Effects of MDMA-like Substances in Healthy Subjects (MDMA-like)

• ClinicalTrials.gov Identifier: NCT04847206
• Recruitment Status: Recruiting
• First Posted: April 19, 2021
• Last Update Posted: December 23, 2021
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Tracking Information

• First Submitted Date: April 1, 2021
• First Posted Date: April 19, 2021
• Last Update Posted Date: December 23, 2021
• Actual Study Start Date: December 1, 2021
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2021)

• Acute subjective effects I [ Time Frame: 18 months ]
  Visual Analog Scales (VAS) assessing the intensity and duration of subjective effects on a scale from 0 - 100 percent with higher scores representing more intense effects
• Plasma levels of MDMA [ Time Frame: 18 months ]
  Assessed 18 times on each study day via blood samples
• Plasma levels of MDA [ Time Frame: 18 months ]
  Assessed 18 times on each study day via blood samples

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 14, 2021)

• Acute Subjective effects II [ Time Frame: 18 months ]
  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"
• Acute Subjective effects III [ Time Frame: 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
• States of Consciousness Questionnaire [ Time Frame: 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")
• Psychological Insight Questionnaire [ Time Frame: 18 months ]
  Assesses the degree of psychological insight caused by a psychedelic experience through 14-items to be answered on a 6-point Likert scale ranging from 0 ("not at all") to 5 ("extremely")
• Autonomic effects I [ Time Frame: 18 months ]
  Assessed 20 times on each study day via systolic and diastolic blood pressure
• Autonomic effects II [ Time Frame: 18 months ]
  Assessed 20 times on each study day via heart rate
• Autonomic effects III [ Time Frame: 18 months ]
  Assessed 20 times on each study day via tympanic body temperature
• Autonomic effects IV [ Time Frame: 18 months ]
  Assessed 7 times on each study day via pupil diameter
• Autonomic effects V [ Time Frame: 18 months ]
  Assessed one time on each study day via ECG (QT-time)
• Plasma levels of oxytocin [ Time Frame: 18 months ]
  Assessed 5 times on each study day via blood samples
• Emotion processing I [ Time Frame: 18 months ]
  Assessed one time on each study day via Face Emotion Recognition Task (FERT).
• Emotion processing II [ Time Frame: 18 months ]
  Assessed one time on each study day via Multifaceted Empathy Test (MET).
• NEO-Five-Factor-Inventory (NEO-FFI) [ Time Frame: Baseline ]
  The 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".
• Freiburger Personality Inventory (FPI-R) [ Time Frame: Baseline ]
  The 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").
• Saarbrücker Personality Questionnaire (SPF) [ Time Frame: Baseline ]
  The 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.
• HEXACO personality inventory [ Time Frame: Baseline ]
  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. The HEXACO uses a 5-point Likert scale ranging from "completely disagree" to "fully agree".
• Defense Style Questionnaire (DSQ-40) [ Time Frame: Baseline ]
  The 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".

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of MDMA-like Substances in Healthy Subjects
• Official Title: Effects of MDMA-like Substances in Healthy Subjects

Brief Summary

The serotonin (5-HT) and oxytocin releaser and so-called "empathogen" 3,4-methylenedioxymethamphetamine (MDMA) acutely produces positive feelings, empathy, and trust. MDMA is used recreationally (ecstasy), as research tool to study 5-HT and oxytocin function, and is investigated for MDMA-assisted psychotherapy.

MDMA is metabolized in part (10%) to the psychoactive metabolite 3,4-methylenedioxyamphetamine (MDA) which itself is also a recreational substance and has also been used to assist psychotherapy in the past. The present study aims to describe and directly compare for the first time the effects of MDMA and MDA in the same healthy volunteers and using modern psychological and psychometric tests.

Additionally, although amphetamines including MDMA and MDA induce mainly positive subjective effects they may also produce negative subjective drug effects including anxiety in particular at the onset of the subjective response and the rapid onset of euphoria may increase the risk of abuse. Additionally, blood pressure may increase rapidly at drug onset. A possible solution to mitigate anxiety, abuse-related rapid euphoria increases and/or rapid blood pressure changes at onset consist of slowing the onset of the drug effect by using a slow-release formulation of MDMA. In the present study, the investigators will characterize the effects of lysine-MDMA and lysine-MDA and compare their effects with MDMA/MDA to test the concept of attenuated effects across both substances.

Detailed Description

3,4-methylenedioxymethamphetamine (MDMA) is used as recreational substance (Ecstasy), research tool to stimulate serotonin (5-HT) and oxytocin release and study associated mood states, and as a potential therapeutic substance to enhance psychotherapy for post-traumatic stress disorder. MDMA is an amphetamine derivative which, unlike prototypical amphetamines, predominantly enhances serotonergic neurotransmission via release of 5-HT through the SERT and it less potently also releases dopamine and norepinephrine through the DA transporter and NE transporter, respectively. Furthermore, MDMA is known to trigger oxytocin release which may contribute to its effects to increase trust, prosociality, and enhance empathy. MDMA is therefore referred to as an "entactogen" or "empathogen". MDMA is currently the only empathogen investigated in substance-assisted psychotherapy but other substances including the MDMA-metabolite 3,4-methylenedioxyamphetamine (MDA) have been used in the past or may be used in the future.

Aim 1: MDA may exert greater perceptual psychedelic-like effects due to a more potent binding to the serotonin 5-HT2A receptor, and it may also act longer than MDMA partly due to a longer plasma half-life. However, effects of MDMA and MDA have never been compared directly in the same study in humans and there is only one modern study that characterized MDA in humans. Therefore, the present study aims to describe and directly compare for the first time the effects of MDMA and MDA in the same healthy volunteers using modern and sensitive psychological and psychometric tests.

Aim 2: Additionally, although amphetamines including MDMA and MDA induce mainly positive subjective effects they may also produce negative subjective drug effects including anxiety in particular at the onset of the subjective response and the rapid onset of euphoria may increase abuse liability. Additionally, blood pressure may increase rapidly at drug onset. A possible solution to mitigate anxiety, abuse-related rapid euphoria increases and/or rapid blood pressure changes at onset consist of slowing the onset of the drug effect by using a slow-release formulation of MDMA/MDA. Alternatively, amphetamines can be linked to the endogenous amino acid lysine forming inactive lysine-amphetamine which then liberates the active amphetamine slowly in the circulation via plasma peptidases. This approach has been implemented with the medication Lisdexamfetamine, which combines lysine with d-amphetamine. In the present study, the investigators will similarly characterize the effects of lysine-MDMA and lysine-MDA to test for attenuated effects across both substances in comparison with MDMA/MDA.

Using a two-factorial study design with four active substance conditions (MDMA vs. MDA and lysine-MDMA vs. lysine-MDA) the investigators will be able to test differences between MDMA and MDA (with and without lysine) as well as between lysinated a non-lysinated substance (regardless of active substance) in the same study and with high statistical power and within one study addressing two aims.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Double-blind, placebo-controlled, 5-period cross-over design with four active substance conditions (equimolar doses of psychoactive substance) and placebo:

1. MDMA (100 mg MDMA-hydrochloride; 84.1 mg MDMA free base) 2) MDA (93.9 mg MDA-hydrochloride; 78.0 mg MDA free base) 3) lysMDMA (171.7mg lysMDMA dihydrochloride; 84.1 mg MDMA free base) 4) lysMDA (165.6 mg lysMDA dihydrochloride; 78.0 mg MDA free base) 5) Placebo

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science

• Condition: Healthy

Intervention

• Drug: 3,4-methylenedioxymethamphetamine
  A moderate dose of 100 mg MDMA will be administered.
  Other Name: MDMA
• Drug: 3,4-methylenedioxyamphetamine
  A moderate dose of 93.9 mg MDA will be administered.
  Other Name: MDA
• Drug: lysine-3,4-methylenedioxymethamphetamine
  A moderate dose of 171.7 mg lysine-MDMA will be administered.
  Other Name: lysine-MDMA
• Drug: lysine-3,4-methylenedioxyamphetamine
  A moderate dose of 165.6 mg lysine-MDA will be administered.
  Other Name: lysine-MDA
• Other: Placebo
  Placebo (Mannitol)

Study Arms

• Experimental: MDMA (100 mg MDMA-hydrochloride)
  MDMA (100 mg MDMA-hydrochloride; 84.1 mg MDMA free base)
  Intervention: Drug: 3,4-methylenedioxymethamphetamine
• Experimental: MDA (93.9 mg MDA-hydrochloride)
  MDA (93.9 mg MDA-hydrochloride; 78.0 mg MDA free base)
  Intervention: Drug: 3,4-methylenedioxyamphetamine
• Experimental: lysine-MDMA (171.7mg lysMDMA dihydrochloride
  lysine-MDMA (171.7mg lysMDMA dihydrochloride; 84.1 mg MDMA free base)
  Intervention: Drug: lysine-3,4-methylenedioxymethamphetamine
• Experimental: lysine-MDA (165.6 mg lysMDA dihydrochloride;
  lysine-MDA (165.6 mg lysMDA dihydrochloride; 78.0 mg MDA free base)
  Intervention: Drug: lysine-3,4-methylenedioxyamphetamine
• Placebo Comparator: Placebo
  Placebo
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 14, 2021): 24
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2023
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age between 18 and 65 years old
2. Sufficient understanding of the German language
3. Understanding of procedures and risks associated with the study
4. Willing to adhere to the protocol and signing of the consent form
5. Willing to refrain from the consumption of illicit psychoactive substances during the study
6. Abstaining from xanthine-based liquids from the evenings prior to the study sessions to the end of the study days
7. Willing not to operate heavy machinery within 48 hours after substance administration
8. Willing to use double-barrier 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 or bipolar disorder in first-degree relatives
4. Hypertension (>140/90 mmHg) or hypotension (SBP<85 mmHg)
5. Hallucinogenic substance or MDMA use more than 20 times or use of any illicit substance within the previous two months (not including cannabis)
6. Pregnancy or current breastfeeding
7. Participation in another clinical trial (currently or within the last 30 days)
8. Use of medication that may interfere with the effects of the study medication
9. Tobacco smoking (>10 cigarettes/day)
10. Consumption of alcoholic beverages (>20 drinks/week)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Matthias E Liechti, MD; 61 328 68 68 ext +41; matthias.liechti@usb.ch

Contact: Isabelle Straumann, MSc; 61 328 43 68 ext +41; isabelle.straumann@usb.ch

• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT04847206
• Other Study ID Numbers: BASEC 2021-00405
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: University Hospital, Basel, Switzerland
• Study Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Not Provided

Investigators

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

• PRS Account: University Hospital, Basel, Switzerland
• Verification Date: December 2021