Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic acting on the serotonin 5-HT2A receptor. LSD is used recreationally and in psychiatric research. First studies suggest efficacy in psychiatric disorders, such as depression and anxiety. SSRIs like paroxetine are first-line treatments for depression and anxiety disorders. Paroxetine acts as a serotonin transporter (SERT) inhibitor. However, the link between this mechanism and its positive effects on mood remains to be established. Several studies suggest a possible downregulation of postsynaptic serotonin (5-HT) receptors such as the 5-HT2A receptor. The aim of the study is to assess whether SERT inhibition reduces expression of the gene coding for the 5-HT2A receptor and the response to LSD.

Participants will be treated with paroxetine (Paroxetine 10 mg daily for 1 week followed by 20 mg daily for 5 weeks) or placebo for 6 weeks. Pretreatment is followed the first study day. A single dose of LSD (0.1 mg) will be administered. Primary study endpoint are the subjective effects on consciousness (5D-ASC total score). Secondary study endpoints include additional psychological measurements, plasma concentrations of LSD and paroxetine, as well as some safety measures (autonomic effects, ECG). The washout between the first study day and the second pretreatment will be at least 2 days. In the second pretreatment period, participants will be treated with placebo or paroxetine (cross-over) for another 6 weeks. This is followed by the second study day and administration of LSD (0.1 mg).

Based on a power analysis the sample size is 24 participants (12 female and 12 male).

Inclusion Criteria:

• Understanding of the German language.
• Understanding the procedures and the risks that are associated with the study.
• Participants must be willing to adhere to the protocol and sign the consent form.
• Participants must be willing to refrain from taking illicit psychoactive substances during the study.
• Participants must be willing to abstain from xanthine-based liquids from the evenings prior to the study sessions and during the sessions.
• Participants must be willing not to drive a traffic vehicle or to operate machines within 48h after substance administration.
• Willing to use double-barrier birth control throughout study participation.
• Body mass index between 18-29 kg/m2.

Exclusion Criteria:

• Chronic or acute medical condition, including a history of seizures.
• Current or previous major psychiatric disorder (e.g. psychotic disorders, mania / hypomania, anxiety disorders).
• Psychotic disorder in first-degree relatives, not including psychotic disorders secondary to an apparent medical reason, e.g. brain injury, dementia, or lesions of the brain.
• Hypertension (SBP>140/90 mmHg) or hypotension (SBP<85 mmHg); QT-time>450 ms (men) or >470 ms (women).
• Use of hallucinogenic substances (not including cannabis) more than 20 times or any time within the previous two months.
• History of acute glaucoma.
• Pregnant or nursing women.
• Participation in another clinical trial (currently or within the last 30 days).
• Use of medications that may interfere with the effects of the study medications (any psychiatric medications and any medication with known pharmacokinetic or pharmacodynamic interactions with paroxetine).
• Tobacco smoking (>10 cigarettes/day).
• Consumption of alcoholic drinks (>20 drinks/week).

Triple (Participant, Care Provider, Investigator)