Effects of MDMA-like Substances in Healthy Subjects

This Phase 1 interventional trial (n=24) will explore the effects of MDMA-like substances in healthy subjects. Conducted by the University Hospital, Basel, Switzerland, the study’s principal investigator is Matthias E. Liechti, Prof. Dr. MD.

The primary aim is to directly compare the effects of MDMA (3,4-methylenedioxymethamphetamine) and its psychoactive metabolite MDA (3,4-methylenedioxyamphetamine) in healthy volunteers. This study is significant for being the first to concurrently evaluate the effects of these two substances using modern psychological and psychometric tests. Another focus is the assessment of lysine-conjugated forms of MDMA and MDA (lysine-MDMA and lysine-MDA) to see if slower-release formulations can mitigate rapid euphoria, anxiety, and blood pressure changes associated with standard MDMA/MDA.

Participants, aged 18-65 and in good health, will be recruited to partake in this study, which excludes those with major psychiatric disorders, recent illicit substance use, or heavy tobacco and alcohol consumption. The trial will use a two-factorial design to assess differences between MDMA and MDA, and their lysine versions, with a keen interest in the onset and intensity of drug effects. Set to be completed by December 2023 (but current status is ‘unknown’), this study aims to contribute substantially to the understanding of MDMA and MDA’s impact on serotonin (5-HT) and oxytocin release and their potential therapeutic applications.

Trial Details

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.

NCT Number NCT04847206

Data attribution

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