Comparative Acute Effects of LSD, Psilocybin and Mescaline

Study Overview
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Brief Summary
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LSD, psilocybin and mescaline are widely used for recreational and ethnomedical purposes. All three substances are thought to induce prototypical psychedelic effects primarily via stimulation of the 5-HT2A receptor. However, there are differences in the substances' molecular structures and receptor activation profiles which may induce differential subjective effects. To date, there are no modern studies comparing LSD, psilocybin and mescaline directly within the same clinical study and research subjects using validated psychometric tools. Therefore, the LPM-Study compares the acute effects of LSD, psilocybin, mescaline and placebo in a double-blind, placebo-controlled, 4-period cross-over design with four treatment conditions: 1) 100 μg LSD, 2) 20 mg psilocybin, 3) 300 or 500 mg mescaline, and 4) placebo.

Detailed Description
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LSD (lysergic acid diethylamide), psilocybin (the active substance in magic mushrooms) and mescaline (the active substance in Peyote and San Pedro cacti) are serotonergic hallucinogens widely used for recreational and/or ethnomedical purposes. LSD, psilocybin and mescaline are thought to induce prototypical psychedelic effects primarily via stimulation of the 5-HT2A receptor. However, there are differences in their molecular structures (LSD: ergoline, psilocybin: tryptamine; mescaline: phenethylamine)and receptor activation profiles which may induce different subjective effects. To date, there are no modern studies comparing these three substances directly within the same clinical study and research subjects using validated psychometric tools. Therefore, the LPM-Study compares the acute effects of LSD, psilocybin, mescaline and placebo in a double-blind, placebo-controlled, 4-period cross-over design with four treatment conditions: 1) 100 μg LSD, 2) 20 mg psilocybin, 3) 300 or 500 mg mescaline, and 4) placebo. The main objective of this study is to determine whether LSD, psilocybin and mescaline produce qualitatively similar subjective alterations of mind and associated brain activity patterns despite their unique receptor activation profiles. The study investigates psychological (psychometry), physiological and neuronal (magnetic resonance imaging) variables. The LPM-Study provides insight into the acute effects profiles of three serotonergic hallucinogens. It will enhance the understanding of psychedelic-induced altered states of consciousness in humans and will be relevant for the fields of psychiatry, psychology, and forensic toxicology.

Official Title
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Comparative Acute Effects of LSD, Psilocybin and Mescaline in a Random-Order Placebo-Controlled Cross-Over Study in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: LSD
* Drug: Psilocybin
* Drug: Mescaline
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 25 and 65 years old Sufficient understanding of the German language Understanding of procedures and risks associated with the study Willing to adhere to the protocol and signing of the consent form Willing to refrain from the consumption of illicit psychoactive substances during the study Abstaining from xanthine-based liquids from the evenings prior to the study sessions to the end of the study days Willing not to operate heavy machinery within 48 hours 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 Current or previous major psychiatric disorder Psychotic disorder or bipolar disorder in first-degree relatives Hypertension (>140/90 mmHg) or hypotension (SBP<85 mmHg) Hallucinogenic substance use (not including cannabis) more than 20 times or any time within the previous two months Pregnancy or current breastfeeding Participation in another clinical trial (currently or within the last 30 days) Use of medication that may interfere with the effects of the study medication Tobacco smoking (>10 cigarettes/day) Consumption of alcoholic beverages (>20 drinks/week) Failure of MRI-related criteria

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind, placebo-controlled, 4-period cross-over design with four treatment conditions
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LSD-100<br>Cross-over within-subject design with all treatment conditions, separated by a wash-out phase of at least 10 days | Drug: LSD<br>* LSD 0.1 mg per os, single dose OR Psilocybin 20 mg per os, single dose OR Mescaline 300 mg per os, single dose OR Placebo<br>|
| Active Comparator: Psilocybin-20<br>Cross-over within-subject design with all treatment conditions, separated by a wash-out phase of at least 10 days | Drug: Psilocybin<br>* Psilocybin 20 mg per os, single dose<br>|
| Active Comparator: Mescaline-300/500<br>Cross-over within-subject design with all treatment conditions, separated by a wash-out phase of at least 10 days | Drug: Mescaline<br>* Mescaline 300 mg or 500 mg per os, single dose<br>|
| Placebo Comparator: Placebo<br>Cross-over within-subject design with all treatment conditions, separated by a wash-out phase of at least 10 days | Other: Placebo<br>* Placebo (Mannitol)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5 Dimensions of Altered States of Consciousness (5D-ASC) | 5D-ASC subscale ratios | 18 months | 
| fMRI resting state functional connectivity (RSFC) | Spontaneous low-frequency fluctuations in BOLD signal during resting state | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale (VAS) | Assesses the intensity and duration of subjective effects on a scale from 0% - 100% with higher scores representing more intense effects | 18 months | 
| States of Consciousness questionnaire (SCQ) | Assesses the emergence and intensity of phenomenons occurring in altered states of consciousness on a 6-point Likert scale ranging from 0 (not at all) to 5 (extremely) | 18 months | 
| Blood pressure | Assessment of sympathetic activation | 18 months | 
| Heart rate | Assessment of sympathetic activation | 18 months | 
| Body temperature | Assessment of sympathetic activation | 18 months | 
| Pupil size | Assessment of sympathetic activation | 18 months | 
| Drug plasma levels | Plasma levels of investigational drugs | 18 months | 
| Oxytocin levels | Levels of oxytocin in blood plasma | 18 months | 
| Blood-derived neurotrophic factor (BDNF) | Blood plasma levels of BDNF | 18 months | 
| Renal clearance values | Renal clearance values of investigational drugs through urine recovery | 18 months | 
| NEO-Five-Factor-Inventory (NEO-FFI) | Assesses personality traits | 18 months | 
| Freiburger Persönlichkeitsinventar (FPI) | Assesses personality traits | 18 months | 
| Saarbrücker Persönlichkeitsfragebogen (SPF) | Assesses personality traits | 18 months | 
| Adjective Mood Rating Scale (AMRS) | Assesses the occurrence and intensity of 60 moods on a 4-point Likert scale ranging from not at all to extremely | 18 months | 
| Mysticism Scale (MS) | Assesses the occurrence and intensity of mystical qualities in altered states of consciousness on a 9-point Likert scale ranging from -4 (extremely inapplicable) to +4 (extremely applicable), with higher values indicating a more intense experience | 18 months | 
| Elliot Humility Scale (EHS) | Assesses the personality trait humility through 13 items on a 5-point Likert scale ranging from strongly disagree to strongly agree | 18 months | 
| Jankowski Humility Scale (JHS) | Assesses the personality trait humility through 18 items on a 5-point Likert scale ranging from not at all to strongly | 18 months | 
| Arnett Inventory of Sensation Seeking (AISS-d) | Assesses personality traits | 18 months |