LSD Treatment for Persons With Alcohol Use Disorder (LYTA)

Investigating the Efficacy and Microstructural Plasticity of LSD Treatment in Patients With Alcohol Use Disorder: A Multicenter, Double-blind, Randomized, Active-placebo-controlled Phase II Neuroimaging Study.

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 up to date, single, high-dose treatment regimes, missing biological assessment for alcohol use, and no consequent assessment of blinding.

This trial will assess the efficacy and safety of two moderate to high doses of LSD to decrease alcohol consumption in patients with AUD. 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 128 patients who have undergone detoxification. Participants will be allocated to one of the two intervention arms (1:1 allocation). Each arm comprises nine study visits (no drug administration) and two study days (involving LSD administration) within 30 weeks. Patients allocated to the control intervention (active placebo group) will receive 10 µg LSD on the first study day and either 10 or 20 µg LSD on the second study day. Patients allocated to the treatment intervention will receive 150 µg LSD on the first study day and either 150 µg or 250 µg LSD on the second study day. The dose will be retained or increased depending on the patient's individual response on the first study day. Participants in the control intervention will be offered to attend an open-label LSD session (150 µg) at week 31. The open-label phase will comprise three additional visits. This trial will further compare the effectiveness of LSD-assisted therapy in both group and individual therapeutic settings. To this end, participants in both drug conditions will be randomly assigned to group or individual settings.

The primary outcome is the mean of percent heavy drinking days after administration of two doses of LSD during the 12 weeks following the second administration. Secondary objectives: The second aim of this study is to explore long-term changes in the cortical thickness, white matter microstructure, resting state functional connectivity (rs-FC) and cerebral blood flow (CBF) of regions associated with addiction pathophysiology. Furthermore, we will assess alterations in depressive symptoms, anxiety, and persisting effects of LSD. We will also assess biological markers of alcohol use and several predictors for treatment-response (genetics, personality traits, blinding, expectancy, and quality of acute drug effects). Lastly, we will compare LSD treatment within a group setting with treatment within an individual setting.

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder (AUD)
• Intervention / Treatment: Drug: LSD; Drug: Active placebo

Detailed Description

Patients will be followed up six months after the second administration in the double-blind phase. At this time point, a predefined subset of the questionnaires used in the main study will be administered (TLFB, SIP-2R, OCDS, drinking goals, self-efficacy, BSCL, BDI, and BAI; see below).

During the open-label phase, patients will be assessed one month after administration. This assessment will include a subset of questionnaires (TLFB, OCDS, BSCL, BAI, BDI, CHIME, WHOQOL-BREF, drinking goals, self-efficacy, and WVQ; see below). In addition, the open-label phase will include assessments of acute drug effects, expectancy, and adverse events (see below).

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Felix Müller, PD Dr. med.; Phone Number: +41 (0)61 325 5111; Email: felix.mueller@upk.ch

Study Locations

• Switzerland
  • Basel, Switzerland
    • Recruiting
    • University Hospital of Psychiatry, University of Basel
    • Principal Investigator: Felix Müller, PD Dr. med.
  • Bern, Switzerland
    • Recruiting
    • University Hospital of Psychiatry, University of Bern
    • Sub-Investigator: Leila Soravia, Prof. Dr. phil.
    • Principal Investigator: Tobias Bracht, Prof. Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key inclusion criteria:

• Age ≥ 25 years
• Participants must meet the DSM-5 criteria for a moderate to severe alcohol use disorder and must intend to stop or decrease their drinking for at least the duration of the study
• Participants must have underwent an alcohol detoxification within the 60 days prior to screening or, in cases where no detoxification is necessary, must have been abstinent for at least 14 days.
• A minimum of 4 HDD within the last 30 days before detoxification or cessation of alcohol use (a HDD is defined as 5 or more standard drinks per day for a man and 4 drinks for a woman; a standard drink is defined as 12 g of alcohol)

Key exclusion criteria:

• Significant alcohol withdrawal symptoms at screening
• Participating or starting in any formal treatment for AUD from visit 1 until completion of the double-blind phase
• Treatment with disulfiram during the study
• Past or present diagnosis of a DSM-5 psychotic or bipolar disorder in subjects or first-degree relatives
• Current suicidality or history of a serious suicide attempt

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Verum; Subjects in the treatment arm will receive 150 μg LSD (first session) and 150 or 250 μg LSD (second session).	Drug: LSD; Moderate to high dose LSD
Active Comparator: Active placebo; Subjects in the control arm will receive 10 µg LSD at the first session and 20 µg LSD at the second session.	Drug: Active placebo; Low dose LSD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent heavy drinking days	The primary outcome is the mean percentage of 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 administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical thickness measured with MRI	Changes in the cortical thickness of the ACC, PCC, and PFC	One month after the first administration, one month after second administration
The volume of the striatum measured with MRI	Changes in the volume of the striatum	One month after the first administration, one month after second administration
White matter microstructure measured with MRI	Changes in white matter microstructure in the cingulum bundle and the PFC-striatal connection pathway	One month after the first administration, one month after second administration
Days to first heavy drinking day	Days to first heavy drinking day after the first and second administration assessed with TLFB	One month after the first administration, one, two, and three months after the second administration
Days to first drinking day	Days to first drinking day assessed after the first and second administration assessed with TLFB	One month after the first administration, one, two, and three months after the second administration
Percent days abstinent	Percent days abstinent after the first and second administration assessed with TLFB	One month after the first administration, one, two, and three months after the second administration
Drinks per drinking day	Drinks per drinking day after the first and second administration assessed with TLFB	One month after the first administration, one, two, and three months after the second administration
Percent heavy drinking days	Percent heavy drinking days assessed with TLFB	One month after the first administration
Adverse consequences of alcohol use	Adverse consequences of alcohol use assessed with the Short Inventory of Problems (SIP-2R) questionnaire	Three months after the second administration
Craving	Craving assessed with the Obsessive Compulsive Drinking Scale (OCDS)	Three weeks after the first administration, three weeks, two and three months after the second administration
Ethyl glucuronide	Ethyl glucuronide (EtG) in hair	Three months after the second administration
Phosphatidylethanol	Phosphatidylethanol (PEth) in blood	At each administration and three months after the second administration
Perceived quality of life across multiple domains	Quality of life assessed with the World Health Organization Quality of Life Scale (WHOQOL-bref)	One and two months after the second administration
Depression	Beck Depression Inventory (BDI)	Three weeks after the first administration, one and three months after the second administration
Anxiety	Beck Anxiety Inventory (BAI)	Three weeks after the first administration, one and three months after the second administration
Various somatic and psychological symptoms	Various somatic and psychological symptoms assessed with the Brief Symptom Checklist (BSCL)	Three weeks after the first administration, one and three months after the second administration
World view	World views will be assessed using the World View Questionnaire (WVQ)	Three weeks after the first administration, three weeks after the second administration
Persisting effects	Persisting effects of LSD assessed with the Persisting Effects Questionnaire (PEQ)	Three months after the second administration
Mindfulness	Mindfulness will be assessed using the Comprehensive Inventory of Mindfulness Experience (CHIME)	Three weeks after the first administration, three weeks after the second administration, two months after the second administration
Acute effects of LSD	Acute effects assessed with the 5 Dimensions of Altered States of Consciousness (5D-ASC)	The day after the first and the day after the second administration
Acute effects of LSD	Acute effects assessed with the Mystical Experience Questionnaire (MEQ30)	The day after the first and the day after the second administration
Acute effects of LSD	Acute effects assessed with the General Change Mechanisms Questionnaire (GCMQ)	The day after the first and the day after the second administration
Acute effects of LSD	Acute effects assessed with the Phenomenological-Autobiographical-Existential Psychedelic Scale extended (PAE-PS-ext)	The day after the first and the day after the second administration
Blinding	Blinding will be assessed directly after session 1 with a self-developed questionnaire that includes participants' guesses of their group assignment and their degree of certainty, rated on a visual analogue scale.	In the evening after the first administration
Expectancy	Expectancy will be assessed with the Credibility / Expectancy Questionnaire (CEQ). Therapists' expectancy will also be assessed	Two weeks before the first administration
Self-efficacy	Self-efficacy will be assessed using a visual analogue scale	Three weeks after the first administration, three weeks after the second administration, two and three months after the second administration
Drinking goals	Drinking goals will be assessed using pre-defined response options	Three weeks after the first administration, three weeks after the second administration, two and three months after the second administration
Safety: Adverse events	Adverse events will be documented at each visit and each session.	Week 0 to week 18
Qualitative Interview	Qualitative interview regarding subjective experiences of acute drug effects, benefits, possible negative effects, as well as the subjective concept of the potential psychological mechanisms	Three months after the second administration

Collaborators and Investigators

• Sponsor: Felix Mueller
• Collaborators: University of Bern

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2026
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: July 24, 2022
• First Posted (Actual): July 26, 2022

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Heterocyclic Compounds, 4 or More Rings; Ergot Alkaloids; Ergolines; Lysergic Acid; Lysergic Acid Diethylamide
• Other Study ID Numbers: 2024-02125

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No