Alcohol Use Disorder (AUD)
Conditions
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 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.
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).
Interventions
DRUGLSD
Moderate to high dose LSD
DRUGActive placebo
Low dose LSD
Sponsors
Felix Mueller
University of Bern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent heavy drinking days | Period of three months after the second administration | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cortical thickness measured with MRI | One month after the first administration, one month after second administration | Changes in the cortical thickness of the ACC, PCC, and PFC |
| The volume of the striatum measured with MRI | One month after the first administration, one month after second administration | Changes in the volume of the striatum |
| White matter microstructure measured with MRI | One month after the first administration, one month after second administration | Changes in white matter microstructure in the cingulum bundle and the PFC-striatal connection pathway |
| Days to first heavy drinking day | One month after the first administration, one, two, and three months after the second administration | Days to first heavy drinking day after the first and second administration assessed with TLFB |
| Days to first drinking day | One month after the first administration, one, two, and three months after the second administration | Days to first drinking day assessed after the first and second administration assessed with TLFB |
| Percent days abstinent | One month after the first administration, one, two, and three months after the second administration | Percent days abstinent after the first and second administration assessed with TLFB |
| Drinks per drinking day | One month after the first administration, one, two, and three months after the second administration | Drinks per drinking day after the first and second administration assessed with TLFB |
| Percent heavy drinking days | One month after the first administration | Percent heavy drinking days assessed with TLFB |
| Adverse consequences of alcohol use | Three months after the second administration | Adverse consequences of alcohol use assessed with the Short Inventory of Problems (SIP-2R) questionnaire |
| Craving | Three weeks after the first administration, three weeks, two and three months after the second administration | Craving assessed with the Obsessive Compulsive Drinking Scale (OCDS) |
| Ethyl glucuronide | Three months after the second administration | Ethyl glucuronide (EtG) in hair |
| Phosphatidylethanol | At each administration and three months after the second administration | Phosphatidylethanol (PEth) in blood |
| Perceived quality of life across multiple domains | One and two months after the second administration | Quality of life assessed with the World Health Organization Quality of Life Scale (WHOQOL-bref) |
| Depression | Three weeks after the first administration, one and three months after the second administration | Beck Depression Inventory (BDI) |
| Anxiety | Three weeks after the first administration, one and three months after the second administration | Beck Anxiety Inventory (BAI) |
| Various somatic and psychological symptoms | Three weeks after the first administration, one and three months after the second administration | Various somatic and psychological symptoms assessed with the Brief Symptom Checklist (BSCL) |
| World view | Three weeks after the first administration, three weeks after the second administration | World views will be assessed using the World View Questionnaire (WVQ) |
| Persisting effects | Three months after the second administration | Persisting effects of LSD assessed with the Persisting Effects Questionnaire (PEQ) |
| Mindfulness | Three weeks after the first administration, three weeks after the second administration, two months after the second administration | Mindfulness will be assessed using the Comprehensive Inventory of Mindfulness Experience (CHIME) |
| Acute effects of LSD | The day after the first and the day after the second administration | Acute effects assessed with the 5 Dimensions of Altered States of Consciousness (5D-ASC) |
| Blinding | In the evening after the first administration | 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. |
| Expectancy | Two weeks before the first administration | Expectancy will be assessed with the Credibility / Expectancy Questionnaire (CEQ). Therapists' expectancy will also be assessed |
| Self-efficacy | Three weeks after the first administration, three weeks after the second administration, two and three months after the second administration | Self-efficacy will be assessed using a visual analogue scale |
| Drinking goals | Three weeks after the first administration, three weeks after the second administration, two and three months after the second administration | Drinking goals will be assessed using pre-defined response options |
| Safety: Adverse events | Week 0 to week 18 | Adverse events will be documented at each visit and each session. |
| Qualitative Interview | Three months after the second administration | Qualitative interview regarding subjective experiences of acute drug effects, benefits, possible negative effects, as well as the subjective concept of the potential psychological mechanisms |
Countries
Switzerland
Contacts
CONTACTFelix Müller, PD Dr. med.
Outcome results
None listed