LSD Treatment for Persons With Alcohol Use Disorder

Study Overview
=================
Brief Summary
-----------------
Alcohol use causes more overall harm than any other drug and is the seventh leading risk factor for both deaths and disability-adjusted life years. Alcohol use disorders (AUD) are among the most common and undertreated mental disorders in developed countries. Pharmacological and psychotherapeutic treatments only show limited efficacy and around 60% of the patients relapse in the short-term after withdrawal. Lysergic acid diethylamide (LSD) was investigated in numerous clinical trials during the 1950s and 1960s. Specifically, the use of LSD in the treatment of AUD was investigated extensively. A pooled analysis of six historical clinical trials demonstrated, that a single dose of LSD significantly reduced alcohol use at three and six months after LSD administration. However, these trials are limited by several factors, including the use of diagnostic standards that are no longer not up to date, single, high-dose treatment regimes, missing biological assessment for alcohol use, and no consequent assessment of blinding. Therefore, the present study aims to evaluate the safety and efficacy of LSD for the treatment of AUD and addresses the shortcomings of previous studies. The trial has a double-blind, active placebo-controlled, randomized, parallel design and will be conducted in specialized treatment centers for addictive disorders in Switzerland. The study will include 126 patients after withdrawal treatment and will primarily assess the efficacy of LSD for the treatment of AUD. Patients will be treated using a 1:1 allocation. Each arm will last 20 weeks and will comprise nine study visits without drug administration and two study days involving LSD or active placebo administration. In the first session, patients in the treatment group will receive a dose of 150 µg LSD, followed by another 150 µg or 250 µg LSD in the second session, which will take place approximately 4 weeks after the first session. The primary outcome is the mean of percent heavy drinking days after administration of two doses of LSD at 3 months follow-up. Additionally, the study will assess neurobiological mechanisms of action and several other measures.

Official Title
-----------------
LSD Treatment for Persons With Alcohol Use Disorder: A Multicenter, Double-blind, Randomized, Active-placebo Controlled Phase II Study

Conditions
-----------------
Alcohol Use Disorder (AUD)

Intervention / Treatment
-----------------
* Drug: LSD
* Drug: Active placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key inclusion criteria: age ≥ 25 years moderate to severe AUD completion of a qualified detoxification for AUD within 30 days prior to screening a minimum of 4 heavy drinking days within the last 30 days before detoxification intention to stop or decrease drinking Key exclusion criteria: significant alcohol withdrawal symptoms at screening participating or starting in any formal treatment for AUD until completion of visit 9 cognitive impairment borderline personality disorder current post-traumatic stress disorder current suicidality or history of a serious suicide attempt significant prodromal symptoms history of a diagnosis of a psychotic or bipolar disorder in subjects or first-degree relatives pregnancy or breast-feeding lack of safe contraception are exclusion criterion for women only

Ages Eligible for Study
-----------------
Minimum Age: 25 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verum<br>Subjects in the treatment arm will receive 150 μg LSD (first session) and 150 or 250 μg LSD (second session). | Drug: LSD<br>* Moderate to high dose LSD<br>|
| Active Comparator: Active placebo<br>Subjects in the control arm will receive 10 µg LSD at the first session and 10 µg LSD at the second session. | Drug: Active placebo<br>* Low dose LSD<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent heavy drinking days | The primary outcome is the mean of percent heavy drinking days after administration of two doses of LSD assessed with the alcohol timeline follow-back (TLFB) questionnaire compared between treatment groups | Period of three months after the second intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortical thickness measured with MRI | Changes in the cortical thickness of ACC, PCC, and PFC | Two weeks before first administration, two and 12 weeks after second administration | 
| The volume of the striatum measured with MRI | Changes in the volume of the striatum | Two weeks before first administration, two and 12 weeks after second administration | 
| White matter microstructure measured with MRI | Changes in white matter microstructure in the cingulum bundle and the PFC-striatal connection pathway | Two weeks before first administration, two and 12 weeks after second administration | 
| Days to first heavy drinking day | Days to first heavy drinking day after first and second administration assessed with TLFB | Three months after the second intervention | 
| Days to first drinking day | Days to first drinking day assessed after first and second administration assessed with TLFB | Three months after the second intervention | 
| Percent days abstinent | Percent days abstinent after first and second administration assessed with TLFB | Three months after the second intervention | 
| Drinks per drinking day | Drinks per drinking day after first and second administration assessed with TLF | Three months after the second intervention | 
| Adverse consequences of alcohol use | Adverse consequences of alcohol use assessed with Short Inventory of Problems | Three months after the second intervention | 
| Craving | Craving assessed with Obsessive Compulsive Drinking Scale | Three months after the second intervention | 
| Ethyl glucuronide | Ethyl glucuronide (EtG) in hair | Screening and three months after the second intervention | 
| Phosphatidylethanol | Phosphatidylethanol (PEth) in blood | Screening, day of first intervention, day of second intervention, three months after the second intervention | 
| General health | General health assessed with General Health Questionnaire | Three months after the second intervention | 
| Depression | Hamilton Depression Rating Scale | Three months after the second intervention | 
| Anxiety | Beck Anxiety Inventory | Three months after the second intervention | 
| Blinding | Blinding will be assessed directly after each session by asking patients and therapists to guess the group assignment (high dose, low dose, don't know) and to provide their degree of certainty (using a visual analogue scale) of their guess. | In the evening after administration 1 (week 4) and administration 2 (week 8), respectively | 
| Safety: Adverse events | Adverse events will be documented at each visit and each session. | Week 0 to week 20 |