Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial

Psychedelic compounds such as N,N-dimethyltryptamine (DMT) have a long history of ritual and clinical use and, more recently, have been investigated for their potential to affect mood and wellbeing. DMT produces rapid-onset psychedelic effects after intravenous administration and acts primarily via serotonergic receptors, notably 5HT2A, with binding to other serotonin receptor subtypes that may be relevant to depression. Previous clinical and naturalistic reports—including studies of ayahuasca, which contains DMT plus other constituents—have suggested improvements in depressive symptoms and wellbeing, but no regulatory-grade, placebo-controlled trials have isolated intravenous DMT in psychedelic-naïve participants to characterise safety, tolerability and pharmacodynamics. James and colleagues designed this Phase I component to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single escalating IV doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy adults. The primary objective was to identify a dose suitable for a subsequent Phase IIa proof-of-concept study in patients with major depressive disorder (Part B), using psychometric measures of the acute psychedelic experience and longer-term wellbeing and anxiety outcomes to inform dose selection alongside safety and tolerability data. PK results and some infusion regimen details are reported elsewhere; this manuscript focuses on the clinical, PD and tolerability findings that guided selection of a dose for Phase IIa.

The study was a randomised, double-blind, placebo-controlled, parallel-group, single ascending dose trial performed to EMA and Good Clinical Practice standards. Four sequential cohorts were enrolled, each with eight participants: up to six received SPL026 and two received matched placebo per cohort. Participants were psychedelic-naïve adults aged ≥25 years, registered with a UK general practitioner, with BMI 18.0–30.9 kg/m2 and no current or past DSM-5 psychiatric disorder, suicidality, or family history of psychotic/bipolar disorder. Two participants were later excluded from analyses because of dosing errors. Study drug (SPL026, 2.5 mg/mL DMT free base) and placebo were administered as a two-phase, 10-minute continuous IV infusion designed to slow the ascent into the psychedelic state: Phase 1 delivered 6 mg over 5 minutes to approach early subjective effects; Phase 2 delivered the remaining dose over 5 minutes (target doses per cohort were 9, 12, 17 and 21.5 mg). Psychological support—based on a time-limited relational psychotherapeutic framework emphasising psychological flexibility (the ACE model augmented with relational and transpersonal elements)—was provided by two trained therapists/psychiatrists across preparation, dosing and integration sessions. Primary safety endpoints included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), suicidality assessed with the Beck Scale for Suicidal Ideation (BSS), clinical laboratory tests, vital signs and ECG. Events inherent to the psychedelic experience were not coded as TEAEs. Acute PD assessments (administered after the dosing experience but before integration) included the Mystical Experience Questionnaire (MEQ), Ego Dissolution Inventory (EDI), Emotional Breakthrough Inventory (EBI), Challenging Experience Questionnaire (CEQ), 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASCQ), a 25-item VAS battery and the Intensity-Rating Visual Analogue Scale (IRVAS), which averaged participant and therapist ratings of experience intensity. Longer-term psychometrics (baseline and days 8, 15, 30 and 90) included WEMWBS (wellbeing), STAI-T (trait anxiety), and a broad set of mood, personality and connectedness measures. EEG was recorded for up to 4 h after dosing; those data are to be reported separately. Statistical analyses were largely descriptive given the Phase I sample size; no formal power calculation was performed. Populations were defined for safety, PD and PK analyses. Acute relationships between Cmax (maximum plasma concentration) and PD scores were examined using Pearson correlations for linear effects and polynomial (quadratic) regression for inverted U relationships, with placebo assigned Cmax = 0. Long-term outcomes were analysed with linear mixed-effects models including dose or z-scored Cmax, time and their interaction as fixed effects and participant as a random intercept. ANOVAs with post-hoc Tukey tests were pre-specified for WEMWBS and STAI-T in dose selection. Multiple comparisons were controlled using Benjamini-Hochberg false discovery rate adjustments.

Thirty-two participants were randomised and received study treatment (age 25–76 years; 25% female; 47% non-white); 30 were evaluated for safety, tolerability and PD after excluding two with dosing errors. Across cohorts there were 24 participants allocated to SPL026 (6 per dose group) and 8 to pooled placebo (2 per cohort). Safety and tolerability: Twenty-five participants (78%) experienced at least one TEAE; 13 participants (41%) reported TEAEs judged drug-related. There were no SAEs, no withdrawals due to TEAEs, and all TEAEs were mild or moderate. The most frequent events were catheter-site reactions (41%), sleep disorders (16%) and headache (13%). Suicidality scores on the BSS were essentially zero at baseline and across follow-up (one isolated minor score that returned to zero and was judged a misunderstanding). Clinical laboratory evaluations showed no changes considered clinically significant; isolated out-of-range values were reported but not judged clinically important. Post-dose vital signs showed transient increases in systolic and diastolic blood pressure that were more frequent at higher SPL026 doses: PCI post-dose systolic blood pressure occurred in 33.3% after 9 mg, 66.7% after 12 mg, 50.0% after 17 mg and 83.8% after 21.5 mg, with the largest individual change a 55% increase at 12 minutes post-dose in one participant. These blood pressure changes were transient and not sustained at 1 h. No pulse rate or temperature abnormalities of PCI were judged clinically significant. Regarding tolerability of the psychedelic experience, all participants from Cohort 2 onwards answered “no” to the question “Do you wish you had not gone through that experience?”, indicating they did not regret participating. Pharmacodynamics and subjective experience: There was a clear SPL026-related increase in MEQ scores versus placebo. Mean MEQ scores by dose were 0.51 (placebo), 2.29 (9 mg), 2.92 (12 mg), 3.74 (17 mg) and 3.00 (21.5 mg) on the MEQ scale reported in the paper. ANOVA showed a significant group effect on MEQ (F(4,30)=5.324, p-adjusted = 0.016), with post-hoc comparisons indicating placebo was lower than 12 mg, 17 mg and 21.5 mg but not significantly different from 9 mg. Nine participants achieved average MEQ scores consistent with complete mystical experience (across dose groups). Analyses relating Cmax to acute PD measures found a significant inverted U-shaped (quadratic) relationship between Cmax and MEQ; this effect was driven mainly by three participants with particularly high Cmax (>80 ng/mL). Excluding those three observations produced a strong positive Pearson correlation between Cmax and MEQ (R = 0.71, p-adjusted = 0.006). Intensity (IRVAS) showed dose-related increases in combined participant/therapist ratings: means were 6.2 (placebo), 49.0 (9 mg), 82.8 (12 mg), 59.3 (17 mg) and 90.9 (21.5 mg). ANOVA for IRVAS was significant (F(4,30)=9.9733, p-adjusted = 0.001). Other acute measures demonstrated SPL026 effects versus placebo for EDI, EBI and certain 5D-ASCQ dimensions (oceanic boundlessness and visionary restructuralization). CEQ scores did not differ significantly across groups. For several acute scales (EDI, EBI, 5D-ASCQ dimensions and VAS items), an inverted U-shaped association with Cmax was observed; when the three highest Cmax observations were excluded, linear positive correlations between Cmax and acute experiential measures were apparent (e.g., EDI R = 0.67, oceanic boundlessness R = 0.62, visionary restructuralization R = 0.61, all p-adjusted <0.05). Wellbeing and longer-term outcomes: Baseline WEMWBS scores were relatively high (range 48–70; mean baseline 61.4), and no significant differences in WEMWBS or STAI-T were observed between SPL026 and placebo at post-dose time points. The majority of longer-term psychometric measures showed no dose-related effects in mixed-effects analyses, and no consistent Cmax × time interactions were detected except for the Agreeableness domain of the Big Five Inventory. Specifically, higher Cmax was associated with a small decrease in Agreeableness from baseline to day 90: χ2(1,N=22)=12.767, p-adjusted = 0.015, with an unstandardised coefficient B = -0.197 per 1 SD increase in Cmax (p = 0.002). Overall, the investigators concluded that SPL026 produced acute psychedelic effects in a dose-related manner without sustained detrimental effects on wellbeing or anxiety in this healthy, psychologically robust sample. Dose selection: Taking safety, tolerability, PD and therapist input into account, the 21.5 mg two-part 10-minute IV infusion (6 mg then 15.5 mg) was selected for progression into the Phase 2a study in participants with moderate–severe major depressive disorder.

The authors present this as the first randomised, placebo-controlled evaluation of IV DMT (SPL026) in psychedelic-naïve healthy participants, and they interpret the findings as supporting the safety, tolerability and feasibility of a two-phase slow IV infusion approach to limit the rapid onset of intense subjective effects. No serious adverse events or withdrawals due to TEAEs were reported, and while transient blood pressure elevations were more frequent at higher doses, investigators judged these changes not clinically significant; they suggest these cardiovascular changes may reflect anticipatory anxiety at onset rather than a direct pharmacological cardiovascular effect, noting no correlation between plasma DMT levels and cardiovascular measures. On tolerability, the study team emphasises that participants did not regret undergoing the experience and that the slower infusion may have enhanced tolerability for psychedelic-naïve individuals. The lack of short- or long-term detrimental effects on wellbeing or anxiety is attributed in part to high baseline wellbeing in this healthy sample, which could create a ceiling effect limiting observable improvements. The authors acknowledge that the Phase I sample size was small and not powered to detect PD differences across doses; they further note that the participant population (healthy, psychologically robust adults) may limit generalisability to broader or clinical populations. The authors highlight the thorough, systematic safety and psychometric assessment as a strength and note that some psychometric differences between SPL026 and psilocybin emerged, meriting future investigation. Finally, the investigators justify selection of 21.5 mg for the Phase 2a study on the basis of acceptable safety and tolerability, the intensity of the elicited psychedelic experience as judged by MEQ and the therapy team, and the expectation that patients with major depressive disorder may require a higher dose to overcome psychological resistance and cognitive rigidity. They conclude that these Phase I data support further clinical evaluation of SPL026 in MDD under supervised conditions with psychological support, while acknowledging the need for larger and longer trials to assess longer-term safety and efficacy in patient populations.