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.

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.

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)