Effects of MDMA Co-administration on the Response to LSD in Healthy Subjects (LSD-MDMA)

The acute subjective effects of serotonin (5-HT)2A receptor stimulation with lysergic acid diethylamide (LSD) 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 LSD is taken (setting). Negative psychedelic effects may cause acute distress to the subject and acute anxiety has been linked to less favourable long-term outcomes in patients experimentally treated with LSD or similar substances for the treatment of depression. The 5-HT and oxytocin releaser 3,4-methylenedioxymethamphetamine (MDMA) reliably induces positive mood up to euphoria, comfort, empathy, and feelings of trust. If administered in combination with LSD, MDMA may increase positive subjective drug effects including positive mood, empathy, and trust and reduce negative emotions and anxiety associated with LSD and overall produce a more positive over negative experience. The present study will assess subjective and autonomic effects of LSD alone and in combination with MDMA.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Lysergic Acid Diethylamide; Other: MDMA Placebo; Drug: 3,4-methylenedioxymethamphetamine; Other: LSD Placebo

Detailed Description

LSD is a so-called "classic" or serotonergic hallucinogen or psychedelic. Its psychedelic effects are mainly attributed to its potent partial serotonin (5-HT) 5-HT2A receptor agonism. The effects of LSD have been frequently investigated in the past in both healthy participants and patients. Several of these studies described robust and sustained effects of LSD in patients suffering from addiction, anxiety and depression. The acute subjective effects elicited by LSD are mostly positive in humans. However, psychedelic substances like LSD 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 LSD 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 yet to be determined. 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. Therefore, there is a need for methods which are capable of reducing bad drug effects while enhancing good drug effects to optimize a psychedelic experience.

The present study uses 3,4-methylenedioxymethamphetamine (MDMA) as a pharmacological tool to optimize LSD's effects profile 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 (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • BS
    • Basel, BS, Switzerland, 4056
      • University Hospital Basel, Clinical Trial Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 25 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 and during the sessions
7. Willing not to operate heavy machinery within 48 h of 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 (SBP>140/90 mmHg) or hypotension (SBP<85 mmHg)
5. Use of hallucinogenic substances (not including cannabis) more than 20 times or any time within the previous two months
6. Use of MDMA more than 20 times or any time within the previous two months
7. Pregnancy or currently breastfeeding
8. Participation in another clinical trial (currently or within the last 30 days)
9. Use of medication that may interfere with the effects of the study medication
10. Tobacco smoking (>10 cigarettes/day)
11. Consumption of alcoholic beverages (>20 drinks/week)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 100 μg LSD + MDMA placebo	Drug: Lysergic Acid Diethylamide; A moderate dose of 100 μg LSD will be administered.; Other Names: LSD; Other: MDMA Placebo; Mannitol capsules instead of capsules containing MDMA
Experimental: LSD placebo +100 mg MDMA	Drug: 3,4-methylenedioxymethamphetamine; A moderate dose of 100 mg MDMA will be administered.; Other Names: MDMA; Other: LSD Placebo; Pure alcohol instead of an alcoholic solution containing LSD
Experimental: 100 μg LSD + 100 mg MDMA	Drug: Lysergic Acid Diethylamide; A moderate dose of 100 μg LSD will be administered.; Other Names: LSD; Drug: 3,4-methylenedioxymethamphetamine; A moderate dose of 100 mg MDMA will be administered.; Other Names: MDMA
Placebo Comparator: LSD placebo+ MDMA placebo	Other: MDMA Placebo; Mannitol capsules instead of capsules containing MDMA; Other: LSD Placebo; Pure alcohol instead of an alcoholic solution containing LSD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute subjective effects I	Visual Analog Scales (VAS) assessing the intensity and duration of subjective effects on a scale from 0% - 100% with higher scores representing more intense effects	12 months
Acute subjective effects II	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"	12 months
Acute subjective effects III	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	12 months
Autonomic effects I	Assessed 18 times on each study day via systolic and diastolic blood pressure	12 months
Autonomic effects II	Assessed 18 times on each study day via heart rate	12 months
Autonomic effects III	Assessed 18 times on each study day via tympanic body temperature	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of LSD	Assessed 18 times on each study day via blood samples	12 months
Plasma levels of MDMA	Assessed 18 times on each study day via blood samples	12 months
Plasma levels of blood-derived neurotrophic factor (BDNF)	Assessed 21 times on each study day via blood samples	12 months
Plasma levels of oxytocin	Assessed 4 times on each study day via blood samples	12 months
Psychological Insight Questionnaire	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")	12 months
States of Consciousness Questionnaire	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")	12 months
Spiritual Realms Questionnaire	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	12 months
Effect moderation through personality traits I	Assessed via NEO-Five-Factor-Inventory (NEO-FFI)	Baseline
Effect moderation through personality traits II	Assessed via Freiburger Personality Inventory (FPI)	Baseline
Effect moderation through personality traits III	Assessed via Saarbrücker Personality Questionnaire (SPF)	Baseline
Effect moderation through personality trait IV	Assessed via HEXACO personality inventory	Baseline
Effect moderation through personality trait V	Assessed via Defense Style Questionnaire (DSQ-40)	Baseline

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): August 22, 2022
• Study Completion (Actual): August 22, 2022

Study Registration Dates

• First Submitted: August 13, 2020
• First Submitted That Met QC Criteria: August 13, 2020
• First Posted (Actual): August 18, 2020

Study Record Updates

• Last Update Posted (Actual): August 23, 2022
• Last Update Submitted That Met QC Criteria: August 22, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Serotonin Receptor Agonists; Serotonin Antagonists; Hallucinogens; Adrenergic Uptake Inhibitors; N-Methyl-3,4-methylenedioxyamphetamine; Lysergic Acid Diethylamide
• Other Study ID Numbers: BASEC 2020-01829

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No