dOccLS: LSD Occupancy of the Serotonin 2A Receptor in the Human Brain

Sponsor

Rigshospitalet, Denmark (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05953038

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators wish to quantify the relation between administered dose of lysergic acid diethylamide (LSD), plasma LSD levels, and occupancy at the serotonin 2A receptor (5-HT2AR) using [11C]CIMBI-36 positron emission tomography.

Condition or Disease	Intervention/Treatment	Phase
Basic Science	Drug: Lysergic Acid Diethylamide Tartrate	Early Phase 1

Detailed Description

Healthy participants will be administered one of a single dose of lysergic acid diethylamide (LSD) between 25 and 200 micrograms equivalent freebase. They will receive [11C]CIMBI-36 positron emission tomography (PET) scans at baseline and twice following LSD administration during peak and declining drug effects. PET scans will be acquired in a simultaneous PET/Magnetic Resonance Imaging (MRI) scanner which will also collect functional brain imaging data. Venous blood samples will be repeatedly drawn during acute drug effects for quantification of plasma LSD levels. Participants will also repeatedly rate their subjective drug intensity on a scale from 0 to 10 during acute drug effects. Together these data will inform the dose-binding relation of LSD at the serotonin (5-HT) 2A receptor, the primary site of action. This data will also inform the relation between 5-HT2A receptor binding by LSD and the induced subjective effects, as well as the effects on functional brain activity as measured with functional MRI.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Each participant will be given one of 25, 50, 75, 100, 125, 150, 175 or 200 micrograms of lysergic acid diethylamide (LSD) equivalent as freebase.Each participant will be given one of 25, 50, 75, 100, 125, 150, 175 or 200 micrograms of lysergic acid diethylamide (LSD) equivalent as freebase.

Masking:

None (Open Label)

Masking Description:

Participants will be blinded with respect to dose only.

Primary Purpose:

Basic Science

Official Title:

Lysergic Acid Diethylamide Occupancy of the Serotonin 2A Receptor in the Human Brain

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LSD dose-ranging group All participants will receive between 25 and 200 micrograms of lysergic acid diethylamide equivalent as freebase, single blinded with respect to dose. Simultaneous PET/MR imaging will be performed during acute drug effects.	Drug: Lysergic Acid Diethylamide Tartrate D-Lysergic Acid Diethylamide (LSD) D-tartrate as oral drinking solution (water / ethanol 20% m/m) Other Names: LSD d-LSD LSD-25

Arm

Intervention/Treatment

Experimental: LSD dose-ranging group

All participants will receive between 25 and 200 micrograms of lysergic acid diethylamide equivalent as freebase, single blinded with respect to dose. Simultaneous PET/MR imaging will be performed during acute drug effects.

Drug: Lysergic Acid Diethylamide Tartrate

D-Lysergic Acid Diethylamide (LSD) D-tartrate as oral drinking solution (water / ethanol 20% m/m)

Other Names:

LSD

d-LSD

LSD-25

Outcome Measures

Primary Outcome Measures

Plasma LSD - serotonin 2A receptor (5-HT2AR) occupancy relation [Within 24 hours following drug administration]
Occupancy will be estimated by comparing non-displaceable binding potential (BPND) values using baseline and intervention rescans as calculated using a simplified reference tissue model (SRTM). Occupancy values will be compared to plasma lysergic acid diethylamide (LSD) levels.

Secondary Outcome Measures

Subjective drug intensity - 5-HT2AR occupancy relation [Within 24 hours following drug administration]
Occupancy will be calculated as described above. Subjective drug intensity is collected during positron emission tomography (PET) scans by asking participants.
fMRI network disintegration - 5-HT2AR occupancy relation [Within 24 hours following drug administration]
functional magnetic resonance imaging (fMRI) data will be used to estimate functional-network connectivity using a standard functional brain atlas. Then the relation between decreases in functional network connectivity and 5-HT2AR occupancy will be estimated.
fMRI brain entropy - 5-HT2AR occupancy relation [Within 24 hours following drug administration]
fMRI brain entropy will be estimated by the shannon entropy of dynamic conditional correlation of within and between network connectivity as well as the lempel-ziv complexity of concatenated binarised blood-oxygen level dependent (BOLD) signals across regions. The relation between each of these measures with 5-HT2AR occupancy will be estimated.
Cerebral perfusion - 5-HT2AR occupancy relation [Within 24 hours following drug administration]
Cerebral perfusion will be estimated using arterial spin labelling. The relation between this measure and 5-HT2AR occupancy will be estimated.
Administered LSD dose - 5-HT2AR occupancy relation [Within 24 hours following drug administration]
Administered dose (25 to 200 mcg) will be compared with peak LSD occupancy to determine what doses produce maximal occupancy at the 5-HT2AR.

Other Outcome Measures

Hysteresis effect of 5-HT2AR binding [Within 24 hours following drug administration]
Estimated dose-occupancy curves derived from the first PET scan and second PET scan will be calculated separately to evaluate whether there are differences in estimated plasma level-occupancy relation at different timepoints following LSD administration which may indicate a hysteresis effect due to peripheral LSD metabolism without unbinding of LSD from the 5-HT2A receptor.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

• Healthy individual between 18-75 years old

Exclusion Criteria:

Current or past history of primary psychiatric illness (The Diagnostic and Statistical Manual of Mental Disorders IV axis-I or World Health Organisation International Classification of Diseases-10 diagnostic classification)
Current or past history of primary psychiatric illness (The Diagnostic and Statistical Manual of Mental Disorders IV axis-I or World Health Organisation International Classification of Diseases-10 diagnostic classification) in a first degree relative (i.e., parents, siblings)
Current or past history of neurological disease, significant somatic condition/disease
Use of medication that could potentially influence results (e.g.., drugs that act on relevant components of the serotonin system or may interfere with metabolism of study drug)
Non-fluent Danish language skills
Profound visual or auditory impairments
Severe learning disability
Pregnancy on the scan date, verified by a pregnancy test (test omitted if confirmed that individual is post-menopausal)
Lactation (females)
Contraindications for magnetic resonance imaging (e.g., pacemaker, claustrophobia, etc.)
Contraindications for positron emission tomography
Alcohol or drug abuse
Allergy to administered compounds
Participant in research study with >10 millisievert exposure within the past year or significant occupational exposure to radioactive substances
Abnormal ECG (ECG indicating current or previous heart disease or predisposition to heart disease, e.g., QT prolongation) or use of QT prolonging medication
Use of psychedelic substance within the preceding six months
Blood donation up to three months before the study (i.e., more than 500ml of blood)
Head injury or concussion resulting in loss of consciousness for more than 2 min
Haemoglobin levels < 7.8 mmol/l for women and 8.4 mmol/l for men
Ferritin levels outside normal range (12-300 µg/L)
Body-weight < 50 kg or > 110kg
body-mass index > 35
Individual assessment by research staff deeming drug administration unsafe due to ethical or psychological circumstance of the participant