOVA with five levels (2, 6, 12, 18 mg and IDE). For cognitive and subjective well‑being measures they used Dose (5 levels) × Time (Baseline, post‑administration, 7 days) models. Vital signs were analysed with Dose × Time (Baseline, 1 h, 3 h) repeated‑measures ANOVAs. Planned contrasts used the 2 mg group as the reference. The alpha criterion was p < 0.05 and the Greenhouse‑Geisser correction was applied when sphericity was violated. Analyses were exploratory and carried out in IBM SPSS Statistics for Windows, Version 26.0. The extracted text does not clearly report other procedural details such as randomisation, blinding, full inclusion/exclusion criteria, or the precise stepwise protocol for the individualized escalation beyond descriptive outcomes.

Dose-related changes in self‑reported psychedelic effects were observed. Higher doses of inhaled 5-MeO-DMT produced significant increases in the intensity of psychedelic experience ratings compared with the lowest 2 mg dose across most instruments, with the exception of the CEQ (challenging experiences), which was not affected by Dose. Planned contrasts consistently indicated higher mean ratings at higher doses versus 2 mg. For the PES and MEQ, all active dose groups showed significantly higher ratings than the 2 mg group. EDI and 5D-ASC ratings generally differed from the 2 mg group after the individualized dose escalation condition. A peak experience, defined as a PES rating ≥75%, was reported by eight participants in total: one participant in the 6 mg group, two in the 12 mg group, one in the 18 mg group, and all four participants in the individualized dose escalation group. During individualized escalation, peak experiences were reached at different steps for different participants: in one person after a single 6 mg inhalation, in two participants after inhalations of 6 and 12 mg, and in others after successive inhalations up to 18 mg. The researchers emphasise pronounced inter‑individual variability in the dose required to achieve a peak experience. Measures of cognition, mood, and subjective well‑being did not show significant changes at 2 hours or at 7 days post‑dose compared with baseline. Vital signs measured at 1 and 3 hours post‑administration were not affected by dose. Adverse events were generally mild and resolved spontaneously. Blood concentrations of 5-MeO-DMT were reported to be low at 1 hour and barely measurable at 3 hours after administration, suggesting rapid metabolism and elimination, but the extracted text notes that the study provides limited pharmacokinetic information. All analyses were described as exploratory in nature.

The researchers interpret their findings as indicating that inhaled GH001 (5-MeO-DMT) elicits dose‑dependent increases in the magnitude of psychedelic experience in healthy volunteers, while causing little distress (low CEQ and anxious ego dissolution ratings). Individualised dose escalation produced the largest and most consistent occurrence of peak experiences, suggesting it may be an efficient way to tailor dosing to individual sensitivity when the clinical aim is to maximise the acute psychedelic experience. The authors introduce the PES as a brief, pragmatic instrument targeting intensity, loss of control and profoundness; they report that PES captured peak experiences in individuals sometimes not identified as having a complete mystical experience by the longer MEQ, EDI or 5D-ASC scales. They note that the PES may be a useful rapid clinical tool but that further validation and comparative performance data are required. Safety and tolerability findings are emphasised: 5-MeO-DMT produced short‑lasting psychoactive effects with no detectable short‑ or longer‑term changes in cognitive or psychomotor function measured at 2 hours and 7 days, and no clinically relevant changes in vital signs at 1 and 3 hours. The low blood concentrations at 1 and 3 hours support rapid elimination and a lack of accumulation after successive doses, although the authors acknowledge that the present data give limited information on full pharmacokinetic profiles and that dedicated pharmacokinetic studies are needed. The authors position their results relative to earlier observational work describing high inter‑individual variability in psychoactive effects and reports of therapeutic benefit in naturalistic settings. They caution that Phase I studies are exploratory and that the current findings require replication in larger samples. They also note that while the magnitude of the psychedelic experience has been associated with therapeutic response for other tryptamines, confirmation of therapeutic efficacy for 5‑MeO‑DMT will require prospective trials in clinical populations; a Phase I/II trial in treatment‑resistant depression (GH001‑TRD‑102; NCT04698603) is cited as ongoing. Limitations acknowledged by the authors include the small sample size, exploratory nature of analyses, and limited pharmacokinetic characterisation.

The researchers conclude that single inhaled doses of 6, 12 and 18 mg GH001 produced peak psychedelic experiences in a minority of healthy participants, whereas an individualized dose escalation regimen produced a peak experience in all participants in that group. Measures of cognition, mood and well‑being were not affected acutely or after 7 days, vital signs were unchanged at 1 and 3 hours, and adverse events were generally mild and self‑limiting. The data suggest substantial inter‑individual variability in the dose required to reach a peak experience and support individualized dose escalation as a practical approach to reliably elicit peak experiences in clinical settings. The authors emphasise the need for replication in larger samples and further validation of the PES and pharmacokinetic characterisation in future studies.