Introduction

Psychedelic agents are distinguished from other classes of psychoactive drugs by their ability to induce intense mental effects on sensory processing, emotion, and various cognitive processes. These substances primarily affect serotonin receptors, involved in mood, perception, and cognition [1]. Unlike other psychoactive substances, they do not promote compulsive use or induce withdrawal syndrome [2] and can produce lasting positive effects in both healthy individuals and psychiatric patients [3].

Classical serotonergic psychedelics, including N, N-dimethyltryptamine (DMT), 5-methoxy-DMT, lysergic acid diethylamide (LSD), and psilocybin, have been used in medicine, religious ceremonies, and rituals. These compounds alter perception and mood by acting as 5-HT2A receptor agonists, without impairing memory or causing delirium, dependence, or addiction [1]. Psychedelics are increasingly recognized for their potential to treat anxiety, depression, post-traumatic stress disorder, obsessive-compulsive disorder, and substance abuse disorder [3,4,5,6,7,8].

Their therapeutic use is categorized into macrodoses, which induce full psychedelic experiences with therapeutic benefits, and microdoses, which involve subperceptual amounts offering subtle long-term benefits like improved mood and anxiety without acute effects [9,10,11,12]. Microdosing is attracting increasing interest for its compatibility with daily activities and broader tolerability [11, 12].

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a tryptamine psychedelic traditionally used by indigenous South American communities and has gained popularity in both recreational and therapeutic contexts [13]. 5-MeO-DMT acts as a fast-acting agonist of serotonin 5-HT1A/5-HT2A receptors in the human brain [8] and is four to ten times more potent than DMT, with a higher affinity for the 5-HT1A receptor [14]. Orally inactive due to metabolism by monoamine oxidase (MAO) enzymes in the gut and liver [14], 5-MeO-DMT is typically administered parenterally via inhalation, intravenous, intramuscular, rectal, sublingual, or intranasal routes [15]. Regardless of the administration route, its effects have a rapid onset and short duration, inducing distortions in perception, emotional intensification, and ego dissolution. The intensity and nature of these effects vary based on dosage, administration method, and individual response [13, 15, 16].

While growing evidence supports the efficacy of psychedelics such as psilocybin, ayahuasca, and LSD for treating psychiatric disorders [4, 17,18,19,20,21,22,23,24], clinical evidence for 5-MeO-DMT is limited to a few clinical trials [6,7,8, 13], anecdotal reports and observational studies in natural environments [5, 15, 25]. Unlike longer-acting psychedelics like psilocybin or LSD [9, 26, 27], 5-MeO-DMT has a rapid onset and brief duration [6, 7, 25], making it potentially suitable for patients less tolerant of prolonged experiences. Its pharmacological profile makes sublingual administration a non-invasive, standardized alternative to inhalation or intravenous routes

To our knowledge, this is the first clinical trial to systematically evaluate the safety, tolerability, pharmacokinetics, and subjective effects, such as perceptual changes, mood alterations, and ego dissolution, of a novel sublingual 5-MeO-DMT formulation administered repeatedly under controlled clinical conditions (NCT06816667). In a double-blind, placebo-controlled design, adults with moderate to high levels of anxiety and/or depression, but without formal psychiatric diagnoses or current treatment, received single weekly doses over four consecutive weeks in one of four parallel groups (6 mg, 9 mg, 12 mg, or placebo).

Previous studies have suggested that doses below 15 mg elicit perceptible yet sub-psychedelic effects, minimizing cognitive or perceptual disruption [6,7,8]. The aim of this study was to identify sub-psychedelic doses that could be safely and repeatedly administered, offering a potential therapeutic opportunity for individuals with mood disorders or reduced well-being. We identified the minimum effective dose capable of producing neurophysiological and psychological changes, while maintaining a favorable safety and tolerability profile. Our findings highlight that 5-MeO-DMT is a safe, fast-acting psychedelic therapy, with sublingual administration improving dose precision, adherence, and feasibility for repeated or outpatient use.

Materials and methods

5-Methoxy-N, N-dimethyltryptamine sublingual formulation

BMND08 is a psychedelic compound from the tryptamine class, specifically 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), free base, CAS No.: 1019-45-0, developed by Mindcore, Biomind Labs (Biomind Labs | Next-Gen Pharma). BMND08 is a research drug product featuring a proprietary sublingual formulation of highly pure, GMP-certified, pharmaceutical-grade 5-MeO-DMT. This sublingual formulation is designed for rapid absorption and controlled delivery. Refer to Supplementary information for detailed product specifications (Supplementary Material I).

Participants

Participant enrollment occurred between October and December 2024, with primary outcome assessments completed by February 2025. Recruitment was conducted via social media and personal invitations (Fig. 1). Eligible participants were adult volunteers aged 40–80 years, who provided written informed consent. They were required to exhibit moderate to high anxiety and/or depression, as measured by the STAI ( ≥20 on both STAI-S and STAI-T) and Beck Depression Inventory (BDI ≥21), but without a confirmed psychiatric diagnosis. A comprehensive clinical and psychiatric evaluation was conducted before enrollment to ensure eligibility and exclude participants who required immediate psychiatric treatment. Participants were instructed to abstain from nicotine for at least two hours, maintain their usual caffeine intake, and avoid alcohol and psychoactive substances for 24 h before and after each session. Exclusion criteria included the use of benzodiazepines, tricyclic antidepressants, stimulant medications (e.g., amphetamines), serotonin-affecting drugs (e.g., ondansetron), or monoamine oxidase inhibitors (MAOIs) within 90 days before enrollment (Supplementary Material II). A total of 114 individuals were screened, 72 were excluded for not meeting the inclusion criteria outlined in Supplementary Material II, and 42 met initial eligibility. Two were disqualified after further evaluation, resulting in 40 enrolled participants, randomized into four groups (n = 10 per group). Four participants dropped out, leaving 9 per group for final analysis (Fig. 1A).

Fig. 1: CONSORT diagram depicting participant flow and schematic timeline of Phase I trial procedures.
figure 1

A Following the prescreening questionnaire, participants were excluded for the following reasons: current antidepressant use (n = 28), residing beyond a reasonable commuting distance (n = 2), declining in-person screening (n = 14), medical conditions (n = 6), not meeting the minimum scores on anxiety or depression scales (n = 15), or being below the minimum age requirement (n = 7). B During in-person screening, two participants (n = 2) were excluded due to a high risk of suicidality. C Timeline of the Phase I trial session (180 min): Participants underwent blood sampling, EEG recordings (baseline and post-dose) (45 min), subjective effect assessments (PES, EDI, MEQ), psychiatric interviews (30 min), neurocognitive testing (30 min), vital sign measurements, and ECG (30 min).

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Study design

The Phase I study employed a randomized, double-blind, placebo-controlled design with four parallel dose arms. Thirty-six adults (21 females, 15 males; aged 41–76) with moderate symptoms of depression and anxiety were randomly assigned to receive placebo or 5-MeO-DMT at 6 mg, 9 mg, or 12 mg (n = 9 per group). Each participant received a single weekly sublingual dose for four consecutive weeks (Fig. 1B). Recruitment strictly adhered to the inclusion criteria, and eligibility required no prior psychedelic experience with tryptamines, ergolines, or phenethylamines. Detailed exclusion criteria are in Supplementary Material II.

Measurements were taken at baseline (Week 0), during the dosing weeks (Weeks 1–4), and at the end of the study (Week 5) to assess safety, toxicity, tolerability, and pharmacokinetics of the sublingual 5-MeO-DMT administration. These assessments included electroencephalograms (EEG), pharmacokinetic analysis, electrocardiograms (ECG), biochemical determinations, cardiovascular assessments, neurocognitive evaluations, and psychiatric questionnaires/scales. The timeline of study sessions is illustrated in Fig. 1C. Validated instruments were used to evaluate the sub-psychedelic experience, focusing on ego dissolution, mystical experiences, and the intensity of the experience. The study followed Good Clinical Practice (GCP), ethical standards of the Declaration of Helsinki (1964), and national regulations under the Argentine Constitution (1994), ensuring patient rights in accordance with ANMAT Disposition 5330/97. The study was approved by the ethics committee (CEI) of the Ministry of Health of San Juan, Argentina (Supplementary Material I). The research was conducted at Dr. Marcial V. Quiroga Hospital, Government of San Juan, by a multidisciplinary team specializing in Neurology, Neuropsychology, Psychiatry, Cardiology, Biochemistry, Pharmacology, and Bioengineering.

Safety

To evaluate the safety, toxicity, and tolerability of sublingual doses of 12 mg, 9 mg, and 6 mg of 5-MeO-DMT, this study monitored vital signs (blood pressure, heart rate, oxygen saturation, respiration rate, body temperature, and ECGs) over six weeks (weeks 0–5).

Biochemical assessments included markers for hematological, renal, hepatic, cardiac, and cellular functions, such as red blood cells, glucose, cortisol, serum creatinine, cholesterol, HDL, LDL, triglycerides, AST, ALT, lactate dehydrogenase (LDH), creatine kinase (CK), CK-MB, and C-reactive protein. Blood and urine samples were collected during the six-week treatment period (Weeks 0–5) after at least 8 h of fasting, before 5-MeO-DMT administration, were immediately centrifuged and analyzed within the same day, with plasma stored at −80 °C for long-term analysis. Adverse events were documented at every visit and during phone calls from the start of the study until its conclusion in week 5, with events being coded according to the Medical Dictionary for Regulatory Activities (MeDRA), version 27.0 [28]. Cognitive function was assessed using verbal fluency tests (FAS) [29], the Paced Auditory Serial Addition Test (PASAT) [30], and the Digit Span Sequencing test (DSS) [31]. Detailed descriptions of cognitive scales are in the Supplementary Information (Supplementary Material II).

Electroencephalogram (EEG) recording, processing and analysis

Participants were given instructions to avoid thinking about anything specific, to remain awake, and to minimize unnecessary eye blinking and body movement. Resting state EEG activity was recorded over a total duration of 45 min beginning with 5 min of baseline recording with eyes closed, followed by 38 min post-administration with eyes closed, and concluding with 2 min with eyes open. EEG data were recorded using an AKONIC BIO-PC system (sampling rate: 256 Hz; pass-band: 0.5–100 Hz). The electrodes were positioned at standard 10–20 locations, with reference and ground electrodes placed at FCz and AFz sites, respectively. The level of [U1] consciousness assessed was wakefulness. The EEG was digitally filtered using a bidirectional low-pass Butterworth filter with a cut-off frequency of 42 Hz. This allowed the evaluation of EEG rhythms and the elimination of 50 Hz line interference. The power spectral density (PSD) of the EEG recording was estimated using Welch’s periodogram. A Hann window was used, in continuous 4-s segments with 50% overlap [32,33,34].

Pharmacokinetics

For pharmacokinetic analysis, EDTA blood samples of approximately 6 mL were obtained to assess a sublingual dose of 12 mg of 5-MeO-DMT. Samples were collected pre-dose (0 min) and post-dose at 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, and 120 min. Pharmacokinetic quantification was performed using a high-resolution MS UHPLC system, specifically the Thermo Dionex Ultimate 3000 with a PDA detector controlled by Chromeleon 7.2 software (Thermo Fisher Scientific, Waltham, MA, USA), coupled with a Thermo Q-Exactive MS focus (Thermo, Bremen, Germany), and utilizing a UHPLC C18 column operated at 25 °C [35, 36]. Pharmacokinetic parameters for 5-MeO-DMT were estimated using non-compartmental analysis based on the average plasma concentration-time profiles. Key parameters included the peak plasma concentration (Cmax) and the time to reach this peak (Tmax), as well as the area under the curve (AUC) for total drug exposure, half-life (t1/2), clearance (Cl), and the apparent volume of distribution (Vd). These parameters were reported as mean ± standard deviation (SD) [27].

Acute subjective ratings of psychedelic effects

To determine the intensity of the acute effects experienced by subjects, retrospective ratings were collected 1 h after 5-MeO-DMT exposure. Subjective ratings included the Peak Experience Scale (PES) [6], the Ego Dissolution Inventory (EDI) [37] and the Mystical Experiences Questionnaire (MEQ) [38, 39]. For detailed descriptions of the rating scales, see Supplementary Information (Supplementary Material I).

Statistical analysis

Statistical analysis of the data was performed using GraphPad Prism 10 software (USA). All variables were evaluated using appropriate descriptive statistics, including means, standard deviations (SD), standard errors of the mean (SEM), medians, ranges, and frequencies. In all cases, normal distribution of the data was verified using the D’Agostino normality test or the Pearson K2 test. The student’s t test (two-tailed), Mann–Whitney U test, or Wilcoxon test was used for comparisons between two groups, as appropriate. For comparisons among three or more groups, data that met the normality criteria were analyzed using ANOVA, repeated measures ANOVA, while data that did not meet normality were analyzed using the Kruskal-Wallis or Friedman test. Linear mixed-effects models were applied to analyze subjective experiences (PES, EDI, MEQ-30), with dose group as a fixed effect, week as a repeated measure, and subject ID as a random intercept, using the lme4 package in R. Numerical data are presented as mean ± SEM, and categorical data are presented as frequencies or percentages. Statistical significance was determined using a threshold of p < 0.05. Pharmacokinetic analysis was performed using a non-compartmental method implemented in R software with the PK package.

Results

Demographics, safety, toxicity and tolerability

The study enrolled 36 volunteers (15 males and 21 females), presenting moderate symptoms of anxiety and depression, randomly assigned to four groups: a placebo group and three groups receiving doses of 5-MeO-DMT (6 mg, 9 mg, and 12 mg) with a weekly dosing regimen over four consecutive weeks. All participants completed the study (Fig. 1B). The participants’ age ranged from 41 to 76 years, and their Body Mass Index (BMI) was measured at baseline (week 0) and again at the end of the 4-week dosing period (week 5). No significant changes in BMI were observed across groups, indicating that the dosing regimen did not affect anthropometric parameters (dependent t test, p > 0.05 in each group). Participants’ demographic and anthropometric data are summarized in Table 1.

Table 1 Demographics and acute adverse events reported with a relationship to the drug (placebo and 5-MeO-DMT) sublingual administration.
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Safety, toxicity, and tolerability were evaluated through the assessment of treatment-emergent adverse events (AEs), vital signs, ECG parameters, and biochemical markers. AEs were defined as those that developed or worsened from the start of 5-MeO-DMT or placebo administration up to the last study visit (week 1 to week 5) and were coded according to the Medical Dictionary for Regulatory Activities (MedDRA 27.0) (Table 1). No serious adverse events leading to study discontinuation occurred, and all AEs were mild (Grade 1), including nausea, headache, muscle discomfort, increased heart rate, and dizziness, all of which resolved spontaneously without corrective treatment. A total of 19 AEs were documented, with the highest incidence in the 12 mg group, accounting for 12 events (63%). The full list of AEs is provided in Table 1. There were no clinically meaningful findings in vital sign measurements (Blood Pressure, Heart Rate, Respiratory Rate, O2 Saturation, Temperature, or ECG) (Supplementary Table I) or in hematological and biochemical values. No significant abnormalities were observed in metabolic function, electrolytes, renal, or liver function (Supplementary Table II).

Neuropsychological tests, measuring semantic and phonological verbal fluency (FAS) and processing speed (PASAT), were administered 90 min after each dose of 12 mg, 9 mg, or 6 mg of 5-MeO-DMT, as well as placebo. No adverse effects on cognitive and executive functions, such as working memory, attentional control, and inhibitory control, were observed at any of the administered doses of 5-MeO-DMT (Supplementary Table III).

Pharmacokinetics

Pharmacokinetic analysis was conducted exclusively in the 12 mg 5-MeO-DMT group using non-compartmental methods (Fig. 2). The maximum plasma concentration (Cmax), the time taken to reach Cmax (Tmax), the area under the curve (AUC), the elimination half-life (t½), the clearance (CL), and the apparent volume of distribution (Vd) were obtained from the concentration-time curve (Fig. 1B). The sublingual dose of 12 mg of 5-MeO-DMT was absorbed with a median Tmax of 20 min post-dose across all volunteers. After reaching a Cmax of 2.23 µg/L, 5-MeO-DMT was then eliminated with a mean t½ of 28.15 min across all volunteers. The area under the curve (AUC) was 105.36 µg·min/L, indicating the total drug exposure over the specified period, quantifying both the extent and duration of the drug presence in the plasma. The clearance (CL) was 0.11 L/min, reflecting the rate at which the drug is removed from the plasma, and the apparent volume of distribution (Vd) was 4.63 L, indicating the degree of drug dispersion throughout the body’s tissues. Our findings suggest that sublingual doses of 12 mg of 5-MeO-DMT demonstrated rapid absorption, efficient clearance, and substantial distribution throughout body tissues, supporting its potential for achieving quick systemic effects with minimal accumulation in the body.

Fig. 2: Plasma concentration–time curve following sublingual administration of 12 mg 5-MeO-DMT.
figure 2

A Schematic representation of the pharmacokinetic curve (mean ± SD) vs. time (min). B Pharmacokinetic parameters include a mean maximum observed plasma concentration (Cmax) of 2,23 µg/L, time to reach Cmax (Tmax) of 20 min, an area under the plasma concentration-time curve (AUC) of 105.36 µg·min/L, an elimination half-life (t½) of 22.15 min, an apparent total clearance (CL) of 0.11 L/min, and a volume of distribution (Vd) of 4.63 L.

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Acute psychedelic experience

Analysis of psychedelic experiences following acute consumption revealed no statistically significant weekly differences in intensity of experience scores (PES) (Fig. 3A–D), ego dissolution (EDI) (Fig. 3E–H), or mystical experiences (MEQ-30) (Fig. 3I–L) within each group (Kruskal-Wallis, p > 0.05).

Fig. 3: Acute psychedelics experience.
figure 3

The figure illustrates the Mean ± SEM ratings per week for each dose group. A–D PES (cutoff point = 75), E–H (EDI), and I–L MEQ (cutoff point = 60). Throughout the 4-week consumption period, scores remained below the thresholds for psychedelic experiences, with no adverse effects on consciousness, perception, or daily functioning. Significant differences were observed between the 12 mg and placebo group for all scales during week 1 (A, E, I) and week 2 (B, F, J) (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05). The 9 mg group exhibited significantly higher scores compared to the placebo group on the PES in week 1 (B) and on the MEQ-30 scales in both week 1 and week 2 (I, J). During weeks 3 and 4, no significant intergroup differences were found on the PES (C, D), EDI (G, H), and MEQ (K, L) scales across any of the dose groups. The dashed line marks the threshold for a psychedelic experience on the PES and MEQ scales.

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As shown in Fig. 3, participants’ scores on the PES and MEQ during the 4-week consumption period remained consistently below the established cutoff points for a significant psychedelic experience (average PES < 75, MEQ < 60), reflecting lower intensity, diminished sensation of loss of control, and reduced depth of experience. The EDI data revealed a consistent reduction in concerns throughout the 4-week consumption period. Importantly, no experiences negatively affected awareness, sensory perception, daily activities, or social behavior.

Intergroup comparisons, the 12 mg group exhibited significant differences compared to the placebo group for all three scales during both week 1 (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05) (Fig. 3A, E, I) and week 2 (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05) (Fig. 3B, F, J). The 9 mg group had significantly higher scores compared to the placebo group on the PES during week 1 (Fig. 3B) and on the MEQ during both the first and second weeks (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05) (Fig. 3I, J). No significant differences were found between the 6 mg group and the placebo group across all three scales over the 4 weeks of consumption (Kruskal-Wallis test, p > 0.05). Additionally, intragroup analyses revealed a significant reduction in EDI scores between weeks 2 and 4 within the 12 mg group (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05), and in MEQ scores between weeks 2 and 3, as well as weeks 2 and 4 within the 9 mg group (Kruskal-Wallis test, Dunn’s Multiple Comparison Test, p < 0.05).

Linear mixed-effects models were used to assess changes in subjective psychedelic experiences over time, with dose as a fixed effect, week as a repeated measure, and subject ID as a random intercept. The analysis revealed significant dose-by-week interactions across PES, EDI, and MEQ-30 scores, indicating distinct temporal trajectories by dose. The 12 mg group exhibited the strongest effects, with increased scores in PES (β = 30.64, p < 0.001), MEQ (β = 23.56, p < 0.01), and EDI (β = 25.34, p < 0.01) during weeks 1 and 2. Post-hoc comparisons confirmed significantly higher MEQ and PES scores at both time points compared to placebo (p < 0.05). The 9 mg group showed more modest increases, while the 6 mg and placebo groups remained stable. These findings support early and dose-dependent subjective effects of 5-MeO-DMT.

Effects of 5-MeO-DMT on EEG power spectrum

The EEG power spectrum analysis revealed differences across the four groups in Delta (1–4 Hz), Theta (4–8 Hz), and Alpha (8–12 Hz) frequencies, measured before (Time: 0 min) and after the administration of 5-MeO-DMT (Time: 15 min) (Fig. 4). Baseline statistical analysis showed no significant differences in alpha power across groups (Kruskal-Wallis tests, p > 0.05), confirming that EEG activity was comparable before drug administration. In the placebo group (Fig. 4A, B), an expected increase in alpha rhythm frequencies was observed when subjects were lying down with their eyes closed, consistent with typical alpha wave behavior in a resting state [33]. In contrast, in the 6 mg 5-MeO-DMT group (Fig. 4C, D), alpha waves remained notably flattened 15 min post-administration compared to the baseline spectrum (at 0 min), indicating a suppression of the usual alpha wave activity despite the eyes-closed condition. Similarly, the 9 mg dosage group (Fig. 4E, F) exhibited a persistent flattening of alpha waves 15 min after 5-MeO-DMT administration, reinforcing the dose-independent suppression effect. The 12 mg dosage group (Fig. 4G, H) also showed a sustained attenuation of alpha wave activity, further suggesting that higher doses of 5-MeO-DMT strongly inhibit the alpha wave increase typically seen during rest [32].

Fig. 4: EEG power spectrum analysis illustrating the effects of 5-MeO-DMT on Delta (1–4 Hz), Theta (4–8 Hz), and Alpha (8–12 Hz) frequencies across different dosage groups.
figure 4

The x-axis represents frequencies (0–15 Hz), and the y-axis indicates power levels. Each spectrum reflects a 4-s signal duration, displaying data from 21 EEG channels at two time points: before (Time: 0 min) and 15 min after administration (Time: 15 min). A, B In the placebo group, the power spectrum at Time 0 shows a prominent peak in the alpha frequency range, consistent with resting-state EEG activity. This peak remains robust 15 min post-administration, indicating typical alpha wave behavior with eyes closed. C, D (6 mg group), E, F (9 mg group), and G, H (12 mg group): At Time 0, before 5-MeO-DMT administration, each group shows a well-defined alpha peak similar to the placebo. However, 15 min post-dose, the alpha activity is markedly suppressed in all three dosage groups, with the degree of suppression increasing with higher doses. This attenuation of alpha waves suggests a dose-dependent suppression effect induced by 5-MeO-DMT. Although, these panels represent individual patient data, similar trends of alpha wave suppression were observed consistently across patients within each dosage group, reinforcing the specific impact of 5-MeO-DMT on alpha frequency activity.

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In addition, similar alterations were observed in the theta (4–8 Hz) and delta (1–4 Hz) frequency bands across all dose levels. While the 6 mg dose resulted in significant flattening of theta and delta waves compared to placebo, this effect was less pronounced than in the 9 mg and 12 mg groups, where the suppression of theta and delta activity was more marked, demonstrating a dose-dependent impact on neural oscillations.

These findings illustrate that 5-MeO-DMT induces a consistent and dose-responsive suppression of neural activity across alpha, theta, and delta bands. The suppression of alpha waves, typically seen during restful states in the placebo group, was notably absent in all 5-MeO-DMT dose groups, suggesting a profound disruption of the brain’s resting-state rhythm. These results emphasize the neurophysiological effects of 5-MeO-DMT and its potential influence on consciousness and brain function, with dose-dependent changes observed across multiple EEG frequency bands

Blinding effect

To assess the effectiveness of blinding, participants completed a brief online questionnaire after the final dosing session, as detailed in Supplementary Material III. Overall, most participants were unable to accurately identify their treatment condition. A generalized linear mixed model revealed no statistically significant effects of dose group, study week, or their interaction on guess accuracy (all p values > 0.05). However, a trend toward higher accuracy was observed in the 9 mg and 12 mg groups, suggesting that the more noticeable pharmacological effects at these doses may have made it easier for participants to identify their treatment. In contrast, blinding appeared more effective in the placebo and lower dose groups (6 mg), where guessing accuracy remained more balanced across weeks. These results support the overall integrity of the blinding procedure (Supplementary Fig. 1).

Discussion

This Phase I clinical trial is the first to evaluate various sub-psychedelic doses of a new sublingual formulation of 5-MeO-DMT. The study involved 36 volunteers with moderate anxiety and depression symptoms. It demonstrated a favorable safety profile and good tolerability, with no significant side effects or treatment-emergent adverse events leading to discontinuation. Mild adverse effects, including nausea, headache, and dizziness, resolved spontaneously and were consistent with previous studies [6, 13, 25, 40]. The 12 mg dose group experienced the highest incidence of side effects; however, these were mild with no psychotic symptoms observed. All participants completed the study without any changes in daily activities, and the four doses (placebo, 6 mg, 9 mg, and 12 mg) did not induce perceptual or behavioral disturbances, allowing them to maintain their regular routines and social interactions. These findings support the favorable safety profile of 5-MeO-DMT, even at higher sub-psychedelic doses.

As previously reported [13, 40], the acute effects of 5-MeO-DMT have a rapid onset and short half-life. Its pharmacokinetic profile shows fast systemic absorption, with a median time to peak plasma concentration of 20 min for the 12 mg dose and minimal accumulation, which is crucial for understanding its therapeutic and experiential effects. These parameters align with previous findings, particularly regarding its elimination half-life, which is consistent with that reported for intranasal administration [6], highlighting the reliability of its kinetics across routes. Although 5-MeO-DMT is rapidly metabolized, prior studies have found its primary metabolite, bufotenine, to be below quantification limits [40], however, this study did not assess its presence or potential effects.

The observed pharmacokinetic properties align with EEG spectral changes, showing reduced alpha, theta, and delta wave activity 15 min post-administration across all dose groups. 5-MeO-DMT produced a dose-dependent suppression of alpha wave activity, with significant reductions detected at 6 mg, 9 mg, and 12 mg doses. Notably, this suppression occurred despite the eyes-closed condition [32, 33], which contrasts with the typical alpha wave increase observed in placebo conditions during eyes-closed resting states. This dose-dependent suppression of alpha waves suggests that 5-MeO-DMT disrupts the brain’s intrinsic resting-state rhythm, underscoring its robust impact on neural activity. These findings contribute to a deeper understanding of the neurophysiological effects of 5-MeO-DMT, emphasizing its potential influence on consciousness and brain function.

Analysis of acute psychedelic experiences revealed no significant within-group differences across weeks, indicating no cumulative effects. Participants’ scores remained below thresholds typically associated with profound psychedelic states. While the 12 mg dose had greater effects than placebo, overall intensity remained modest, confirming its sub-psychedelic classification. Although 5-MeO-DMT is not typically associated with pharmacological tolerance, repeated use was associated with a progressive attenuation of subjective effects. This pattern may reflect psychological accommodation, such as reduced novelty, shifting expectations, or integration of weekly prior experiences, rather than true pharmacodynamic tolerance. Larger studies are needed to clarify whether this reflects adaptation or tolerance.

Importantly, one strength of this study was the preservation of blinding integrity, as most participants were unable to accurately identify their treatment condition. Although a trend toward greater accuracy emerged in the higher dose groups, blinding remained effective, particularly in the 6 mg and placebo groups.

These results represent a meaningful advancement in the field, demonstrating that 5-MeO-DMT is well tolerated across the tested doses and does not raise substantial safety concerns. This pioneering study provides a strong foundation for future research by establishing the feasibility of sublingual administration and offering critical safety and pharmacokinetic data. While this study focused on safety, tolerability, and pharmacokinetics, the favorable safety profile and observed neurophysiological effects support the rationale for further investigation. Efficacy-related outcomes are currently being analyzed and will be reported in a follow-up publication.