Basic Science
Conditions
Keywords
Lysergic acid diethylamide, PET, Psychedelic, Hallucinogen, Physiological Effects of Drugs, Psychotropic Drugs, Ergolines, Serotonin, Serotonin Agents, Neurotransmitter Agents, Molecular Mechanisms of Pharmacological Action
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.
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.
Interventions
D-Lysergic Acid Diethylamide (LSD) D-tartrate as oral drinking solution (water / ethanol 20% m/m)
Sponsors
Rigshospitalet, Denmark
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
Participants will be blinded with respect to dose only.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Denmark
Contacts
PRINCIPAL_INVESTIGATORGitte M Knudsen, DMsc, MD
Rigshospitalet, Denmark
Outcome results
None listed