A clinical trial of 5 mg psilocybin plus psychological support vs 25 mg psilocybin plus psychological support in adults with generalised anxiety disorder

Approved 24/09/2024, East of Scotland Research Ethics Service (EoSRES) (Tayside Medical Science Centre, George Pirie Way, Ninewells Hospital, Dundee, DD1 9SY, United Kingdom; +44 1224 558458; tay.eosres@nhs.scot), ref: 24/ES/0060

The efficacy of two doses of 25 mg psilocybin with psychological support versus two doses of 5 mg psilocybin with psychological support in the reduction of GAD symptoms in participants with severe GAD (who may or may not be taking concurrent selective serotonin reuptake inhibitor (SSRI) antidepressant). This will be calculated by assessing the change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at week 8, irrespective of treatment discontinuation.

1. Change in GAD symptoms measured using Generalised Anxiety Disorder 7-item Scale (GAD-7) from baseline to weeks 4, 8, 11, 20 and 29. The GAD-7 score is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of “not at all,” “several days,” “more than half the days,” and “nearly every day,” respectively, and then adding together the scores for the seven questions. GAD-7 total score for the seven items ranges from 0 to 21, with scores of 5, 10, and 15 representing cut-points for mild, moderate, and severe anxiety, respectively.
2. Change in GAD symptoms measured using HAM-A from baseline to weeks 3, 4, 7, 11, 20 and 29. Each item is scored on a basic numeric scoring of 0 (not present) to 4 (severe): >17/56 is taken to indicate mild anxiety; 25–30/56 is considered moderate–severe.
3. Rates of GAD clinical response (>50% reduction in baseline HAM-A) and remission (>7 on HAM-A) at weeks 3, 4, 8, 11, 20 and 29.
4. Change in impairment of functioning via the change in Sheehan Disability Scale (SDS) from baseline to weeks 4, 8, 11, 20 and 29. Respondents are asked to indicate how much their symptoms have disrupted their regular activities over the past week, and each subscale can be scored independently or combined into a single total score representing a global impairment rating, ranging from 0 to 30, with higher scores indicative of significant functional impairment. Subscale scores greater than 5 suggest impairment in that subscale area.
5. Change in satisfaction with quality of life via change in Warwick–Edinburgh Mental Well-being Scale (WEMWBS) from baseline to weeks 4, 8, 11, 20 and 29. The scale is scored by summing responses to each item answered on a 1 to 5 Likert scale. The minimum scale score is 14 and the maximum is 70.
6. Change in loss of workplace productivity via the change in Lost Workplace Productivity (LWP) measure from baseline to weeks 4, 8, 11, 20 and 29. Lost productivity is calculated as follows: LWP = A + [B *(1-C)]. Where A = Hours Missed from paid job(s) because of symptoms, B = Hours working at paid job(s) despite interference of symptoms, C = Percent effectiveness while working at paid job(s). Variables A and B are collected via the SDS. Variable C is collected through an additional question asking participants to estimate “On days that you went to school or work in the last week despite feeling impaired by your symptoms, how effective do you feel that you were?” This is scored as a percentage where 0% = completely impaired; no work was achieved and 100% = completely unimpaired; achieved the same amount of work as without symptoms.
7. Change in utilisation of healthcare services via the change in Healthcare Utilisation (HU) measure from baseline to weeks 4, 8, 11, 20 and 29. Frequency data will be collected on previous 3-month utilisation of various healthcare services including primary care (visits to GPs, health clinics, psychologists, psychiatrists, dentists, physiotherapists, counsellors, mental health clinic or other primary care providers), hospitalisations, and emergency department (ED) visits.
8. Change in depression symptoms via the change in Patient Health Questionnaire - depression module (PHQ-9), measured from baseline to weeks 4, 8, 11, 20 and 29Participants rate how often they have been bothered by a given symptom over the past two weeks, with response options 0 (not at all), 1(several days), 2 (more than half the days) 3 (nearly every day). Total scores range from 0 to 27 with scores of ≥5, ≥10, ≥20 representing mild, moderate and severe levels of depression, respectively, and a total score above 10 suggestive of meeting diagnostic criteria for MDD.
9. Emotional breakthrough during the psychedelic experience measured using the Emotional Breakthrough Inventory (EBI) at each dosing session. The EBI consists of six statements such as “I felt able to explore challenging emotions and memories” and asks about “emotional release”, “closure”, “emotional breakthrough” and “resolution of conflict”. Participants rate the extent to which they agree with each statement on a 0–100 scale (with 0 being “No, not more than usually” and 100 being “Yes, entirely or completely”).
10. Safety and tolerability via adverse events (AE) associated with participation in the trial including vitals (blood pressure, heart rate, respiratory rate, temperature), Electrocardiogram (ECG) and Colombia Suicide Severity Rating Scale (C-SSRS) from baseline through to week 29.
11. Proportion of the total number of participants who complete both dosing sessions.
12. Efficacy of masking via the efficacy of masking questionnaire at each dosing session (Visit 6 and Visit 10). The response will be captured using a 5-point Likert-type scale with anchors: I am positive I received the high dose drug, I think I received the high dose drug, I cannot tell whether I received the high dose drug or the low dose drug, I think I received the low dose drug, I am positive I received the low dose drug.

Exploratory outcome measures:
13. The correlation between participants’ expectancy of improvement, GAD symptoms and patient impressions of change in each arm via the Credibility-Expectancy Questionnaire (CEQ) at each dosing visit and HAM-A and Patient Global Impression of Change (PGIC) at weeks 4, 8, 11, 20 and 29.
14. The correlation between therapeutic alliance and rapport, the quality of the psychedelic experience and GAD symptoms in each arm via the Sesson Rating Scale (SRS) at each psychological support session, EBI at each dosing session and HAM-A at weeks 4, 8, 11, 20 and 29.

EEG/ECG outcome measures:
1. Change in resting-state connectivity and complexity and heart rate variability via 10 min resting-state EEG and ECG at baseline and weeks 4, 8, and 29. These are collected during two resting state conditions: eyes open (EO) for a 5-minute duration and eyes closed (EC) for another 5 minutes. During the eyes-open condition, participants are directed to concentrate on a cross displayed on the screen, and for the eyes-closed condition, participants are instructed to remain relaxed while ensuring they do not fall asleep.
2. Change in neural responses to emotional faces via the Emotional faces task (EEG, performance and ECG) at baseline and weeks 4, 8, and 29. During the training session of the task, 36 face images with either a happy, sad or neutral expression are sequentially presented to the participant and subsequently repeated for a total of two views and the participant is instructed to memorize the images. Following the training session, the same target images are interspersed in 36 additional nontarget emotional face images. The participant indicates whether the images are target or nontarget with a keystroke. For each acquisition, three repetitions of the task are administered sequentially for a total of 108 Target and 108 nontarget stimuli for analysis and a total duration of 24 minutes.
3. Change in auditory habituation via the Auditory Oddball task (EEG, performance and ECG) at weeks 4, 8 and 29. The AO task plays a standard tone with a frequency of 1000 Hz (non-target) and a duration of 150 ms, and a deviant tone with a frequency of 500 Hz (target) with a duration of 150 ms. Participants are instructed to press the space bar as quickly as possible in response to the deviant (target) tone and ignore the standard (non-target) tone. A total of 500 stimuli (80 percent standard and 20 percent deviant) will be played with an inter-stimulus interval of 1 second. The total task duration is 8 minutes.
4. Correlation between change in resting-state EEG connectivity with change in clinical measures via the resting-state EEG/ECG correlates of HAM-A, GAD-7, SDS, WEMWBS, LWP, HU and PHQ-9 at baseline, week 4, 8 and 29. Correlation between change in neural responses to emotional faces and change in clinical measures via the Emotional faces tasks and auditory oddball EEG correlates of HAM-A, GAD-7, SDS, WEMWBS, LWP, HU & PHQ-9 at baseline and week 4, 8 and 29.