Acute Effects of MDMA Co-administration on the Response to Psilocybin in Healthy Subjects (MDMA-Psilo)

May 20, 2025 updated by: University Hospital, Basel, Switzerland
The acute subjective effects of serotonin (5-HT)2A receptor stimulation with psilocybin in humans are mostly positive. However, negative effects such as anxiety, paranoid thinking, or loss of trust towards other people are common effects, depending on the dose administered, the personality traits of the person consuming it (set), or the environment in which psilocybin is taken (setting). Negative psychedelic effects may cause acute distress to the subject and acute anxiety has been linked to less favorable long-term outcomes in patients experimentally treated with psilocybin or similar substances for the treatment of depression. The 5-HT and oxytocin releaser 3,4-methylenedioxymethamphetamine (MDMA) reliably induces positive mood, euphoria, comfort, empathy, and feelings of trust. If administered in combination with psilocybin, MDMA may increase positive subjective drug effects including positive mood, empathy, and trust and reduce negative emotions and anxiety associated with psilocybin and overall produce a more positive over negative experience. The present study will assess subjective and autonomic effects of psilocybin alone and in combination with MDMA.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Psilocybin is a classic serotonergic psychedelic. Clinically, the acute effects of psilocybin last shorter than those of lysergic acid diethylamide (LSD) but are qualitatively very similar. Currently, psilocybin is the most investigated psychedelic substance among the classic psychedelics including LSD, psilocybin, mescaline, and dimethyltryptamine (DMT). Psilocybin is capable of inducing exceptional subjective effects such as a dream-like alteration of consciousness, affective changes, psychological insight, visual imagery, pseudo-hallucinations and ego-dissolution. The acute subjective effects elicited by psilocybin are mostly positive in humans. However, psychedelic substances like psilocybin may also cause unpleasant subjective effects like negative thoughts, rumination, anxiety, panic, paranoia, loss of trust towards other people and perceived loss of control, depending on the dose of psilocybin used, the personality traits of the person consuming it (i.e. 'set'), the environment in which it is consumed (i.e. 'setting'), and other factors. Acute negative psychological effects are considered the main risk of psychedelic substance use in humans. Inducing an overall positive acute response to the psychedelic is critical because several studies showed that a more positive experience is predictive of a greater therapeutic long-term effect of the psychedelic. The present study uses 3,4-methylenedioxymethamphetamine (MDMA) as a pharmacological tool to optimize the effects of psilocybin by inducing positive mood. MDMA is an amphetamine derivative which, unlike prototypical amphetamines, predominantly enhances serotonergic neurotransmission via release of 5-HT through the serotonin transporter (SERT). Furthermore, MDMA is known to trigger oxytocin release which may contribute to its effects to increase trust, prosociality, and enhanced empathy. The state of well-being induced by MDMA including increased activation and emotional excitation is known to be associated with a better response to psychedelics. Due to its psychological profile, MDMA could be a reliable pharmacological tool to serve as an optimizer of a psychedelic experience by inducing positive emotions.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. Age between 25 and 65 years.
  2. Understanding of the German language.
  3. Understanding the procedures and the risks that are associated with the study.
  4. Participants must be willing to adhere to the protocol and sign the consent form.
  5. Participants must be willing to refrain from taking illicit psychoactive substances during the study.
  6. Participants must be willing to drink only alcohol-free liquids and no coffee, black or green tea, or energy drink after midnight of the evening before the study session, as well as during the study day.
  7. Participants must be willing not to drive a traffic vehicle or to operate machines within 48 h after substance administration.
  8. Willing to use effective birth control throughout study participation.
  9. Body mass index between 18-29 kg/m2.

Exclusion Criteria:

  1. Chronic or acute medical condition
  2. Current or previous major psychiatric disorder
  3. Psychotic disorder in first-degree relatives, not including psychotic disorders secondary to an apparent medical reason, e.g. brain injury, dementia, or lesions of the brain.
  4. Hypertension (SBP>140/90 mmHg) or hypotension (SBP<85 mmHg)
  5. Illicit substance use (not including cannabis) more than 20 times or any time within the previous month
  6. Pregnant or nursing women.
  7. Participation in another clinical trial (currently or within the last 30 days).
  8. Use of medications that may interfere with the effects of the study medications.
  9. Tobacco smoking (>10 cigarettes/day).
  10. Consumption of alcoholic drinks (>15 drinks/week).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 20 mg Psilocybin + MDMA placebo
Drug: Psilocybin
A moderate dose of 20 mg psilocybin will be administered.
Drug: 3,4-Methylenedioxymethamphetamine placebo
Mannitol capsules instead of capsules containing MDMA.
Experimental: Psilocybin placebo + 100 mg MDMA
Drug: 3,4-Methylenedioxymethamphetamine
A moderate dose of 100 mg MDMA will be administered.
Drug: Psilocybin placebo
Mannitol capsules instead of capsules containing psilocybin.
Experimental: 20 mg Psilocybin + 100 mg MDMA
Drug: Psilocybin
A moderate dose of 20 mg psilocybin will be administered.
Drug: 3,4-Methylenedioxymethamphetamine
A moderate dose of 100 mg MDMA will be administered.
Placebo Comparator: Psilocybin placebo + MDMA placebo
Drug: 3,4-Methylenedioxymethamphetamine placebo
Mannitol capsules instead of capsules containing MDMA.
Drug: Psilocybin placebo
Mannitol capsules instead of capsules containing psilocybin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute Subjective effects I
Time Frame: through study completion, an average of 18 months
The Visual Analog Scales (VAS) assesses the intensity and duration of the subjective effect on a scale from 0 - 100 percent with higher scores representing more intense effects. Assessed 12 times on each study day
through study completion, an average of 18 months
Acute Subjective effects II
Time Frame: through study completion, an average of 18 months
The Adjective Mood Rating Scale (AMRS) assesses the occurrence and intensity of 60 moods on a 4-point Likert scale ranging from "not at all" to "extremely".
through study completion, an average of 18 months
Acute Subjective effects III
Time Frame: through study completion, an average of 18 months
5 Dimensions of Altered States of Consciousness (5D-ASC) consisting of 94 items to be rated on a visual analog scale (0-100 mm), with higher values indicating stronger effects.
through study completion, an average of 18 months
Acute autonomic effects I (blood pressure)
Time Frame: through study completion, an average of 18 months
Blood pressure (systolic and diastolic) will be measured with an automatic oscillometric device.
through study completion, an average of 18 months
Acute autonomic effects I (heart rate)
Time Frame: through study completion, an average of 18 months
Heart rate will be measured with an automatic oscillometric device.
through study completion, an average of 18 months
Acute autonomic effects III (body temperature)
Time Frame: through study completion, an average of 18 months
Body temperature will be measured with an ear thermometer.
through study completion, an average of 18 months
Acute autonomic effects IV (ECG QT-time)
Time Frame: through study completion, an average of 18 months
An ECG will be performed twice: once before and once after substance administration.
through study completion, an average of 18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect moderation by personality traits I (NEO-FFI)
Time Frame: Baseline
Personality traits are known to affect subjective responses to psychoactive substances and are assessed for explorative future analysis of pooled data. The NEO Five Factor Inventory (NEO-FFI) is a self-description questionnaire with 60 items for the measurement of the "big five": neuroticism, extraversion, openness, agreeableness, and consciousness. It uses a 5-point Likert scale ranging from "completely disagree" to "fully agree".
Baseline
Effect moderation by personality traits II (FPI-R)
Time Frame: Baseline
Personality traits are known to affect subjective responses to psychoactive substances and are assessed for explorative future analysis of pooled data. The Freiburger Personality Inventory (FPI-R) version comprises 138 items and covers 12 dimensions of personality: life satisfaction, social orientation, performance orientation, inhibition, excitability, aggressiveness, stress, physical complaints, health concerns, openness, as well as the secondary factors according to Eysenck's Extraversion and Emotionality (Neuroticism). It uses a 2-point scale ("true" and "not true").
Baseline
Effect moderation by personality traits III (SPF)
Time Frame: Baseline
Personality traits are known to affect subjective responses to psychoactive substances and are assessed for explorative future analysis of pooled data. The Saarbrücker Persönlichkeitsfragebogen (SPF) defines empathy as the "reactions of one individual to the observed experiences of another." It assesses 28-items on a 5-point Likert scale ranging from "Does not describe me well" to "Describes me very well". The measure has 4 subscales (Perspective Taking, Fantasy, Empathic Concern, Personal Distress) each made up of 7 different items.
Baseline
Effect moderation by personality traits IV (HEXACO)
Time Frame: Baseline
Personality traits are known to affect subjective responses to psychoactive substances and are assessed for explorative future analysis of pooled data. The HEXACO personality inventory is a six-dimensional model of human personality with 100 items.The six factors are: Honesty-Humility, Emotionality, Extraversion, Agreeableness, Conscientiousness and Openness to Experience.
Baseline
Effect moderation by personality traits V (DSQ-40)
Time Frame: Baseline
Personality traits are known to affect subjective responses to psychoactive substances and are assessed for explorative future analysis of pooled data. The Defense Style Questionnaire (DSQ-40) can provide scores for 20 individual defenses, and scores for the three factors "mature", "neurotic", and "immature". Each item is evaluated on a scale from 1 to 9, where "1" indicates "completely disagree" and "9" indicates "fully agree".
Baseline
Peak plasma concentration (Cmax) of MDMA and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Time to peak plasma concentration (Tmax) of MDMA and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Area under the plasma concentration vs. time curve (AUC) of MDMA and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Elimination half-life values of MDMA and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Peak plasma concentration (Cmax) of Psilocybin and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Time to peak plasma concentration (Tmax) of Psilocybin and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Area under the concentration vs. time curve (AUC) of Psilocybin and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Elimination half-life values of Psilocybin and metabolites
Time Frame: through study completion, an average of 18 months
Assessed via blood samples. Findings will be described descriptively.
through study completion, an average of 18 months
Plasma concentration of Oxytocin
Time Frame: through study completion, an average of 18 months
Assessed via blood samples.
through study completion, an average of 18 months
States of Consciousness Questionnaire
Time Frame: through study completion, an average of 18 months
Assesses the emergence and intensity of phenomenons occurring in altered states of consciousness on a 6-point Likert scale ranging from 0 ("not at all") to 5 ("extremely")
through study completion, an average of 18 months
Spiritual Realms Questionnaire
Time Frame: through study completion, an average of 18 months
Assesses the spiritual phenomenons elicited by psychedelic substances through 11 main questions to be answered on a total of 65 sub-ordered 100mm visual analog scales once on each study day
through study completion, an average of 18 months
Subacute effects on general and mental well-being I (WEMWBS)
Time Frame: through study completion, an average of 18 months
The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) is a 14-item questionnaire, that covers different concepts associated with positive mental health, including both hedonic and eudaimonic aspects, positive affect, satisfying interpersonal relationships and positive functioning. For each item an ordinal five point frequency answer format, ranging from 1 = none of the time" to 5 = "all of the time" is applied.
through study completion, an average of 18 months
Subacute effects on general and mental well-being II (GHQ-12)
Time Frame: through study completion, an average of 18 months
The General Health Questionnaire (GHQ-12) consists of a 12-item questionnaire with a four-point response scale assessing general psychological discomfort.
through study completion, an average of 18 months
Subacute effects on general and mental well-being III (SPANE)
Time Frame: through study completion, an average of 18 months
The Scale of Positive and Negative Experience (SPANE) is a 12-item questionnaire to capture the affective component of subjective well-being. 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".
through study completion, an average of 18 months
Subacute effects on general and mental well-being IV (BFW/E)
Time Frame: through study completion, an average of 18 months
The "Positive Attitude towards Life" is an 8-item subscale of the 39-item Bern Subjective Well-Being Questionnaire for adults. A six-point rating scale ranging from 1 ('strongly disagree') to 6 ('strongly agree') is used to rate the attitude towards life.
through study completion, an average of 18 months
Subacute effects on general and mental well-being V (GLS)
Time Frame: through study completion, an average of 18 months
Global life satisfaction is assessed based on a single item life satisfaction measure which is a simple, yet widespread approach. The question is 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'?".
through study completion, an average of 18 months
Adverse effects (acute and subacute)
Time Frame: through study completion, an average of 18 months
The 2011 revised Beschwerden-Liste (B-LR) consists of a 40-item list covering a wide variety of symptoms and complaints that are answered with a four-point intensity-scoring ranging from "not at all" to "strong".
through study completion, an average of 18 months
Effects on Appreciation
Time Frame: through study completion, an average of 18 months
The Appreciation Scale (AS) comprises 57 items used to measure aspects of appreciation. Subjects are asked to rate themselves 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 are summed up to yield a score representing the overall degree of appreciation (or level of appreciativeness), with higher scores indicating more of the positive construct.
through study completion, an average of 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Basel, Switzerland

Investigators

  • Principal Investigator: Matthias E Liechti, Prof. Dr. MD, University Hospital Basel, Basel, Switzerland

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 3, 2025

Primary Completion (Estimated)

July 1, 2026

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

January 31, 2025

First Submitted That Met QC Criteria

March 13, 2025

First Posted (Actual)

March 19, 2025

Study Record Updates

Last Update Posted (Actual)

May 21, 2025

Last Update Submitted That Met QC Criteria

May 20, 2025

Last Verified

May 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BASEC 2024-00893

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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