Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment

Uthaug and colleagues frame 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a short-acting tryptamine with growing use in naturalistic and ceremonial settings for spiritual exploration and to address mood problems. Earlier research and surveys suggest 5-MeO-DMT produces intense but brief mystical-type effects, has a low addiction liability, and may share therapeutic potential with related serotonergic psychedelics such as DMT-containing ayahuasca or psilocybin. Preclinical and in vitro studies indicate that DMT-like compounds can modulate immune function and neurogenesis, and the immune hypothesis of psychiatric disease motivates assessing links between inflammatory processes and mental health outcomes following psychedelic exposure. The present study set out to prospectively examine acute neuroendocrine and inflammatory responses, and short-term changes in affect and mindfulness-related capacities, after inhalation of vaporised synthetic 5-MeO-DMT in a naturalistic setting. Primary aims were to measure salivary cortisol and inflammatory markers (IL-6, CRP, IL-1β), and secondary aims were to assess changes in depression, anxiety, stress, satisfaction with life, and facets of mindfulness, plus whether subjective psychedelic intensity related to biomarker or mental-health changes. The investigators hypothesised reductions in mood symptoms and exploratory links between psychometric changes and salivary stress/immune markers.

This was a prospective, naturalistic observational study conducted at a facilitator-led session site in Prague, Czech Republic. Participants were approached when they signed up for a one-on-one inhalation session and gave written informed consent on location. Eleven volunteers completed baseline and immediate post-session assessments on site; ten of these completed an online 7-day follow-up. Exclusion criteria reported were non-fluency in English, current medication use, and age under 18; no participants were excluded. The sample comprised eight males and three females (mean age 33.0 years, SD = 8.59), most from Europe (N = 8) and three from North America. All reported prior psychedelic use; nine were naive to 5-MeO-DMT and two had used it previously. Motivations for use were heterogeneous and some participants had used other substances in the previous week. Sessions occurred in a yoga studio and were facilitated by a male practitioner trained in Holotropic Breathwork who had been administering 5-MeO-DMT in similar settings for about 2 years. Dosing was individualised: participants received between one and four inhalations spaced 8–25 minutes apart, with per-inhalation doses reported between 3 and 24 mg and summed session totals ranging approximately 17–61 mg. Additional procedural details about setting are said to be in an appendix that is not included in the extracted text. Assessments were collected at three time points: baseline (about 30 minutes prior to the session), immediately post-session (within 1–1.5 hours after the session ended), and at 7 days. On site, participants completed a 15-minute battery including the Depression, Anxiety and Stress Scale-21 (DASS-21), Satisfaction With Life Scale (SWL), Five Facets Mindfulness Questionnaire (FFMQ-39), and, post-session, the Ego Dissolution Inventory (EDI) and the 5-Dimensional Altered States of Consciousness scale (5D-ASC). Saliva was collected into Saliva Collection Aid tubes, frozen on dry ice, and later assayed. Salivary assays: duplicate high-sensitivity ELISAs measured cortisol, IL-6, CRP, and IL-1β following manufacturer protocols. Samples were centrifuged and diluted prior to assay; intra- and inter-assay coefficients of variation were reported as <10% and <15%, respectively. For statistics, the authors used linear mixed models (repeated measures ANOVA logic) to test session effects across the three time points, with contrasts between baseline and post-session or follow-up. For the saliva ELISA data, paired Student's t-tests compared baseline and immediate post-session concentrations. Correlations (Pearson's r) examined associations between psychedelic-experience scales, psychometric outcomes, and biomarker changes. Effect-size metrics reported included Cohen's d, Hedges' g, and partial eta-squared (ηp2). The alpha threshold was p < 0.05.

Sample and adverse events: Eleven participants provided baseline and immediate post-session data; ten completed the 7-day follow-up. During sessions, 45.5% (5/11) reported adverse effects immediately post-session (for example transient fear, confusion, vomiting or throat irritation); 27.3% (3/11) reported adverse effects in the subsequent 7 days (muscle tension, insomnia). No participant had a clinician-diagnosed mental-health disorder, although four reported past problems (depression, anxiety, or PTSD). Subjective psychedelic experience: Mean ego-dissolution (EDI) was 51.84% (SD = 29.49). On the 5D-ASC, mean (SD) scores for the five key dimensions were oceanic boundlessness 46.88% (30.11), anxious ego dissociation 23.83% (15.80), visual restructuralization 27.16% (22.76), auditory alterations 14.39% (14.37), and reduction of vigilance 22.34% (8.61). Top-rated subscales were experience of unity 53.82% (36.25), blissful state 51.35% (38.94), and disembodiment 49.58% (30.84). Biomarkers: Paired comparisons showed a significant immediate post-session increase in salivary cortisol (mean difference MD = 0.21 μg/dL; p < 0.001) and a significant decrease in salivary IL-6 (MD = 3.51 pg/mL; p < 0.001). No statistically significant changes were observed for salivary CRP or IL-1β. Baseline biomarker values for participants were reported to be within the physiological ranges cited by the authors (cortisol 0.15–0.65 μg/dL; IL-6 5–25 pg/mL; CRP <3 ng/mL; IL-1β 50–200 pg/mL). Subjective affect and mindfulness: Repeated-measures analyses indicated significant session effects for anxiety (DASS-21) F(2,19.380) = 6.023, p = .009, ηp2 = 0.38; depression (DASS-21) F(2,9.979) = 8.104, p = .008, ηp2 = 0.18; and non-judgment facet of the FFMQ F(2,?) = 14.018, p = .001, ηp2 = 0.45 (the extracted df for the non-judgment F-test was not fully clear). Contrasts showed a reduction in depression immediately post-session versus baseline (p = .049, Cohen's d = 0.31) and an increase in non-judgment post-session (p = .017, Cohen's d = 0.36). At 7-day follow-up there were reductions versus baseline in stress (p = .043, Hedges' g = 0.67), anxiety (p = .010, Hedges' g = 0.40), and continued increase in non-judgment (p = .001, Hedges' g = 0.51). A reduction in depression at follow-up approached significance (p = .073, Hedges' g = 0.30). The authors characterise these affect changes as subtle in magnitude. Dose and correlations: Dosing varied by participant; no significant correlations were found between total dose and measures of psychedelic experience, salivary biomarkers, or psychometric outcomes (reported r values ranged approximately from −0.499 to 0.240). There were no correlations between the immediate mean differences in salivary cortisol or IL-6 and ratings of the psychedelic experience (EDI, 5D-ASC). However, several statistically significant correlations were reported between other biomarkers and subjective measures: salivary IL-1β was negatively correlated with ego-dissolution (r = −0.679; p = .022) and experience of unity (r = −0.622; p = .041). Salivary CRP showed negative correlations with multiple 5D-ASC dimensions (for example oceanic boundlessness r = −0.769, p = .006; spiritual experience r = −0.720, p = .012; insightfulness r = −0.778, p = .005) and a positive correlation with anxiety (r = .664; p = .026). Additionally, CRP correlated negatively with FFMQ awareness (r = −0.714; p = .014) and non-judgment (r = −0.720; p = .012). IL-1β correlated negatively with satisfaction with life (r = −0.874; p = .000) and positively with depression (r = .637; p = .023) in post-session data. The extracted text reports further correlations between experience ratings and later psychometric outcomes, indicating that stronger psychedelic experience related to greater increases in non-judgment and larger decreases in depression, anxiety and stress.

Uthaug and colleagues interpret their findings as evidence that inhalation of vaporised synthetic 5-MeO-DMT produces a moderate psychedelic experience accompanied by rapid neuroendocrine and inflammatory changes and short-term improvements in affective and mindfulness-related measures. The authors note that EDI and 5D-ASC ratings were qualitatively similar but lower in magnitude than prior reports from toad-secretion inhalation studies, and they discuss several possible reasons for between-study differences including smaller sample size here, variable dosing, individual differences in inhalation technique and metabolism, and psychological set and setting. Regarding biomarkers, the investigators highlight the immediate cortisol increase and concurrent decrease in salivary IL-6. They propose two non-mutually exclusive explanations: a stress-like neuroendocrine response to the acute psychedelic experience leading to cortisol-mediated suppression of inflammation, and direct receptor-mediated immunomodulatory actions of 5-MeO-DMT (for example via 5-HT2A and sigma-1 receptors). The authors caution that the observed IL-6 change was of relatively small effect size and that saliva was used as a surrogate for plasma; nonetheless, they suggest the results point to a possible anti-inflammatory action warranting further study. On subjective outcomes, inhalation of 5-MeO-DMT was associated with immediate reductions in self-reported depression and increases in non-judgment, with further reductions in anxiety and stress apparent at 7 days. The authors link these patterns to prior findings with ayahuasca, psilocybin and toad-secretion 5-MeO-DMT, noting that stronger acute psychedelic experiences correlated with larger short-term improvements in non-judgment and affect. They emphasise that psychometric changes could also reflect non-pharmacological factors such as expectancy and the uncontrolled set and setting, but contend that the correlations between experience intensity and outcome make a pharmacological contribution plausible. Key limitations acknowledged by the authors include the small sample size, lack of placebo or control condition, self-selected volunteer sample and potential social desirability or expectancy bias, variable and self-determined dosing, and the naturalistic (non-laboratory) setting. They recommend replication in larger, placebo-controlled experimental designs to confirm the preliminary biomarker and mental-health findings and to better characterise dose–response relationships and safety.