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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
24
Paroxetine (per os) will be used as pharmacological tool to downregulate 5-HT1/2 receptors.
LSD (per os) will be used to see if 5-HT 1/2 receptors were downregulated by paroxetine.
Placebo (per os) for the Paroxetine condition will be used to compare the data from the study day with LSD between both arms.
Clinical Pharmacology & Toxicology, University Hospital Basel
Basel, Switzerland
5 dimensions of altered state of consciousness (5D-ASC) total OAV score
Visual analog scale consisting of 94 items. Constructed of five scales and allows assessing mood, anxiety, derealization, depersonalization, changes in perception, auditory alterations, and reduced vigilance. Scales will be presented as 100 mm long horizontal lines marked with vertical lines by the participant.
Time frame: Study sessions per participant will be separated by at least 43 days
Visual Analog Scales (VAS) good effect rating
VAS will be presented as 100 mm long horizontal lines marked with "not at all" on the left and "extremely" on the right. The following VAS items will be used: "any drug effect", "good drug effect", "bad drug effect", "drug high", "anxiety", "nausea", "feeling depressed", "alteration of vision", "alterations of hearing", "sounds seem to influence what I see", "alteration of sense of time", "the boundaries between myself and my surroundings seem to blur", "I gain insights into contexts that were previously were inscrutable to me", "talkative", "open", "trust" and "the context of my thought is personal/impersonal". Subjects will mark the scale with vertical lines.
Time frame: Study sessions per participant will be separated by at least 43 days
Adjective mood rating scale (AMRS)
The adjective mood rating scale (AMRS or EWL60S) is a 60-item Likert scale that allows repeated assessment of mood in 6 dimensions: activation, inactivation, well-being, anxiety/depressed mood, extroversion and introversion, and emotional excitability.The AMRS consists of subscales measuring "activation", "positive mood", "extroversion", "introversion", "inactivation", and "emotional excitability.
Time frame: Study sessions per participant will be separated by at least 43 days
States of consciousness questionnaire (SCQ)
This 100-item questionnaire is rated on a six-point scale. Forty-three items embedded into this questionnaire comprise the Mystical Experience Questionnaire (MEQ). which is sensitive to the effects of psilocybin. The 43 items provide scale scores for each of seven domains of mystical experiences: internal unity (pure awareness, a merging with ultimate reality), external unity (unity of all things, all things are alive, all is one), sense of sacredness (reverence, sacred), noetic quality (encounter with ultimate reality, more real than everyday reality), transcendence of time and space, deeply felt positive mood (joy, peace, love), paradoxicality/ineffability (claim of difficulty in describing the experience in words). We will also derived the four scale scores of the newly validated revised 30-item MEQ: mystical, positive mood, transcendence of time and space, and ineffability.
Time frame: Study sessions per participant will be separated by at least 43 days
Spiritual Realm Questionnaire (SRQ)
This questionnaire has recently been developed by linguist and psychologist K. Stocker, Swiss Federal Institute of Technology Zürich and University of Zürich, to rate psychedelic (entheogenic) experiences with a focus on spiritual aspects insufficiently covered by the 5D-ASC and SCQ. The scale includes 11 main questions to be answered on a total of 65 sub-ordered visual rating scales. Results will be used to validate the scale and will be analyzed similar to the 5D-ASC using paired t-tests and comparing the constructs defined by the 11 main questions contained within the four main dimensions religious-psychological spirituality spectrum of humanity, human condition and life meaningfulness, dealing with personal problems, and worldview/belief.
Time frame: Study sessions per participant will be separated by at least 43 days
Psychological Insight Questionnaire (PIQ)
This is a newly developed instrument to assess the degree to which an event has facilitated acute insight and gained awareness into emotions, behaviors, beliefs, memories, or relationships. The 14 items resulting from a recent validation process are to be rated on a 6-point Likert scale ranging from 0 = "No; not at all" to 5 = "Extremely (more than ever before in my life)".
Time frame: Study sessions per participant will be separated by at least 43 days
Blood pressure
Repeatedly measured using blood pressure / pulse apparatus (mmHg scale)
Time frame: Study sessions per participant will be separated by at least 43 days
Heart rate
Repeatedly measured using blood pressure / pulse apparatus (beats per minute scale)
Time frame: Study sessions per participant will be separated by at least 43 days
Body temperature
Repeatedly measured using ear thermometer (degree Celsius scale)
Time frame: Study sessions per participant will be separated by at least 43 days
Plasma concentrations of paroxetine
Paroxetine plasma concentrations will be measured repeatedly over time using LC-MS/MS techniques (nanogram per milliliter scale)
Time frame: Study sessions per participant will be separated by at least 43 days
Plasma concentrations of LSD
LSD plasma concentrations will be measured repeatedly over time using LC-MS/MS techniques (nanogram per milliliter scale)
Time frame: Study sessions per participant will be separated by at least 43 days
HTR gene expression
Messenger ribonucleic acid (mRNA) expression levels in whole blood as a peripheral marker of spiny neuronal gene (CNS) expression will be used to measure expression of HTR genes as well as expression of the SERT gene.
Time frame: Study sessions per participant will be separated by at least 43 days
Changes in the electrocardiogram (ECG)
Corrected QT time (QTc) will be measured twice on the study days (baseline and at peak drug effect) to examine possible drug-induced changes in the ECG as well as a safety measure (millisecond scale).
Time frame: Study sessions per participant will be separated by at least 43 days
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