Effects of MDMA-like Substances in Healthy Subjects

NCT ID: NCT04847206

Last Updated: 2024-08-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

23 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-12-01

Study Completion Date

2024-06-18

Brief Summary

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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

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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.

Conditions

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Healthy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

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
Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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MDMA (100 mg MDMA-hydrochloride)

MDMA (100 mg MDMA-hydrochloride; 84.1 mg MDMA free base)

Group Type EXPERIMENTAL

3,4-methylenedioxymethamphetamine

Intervention Type DRUG

A moderate dose of 100 mg MDMA will be administered.

MDA (93.9 mg MDA-hydrochloride)

MDA (93.9 mg MDA-hydrochloride; 78.0 mg MDA free base)

Group Type EXPERIMENTAL

3,4-methylenedioxyamphetamine

Intervention Type DRUG

A moderate dose of 93.9 mg MDA will be administered.

lysine-MDMA (171.7mg lysMDMA dihydrochloride

lysine-MDMA (171.7mg lysMDMA dihydrochloride; 84.1 mg MDMA free base)

Group Type EXPERIMENTAL

lysine-3,4-methylenedioxymethamphetamine

Intervention Type DRUG

A moderate dose of 171.7 mg lysine-MDMA will be administered.

lysine-MDA (165.6 mg lysMDA dihydrochloride;

lysine-MDA (165.6 mg lysMDA dihydrochloride; 78.0 mg MDA free base)

Group Type EXPERIMENTAL

lysine-3,4-methylenedioxyamphetamine

Intervention Type DRUG

A moderate dose of 165.6 mg lysine-MDA will be administered.

Placebo

Placebo

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

Placebo (Mannitol)

Interventions

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3,4-methylenedioxymethamphetamine

A moderate dose of 100 mg MDMA will be administered.

Intervention Type DRUG

3,4-methylenedioxyamphetamine

A moderate dose of 93.9 mg MDA will be administered.

Intervention Type DRUG

lysine-3,4-methylenedioxymethamphetamine

A moderate dose of 171.7 mg lysine-MDMA will be administered.

Intervention Type DRUG

lysine-3,4-methylenedioxyamphetamine

A moderate dose of 165.6 mg lysine-MDA will be administered.

Intervention Type DRUG

Placebo

Placebo (Mannitol)

Intervention Type OTHER

Other Intervention Names

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MDMA MDA lysine-MDMA lysine-MDA

Eligibility Criteria

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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)
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University Hospital, Basel, Switzerland

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Matthias E Liechti, Prof. Dr. MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

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University Hospital Basel, Clinical Trial Unit

Basel, Canton of Basel-City, Switzerland

Site Status

Countries

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Switzerland

References

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Straumann I, Vizeli P, Avedisian I, Erne L, Noorshams D, Vukalovic I, Eckert A, Luethi D, Rudin D, Liechti ME. Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants. Neuropsychopharmacology. 2025 Sep 25. doi: 10.1038/s41386-025-02248-3. Online ahead of print.

Reference Type DERIVED
PMID: 40999236 (View on PubMed)

Other Identifiers

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BASEC 2021-00405

Identifier Type: -

Identifier Source: org_study_id

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