0.4 mg/min 5-MeO-DMT will be administered intravenously for a total infusion duration of 30 min.

0.6 mg/min 5-MeO-DMT will be administered intravenously for a total infusion duration of 30 min.

0.8 mg/min 5-MeO-DMT will be administered intravenously for a total infusion duration of 30 min.

Placebo (saline) is administered for a total infusion duration of 30 min.

A routine safety laboratory blood test is performed at the screening (Session 1) and at the end of study visit (Session 3) including creatinine, alanine aminotransferase (ALAT), aspartate transaminase (ASAT), hemoglobin, hematocrit, white blood cell count, red blood cell count, and platelet cell count (total of 7.3 ml blood).

Blood pressure, heart rate, and body temperature will be recorded at baseline and repeatedly throughout the drug administration session (Session 2). Blood pressure (systolic and diastolic) and heart rate will be measured with an automatic oscillometric device. Measurements will be taken in supine position. For blood pressure, duplicate measurements will be performed.

The Adverse effects list (= Beschwerdenliste) is a self-reporting tool to assess physical and general discomfort. We will use the 2011 revised version, which consists of a 40-item list to assess physiological complaints throughout the study sessions. The BL-R covers a wide variety of symptoms and complaints that are answered with a four-point Likert scale ranging from "not at all" to "strong". We added several items that have been frequently observed in previous research with psychedelics by the several research groups. The scale will be administered at baseline and at the end of the substance administration session (Session 2).

The Swiss Psychedelic Side Effects Inventory (SPSI) has recently been developed and validated by an expert panel, leveraging insights from previous research to enhance the assessment of clinically relevant side effects in studies of psychedelic-assisted therapy. The SPSI assesses 32 potential side effects, along with standardized follow-up questions about their severity, impact, treatment-relatedness, and duration. The scale provides total scores for the number, severity, and impact of side effects, as well as an overall score representing the burden of side effects within a specified timeframe. The scale will be administered at the end of study visit (EOS, Session 3).

The C-SSRS is a suicide risk assessment tool that assesses suicidal ideation and behavior and has repeatedly been shown to accurately predict suicide risks across different populations. The C-SSRS includes the two main domains suicidal ideation and suicidal behaviour. The suicidal ideation domain will be rated based on "Yes"/"No" responses to each of the following types of ideation: 1) wish to be dead, 2) non-specific ideal active suicidal thoughts, 3) active suicidal ideation with any methods (no plan) without intent to act, 4) active suicidal ideation with some intent to act without a specific plan, and 5) active suicidal ideation with a specific plan and intent. The highest numbered item rated "yes" will be scored to assess the suicidal ideation score. If suicidal ideation is present, the intensity of suicidal ideation will be measured (frequency, duration, controllability, deterrents, and reasons for suicidal ideation).

Visual analog scale consisting of 94 items. Constructed of five scales and allows assessing mood, anxiety, derealization, depersonalization, changes in perception, auditory alterations, and reduced vigilance. Scales will be presented as 100 mm long horizontal lines marked with vertical lines by the participant.

The States of Consciousness Questionnaire has been widely used in clinical trials with psychedelics to assess changes in perception, moods, thought, and self-awareness, with a focus on spiritual or mystical-type experiences. The original SCQ comprises 100 items rated on a six-point scale. The SCQ will be analyzed using the psychedelic experience scale (PES48). The PES48 is a revised and psychometrically validated factor structure derived from the SCQ, consisting of 48 of its 100 items. In addition to the four core dimensions measured by the Mystical Experience Questionnaire (MEQ30/MEQ43)--Mystical Experience, Positive Mood, Transcendence of Time and Space, and Ineffability-the PES48 includes four additional subscales: Paradoxicality, Connectedness, Visual Experiences, and Distressing Experience. Data on each domain scale will be expressed as a percentage of the maximum possible score.

The Ego Dissolution Inventory (EDI) is an 8-item self-report questionnaire originally developed and validated in English to assess transient alterations in self-experience during psychedelic states. The scale measures the extent of ego dissolution, i.e., the subjective loss of one's sense of self and boundaries between self and environment, which represents a core feature of the psychedelic experience. A German translation and psychometric validated version of the EDI is used.

The Near-Death Experience Content (NDE-C) scale is a modified version of the NDE-scale. It assesses 20 items rated on a 5-point Likert scale. It is a tool to assess dimensions of near-death experience and has been psychometrically validated. We will use a slightly modified, non-validated version translated into German language. Specifically, we added six new items assessing dimensions of fear, non-existence, loneliness, void, and borderline experience in more detail. The scale will be administered once, 3 h after drug administration and subjects.

The Emotional Breakthrough Inventory Plus (EBI+) contains all six items of the EBI, plus 12 additional items (i.e., 18 items in total) developed by the psychologist and linguist K. Stocker (University Hospital Basel/University Basel and ETH Zurich).

The 6-item Emotional Breakthrough Inventory (EBI) is a reliable and validated measure of cathartic release and resolution of difficult emotions or trauma following a psychedelic experience. Completion of the EBI+ will take around 10 to 15 minutes.

This questionnaire rates psychedelic experiences with a focus on phenomenological, autobiographical, and existential psychedelic experiences. The scale includes 12 main questions to be answered on a total of 78 sub-ordered visual rating scales (sub-ordered visual rating scales mostly only need to be answered when the answer to the main question is "yes"). The last major question with eight sub-ordered visual rating scales of the PAE-PS is on worldview/beliefs.

Blood samples to assess endocrine effects (prolactin, cortisol, oxytocin) of 5-MeO-DMT will be collected before and after substance administration.

Plasma concentration of 5-MeO-DMT and Metabolites after substance administration. Calculated via blood samples.

The FPI is a well-validated psychological personality questionnaire, widely used in psychological research and for diagnostic purposes. It comprises 138 items compiled into 10 scales for the assessment and scoring of the following personality traits: life satisfaction, social orientation, achievement orientation, inhibitedness, excitability, aggressiveness, strain, physical complaints, health concern, frankness, extraversion, emotionality. The FPI will be completed once.

The NEO Five-Factor Inventory (NEO-FFI) is a multidimensional personality inventory, comprising 60 items. It evaluates the "BIG 5" personality traits: Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. The NEO-FFI will be completed once.

Trait resilience will be assessed using the Connor-Davidson Resilience Scale (CD-RISC). A previously validated german version of the CD-RISC-10, containing 10 items, will be used.

Trait connection to nature will be explored using the ABC connectedness to nature scale (ABC-CNS). The questionnaire is partly based on a previous scale named the Connectedness to nature scale. We translated the questionnaire into german language.

The Appreciation Scale (AS) comprises 57 self-rating items measuring eight aspects of appreciation, i.e. "Have focus", "Awe", "Ritual", "Present Moment", "Self/Social Comparison", "Gratitude", "Loss/Adversity", and "Interpersonal". Subjects are asked to rate the statements on a scale from 1 to 7 in terms of either attitude intensity ('strongly disagree' to 'strongly agree') or frequency ('never' to 'more than once a day'). Scores on the subscales can be summed up to yield a score representing the overall degree of appreciation (or level of appreciativeness), with higher scores indicating higher appreciation levels. The questions will be administered twice.

The Scale of Positive and Negative Experience (SPANE) is a 12-item questionnaire to capture the affective component of subjective well-being. It reflects a person's balance between pleasant and unpleasant affect in life. The SPANE includes six items to assess positive feelings and six items to assess negative feelings. The feelings are reported on a 5-point scale ranging from 'very rarely' to 'very often or always'. The SPANE provides an overall affect balance score and may be divided into positive/negative feelings scales. The scale will be administered three times.

Global life satisfaction is assessed based on a single item life satisfaction measure which is a simple, yet widespread approach. The specific wording of the question is adopted from the Swiss household panel study which is a representative survey of the Swiss population. The question can be answered on a 11-point scale: "In general, how satisfied are you with your life if 0 means 'not at all satisfied' and 10 means 'completely satisfied'?". The question will be administered three times.

The CEQ is a validated instrument designed to assess participants' beliefs about the credibility of the treatment and their expectations for improvement. Since the original questionnaire is intended for clinical trials involving patients, it has been adapted for the specific context of this study in healthy participants. Four items will be used to assess expectations regarding the psychoactive effects of 5-MeO-DMT: 1. How strongly do you expect to feel subjective effects? 2. How strongly do you actually believe that you will experience subjective effects? 3. How strongly do you expect the effects of 5-MeO-DMT to be pleasant or positive? 4. How strongly do you expect the effects of 5-MeO-DMT to be unpleasant or distressing? The items are rated on a scale from 1 ("not at all") to 9 ("very").

Urine samples will be collected throughout the whole time interval up to 3 hours after substance administration to assess the urinary excretion profile of 5-MeO-DMT and its metabolites.