Lysergic Acid Diethylamide (LSD) in Palliative Care

Study Overview
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Brief Summary
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Background: Terminally ill patients often experience significant psychosocial distress having depressed mood, death anxiety, pain, and an overall poor quality of life. Recent evidence from pilot studies suggests that serotonergic hallucinogens including lysergic acid diethylamide (LSD) and psilocybin produce significant and sustained reductions of depressive symptoms and anxiety, along with increases in quality of life, and life meaning in patients suffering from life-threatening diseases. Additionally, serotonergic hallucinogens may produce antinociceptive effects. Objective and Design: The study aims to evaluate effects of LSD on psychosocial distress in 60 patients suffering from an end-stage fatal disease with a life expectancy ≥12wks and ≤2yrs in an active placebo-controlled double-blind parallel study. Patients will be allocated in a 2:1 ratio to one of the two intervention arms receiving either two moderate to high doses of LSD (100 µg and 100 µg or 100 µg and 200 µg) as intervention and two low doses of LSD (25 µg and 25 µg) as active-placebo control.

Official Title
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Lysergic Acid Diethylamide (LSD) in Palliative Care: a Randomised, Double-blind, Active-placebo Controlled Phase II Study (LPC-Study)

Conditions
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Palliative Care, Pain, Anxiety, Depression, Demoralization, Psychological Distress, Quality of Life, Caregiver Burden, Fear of Death, Existential Distress

Intervention / Treatment
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* Drug: Lysergic Acid Diethylamide Tartrate
* Drug: Lysergic Acid Diethylamide Tartrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 25 years. End-stage fatal disease of any cause with a life expectancy ≥ 12 weeks and ≤ 2 years Sufficient understanding of the study procedures and risks associated with the study. Participants must be willing to adhere to the study procedures and sign the consent form. Participants must be willing not to drive a traffic vehicle or to operate machines within 24 h after LSD administration. Participants must complete an actual Emergency Medical Directive Exclusion Criteria: Life expectancy < 12 weeks Known hypersensitivity to LSD Requiring ongoing concomitant therapy with a psychoactive prescription drug which might interfere with the study drug, and unable or unwilling to comply with the washout period. Current use of a potent drug CYP2D6 inhibitor Women who are pregnant or nursing or intend to become pregnant during the course of the study. Somatic disorders including CNS involvement of cancer, epilepsy with a history of seizures, history of delirium, end-stage heart failure (NYHA IV), untreated hypertension or insufficiently treated hypertension, angina pectoris, severe liver disease or severely impaired renal function, or other that in the judgement of the investigators pose too great potential for side effects. Inability to follow the procedures of the study, e.g., due to language problems, psychological disorders, dementia, etc. of the participant. Participation in another study with an investigational drug within the 30 days preceding and during the present study concomitant diagnosis of past or present psychotic disorder concomitant diagnosis of past or present bipolar disorder substance use disorder (within the last 2 months, except nicotine, opioids used for analgesia, and benzodiazepine treatment for anxiety). Weight < 45 kg Suicidal ideation with active intent or plan to act on suicidal thoughts as assessed by the treating investigator.

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment arm<br>Subjects in the treatment arm will receive 100 μg LSD (first session) and 100 or 200 μg LSD (second session) per os. | Drug: Lysergic Acid Diethylamide Tartrate<br>* 100 or 200 μg p.o.<br>* Other names: LSD;|
| Active Comparator: control arm<br>Subjects in the control arm will receive 25 μg LSD (first session) and 25 μg LSD (second session) per os. | Drug: Lysergic Acid Diethylamide Tartrate<br>* 25 μg p.o.<br>* Other names: LSD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in state anxiety assessed by questionnaire (state anxiety inventory, STAI-S) compared with active placebo | State anxiety inventory (STAI-S) scores, 20 items | baseline, 2 weeks after second intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in state anxiety assessed by questionnaire (state anxiety inventory, STAI-S) compared with active placebo | State anxiety inventory (STAI-S) scores, 20 items | baseline, 2 days after each intervention, 4 weeks, 6 weeks, and 9 weeks after second intervention | 
| Changes in pain levels assessed by questionnaire compared with active placebo | numeric rating scale (NRS) scores ranging from 0 (no pain) to 10 (maximum imaginable pain) | baseline, 2 days after each intervention and 2 weeks after second intervention; 4 weeks, 6 weeks, and 9 weeks after second intervention | 
| Changes in opioid use (dosages of opioids unified according to equivalent dosages of oral morphine) compared with active placebo |  | concomitant medication will be assessed several times over whole study duration up to 9 weeks after second intervention | 
| Changes in spiritual well-being assessed by questionnaires (Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being; The 12-item Spiritual Well-Being Scale (FACIT-Sp-12)) compared with active placebo | Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being; The 12-item Spiritual Well-Being Scale (FACIT-Sp-12) scores | baseline, 2 days after each intervention and 2 weeks after second intervention; 4 weeks, 6 weeks, and 9 weeks after second intervention | 
| Changes in demoralization assessed by questionnaires (Demoralization Scale II (DS-II)) compared with active placebo | Demoralization Scale II (DS-II) scores | baseline, 2 days after each intervention and 2 weeks after second intervention; 4 weeks, 6 weeks, and 9 weeks after second intervention | 
| Changes in quality of life assessed with a single-item question compared with active placebo | single-item question how satisfied are you currently with your physical and emotional well-being rated on a 7-point scale (1 dissatisfied, 7 satisfied) | baseline, 2 days after each intervention and 2 weeks after second intervention; 4 weeks, 6 weeks, and 9 weeks after second intervention | 
| Changes in anxiety, pain levels, quality of life, demoralization, and spiritual well-being shortly after first intervention compared with scores shortly after second intervention | State anxiety inventory (STAI-S), NRS, QoL single-item, Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being; The 12-item Spiritual Well-Being Scale (FACIT-Sp-12), and Demoralization Scale II (DS-II) scores | post drug visit 1-3 compared with post drug visit 4-6 | 
| Changes in patient's depression, isolation, anxiety, fear and denial of imminence of death, and pre-occupation with pain using investigator-ratings compared with active placebo | Emotional Condition Rating Scale (ECRS) scores, Hamilton depression (GRID-HAM-D17) and Hamilton anxiety rating scale (HAM-A) scores | baseline, one day before second intervention and 2 and 9 weeks after second intervention | 
| Changes in patient's behaviour and attitudes rated by community observers compared with active placebo | community observer rating: rating of the participant's behaviour and attitudes on 11 items by a contact person | baseline, before second intervention and 2 weeks and 9 weeks after second intervention | 
| Changes in caregiver burden assessed by questionnaire compared with active placebo | Zarit Burden Inventory (ZBI) scores completed by caregiver, total score | baseline, before second intervention and 2 weeks and 9 weeks after second intervention | 
| Associations between acute LSD effects assessed with questionnaires and long-lasting therapeutic effects assessed with questionnaires | acute effects will be assessed using the Mystical experience Questionnaire (MEQ30) and visual analogue scales (VASs) | 2,4,6, and 9 weeks after second intervention | 
| Changes in burden of suffering assessed with the Pictorial Representation of Illness and Self-Measure (PRISM) compared with active placebo |  | baseline, 2 days after each intervention, 2 weeks and 9 weeks after the second intervention | 
| Qualitative description of subjective changes after intervention assessed with semistructured interviews |  | baseline, 2 days after each intervention, 2 weeks and 9 weeks after second intervention | 
| Expectancy as a mediator for treatment effects assessed with questionnaire | modified version of the Credibility / Expectancy Questionnaire (CEQ) | baseline | 
| Assessment of adverse events (AE) | grading according to Common Terminology Criteria for Adverse Events CTCAE Version 5.0, safety measures | during the whole study duration up to 9 weeks after second intervention | 
| Physical and general discomfort during drug sessions using standardized questions (adapted list of complaints) | adapted list of complaints (LC), safety measures | before and 12 hours after drug administration | 
| Changes in vital signs during drug sessions | monitoring blood pressure and heart rate with an automatic oscillometric device, safety measure | before and up to 12 hours after drug administration | 
| Changes in vital signs during drug sessions | monitoring body temperature using an ear thermometer, safety measure | before and up to 12 hours after drug administration |