Clinical trial NCT06884514: Acute Effects of MDMA Co-administration on the Response to Psilocybin in Healthy Subjects
Official title: Acute Effects of MDMA Co-administration on the Response to Psilocybin in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Healthy
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2025-03-19
Enrollment: 24
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-blind, placebo-controlled, 4-period cross-over design with three active substance conditions and placebo:

1. 20 mg Psilocybin + MDMA placebo
2. Psilocybin placebo + 100 mg MDMA
3. 20 mg Psilocybin + 100 mg MDMA
4. Psilocybin placebo + MDMA placebo
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Acute Subjective effects I
timeFrame: through study completion, an average of 18 months
measure: Acute Subjective effects II
timeFrame: through study completion, an average of 18 months
measure: Acute Subjective effects III
timeFrame: through study completion, an average of 18 months
measure: Acute autonomic effects I (blood pressure)
timeFrame: through study completion, an average of 18 months
measure: Acute autonomic effects I (heart rate)
timeFrame: through study completion, an average of 18 months
measure: Acute autonomic effects III (body temperature)
timeFrame: through study completion, an average of 18 months
measure: Acute autonomic effects IV (ECG QT-time)
timeFrame: through study completion, an average of 18 months
Secondary outcomes:
measure: Peak plasma concentration (Cmax) of MDMA and metabolites
timeFrame: through study completion, an average of 18 months
measure: Time to peak plasma concentration (Tmax) of MDMA and metabolites
timeFrame: through study completion, an average of 18 months
measure: Area under the plasma concentration vs. time curve (AUC) of MDMA and metabolites
timeFrame: through study completion, an average of 18 months
measure: Elimination half-life values of MDMA and metabolites
timeFrame: through study completion, an average of 18 months
measure: Peak plasma concentration (Cmax) of Psilocybin and metabolites
timeFrame: through study completion, an average of 18 months
measure: Time to peak plasma concentration (Tmax) of Psilocybin and metabolites
timeFrame: through study completion, an average of 18 months
measure: Area under the concentration vs. time curve (AUC) of Psilocybin and metabolites
timeFrame: through study completion, an average of 18 months
measure: Elimination half-life values of Psilocybin and metabolites
timeFrame: through study completion, an average of 18 months
measure: Plasma concentration of Oxytocin
timeFrame: through study completion, an average of 18 months
measure: States of Consciousness Questionnaire
timeFrame: through study completion, an average of 18 months
measure: Spiritual Realms Questionnaire
timeFrame: through study completion, an average of 18 months
measure: Subacute effects on general and mental well-being I (WEMWBS)
timeFrame: through study completion, an average of 18 months
measure: Subacute effects on general and mental well-being II (GHQ-12)
timeFrame: through study completion, an average of 18 months
measure: Subacute effects on general and mental well-being III (SPANE)
timeFrame: through study completion, an average of 18 months
measure: Subacute effects on general and mental well-being IV (BFW/E)
timeFrame: through study completion, an average of 18 months
measure: Subacute effects on general and mental well-being V (GLS)
timeFrame: through study completion, an average of 18 months
measure: Adverse effects (acute and subacute)
timeFrame: through study completion, an average of 18 months
measure: Effects on Appreciation
timeFrame: through study completion, an average of 18 months
measure: Effect moderation by personality traits I (NEO-FFI)
timeFrame: Baseline
measure: Effect moderation by personality traits II (FPI-R)
timeFrame: Baseline
measure: Effect moderation by personality traits III (SPF)
timeFrame: Baseline
measure: Effect moderation by personality traits IV (HEXACO)
timeFrame: Baseline
measure: Effect moderation by personality traits V (DSQ-40)
timeFrame: Baseline
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel
Study officials:
affiliation: University Hospital Basel, Basel, Switzerland
name: Matthias E Liechti, Prof. Dr. MD
role: PRINCIPAL_INVESTIGATOR
References: