Effects of SERT Inhibition on the Subjective Response to LSD in Healthy Subjects

LSD

Brief Summary

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.

Intervention / Treatment

2-period cross-over, randomized, double-blind (paroxetine vs. placebo) study
  • Paroxetine (DRUG)
    Paroxetine (per os) will be used as pharmacological tool to downregulate 5-HT1/2 receptors.
  • Lysergic Acid Diethylamide (DRUG)
    LSD (per os) will be used to see if 5-HT 1/2 receptors were downregulated by paroxetine.
  • Placebo (DRUG)
    Placebo (per os) for the Paroxetine condition will be used to compare the data from the study day with LSD between both arms.

Condition or Disease

  • Healthy

Phase

  • Phase 1

    • Study Design

    Study type: INTERVENTIONAL
    Status: Active, not recruiting
    Study results: No Results Available
    Age: 25 Years to 65 Years
    Enrollment: 24 (ESTIMATED)
    Funded by: Other
    Allocation: Randomized
    Primary Purpose: Basic Science

    Masking

    Triple (Participant, Care Provider, Investigator)

    TRIPLE:
    • Participant
    • Care Provider
    • Investigator

    Clinical Trial Dates

    Start date: Oct 24, 2022 ACTUAL
    Primary Completion: Apr 01, 2024 ESTIMATED
    Completion Date: Apr 01, 2024 ESTIMATED
    Study First Posted: Jan 03, 2022 ACTUAL
    Last Updated: Aug 30, 2023

    Sponsors / Collaborators

    Lead Sponsor: University Hospital, Basel, Switzerland
    Lead sponsor is responsible party
    Responsible Party: N/A

    Location

    Basel, Basel-Stadt, Switzerland

    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).

    Participant Groups

    • Pretreatment with paroxetine (10 mg daily for 1 week followed by 20 mg daily for 5 weeks, per os), followed by administration of LSD (0.1 mg, per os) on the study day

    • Pretreatment with placebo for 6 weeks (mannitol, per os), followed by administration of LSD (0.1 mg, per os) on the study day

    Eligibility Criteria

    Sex: All
    Minimum Age: 25
    Maximum Age: 65
    Age Groups: Adult / Older Adult
    Healthy Volunteers: Yes

    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).

    Primary Outcomes

    • 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.

    • 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.

    Secondary Outcomes

    • 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.

    • 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.

    • 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.

    • 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)".

    • Repeatedly measured using blood pressure / pulse apparatus (mmHg scale)

    • Repeatedly measured using blood pressure / pulse apparatus (beats per minute scale)

    • Repeatedly measured using ear thermometer (degree Celsius scale)

    • Paroxetine plasma concentrations will be measured repeatedly over time using LC-MS/MS techniques (nanogram per milliliter scale)

    • LSD plasma concentrations will be measured repeatedly over time using LC-MS/MS techniques (nanogram per milliliter scale)

    • 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.

    • 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).

    More Details

    NCT Number: NCT05175430
    Acronym: SERT-LSD
    Other IDs: BASEC 2021-02223
    Study URL: https://clinicaltrials.gov/study/NCT05175430
    Last updated: Sep 29, 2023