Clinical trial NCT05163496
Conditions: Burnout, Caregiver Burnout, Professional COVID-19 Depression Post Traumatic Stress Disorder Moral Injury
Keywords: psilocybin psychedelic assisted psychotherapy
Sponsor: University of Washington
Start date: 2022-03-03; Completion date: 2024-06-30
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to investigate the effects of a single dose of psilocybin, delivered in the contextof pre- and post-dose psychotherapy, on symptoms of depression and burnout suffered by healthcare clinicians as a result of frontline work in the COVID pandemic.

Detailed description:
Aim 1:

To assess short- and longer-term effects of psilocybin-assisted psychotherapy (PAP) on symptoms of depression experienced by physicians and nurses with frontline work exposure in the COVID pandemic.

Hypothesis 1.1: Compared to active placebo, PAP will result in short term improvement in symptoms of depression 1 day and 1 week after the psilocybin dose session. Hypothesis 1.2: Compared to active placebo, PAP will result in longer term improvement of symptoms of depression 4 weeks after the medication dosing session. The primary outcome will be a comparison between the psilocybin 25 mg vs control groups of a combination of depression symptoms measured at 4 weeks post medication dose session. 1.1.2. Aim 2: To explore short- and longer-term effects of psilocybin-assisted psychotherapy (PAP) on symptoms of burnout experienced by physicians and nurses with frontline work exposure in the COVID pandemic. Hypothesis 2.1: Compared to active placebo, PAP will result in short term improvement in symptoms of burnout 1 day and 1 week after the psilocybin dose session.

Arms: arm 1: psychedelic assisted psychotherapy + 25mg psilocybin arm 2: Psychedelic assisted psychotherapy + 250mg niacin
Interventions: intervention 1: Psilocybin (Usona Institute) intervention 2: Active placebo
Intervention descriptions: intervention 1: PAP + psilocybin 25 mg intervention 2: PAP + niacin 250mg

Protocol documents:
Prot_SAP_000.pdf: 
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Study Title:  
A randomized, placebo-controlled trial of psychedelic-assisted psychotherapy with single dose 
psilocybin for frontline clinicians experiencing COVID-related symptoms of depression and burnout 
 
 
 
 
 
Principal Investigator:  
Anthony Back MD 
University of Washington 
 
 
IND/IDE Sponsor:  
Anthony Back MD  
 
 
Protocol number: 
BACK001 
 
 
Revision 
July 18, 2022 
Version 1.16 
 
 
Funded by:  
Steven and Alexandra Cohen Foundation 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
Introduction ................................................................................................................................................ 3 
2. 
Study Design and Endpoints ....................................................................................................................... 16 
3. 
Research Materials and Measures .............................................................................................................. 18 
4. 
Participant Inclusion and Exclusion Criteria................................................................................................. 22 
5. 
Study Agent .............................................................................................................................................. 25 
6. 
Study Procedure and Schedule ................................................................................................................... 26 
7. 
Payments for Participation (Economic Considerations) ............................................................................... 32 
8. 
Assessment of Safety ................................................................................................................................. 32 
9. 
Statistical Considerations ........................................................................................................................... 36 
10. 
Ethics/Protection of Human Subjects ..................................................................................................... 37 
11. 
Data Handling and Record Keeping ........................................................................................................ 38 
12. 
Publication and Data Sharing Policy ...................................................................................................... 39 
13. 
Study Administration and Leadership ..................................................................................................... 39 
14. 
Conflict of Interest Policy ....................................................................................................................... 39 
15.  
References ............................................................................................................................................ 39 
 
 
 


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1. 
Introduction 
1.1. 
Statement of Purpose. 
We aim to investigate the effects of a single dose of psilocybin, delivered in the context 
of pre- and post-dose psychotherapy, on symptoms of depression and burnout suffered by 
healthcare clinicians as a result of frontline work in the COVID pandemic.  
 
1.1.1 
Aim 1:  
To assess short- and longer-term effects of psilocybin-assisted psychotherapy (PAP) on symptoms 
of depression experienced by physicians and nurses with frontline work exposure in the COVID pandemic. 
Hypothesis 1.1: Compared to active placebo, PAP will result in short term improvement in 
symptoms of depression 1 day and 1 week after the psilocybin dose session.   
Hypothesis 1.2: Compared to active placebo, PAP will result in longer term improvement of 
symptoms of depression 4 weeks after the medication dosing session. The primary outcome will be a 
comparison between the psilocybin 25 mg vs control groups of a combination of depression symptoms 
measured at 4 weeks post medication dose session.    
 
1.1.2. Aim 2:  
To explore short- and longer-term effects of psilocybin-assisted 
psychotherapy (PAP) on symptoms of burnout experienced by physicians and nurses with frontline work 
exposure in the COVID pandemic. 
Hypothesis 2.1: Compared to active placebo, PAP will result in short term improvement in 
symptoms of burnout 1 day and 1 week after the psilocybin dose session.  
 
1.2. 
Background and Rationale 
The COVID19 pandemic is associated with significant psychological morbidity for 
physicians and nurses with frontline work exposure. The experiences of these physicians and 
nurses include multiple, intense exposure to patients who are suffering and dying, stress related 
to clinical decision making under extreme uncertainty especially at the beginning of the 
pandemic, prolonged periods of work and vigilance leading to physical and emotional 
exhaustion, fear for their own safety and their families’ safety, and often extended separations 
from family related to self-quarantining because of risk to their families. In addition, stress from 
preparing for crisis standards of care that would require clinicians to make rationing decisions, 
moral injury from feeling that they were prevented from doing their best work, and 
disillusionment from layoffs that many health systems made to protect their financial status 
have compounded these stressors. Interviews of physicians and nurses published in the lay 
press have emphasized that ‘we’ll never be the same’1-3 and also that psychological morbidity 
occurs in physicians and nurses with no prior history of mental health issues or treatment.4-6  
The psychological morbidity for frontline physicians and nurses includes symptoms of 
depression, anxiety, burnout and post-traumatic stress. Front-line clinicians (physicians, nurse 
practitioners, physician assistants, nurses) in the COVID pandemic are experiencing high levels of 
psychological sequelae related to distress experienced in direct clinical care. In a study of health 
care workers in Wuhan, China, “a considerable proportion of participants reported symptoms of 
depression (634 [50.4%]), anxiety (560 [44.6%]), insomnia (427 [34.0%]), and distress (899 
[71.5%]).”7  In addition, “frontline health care workers engaged in direct diagnosis, treatment, 
and care of patients with COVID-19 were associated with a higher risk of symptoms of 
depression (OR, 1.52; 95%CI, 1.11-2.09; P = .01), anxiety (OR, 1.57; 95%CI, 1.22-2.02; P < .001), 
insomnia (OR, 2.97; 95%CI, 1.92-4.60; P < .001), and distress (OR, 1.60; 95%CI, 1.25-2.04; P < 
.001).7 A qualitative study found that “The intensive work drained health care providers 
physically and emotionally.”8  A physician suicide in the US to date attributed to medical work in 


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hospitals overwhelmed with COVID is notable for the complete lack of any depressive history in 
a physician who contracted COVID herself, returned to work, was hospitalized for severe 
depressive symptoms, and took her own life days after discharge.9  
These psychological symptoms of stress are somewhat different than existing DSM classifications 
of depression and anxiety disorders. An unpublished but publicly released national study of health care 
workers demonstrates that symptom severity is clearly related to intensity of exposure.10 Stressor 
frequency scores correlated significantly with PCL5 scores (R=.57, p<1e-8), PHQ scores (R=.35, P<.001), ISI 
scores (R=.38, p<1e-4), and GAD7 scores (R=.39, p<.001), likelihood of staying in current occupation (R=-
.39,p<1e-4), and trouble doing usual work (R=.33,p<.001). 51% of HCW and 44% of FR indicated decreased 
likelihood of staying in their current occupation. PCL5 scores substantially mediated the association 
between stress frequency scores and work function impairment. 
The implications for the medical workforce that the US needs for the continuing pandemic are 
substantial. An unpublished but publicly released survey of clinicians carried out by the Larry A Green 
center and the Primary Care Collaboration reported that 19% of survey respondents reported that 
clinicians in their practice had retired early because of COVID-19 or were planning on it.11 
Existing interventions for first responders, treated in disaster situations with some 
similarities to COVID have shown no impact on these psychological sequelae. A 2012 
systematic review concluded that “the literature is startlingly sparse and is not sufficient for 
evidence-based recommendations for first responders.12 A more recent 2020 systematic review 
of psychological interventions for first responders was also unable to find enough evidence to 
name any best practices.13 Thus while many physicians and nurses are already turning to existing 
treatments with antidepressant medications and psychotherapy, there is as yet no data 
supporting efficacy of these treatments—and data suggests that physicians in particular are not 
willing to be treated with antidepressants. In a study of over 700 resident physicians, where 17% 
scored positive for depression, only about a quarter of those scoring positive were receiving 
treatment (either prescribed through formal treatment, informally through a colleague, or self-
prescribed) for depression.14  Physicians have a negative incentive to seek any type of mental 
health care as many state licensing agencies require physicians to report mental health 
treatment and make this information publicly available. 
Psychedelic-assisted psychotherapy is a new, promising form of treatment for depression and 
other mental health disorders. Although psychedelic medications were widely used by psychiatrists in the 
1950s and 1960, and considered a ‘major breakthrough’ in the treatment of depression and other mental 
health conditions, changes in federal legislation banning the use of psychedelics heavily impacted the use 
of psilocybin, LSD, and other medications in 1970 with the Controlled Substances Act.15 Due to these 
changes, the available studies are from the 1950s and 1960s and these studies  often did not have the 
level of scientific rigor or gather the types of data that is commonplace today. However, self-reported user 
experience indicates that psychedelics are quite safe. The 2010 National Survey on Drug Use and 
Health, reporting a survey of 57,873 randomly selected Americans about their drug history , found that 
about 32 million Americans (or 17% of adults between 21 and 64) have used any psychedelic drugs at least 
once in their lifetimes.16  (The survey is limited as participants were not asked when they had used 
psychedelic medications.) 
 
A new wave of studies, starting in 2018, have shown that psychedelics, given in the context of 
carefully designed psychotherapy, can improve symptoms of depression for weeks and in some people, 
years. Randomized clinical trials of psychedelic-assisted psychotherapy, mostly using pharmaceutical grade 
synthesized psilocybin (the psychedelic in ‘magic mushrooms’) have shown strikingly positive findings, and 
led to a FDA designation for psilocybin as a ‘breakthrough treatment’.17 Earlier this year a randomized 
study of psilocybin-assisted psychotherapy for major depression (not treatment-resistant depression) 
showed strongly positive results.18 “The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 
[5.7]) in the immediate treatment group were statistically significantly lower than the scores 


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at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed 
treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95%CI, 1.4-3.0; 
P < .001) and week 8 (Cohen d = 2.6; 95%CI, 1.7-3.6; P < .001).” Moreover, the antidepressant effect was 
immediate—noted by participants on the first day after undergoing the supervised psilocybin ingestion.  
 
Because major depressive disorder typically has a different antecedent history than specific trigger 
of COVID pandemic work exposure suffered by physicians and nurses, another group of patients with 
depressive symptoms following a trigger is a useful comparison—patients with cancer. In two randomized 
studies of patients with cancer—many with incurable cancer—suffering symptoms of depression and 
anxiety, treatment with psilocybin-assisted psychotherapy resulted in very significant improvements in 
symptoms after a single treatment sequence of preparation psychotherapy, medication dosing with 
supervision, and follow up integration psychotherapy. In the study conducted by Ross at NYU19 (a 
consultant to this proposal), the results indicated “For each of the six primary outcome measures (HADS T, 
HADS A, HADS D, BDI, STAI S, STAI T), there were significant differences between the experimental and 
control groups (prior to the crossover at 7 weeks post-dose 1) with the psilocybin group 
(compared to the active control) demonstrating immediate, substantial, and sustained (up to 7 weeks 
post-dosing) clinical benefits in terms of reduction of anxiety and depression symptoms.”  
The scientific mechanism for these findings is that treatment with psilocybin-assisted 
psychotherapy occasions a kind of ‘reset’ in ruminative, self-critical inner narratives—patterns which can 
be completely changed with psychotherapy and psilocybin. One of the leading researchers in the field, at 
Imperial College London writes in a 2020 review in Cell that “We suggest one way of looking at the 
difference between them is that current medicines [e.g., SSRIs] suppress symptoms in a similar way that 
insulin suppresses hyperglycemia in diabetes. Standard antidepressants protect against the stressors 
that lead to and perpetuate depression, but don’t directly access and remedy underlying biopsychosocial 
causes. In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain via the 
effects of the drugs to facilitate insight and emotional release and, with psychotherapeutic support, a 
subsequent healthy revision of outlook and lifestyle.”15  
 
At the neurological level, psychedelics appear to open ‘a therapeutic window’ by dysregulating 
activity in brain circuits and systems that encode habits of thought and behavior. Psilocybin, perhaps the 
most intensively studies of the psychedelics, is a 5-Hydroxytryptamine 2A (5-HT2A) receptor agonist.20 The 
5-HT2A receptor is maximally expressed in the cerebral cortex, and thus treatment with psilocybin 
dysregulates cortical function that is associated with predictive processing that the brain normally 
undertakes to enable an individual to make decisions throughout the day. These psilocybin-induced 
changes in predictive processing result in both the altered perceptions often reported by individuals in the 
first 6 hours after ingesting psilocybin and more importantly, altered cognitions that can persist after the 
psilocybin effect has worn off—and these new cognitions are insights that are reinforced and articulated 
during the follow up integration psychotherapy.15  
Psychedelic-assisted psychotherapy with psilocybin has the evidence profile best suited to treat 
clinician COVID-related distress of all tested psychedelics because of its documented efficacy with 
symptoms of depression. To be fair, there is limited evidence for psilocybin-assisted psychotherapy to 
address symptoms of post-traumatic stress disorder, and a Phase 3 study is currently underway testing the 
efficacy of MDMA-assisted psychotherapy for PTSD from other causes.21 However, the MDMA Phase 3 
study does not target frontline clinicians, and is not designed to study clinician COVID-related distress. The 
suitability of MDMA for COVID-related distress is less clear in that no recent evidence exists to support the 
efficacy of MDMA-assisted psychotherapy for existential distress. There are older studies of MDMA for 
cancer patients, but those studies were conducted before validated measures of existential distress or 
post-traumatic stress were available,22 and ongoing studies have not been reported. Overall, because 
frontline clinician distress appears to contain major components of anxiety, depression, and existential 
distress, at this point in the state of the science, psilocybin is the psychedelic medication with the 
evidence profile best suited for COVID-related distress. 


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Psilocybin will be used in a proven pre- and post-dose psychotherapeutic process defined by 
prior research conducted by Griffiths and Ross.19,23 In these studies, psychotherapy involved 2 trained 
therapists for each study participant, and included Preparation sessions conducted in for 6-8 hours total 
(in 3 sessions) prior to a Psilocybin Dose session, followed by Integration sessions for 6-8 hours (again in 3 
sessions). These studies reported a few toxicities, and no severe adverse events. This psychotherapeutic 
context of Preparation/Psilocybin Dose/Integration was extremely well tolerated and resulted in 
improvements in anxiety, depressive symptoms, and existential distress that were statistically significant 
and clinically meaningful. Cancer patients who participated in the Griffith and Ross studies described in 
qualitative interviews how their existential issues came to have different meanings after their 
participation in the study in ways that allowed them to cope better, face death with less fear, and 
experience better quality of life.24 Because this proposal involves psychedelic-assisted psychotherapy with 
a new indication and new target population for psychedelic-assisted psychotherapy, the scientific 
approach most likely to yield valuable results would use a psychotherapeutic process that has been 
proven. 
 
1.3. 
Potential Benefits and Risks 
1.3.1 
Benefits 
 
Subjects in this study may experience relief of symptoms from depression and burnout, 
but it is unknown whether these short term benefits will translate into significant, long-term 
benefits. 
 
1.3.2 
Potential Benefits 
 
Participating physicians and nurses may benefit from the medical and psychiatric evaluations 
that they receive from participating in the study, which will be more evaluation that most of them 
receive during their routine work. Some participants may benefit by learning about depression, mood 
disorders, and burnout, and by gaining insight about their symptoms through participation in the 
study.  
 
The medical knowledge gained by this study may contribute to the understanding of clinician 
depression and burnout and could benefit future clinicians affected by symptoms of depression and 
burnout as a result of the work during the COVID pandemic.  
In addition, knowledge gained by this study could lead to development of a novel therapy for 
clinicians who have been severely affected by their clinical work in the COVID pandemic.  
 
1.3.3. Risks to Participants 
1.3.3.1. Risk of the experimental medication (synthesized psilocybin).  
According to the most recent and comprehensive review, serotonergic psychedelic 
medications “are generally considered to be physiologically safe molecules” that chiefly alter 
consciousness.25 Recent reviews and searches of the literature indicate that 
psilocybin is not associated with harm or damage to any organ or system in the body.26 
Psilocybin can produce changes in blood pressure and heart rate, but these changes are not as 
strong or consistent as those seen after psychostimulants (amphetamines), and sometimes 
these changes only occur at one time point.25 More consistently, psilocybin can produce 
rapid and intense changes in mood including periods of anxiety or panic. Both these 
physiological and psychological effects are transient and do not last beyond the duration of 
drug effects. 
Researchers studying the effects of 30 mg psilocybin took precautions similar to the 
ones we will use in this study, and no reactions requiring pharmacological intervention 
occurred.23,27 


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1.3.3.1.a. Safety and Pharmacology of Psilocybin (mushroom-derived, and synthesized) 
Studies in humans and nonhuman animals indicate that psilocybin has very low 
toxicity .28,29 The LD50 ranged from 285mg/kg in rats and mice.30 The maximum tolerated dose 
of psilocybin in humans has not been defined or established. The best estimate of a lethal 
dose for pure psilocybin in humans is about 19 grams. The full dose of psilocybin that will be 
administered in this study is 1/100 times of the established LD50 in nonhuman animals and in 
humans. A Phase I trial of psilocybin completed in 2019 at oral doses of up to 0.6 mg/kg 
demonstrated no serious adverse events.31 Psilocybin is not associated with disease or 
damage to any organ or system.29 More commonly, damage or disease to organs (as renal 
failure) is associated with mistakenly consuming poisonous mushrooms under the belief that 
they are psilocybin-containing mushrooms.32 
Three cases of death possibly related to the direct toxic effects of Psilocybe 
mushrooms (the natural source of psilocybin) have been reported in the world literature. One 
fatality occurred in a post-cardiac transplant patient who ingested Psilocybe mushrooms.33 
It is not known however whether psilocybin was the proximal cause of death or whether death 
occurred secondary to the cardiac stimulant phenethylamine, which is also present in the 
mushrooms. In the French literature, another fatality linked to Psilocybe mushroom use was 
associated with far higher blood concentrations of the active metabolite of psilocybin than 
would be expected with the doses proposed in this study.34 A final fatality  from Psilocybe 
mushroom ingestion was mentioned in a 1961 review but was poorly characterized, with no 
psilocin concentrations were reported.35 
In a review of other adverse effects of psilocybin from Psilocybe mushrooms, an 
additional 10 individuals were reported to have experienced accidental deaths associated with 
Psilocybe mushroom ingestion (van Amesterdam et al. 2012). In most cases, these accidental 
deaths resulted from falls from buildings. Given the documented history of use of Psilocybe 
mushrooms in a variety of societies and cultures, that there are only 3 known fatalities at best 
indirectly linked to the physiologic effects of mushroom ingestion is an argument for the 
general safety of this natural product. We believe that the use of synthesized psilocybin will 
decrease the risk of cardiac toxicity by avoiding any additive or synergistic effect of 
phenylethylamine. Further, a recent review of the potential harm of the ingestion of 
Psilocybe mushrooms by the Dutch medicinal advisory board found that the risk of acute or 
chronic toxicity was low (van Amsterdam, Opperhuizen, and van den Brink 2011). 
The source of synthesized psilocybin used in this study is the Usona Institute.36 The 
Usona Institute is a non-profit medical research organization founded in 2014, and has 
developed synthesized psilocybin for use in investigator-initiated studies and Usona 
Institute-sponsored studies (currently underway for Major Depressive Disorder). The Usona 
Institute synthesized psilocybin has been used in a variety of studies, including open-label, 
dose-escalation studies in healthy volunteers, patients with obsessive compulsive disorder, 
alcohol use, nicotine use, and in randomized studies involving patients with depression and 
cancer.19,37-40 
To date, over 2000 participants have received synthesized psilocybin under controlled 
conditions in scientific studies with no reports of the occurrence of a significance of adverse 
events deemed to be associated with drug administration. The most commonly reported 
adverse events from the scientific literature are psychological in nature and include the 
induction of negative emotional states and paranoid/delusional thinking during psilocybin 
sessions, as well as far less frequent reports of Hallucinogen Persisting Perception Disorder 
(HPPD).26 A review of studies conducted worldwide between 1999 and 2008 identified only 


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one subject (out of 110) who experienced any persistent perceptual symptoms associated 
with HPPD and these symptoms were mild, brief, and resolved within three days of psilocybin 
exposure.41 Rates of prolonged psychiatric symptoms of any kind following psilocybin 
exposure in healthy study participants are estimated to be 0.08-0.09%. As in the phase 2 
studies, common physical adverse events associated with psilocybin administration include 
increased BP and heart rate, nausea, and headaches. In the phase 2 studies of cancer 
related anxiety and depression no cases of HPPD were identified and no participants 
developed any symptoms of paranoia or anxiety that required pharmacological intervention or 
anything more than reassurance from session facilitators.19,23 In a survey of 1993 individuals 
in the context of unsupervised, illicit use of psilocybin-containing mushrooms, 11% put self 
or others at risk of physical harm. Of the respondents, 2.6% behaved in a physically 
aggressive or violent manner and 2.7% received medical help. Of those whose experience 
occurred >1 year before, 7.6% sought treatment for enduring psychological symptoms. 3 
cases appeared associated with onset of enduring psychotic symptoms and 3 cases with 
attempted suicide.42 
To date, there have no reports of physical harm in patients who have received 
psilocybin under controlled conditions, and no fatalities have been associated with its use in 
a controlled clinical trial. The difference in the side-effect profile between the unknown 
doses of psilocybin-containing mushrooms consumed in an uncontrolled setting and dose- 
controlled medically prepared oral psilocybin consumed in a controlled setting is thought to be 
in part doe the focus on the set and setting of the experience. The set refers to the 
emotional/cognitive/behavioral state/mindset and expectations of study participants just prior 
to psilocybin exposure and setting refers to the physical environment in which the exposure 
occurs.43 
There are no confirmed reports of an overdose of synthesized psilocybin. In the United 
States, use of chemically synthesized psilocybin does not occur.44 Although psilocybin in the 
form of mushrooms is sometimes used non-medically, medical emergencies due to psilocybin 
mushrooms are very rare (psilocybin is mentioned in only 0.1% of drug-related emergency 
department visits).45 It can be anticipated that an overdose of psilocybin might present in a 
manner similar to “serotonin syndrome”. Removal of any residual gastric drug, supportive care, 
and cautious administration of a serotonin antagonist such as risperidone are reasonable 
interventions; however, to date no cases have described similar responses with respect to 
psilocybin, and the doses of psilocybin that might provoke these physiological effects would be 
many times greater than even the highest doses used in early human studies. 
 
1.3.3.1.b. Common side effects of psilocybin 
Common acute side effects of psilocybin are almost all psychological, and include 
anxiety, changes in thought (experiencing thinking speeding up or slowing down), changes in 
motion perception, changes in time perception (time slowing down or speeding up), 
depersonalization (feeling as if one is “outside oneself”), derealization (feeling as if the world is 
unreal or as if one is “in a dream”), dizziness, fatigue, impaired concentration, inattention, mood 
lability (rapid and sometimes profound changes in mood), nausea, nervousness, parasthesias 
(strange bodily sensations or feelings), perceptual alterations (general), altered time perception, 
alteration in visual perception (distortions, illusions and imagery seen with eyes open or closed), 
and unusual thought or feelings about the self or the world.25,41,46 Most of these effects are 
acute and last no longer than six hours. For the most part, people receiving psilocybin were able 
to interact, and maintained insight concerning the nature and source of their experience. 
However, some participants occasionally exhibited paranoid ideation or temporarily lost insight 
into the experimental situation.41,46 


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Psilocybin produces mild sympathetic system activation. Physiological effects include 
pupillary dilation and detectable but moderate increases in blood pressure or heart rate . 46 
Researchers sometimes detected changes in blood pressure and heart rate only at one point in 
time, as sixty minutes after drug administration.25 These effects are transient and are 
generally gone approximately six hours after drug administration. People in previous human 
studies have tolerated doses of psilocybin equal to or greater than the doses employed in 
this study. Researchers studying  the effects of 30 mg psilocybin took precautions similar to 
the ones we will use in this study and no reactions requiring pharmacological intervention 
occurred.27 
 
1.3.3.1.c. Acute side effects 
Anxiety. The most likely potential adverse effect of psilocybin is anxiety, or possibly 
panic, delusion, and cognitive impairments, particularly at higher doses (> 25 mg po) during 
the period of acute drug action. In recent studies of psilocybin in healthy humans conducted 
over the past  15 years, no adverse reactions other than the expected occasional episodes of 
fear or anxiety during the time of drug effect have been reported.25,29 Such transient 
episodes of fear or anxiety respond well to reassurance and have not required 
pharmacological intervention. Some individuals have been reported to develop paranoid and 
psychotic states while under the influence of psilocybin. 
Insomnia. Although rare, insomnia following psilocybin administration has been 
reported in the literature; it has been described as self-limiting and responded well to 
reassurance from the study team.41 In the event that a participant experiences insomnia, a 
study physician may initially prescribe a sleep aid (i.e. diphenhydramine or hydroxyzine) and 
if the initial reassurance, education about sleep hygiene and pharmacological intervention 
was unsuccessful, a one-time dose of short-acting benzodiazepine (specifically lorazepam) 
and/or zolpidem will be considered. 
 
1.3.3.1.d. Prolonged side effects 
There is the possibility of prolonged adverse psychological reactions, such as psychosis 
and depression. It is generally believed that individuals with previous psychiatric conditions, 
particularly psychosis or mania, are at an increased risk for hallucinogen-induced psychosis.29 
Thus, psilocybin administered to a participant with a history of psychosis or mania could 
precipitate enduring psychiatric illness such as schizophrenia. This risk is very low, but 
cannot be excluded completely.47 For this reason, all potential participants with personal or 
family histories of Schizophrenia, Psychotic Disorder, or Bipolar I or II disorder are to be 
excluded from participation. Nevertheless, although the risk is believed to be minimal, it is 
possible that some participants may develop a brief intense psychological reaction while 
under the influence of psilocybin. 
The low rate of late psychological symptoms is consistent with a summary of such 
effects from 110 psilocybin research participants reported in a meta-analysis conducted by 
Studerus et al in their laboratory.41 In that report, 7 participants endorsed negative changes 
in psychological well-being, but only 1 participant (0.9%) reported a level of distress 
sufficient for him to contact the researchers. Those symptoms resolved after a few sessions 
with an experienced psychotherapist. 
Investigators at the Johns Hopkins Center for Psychedelic and Consciousness Studies 
recently completed an internet survey of hallucinogen users who reported having a 
challenging experience after taking psilocybin mushrooms.42 The rates and severity of both 
acute and enduring problems shown in the survey are notably higher than those observed in 


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laboratory research studies involving administration of high doses of psilocybin to carefully 
screened, well-prepared, and closely monitored volunteers. This observation appears to 
support the efficacy of the standard screening, preparation, monitoring, and follow-up 
procedures designed to minimize the possibility of any enduring problems. 
 
1.3.3.2. Potential risks of Niacin (active-placebo-control agent) 
A participant's symptoms of depression or burnout could change or perhaps worsen 
during the course of the study, as symptoms might change if that individual were not 
participating in the study. However, there is no reason to believe that niacin as an active-
placebo-control would exacerbate symptoms of depression or burnout. Niacin has expected 
physiological side effects that make it well suited to be used as an active placebo, including 
flushing, tingling, itching, and redness of the face, arms, and chest, as well as headaches, and 
these are documented to be transient. Other minor, transient, and occasional side effects 
include upset stomach, intestinal gas, and dizziness. Participants will be informed about these 
potential side effects, and they will be monitored throughout the drug administration visits. 
 
1.3.3.3. Potential risks of changes or delay in participant treatments being received prior to 
screening 
Participants will be asked to refrain from starting new medications, including OTC 
supplements, during the procedures involved in this study. Should circumstances warrant a 
change in treatment, then participants will be asked to immediately notify the study team. If 
medically warranted, the participant begins to experience a decline, or their provider believes 
a treatment change is necessary, then the participant will be withdrawn from the study and 
encouraged to seek treatment. 
For participants who are tapering and discontinuing antidepressant medications 
prior to entering the study, the following safety measures will be taken: 
• 
Participants will be required to discuss changes in their antidepressant 
medication with their own prescribing provider, and to provide the study 
staff with a written note from the provider describing the plan. 
• 
Study staff will be in contact with a participant who is tapering their 
antidepressant medication weekly with a phone safety assessment that will 
involve use of the C-SSRS. (These safety assessments are not designated as a 
‘study visit’ so do not appear in the study visit flowsheets in Section 3.1 that 
summarize research procedures). 
• 
Participants will be required to provide the name of at least one adult who 
will be in continuous contact with them during the taper and 
discontinuation period. 
 
1.3.3.4. Risk of Emotional Responses, Discomforts During Administration & follow-up meetings. 
During preparation, medication dosing, and integration sessions, participants will be 
asked to think about and to discuss their thoughts and emotions about their experiences 
working in the COVID pandemic, including the impact that these experiences have had on their 
lives. They may experience emotional responses to speaking about these thoughts, feelings, and 
concerns. The medication dosing session will take place at Harborview Medical Center and will 
be staffed by two investigators. The PI and/or investigators who will be present during the drug 
session will meet the patient at least 3 times prior to the medication dosing session. This will be 
done as part of psychoeducation that provides the participant with expectations for what to 
expect during the sessions. 


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1.3.3.5. Risks from routine medical evaluations.  
The other risks involved in this research are generally considered minimal and include 
those normally associated with clinical care or research such as psychiatric evaluations, 
medical examinations, lab work - urine drug screening, blood draws, and research 
questionnaires. 
Psychiatric Evaluations. Participants must answer personal questions, which may 
feel unpleasant or tiring, or may find discussing their symptoms and their illness during the 
psychiatric evaluation unpleasant or upsetting. Screening is necessary to assess participant 
eligibility. The major disadvantages of these assessments are the time that it takes to 
complete them. These clinical and research methods represent minimum risk(s). 
Blood draws and urine tests for routine screening, including pregnancy testing. 
Participants will undergo a blood draw for a comprehensive metabolic panel, pregnancy 
test, liver panel. These tests prior to the psilocybin session allow the investigators to ensure 
that there are no contraindications to subjects' participation in the study, such as liver 
function abnormalities which could produce higher than expected levels of psilocybin. 
Higher levels of psilocybin may produce prolonged duration or greater intensity of subjective 
effects. Weighing the risks and benefits of a blood draw versus potentially unpredictable 
levels of psilocybin, the liver panel conveys more benefits than risks. Serum pregnancy and / 
or urinary pregnancy testing will be conducted at the screening visit to avoid the risk of 
unintended psilocybin exposure in utero. Less than 50mL will be drawn per collection. There 
will be a single blood draw over the course of study. The blood draw may produce 
temporary discomfort as a result of sampling blood, and discomfort or bruising at the blood 
drawing site. The urinary drug screen is necessary to verify abstinence from illicit substances 
or nonprescription stimulants prior to the psilocybin session. 
 
1.3.3.6. Reproductive Risks  
 
While some women who choose to participate in the study will be post-menopausal, so 
the pregnancy will not be possible, pre-menopausal women who could bear children could be at 
reproductive risk. There have been no systematic studies of the effect of psilocybin in utero, 
but also no case reports of birth defects resulting from psilocybin use. Thus, the reproductive 
risks seem minimal, but are not well characterized. We will screen all participants who are 
pre-menopausal women with pregnancy tests, and counsel them to use birth control until 
after their medication session.  
1.3.3.7.  Risks of privacy and confidentiality 
 
There is a special potential risk to study participants because of their profession. Doctors in 
some states are required to report any mental health condition that may affect their performance to 
the state licensing board. If not mitigated, these risks could lead to reputational damage and even 
damage to their employability. The same requirement is not mandated for advance practice providers 
or nurses, but those clinicians could still face reputational damage if their participation in this study 
were made public. To mitigate this risk, we have applied for an FDA Certificate of Confidentiality, and 
all data will be entered using a study code.  
 
 
 
 
 


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Version 1.16, July 18, 2022 
 
 
1.3.3.8. Minimizing participant risks 
The anticipated risks and risk mitigation strategies that will be used are summarized 
in the Table below. 
Anticipated risk 
Risk mitigation strategies 
Occurrence of risk 
in recent published 
studies since 2000 
Changes to any 
treatments a 
participant is 
receiving prior to 
study screening and 
enrollment 
1. Clear communication with potential 
participants about existing treatments (for 
example need to taper SSRI before study 
entry). 
2. Coordination between PI and participants 
mental health provider. 
 
Published studies 
do not report 
numbers of 
participants who 
had complications 
related to changing 
treatments prior to 
screening.  
 
Worsening of 
participant mental 
health symptoms 
during the study 
1. Weekly phone calls from study staff to 
check in re participant well-being are part of 
the study procedures. 
2. Mental health symptoms will be assessed 
by study therapists during all preparation and 
integration psychotherapy sessions, and 
therapists will discuss with participants and 
the study team (at a weekly meeting or 
urgently with the PI) any issues that may 
warrant a change in study procedures.  
 
This risk has not 
been reported in 
published studies 
since 2000. 
 
Increase in 
participant suicidality 
during the study 
1. All participants will be screened with the 
Columbia Suicidality Screening instrument at 
preparation, medication days, integration 
sessions, and at follow up measurements. 
2. If an increase in suicidality is measured, 
study staff will notify the PI immediately and 
arrangements for appropriate evaluation will 
be made with the attending psychiatrist on 
call at Harborview Medical Center. 
This risk has not 
been reported in 
published studies. 
Intense psychological 
reactions during the 
medication session 
1. All study therapists will have training 
specifically for this issue. 
2. the therapist manual lays out first-line and 
second-line interventions (which are non-
pharmacologic), as well as indications about 
when to notify the PI Dr Back. These 
interventions are based on consultation and 
experience at other academic centers where 
research with synthesized psilocybin has been 
conducted (NYU, Yale, Johns Hopkins). 
This risk has been 
reported in up to 
40% of 
participants. In all 
instances, these 
reactions have 
been managed 
with non-
pharmacologic 
interventions, and 


Page 13 
Version 1.16, July 18, 2022 
 
 
 
the reactions have 
been transient. 
Discomfort resulting 
from study 
questionnaires 
1. All participants will be informed that they 
may take a break at any time from 
questionnaires and that study staff are 
available to discuss issues that warrant follow 
up. 
 
This risk has not 
been reported. 
Confidentiality of 
participant identity 
1. Because doctors in some states are 
required to report any mental health 
condition that may affect their performance 
to the state licensing board, we have 
submitted a request to the FDA for a 
Certificate of Confidentiality. 
 
No prior studies 
have had 
participant 
inclusion criteria 
that specify 
doctors and 
nurses. 
Reproductive risks 
1. All female potential participants will be 
asked about their menopausal status at 
screening, and pre-menopausal participants 
will undergo a pregnancy test. 
As noted above, 
the reproductive 
risks seem 
minimal, although 
they are not well 
characterized. 
Length of study for 
subjects who were 
taking medications 
prior to study entry 
and who are 
randomized to 
placebo 
1. The study team will clearly communicate 
with potential subjects during consent 
conversations to ensure eligible subjects 
know they may be off their medications 
longer if they are assigned the placebo group 
and then chose the open-label psilocybin 
session following un-blinding. We will 
recommend that individuals taking 
medications that need to be stopped, discuss 
this with their provider(s), family, and any 
other trusted people, prior to agreeing to 
participate in the study.  
 
2. Minimize the time for subjects who are 
randomized to the placebo group to an open-
label psilocybin session. We anticipate that 
arranging and scheduling an open-label 
psilocybin session will take 1-2 weeks. During 
this time, subjects will be followed weekly and 
will have an additional preparation 
psychotherapy session, and every weekly 
contact will include administration of the C-
SSRS suicidality screen to minimize risk to these 
subjects. We judge that this additional risk of 1-
2 weeks off antidepressants is acceptable given 
This risk has not 
been reported. 


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Version 1.16, July 18, 2022 
 
 
that these subjects will be monitored closely.  
 
 
A detailed therapist manual outlines procedures for every contact session with 
participants, and for participant issues that could represent risk, the manual outlines 
responses to minor, moderate, and severe side effects with first-line, second-line, and 
indications to call the PI by phone for urgent or emergent issues. Research staff including the 
investigators and PI will be available to evaluate any change in a participant’s condition. 
Participants will be asked to contact us at any time if any unpleasant effects occur and will 
be contacted by study staff at least weekly during study participation. A study physician will 
be at the study site on medication dosing days to manage psychiatric emergencies.  
Synthesized psilocybin: Reviews of the drug and the literature indicate that the 
physiological and psychological effects are transient. The patient will be monitored at all 
times by trained research and/or medical staff. The study medical doctors and nursing staff 
who are trained in dealing with drug challenge studies (such as ketamine, psilocybin, 
yohimbine, and various cannabis compounds) will remain in attendance during the entire 
session. Participants will be asked to remain on the CNRU until effects wear off. Procedures 
will be immediately stopped if participants request or if they are exhibiting significant 
distress. To minimize risk associated with synthesized psilocybin, participants will undergo a 
thorough screening for contraindicated psychological conditions or interacting medications. 
Dosing with psilocybin must be performed in a setting that minimizes distraction and 
interruption, and the participant must be attended following the dose by research staff 
trained in providing reassurance and a safe environment until the effects of the single dose 
have dissipated. 
The PI may prescribe a designated rescue medication in the event of symptoms that 
require it during or after the medication dosing session. Rescue medications may be a 
benzodiazepine, zolpidem, or other anxiolytic or sedative according to the physician's clinical 
judgment. 
Following the investigator brochure, although there have been no reports of their use in 
well-reported clinical trials with oral psilocybin, medications will be available for the treatment 
of causal symptomatic hypertension, agitation, or severe psychosis. Typically, these supplies are 
two dosage units of labetalol, nitroglycerin, lorazepam and/or diazepam, and risperidone or 
similar orally- disintegrating antipsychotic.  
 
If any participant presents with an adverse reaction to the psychopharmacological 
agent as reported by them or assessed by a member of the research team, we will discontinue 
the study and call for medical assistance. Finally, the participant may be withdrawn from the   
study if his/her withdrawal is in the best interests of either the participant or of the research 
(e.g., due to a medical condition making the procedures unsafe or any condition making 
interpretation of the results difficult). 
Niacin: (active-placebo-control agent): There is no reason to believe that niacin would 
exacerbate symptoms of depression or burnout or PTSD. Participants will be informed about 
Niacin's potential side effects, and they will be monitored throughout the drug administration 
visits. The rationale for using an active-placebo-control agent rather than active low dose of 
psilocybin (ranging 2mg -4mg), which have been used in the recent palliative care studies is 
because a partial response has been reported even with these low doses.  


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Changes or delays in treatments being received prior to screening: Participants will 
be asked to refrain from starting new medications to allow the participant and this study to 
safely proceed. If medically warranted, or the participant begins to experience a decline, or 
their provider believes a treatment change is necessary, then the participant will be 
withdrawn from the study and encouraged to seek treatment.  
Involuntary holding, overnight for safety: The medical staff will closely monitor the 
participant's medical status during study administration. The staff take whatever medical 
steps are safely possible to reduce the need for an additional holding period including 
ongoing evaluations during the testing period. However, if there was concern about 
participants being a risk to themselves or others during the study, or if investigator feels it is 
medically necessary, and/or if the participant is not compliant, then the participant may 
need to be involuntarily held for his/her own safety. If a participant requires overnight 
observation, the participant’s medication would be unblinded to maximize the information 
available to the treating inpatient team. Participants will be discharged after the study 
physician believes that it is safe to do so. 
Emotional Responses and Discomforts During Psilocybin Medication Session, and 
follow-up appointments: Trained staff will be on hand to help participants deal with their 
responses to the study. The therapist manual outlines first- and second-line interventions 
for emotional responses or any psychological reactions that may be experienced. In studies 
since 2000 conducted at academic research centers, no participants required ‘rescue’ 
medication for psychological reactions—they were all managed with non-pharmacologic 
interventions.  
Administration and follow-up appointments: Only the trained clinical staff will conduct 
such sessions. Staff will assist patients who require help with their anxiety. The anxiety 
experienced is no more than normally reported in any standard therapeutic session. 
Psychiatric evaluation and clinical assessments: All participants must first give 
permission for the investigators to review medical records and later undergo a psychiatric 
evaluation and a urinary drug screen to ensure that participants are eligible to be in the study. 
We will try to schedule and to complete tasks quickly. Each participant is told that he/she 
does not have to answer any question that he/she does not want to answer, but that the 
questions about suicidal ideation and behaviors, including the complete C-SSRS, are required 
to participate in this study. Only the trained clinical will conduct these evaluations and all 
exercise utmost sensitivity. 
Routine labs: Screening is necessary to assess participant eligibility and to uncover 
sometimes unknown contraindications. We minimize risk by having only skilled medical staff 
conduct the brief physical examination rule out any cardiac abnormalities.  
Urine toxicology and blood draws. We minimize medical risk by having skilled nurses 
and phlebotomists do our blood drawing. If a blood draw produces temporary discomfort, 
then nursing staff can offer ice or cool compresses. There is also a remote possibility of 
inflammation or infection at the blood drawing site. Liver panel results will allow the 
investigators to detect poor metabolism, which could produce higher than expected levels of 
psilocybin. Higher levels of psilocybin may produce prolonged duration or greater intensity of 
subjective effects. Weighing the risks and benefits of a blood draw versus potentially 
unpredictable levels of psilocybin, the liver panel conveys more benefits than risks. The 
urinary drug screen is necessary for verifying the participant’s report of current substance use 
and to eliminate potential risks of interactions of the study medications with other 
medications needed by the participant. Subjects are informed of this testing in advance of 


Page 16 
Version 1.16, July 18, 2022 
 
 
the screening appointment and may choose to not participate in the study. 
Study questionnaires. The research staff will inform all participants that they may 
take breaks while completing questionnaires, or stop if they are experiencing too much 
frustration, or anxiety. Participants may take breaks from completing measures and online 
tasks. Ratings will be administered with sensitivity by trained staff, either on paper instruments 
or online portals utilizing secure servers and data capture systems. All online responses will 
be captured on secure servers. This use of online measures speeds up the assessment process 
and seems to reduce some subject stress. All information will be kept strictly confidential. 
Returning to work. Participants will be required to wait 48 hours after a medication 
dosing session before returning to work. 
 
1.3.4. Confidentiality 
All participant records, paper or electronic, will be stored in locked offices and 
password-protected encrypted drives that will be accessible only to the principal investigator 
and other study personnel. Research databases will be coded (all identifiers except id 
number will be removed) during data analyses and are also kept on secure servers or 
encrypted computers. 
We have requested from the FDA a Certificate of Confidentiality for this study to 
protect the identities of participants. 
 
2. 
Study Design and Endpoints 
 
2.1 
Description of the Study Design 
This is a randomized, double-blind, placebo-controlled study that offers participants 
randomized to the placebo arm the option to receive open-label psilocybin after primary 
outcome measurements have been completed. 
 
 
 
 
2.2. 
Research Methods and Design 
This study tests a hypothesis that a single session of psilocybin (the ‘medication dosing’ 
session) in the context of pre- and post-dose psychotherapy will result in improvement of 
symptoms of depression and burnout measured 4 weeks post-dose. This study hypothesis will 
be tested in a single site, double-blind, randomized controlled design involving 30 clinician 
participants that will compare effects of a single 25mg oral dose of psilocybin to a 100 mg of 
niacin (active placebo). The primary outcome measurements will be collected 4 weeks after 


Page 17 
Version 1.16, July 18, 2022 
 
 
the psilocybin dose, after which the participant group assignment will be unblinded, and 
participants who received niacin will be offered the opportunity to have a second dose 
session with a 25 mg dose (with pre- and post-dose psychotherapy).  
Precautions will be taken to reduce potential for COVID exposure, following FDA 
guidance (https://www.fda.gov/media/136238/download): 
• 
Some psychotherapy sessions can be conducted by video, although at least one 
preparation session and one integration session will be done in person. 
• 
COVID-19 screening procedures mandated by UW Medicine will be followed per 
UW Medicine policy. Currently UW Medicine policies require a basic symptom 
check before ambulatory care encounters, for example.  
• 
Participants will be tested for COVID using a rapid antigen test on the morning 
of their medication session, and therapists will also be tested on the morning of 
the participant’s medication session. 
• 
Physical distancing will be maintained as much as possible. 
 
2.3. 
Study Endpoints 
 
2.3.1. Primary Endpoint 
The primary endpoint will assess symptoms of depression using the Montgomery-
Asberg Depression Rating Scale (MADRS), a clinician-assessed instrument, at 4 weeks post 
psilocybin-assisted psychotherapy vs control psychotherapy. We expect at least 50% of 
participants treated with psilocybin to have a 35% reduction in their MADRS compared to 
baseline, which is a clinically significant difference compared to the control arm. 
 
2.3.2. Secondary Endpoints 
• 
Assess symptoms of depression using the Montgomery-Asberg Depression Rating 
Scale (MADRS) prior to the primary endpoint at 1 week post psilocybin-assisted 
psychotherapy vs control psychotherapy. 
• 
Assess symptoms of depression using the MADRS after psilocybin administration 
(for patients randomized to psilocybin or who receive open-label psilocybin) at 1 
week, 4 weeks, 8 weeks, 12 weeks, and 6 months. 
• 
Assess symptoms of burnout using the Stanford Fulfillment Index (SFI) at 4 
weeks post medication administration. We expect at least 50% of participants 
treated with psilocybin to show a reduction in the SFI work exhaustion and 
interpersonal disengagement subscales by at least 25% (from “a lot” to 
“moderately”).  
• 
Assess symptoms of burnout after psilocybin administration (for patients 
randomized to psilocybin or who receive open-label psilocybin) at 1 week, 4 
weeks, 8 weeks, 12 weeks, and 6 months. 
• 
Another secondary endpoint will assess symptoms of post-traumatic stress 
using the PCL5, measured at 1 week and 4 weeks after the medication session. 
We expect at least 50% of participants treated with psilocybin to show a reduction 
in PCL5 scores by at least 10 points (the clinically meaningful threshold for 
improvement). 
• 
Assess symptoms of post-traumatic stress using the PCL5 after psilocybin 
administration (for patients randomized to psilocybin or who receive open-
label psilocybin) at 1 week, 4 weeks, 8 weeks, 12 weeks, and 6 months. 
• 
A 10% or less difference in the rate of adverse events between the treatment 
and control arms at all study visits. 


Page 18 
Version 1.16, July 18, 2022 
 
 
 
 
 
2.3.3. Exploratory Endpoints 
To test hypotheses concerning psychological therapeutic mechanisms, we will assess 
correlation and mediational influence of self-reported mystical states 
and psychological flexibility on changes in primary and secondary outcomes. 
Exploratory endpoint A: Intensity of mystical experience (measured at the end of the 
medication dosing session), using the validated Mystical Experience Questionnaire. The 
hypothesis is that this will be a significant mediator of improvements in symptoms of depression 
and burnout. 
Exploratory endpoint B: Psychological flexibility, using the AAQII, measured at 4 weeks 
after the medication dosing session. The hypothesis is that this will serve as a mediator of 
burnout. 
Exploratory endpoint C: Interoceptive awareness, using the Multidimensional 
Assessment of Interoceptive Awareness.48 The hypothesis is that this will be a mediator of 
improvements in symptoms of burnout.  
 
3. 
Research Materials and Measures 
3.1. 
Research Procedures 
Participants will complete self-report and clinician-administered measures at baseline, prior to the 
medication dosing session, and at designated study visits (see figure next page). 
 
 
 
 
Schedule for Activities during Randomized Phase 
Purpose 
Screen 
Prep 
Prep 
Medi-
cation 
Inte- 
gration 
Inte-
gration 
Inte- 
gation 
Follow 
-up 
Study day (approx) 
-21-14  
-7 
-1 
0 
1 
8 
15 
28 
Visit number  
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Research activity 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Eligibility Determination 
X 
 
 
 
 
 
 
 
Medical exam 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Caregiver contact info 
X 
 
 
 
 
 
 
 
Blood draw 
X 
 
 
 
 
 
 
 
Pregnancy screen (if applicable) 
X 
 
 
X 
 
 
 
 
PI review of inclusion/exclusion 
X 
 
 
 
 
 
 
 


Page 19 
Version 1.16, July 18, 2022 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Mental health evaluation 
 
X 
 
 
 
 
 
 
Education re expectations 
X 
X 
 
 
 
 
 
 
Preparation psychotherapy 
 
X 
 
 
 
 
 
 
Urine screen 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
Medication (psilocybin or control) 
 
 
 
X 
 
 
 
 
Medication dosing monitoring 
 
 
 
X 
 
 
 
 
Integration psychotherapy 
 
 
 
 
X 
X 
X 
 
Adverse event reporting 
 
 
 
X 
X 
X 
X 
 
Un-blinding  
 
 
 
 
 
 
 
X** 
 
 
 
 
 
 
 
 
 
Measures 
 
 
 
 
 
 
 
 
Mont-Asberg Depression (MADRS) 
X 
X 
 
 
X 
X 
 
X 
Beck Depression Scale 
X 
 
 
X 
X 
 
X 
Stanford Fulfillment Index 
X 
 
 
X 
X 
 
X 
Post-traumatic stress (PCL5) 
 
X 
 
 
X 
X 
 
X 
Likelihood to leave job 
 
X 
 
 
X 
X 
 
X 
Self-reported mystical exp 
 
 
 
X 
 
 
 
 
Moral injury symptom scale 
 
X 
 
 
 
 
X 
Psychedelic Music Questionnaire 
 
 
 
 
X 
 
 
Psychological flexibility (AAQII) 
 
X 
 
 
 
X 
X 
Interoceptive awareness (MAIA2) 
 
X 
 
 
X 
X 
X 
Suicidality (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative interview 
 
 
 
 
 
 
 
X 
Adverse events, Suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
**The unblinding will be done after the study coordinator has verified that the Day 28 
measures have been completed. 
 
 
Follow up measures for participants randomized to psilocybin 
Purpose 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Study day (approx.) 
56 
84 
180 
Visit number 
V8 
V9 
V10 
 
 
 
 
Measures 
 
 
 
Mont-Asberg Depression (MADRS) 
X 
X 
X 
Beck Depression Scale 
X 
X 
X 
Stanford Fulfillment Index 
X 
X 
X 
Post-traumatic stress (PCL5) 
X 
X 
X 
Likelihood to leave job 
X 
X 
X 
Psychological flexibility (AAQII) 
X 
X 
X 
Interoceptive awareness (MAIA2) 
X 
X 
X 
Suicidality (C-SSRS) 
X 
X 
X 
Qualitative interview 
 
 
 
Adverse events 
X 
X 
X 
 
 
3.1.1. Clinician administered measures 
 
1. Montgomery Asberg Depression (MADRS)49 


Page 20 
Version 1.16, July 18, 2022 
 
 
 
2. Columbia Suicide Severity Rating Scale (C-SSRS)50 
 
3. Qualitative interview post-psilocybin 
 
3.1.2. Self-report measures 
1. Beck Depression Scale II51  
 
2. Stanford Fulfillment Index (Burnout) (baseline and 4 weeks only)52 
 
3. Post-traumatic stress symptoms (PCL5)53 
 
4. Professional likelihood of leaving10  
 
5. Self-reported mystical experience (MEQ30) (day of journey only)54 
6. Moral injury symptom scale-Health Professionals Version54b 
 
7. Psychological Flexibility (AAQII)55 
8. Music experience questionnaire (day of journey only) [Mendel Kaelen, personal 
communication] 
9. Multidimensional Assessment of Interoceptive Awareness (MAIA2)48 
 
3.1.3. Initial Research procedures: 
Phone Pre-screen. Because of a large number of interested potential participants, a 
pre-screening procedure has been developed to reduce burden on potential participants by 
performing more detailed pre-screening prior to an in-person screening visit (this will allow 
people likely to be ineligible because of low symptom scores to avoid the in-person 
screening visit). During a phone pre-screening call, the potential participant will be sent a link 
to a version of the MADRS that has been adapted for self-administration (MADRS-S). The 
MADRS-S is designed for self-assessment, and correlates reasonably well with the clinician-
administered MADRS that is being used as an eligibility criterion.(G. Bondolfi, F. Jermann, B. 
Weber Rouget, M. Gex-Fabry, A. McQuillan, A. Dupont-Willemin, J.-M. Aubry, C. Nguyen, Self- 
and clinician-rated Montgomery–Åsberg Depression Rating Scale: Evaluation in clinical practice, 
Journal of Affective Disorders, Volume 121, Issue 3, 2010, p 268-272). The online pre-screen 
MADRS-S will not collect any identifying information and will calculate a total score, which will 
be available to the study coordinator at the time of the phone call. The study coordinator will 
inform the caller whether their score is in a range (19 or above) that they will likely meet the 
eligibility criteria for the study . The pre-screen MADRS-S score will only be used for pre-screen 
phone calls and will not be used as a study measurement.  
In-person screening visit. At the study screening visit, the study, the conditions, and the 
procedures involved, will be explained, and discussed with each subject. Each participant will 
have a chance to ask questions and to receive answers before making a final decision whether 
to participate. Participants who decide to participate will document their informed consent. For 
safety, after completing the consent, the participants may designate 2 adults who will be 
expected to have continuing contact with the subject, who may provide patient transportation, 
and who may observe changes in the participants’ behavior and attitude that warrant 
notification of the research staff and/or PI. The screening visit will include the clinician-
administered MADRS, and to be eligible for the study a MADRS score of 20 or greater is 
required. 
 
3.1.4. Study Research Evaluations and Procedures  
Medication and lifestyle changes may be required of all participants. All participants will 
be required to taper off and discontinue use of antidepressants (such as SSRIs) before 
starting the study and cannot take antidepressants during the study even if they were 
taking them before study entry. Participants who were taking antidepressants before 


Page 21 
Version 1.16, July 18, 2022 
 
 
study entry will need to be off them for five half- lives of the drug plus 2 weeks before 
starting the study and will be required to stay off their medication until after they have 
completed the primary outcome measurements on day 28. After unblinding (as early as 
day 28, after primary outcome measurements are received). Subjects who were 
randomized to psilocybin will be able to resume antidepressants in consultation with 
their provider. Subjects who were randomized to placebo will need to stay off their 
antidepressants if they wish to have an open-label psilocybin medication session, and 
after their open-label psilocybin session they will need to stay off their medication until 
at least day 29 post-open-label-psilocybin, until after they have completed the day 28 
post-open-label-psilocybin outcome measurements. If a participant randomized to 
placebo does not wish to have an open-label psilocybin medication session, they will be 
able to resume their antidepressants after their primary outcome measurements in 
consultation with their provider, as early as day 29 post-open-label-psilocybin. They will 
also need to abstain from tobacco products, alcohol, or any recreational drugs such as 
marijuana during the study. Study personnel may obtain a release to contact the 
participant's prescribing provider to discuss current prescriptions and medication 
history. This is decided on a case by case basis upon the discretion of the PI. 
Medication contraindications will include anti-seizure medications, insulin and oral 
hypoglycemics, hypertension medications that act on the central nervous system (clonidine 
and aldomet specifically), cardiovascular medications and the following psychotropic 
medications: anti-psychotics (first and second generation agents), anti-depressants and 
mood stabilizers. Psychotropic medications cannot be taken in the previous two weeks, 
with Prozac (fluoxetine) not being taken within the last 5 weeks prior to receiving any study 
agents. Participants may only take prn (as needed) benzodiazepines (i.e., lorazepam) up to 
three days before the session. Participants will refrain from taking any medications the day of 
either the experimental psilocybin medication dosing or active-placebo-control medication 
dosing session, except prescribed opiate pain medication or over-the-counter non-narcotic 
pain medication at any time. It will also be necessary to refrain from drinking alcoholic 
beverages the day before, the day of, and the day after each medication dosing session. 
Physical exam, and blood and urine tests are required at the screening visit to meet 
eligibility criteria. As part of the study participants will have a physical examination, and 
screening blood (including a comprehensive metabolic panel, chemistries, hematological tests) 
and screening urine toxicology tests (for medications as described in Section 1.3.3.8; and 
pregnancy for female participants of childbearing potential). These results will also become 
part of the research case record. 
Randomization and One-time Administration of the Study Medications Psilocybin or 
active- placebo-control Niacin. Psilocybin and niacin (active-placebo-control agent) will be 
administered in identically appearing opaque capsules with approximately 180ml of water. 
The dose of psilocybin will be 25 mg, which has been recently demonstrated to be as 
effective as a body weight-adjusted dose.56 The dose of niacin will be 100 mg, and GMP niacin 
will be provided by the Usona Institute. In the study, half of the participants will be 
randomized to receive psilocybin (n=15) or the active-placebo-control, niacin (n=15). Following 
the first treatment session of either the active agent or active-placebo- control, participants 
who were randomized to receive active-placebo-control will be offered the option to receive 
open-label psilocybin. (The blind will be broken after Day 28 to make this determination; 
this is after our primary endpoint which is collected on Day 28. The study rater (for clinician-
administered measures) wil remain blinded to the treatment assignment. Data will be 
collected from all subjects after open-label treatment for descriptive purposes, but these data 
will not be analyzed as part of our primary analysis plan. 


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Clinical Assessments and Study Evaluations. Online surveys and measures will be 
offered using secure data capture systems, using online or paper documents. These 
evaluations will include self-report questionnaires and clinician administered measures. This 
testing may last up to 1 to 2.5 hours. 
Research study measures, follow-ups and assessments are outlined (in Tables below) 
and represent study specific clinician administered and self-administered measures. Safety 
measures and checks will be completed at some study visits: vital signs, adverse events, 
spontaneously reported reactions, general well-being, medications, and changes to any 
medications. 
All participant responses to measures and assessments will be recorded either on 
traditional paper formats and scanned to a secure server, or in online data capturing systems 
which instantly upload responses or surveys to a secure server. All portable digital 
participant data will be uploaded immediately and stored in secure databases, on password-
protected computers in locked offices, and on secure servers. 
 
3.1.5. Study Environment 
Research visits and the medication dosing session will be conducted at Harborview Medical 
Center. The screening, consent, preparation, and integration visits will occur at the Virology Research 
Clinic at Harborview Medical Center in the Ninth and Jefferson Building on the 11th floor. These visits will 
occur in a clinic room designed for outpatient, non-procedural visits, and this is a private room that is 
equipped with comfortable chairs and a window, appropriate for psychotherapy visits. This clinic is 
dedicated research space that is a non-CRBB space and is directed by Dr. Anna Wald. 
The medication sessions will occur at Harborview Medical Center, in the Sleep Lab. These research 
visits will occur during the day when the clinic is not in session, in a room used for nighttime sleep studies. 
These are private, quiet rooms that are outfitted like hotel rooms with minimal equipment, a comfortable 
bed, art prints on the walls, chairs for therapists, and a private bathroom.  
 
3.1.6. Study Enrollment and Withdrawal 
Participant Population – physicians and nurses with moderately severe symptoms of 
depression. Participants meeting study inclusion / exclusion criteria after careful screening and 
examination will be invited to participate and will be provided with all the information 
needed to provide an informed consent. We will recruit 30 adult participants (25 to 65 years) 
of both sexes with clinically significant symptoms of depression. 
 
4. 
Participant Inclusion and Exclusion Criteria 
4.1. 
Inclusion Criteria 
a. Participants must be physicians or nurses or advance practice providers (nurse 
practitioners or physician assistants) with at least 1 month of frontline clinical 
experience during the COVID pandemic who rate at least 2 of 4 items from the COVID 
Exposure index as ‘more than half the days’ during their peak 2 week period of 
exposure: 
i. Caring for someone critically ill with COVID-19, or who became critically ill while you 
were involved. 
ii. Working longer hours than usual in order to provide assistance or care to individuals 
with COVID-19 
iii. Witnessing or responding to a death related to COVID-19, or losing a patient you had 
been caring for to COVID-19 
iv. Caring for patients who have died without family physically present due to COVID-19 
precautions 


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b. Have a Montgomery-Asberg clinician-administered depression score >21, indicating 
moderately severe symptoms. This measurement is clinician-administered and will be 
performed by a study team member who is not a therapist, who will receive special 
training. 
c. Have had persistent symptoms despite at least one medication and/or therapy trial 
of standard care treatment for depression. 
d. English speaking – able to understand the process of consent and the risk and 
benefits associated with the study, and able to give written informed consent. 
e. Must be willing to sign a medical release for the investigators to communicate 
directly with their therapist and doctors to confirm a medication and/or medical 
history. This is decided on a case by case basis upon the discretion of the PI. 
f. Must be driven home after the medication dosing session by a driver (which could 
be a friend, family, rideshare or taxi). 
g. Must provide at least one adult to have continuous contact with the participant, 
provide participant transportation, monitor changes in the participant’s 
behavior, and notify research staff of behavior changes. 
h. Has been off selective serotonin inhibitors for five half-lives of the drug plus 2 
weeks. 
i. Must avoid taking any psychiatric medications or starting a new psychiatric 
medication during the study. Should participant's doctor recommend starting a 
new psychiatric medication, participant will be required to notify the study team 
and the subject would withdraw from the study 
j. Must provide a contact (relative, spouse, close friend, or other caregiver) who is 
willing and able to be reached by the Clinical Investigators in the event of a 
participant becoming suicidal.  
k. Must have a negative pregnancy test at study entry and prior to each medication 
dosing session if able to bear children and must agree to use adequate birth 
control. 
l. Are willing to commit to preparation sessions, medication dosing sessions, integration 
sessions, to complete evaluation instruments and commit to be contacted for all 
necessary telephone contacts. 
 
 
4.2. 
Exclusion Criteria. 
a. Personal or immediate family history of schizophrenia, bipolar affective disorder, 
delusion disorder, paranoid disorder, or schizoaffective disorder. 
b. Suicidal ideation with a C-SSRS > 3 
c. Current substance abuse disorder (except in the case of mild alcohol use) 
d. Neuroleptic and SSRI medications that cannot be tapered and discontinued in 
conjunction with the participant’s prescribing physician. 
e. Unstable neurological or medical condition; history of seizure, chronic/severe 
headaches. 
f. Positive urine pregnancy test at the time of screening 
g. Any unstable medical condition that my render study procedures unsafe based on the 
medical history performed as part of the screening procedures, including active 
cardiac medical issues such as ongoing angina, uncontrolled hypertension, or recent 
cardiac ischemia requiring medical attention (within the past 3 months 
h. Any use of psychedelic drugs within the prior 12 months. 
i. Use of tramadol, due to the potential for serotonin syndrome with concomitant use of 


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psilocybin. 
j. Allergy to niacin (N.B. the investigators will inform participants that flushing, redness, 
tingling, and headache are normal side effects that do not predict anaphylaxis, which 
although reported is extremely rare). 
k. Individuals who are on MOAI (monoamine oxidase inhibitors) or who have a known 
sensitivity to the drug or its metabolites. Psilocybin is contraindicated in medications 
that are known UGT (UDP-glucuronosyltransferase) enzyme modulators. The 
concurrent use of SSRI/SNRI meds is assumed to be contraindicated due to the 
potential to increase the risk of serotonin syndrome and/or to attenuate the binding 
of psilocin to the HT2A receptor. 
 
 
4.3. 
Medication management  
Medication contraindications will include anti-seizure medications, insulin and oral 
hypoglycemics, certain hypertension medications (clonidine, and aldomet specifically), cardiovascular 
medications and the following psychotropic medications: anti-psychotics (first and second generation 
agents), anti-depressants and mood stabilizers. Psychotropic medications cannot be taken in the 
previous two weeks, with Prozac (fluoxetine) not being taken within the last 5 weeks prior to receiving 
any study agents. Participants may only take prn (as needed) benzodiazepines (i.e., lorazepam) up to 
three days before the session. 
Participants will refrain from taking any medications the day of medication dosing session, except 
prescribed opiate pain medication or over-the-counter non-narcotic pain medication at any time. It will 
also be necessary to refrain from alcohol the day before, the day of, and the day after each medication 
dosing session. 
Participants must agree to: 
a. Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
Medication Dosing Session 
b. Refrain from the use of any exclusionary medications. Except in the case that the PI 
prescribes benzodiazepine or zolpidem for insomnia. 
c. Refrain from use caffeine or nicotine for two hours before and six hours after 
ingesting the drug, or until research staff deem it safe to do so. 
 
4.4. 
Strategies for Recruitment and Retention 
Participants will be recruited through social media and professional organizations (i.e., 
Northwest Healthcare Response Network—the organization that has coordinated the clinician 
response to the COVID pandemic in Washington state). Because eligible participants will be 
physicians and nurses, we anticipate a general familiarity with clinical trials, although not for a trial 
involving PAP. An informational website will be created to enable potential participants to 
understand the study purpose, inclusion criteria, exclusion criteria, and study email and phone 
number. 
 
4.5. 
Participant Withdrawal or Termination 
Participants may withdraw their consent for use of their data and/or terminate 
participation in the study at any moment during the study by calling the Principal 
Investigator or a member of the research team. To revoke authorization of the use and 
disclosure of Personal Health Information, the participant must follow-up the phone call by 
submitting a request in writing to the Principal Investigator. In this event, the Principal 
Investigator will indicate in the data base that consent from the participant is no longer 
active, and that data can no longer be used.  


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A participant may be withdrawn from the research for any of the following reasons:   
(1) A participant will be withdrawn if they become actively suicidal 
(2) A participant will be withdrawn if during the preparation visits, they show 
signs of severe personality disorder that was not evident in the screening 
visit.  
(3) A participant may be withdrawn if their withdrawal is in the best interests of either 
the participant or of the research (e.g., due to a medical condition making the 
procedures unsafe or any condition making interpretation of the results difficult). 
(4) A participant may be withdrawn if they are unable to comply with study visits (e.g., they 
miss their preparation visits without explanation).  
 
 
4.6. 
Premature Termination or Suspension of Study 
The Principal Investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting quarterly safety reviews. During the review process the 
principal investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Likewise, the principal investigator will 
periodically review the collection, storage, and distribution practices associated with clinical 
data bank, and determine whether changes to enhance confidentiality and privacy are 
required. 
The Principal Investigator, the Medical Monitor and the IRB have the authority to stop 
or suspend the study or require modifications. 
 
5. 
Study Agent 
Synthesized psilocybin, the study drug, is a 4-hydroxy-N,N-dimethyltryptamine and 
occurs in nature in many species of mushrooms, including the genera Psilocybe, Conocybe, 
Gymnopilus, Panaeolus, and Strophparia. Its chemical formula is C12H17N2O4P. Psilocybin is a 
potent agonist at 5-HT2A/C, and their binding potency to these receptors correlates with 
human potency as hallucinogens [7]. Psilocybin has been administered to normal volunteers 
to measure physiological and psychological parameters at doses ranging from 0.045mg/kg to 
0.43mg/kg [45; 51]. It has also been safely administered to patients with OCD at doses 
ranging from 0.025mg/kg to 0.3mg/kg. 
After the FDA has approved the content of the protocol, the psilocybin will be provided by the 
Usona Institute, Inc., 2800 Woods Hollow Rd. Madison, WI 53711, who will provide this information as a 
supplement to this IND application. The Usona Institute utilizes a contract manufacturing 
organization (CMO) to manufacture GMP psilocybin, and the CMO is Almac Pharma Services Limited, 
Seagoe Industrial Estate, Portadown, Craigavon, BT63 SUA, United Kingdom. Using a 222 DEA form, the 
psilocybin will be shipped to Dr Back to be stored in DEA safe located in the Investigational Pharmacy 
at Harborview Medical Center. To safeguard the psilocybin, a special storage safe will be approved by 
DEA to store only the psilocybin. Designated staff will be the only personnel with access to the 
psilocybin. Both the active and placebo will be prepared by designated study staff by a compounding 
process. The UW Investigational Pharmacy (IDS) will store and track the accountability of the 
psilocybin.  A log of the psilocybin accountability, compounding, and release to the study team will be 
kept by the designated IDS staff. This will provide strict safeguarding and accounting of the agent both 
for internal and external regulatory agencies. The sponsor-investigator will be the DEA Schedule 1 
license holder and will dispense the drug directly to study participants. 
 
 


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6. 
Study Procedure and Schedule 
This study will use a randomized, placebo-controlled, double-blind design to examine 
the clinical and neural effects of psilocybin-assisted psychotherapy with either synthesized 
psilocybin (25 mg) or placebo (niacin 100 mg), given along with non-drug preparatory and 
integrative psychotherapy sessions. The duration of the randomized study phase is from 
consent until two weeks after drug administration, which is approximately 6 weeks. The 
blind will be broken at 4 weeks after measures have been completed, and the participants 
who received placebo will be offered the option to receive open-label psilocybin. In addition to 
the baseline assessments and medical evaluation, the study will consist of at least two 
Preparation sessions with the study therapists, the medication dosing session (which will require 
at least 7 hours), and post-medication session Integration sessions, starting the following 
morning after the medication dosing session and continuing at 2 weeks, 3 weeks, and 4 weeks 
post-medication. These integration sessions may be conducted by secure videoconference. 
 
 
6.1. 
Randomization Blinded Study Phase 
Upon completion of the Preparation sessions, participants will be assigned to one of 
the two conditions for the Medication Dosing session: the experimental condition 
(synthesized psilocybin 25mg) or placebo (niacin). The randomization will be performed by IDS 
and capsules will be placed in envelopes for each participant. Randomization will be 
stratified by profession (physician vs nurse) and ethnicity (Black or Hispanic vs other).  
Psilocybin and niacin will be administered in identically appearing opaque, size 0 
gelatin capsule with approximately 180ml of water. The dose of psilocybin will be 25 mg and 
the niacin will be 100 mg. Each participant will have the option of participating in the 
medication dosing sessions. In the study, half of the participants will be randomized to receive 
psilocybin (n=15) or the placebo, niacin (n=15). Following the first treatment session of either 
the active agent or placebo, participants who were randomized to receive placebo will be 
offered the option to receive open-label psilocybin. (The blind will be broken at 4weeks to 
make this determination, after primary endpoint measures have been collected. Clinical 
raters will remain blind to the treatment assignment). Data will be collected from all subjects 
after open-label treatment for descriptive purposes, but these data will not be analyzed as 
part of our primary analysis plan. 
The participant’s condition assignment will be maintained from randomization until 
the 4 week unblinding. If there is an adverse event or other emergency requiring knowledge 
of participant’s condition assignment, as when pharmacological intervention is necessary, the 
blind may be broken for an individual participant. In this case, the study raters who will 
administer the questionnaires will remain blind to the participant’s condition assignment. 
Participants in the placebo condition will be eligible for an open-label study 
continuation. They will be re-screened after the blind is broken to make sure they still meet 
study criteria. If they are eligible and choose to enroll in the open-label continuation, they 
may do so, undergoing psilocybin-assisted sessions occurring within another seven to 14-day 
period. 
The open-label phase of the study will follow nearly identical procedures to those 
used in the randomized phase. Participants will be re-assessed on all study measures following 
the same schedule of the randomized phase. Participants need not complete any portion of 
the open-label phase or the several follow up phases for their participation in the study to 
be considered completed. 
 


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6.2.  
Study schedule for participants by visit 
 
6.2.1. Screening and Informed consent  
Prior to participation in this research, subjects will receive a brief secure online screening survey 
and then if eligible, will be screened by phone to determine preliminary eligibility. All subjects will be 
informed about the phone screening and what the screening process involves. 
All potential participants will be told that we collect demographic information, relevant 
medical history, and psychiatric history during the screening process. Screening data are entered 
directly into a secure online database and are considered a source document. 
All seemingly eligible subjects will be told that they need to come in for baseline screening 
visit, and will be informed about baseline questionnaires, clinician assessment, blood draw, and 
pregnancy test (if applicable) to ensure their eligibility. Subjects are free to decline participation at 
this point or to discontinue participation at any future point and to withdraw from consideration. 
Some potential participants live in another state, and it may not be feasible to have them 
come for an in-person screening visit. In this case we will conduct the screening interview utilizing secure 
video communication platforms. We will ask these participants to send us their most recent physical, 
and blood work (recent as of 1 month from the screening visit will be allowed). This will be faxed to 
the PI and reviewed for potential participation. A remote urine test will be ordered for the screening 
process of remote participants.   
Prior to obtaining informed consent, the PI will confirm that the participant meets all 
study inclusion and exclusion criteria. The investigator or research staff member obtaining 
consent will ask the participant to provide a brief summary of the study to ensure they 
understand what is being asked of them and any potential risks and benefits.  
Note that if a female subject is pregnant, or breast-feeding, or does not agree to use an 
approved birth control method (i.e., oral, injectable, or implant birth control, condom, 
diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with 
vasectomy) she will be excluded. 
Findings of pregnancy, active cardiac medical issues, abnormal liver function, 
abnormal renal function, or abnormal blood counts, and any lab indicating an undiagnosed 
illness would exclude a participant from moving on to the preparation 1 visit. When 
screening requirements have been met, participants will have a visit with the PI and/or key 
study personnel in which the study, the scheduling and the procedures will be reviewed. All 
participants' questions will be answered prior to obtaining an informed consent. 
After providing informed consent, the participant will complete initial measures. Note 
that randomization to the psilocybin or control (niacin) treatment groups will occur at the end of 
visit 2. 
 
6.2.2.  Preparation visits (Visits 1, 2) 
 
Preparation for the medication dosing session (psilocybin or control) consists of 2 
meetings for a total of 5-6 hours in the 2 weeks before the medication dosing session. The main 
purpose of the preparation meetings is to develop rapport and trust, which helps minimize the 
risk of fear or anxiety reactions during the psilocybin sessions. Additional meetings and contact 
hours will be scheduled if it is judged necessary to establish rapport and trust. Consistent with 
other published psilocybin protocols, the participant’s life history and current situation in life will 
be reviewed, and intentions and expectations for the psilocybin sessions will be discussed. Audio 
or video recordings (with coded id number) of this session will be made to allow the 
participant and the investigator-therapists to review preparation sessions. 
 


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6.2.3. Medication Dosing session (Visit 3) 
 
Procedures for psilocybin administration and the conduct of the session will be similar to 
procedures used in studies with psilocybin conducted at New York University, Johns Hopkins, 
and Yale. Participants will be instructed to consume a low-fat breakfast before reporting to the 
clinic room for the psilocybin sessions. Before psilocybin administration, urine pregnancy test 
will be conducted in females of childbearing potential, and a negative pregnancy test will be 
required in order to continue in the medication session. Participants and staff will also complete 
pre-session questionnaires. Before each psilocybin session, study personnel will interview the 
participant. If the investigator believes that the session is contraindicated, the session will be 
cancelled or postponed. 
 
Psilocybin will be administered in opaque gelatin capsules with approximately 100 ml 
water. At least one therapist, under the supervision of the investigators, will be present in the 
room and available to respond to participants’ physical and emotional needs during the full 
course of the session (at least 7 hours). A physician on the study team will be immediately 
available via pager or mobile phone for at least 3 hours or until the peak effects of psilocybin 
have subsided, whichever is longer. 
 
During the session, participants will lie on a couch, wear eyeshades, and listen to a 
program of music through headphones. The participant will be encouraged to focus her or his 
attention inward. The eyeshades and music are intended to encourage this inward reflection. 
Heart rate and blood pressure will be measured pre drug administration, at 30, 60, 90, 120 
minutes after drug administration, and then at least hourly until at least 6 hours after drug 
administration and until drug effects have subsided. Heart rate and blood pressure assessments 
will be obtained after the participant has been sitting or recumbent for at least 5 minutes. 
Sessions are expected to last approximately 7 to 10 hours. A sample schedule for the medication 
dosing session is as follows: 
 
Approximate Time 
Procedure or Action 
09:00 
Urine pregnancy test for females of childbearing potential, 
participant acclimates to environment, completes measures. 
09:30 
Baseline BP, Pulse, Temp. 
Medication Administration.  
Begin video recording. 
10:00 
BP, Pulse 
10:30 
BP, Pulse 
11:00 
BP, Pulse 
11:30 
BP, Pulse 
12:30 
BP, Pulse 
13:30 
BP, Pulse 
14:30 
BP, Pulse 
15:30 
BP, Pulse 
16:30 
BP Pulse. 
Assessment for discharge home. 
 
 
At about the same time of each heart rate/blood pressure measurement, monitors will complete 
notations in the Medication Day Case Report Form to rate the presence and intensity of behaviors, signs, 
and reported symptoms, including sleepiness, amount of speech, anxiety, stimulation/arousal, 


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Version 1.16, July 18, 2022 
 
 
tearing/crying,nausea/vomiting, yawning, restlessness, feelings of unreality, visual changes, euphoria, and 
peacefulness. Video and audio recordings will be made throughout the session, as allowed by participants. 
Participants will be encouraged to lie comfortably in bed wearing eye shades during the first 
few hours of the experience and to listen to pre-selected music chosen by the study staff. Two team 
members will remain with the participants the entire time and be available for any processing of 
intrapsychic material made manifest by the treatment.  
If participants experience or report on any adverse effects or if the research staff feels that at the 
end of testing, that the participant has any adverse effects, participants will be asked / required to remain 
until effects wear off and medically cleared by the PI. Medical assistance will be offered. The 
investigators will query participants about suicidal ideation or intent during screening, and prior to 
each psilocybin session. Participants who evidence suicidal ideation or intent will be withdrawn from the 
study and referred to appropriate psychiatric care. 
In the event that participants experience distressing anxious symptoms during the drug 
session, the clinical personnel in attendance (the principal investigator and team member) will 
initiate verbal communication designed to reorient and reassure that participant. The occurrence and 
intensity of anxiety or panic responses can be reduced through providing participants with information 
on potential drug effects, supervision, and monitoring of participants for the duration of drug effects. 
The goal in this study is to treat participants undergoing anxiety or panic reactions first by verbal and 
psychological interventions and using anxiolytic medication only after verbal and psychological 
interventions have failed, and if participants are endangering themselves or others. Residual 
symptoms will be addressed during the frequent follow-up psychotherapy visits with the 
investigators. 
 
At the end of the medication dosing session: 
o Participants will complete paper or computer-based questionnaires designed to assess 
acute subjective experiences associated with the medication dosing session.  
o Study therapists will the participant’s mood and suicidality with the C-SSRS.  
o Participants will also be asked to write a narrative description of the experience of the 
psilocybin session before their next in-person meeting. 
o Participants will remain under observation until both the participant and investigator 
agree that their perception, cognition, functioning, and judgment are no longer 
impaired by the medication. 
o Participants will be discharged in the company of the adult who is providing 
continuous contact. 
 
6.2.4. Integration sessions (Visit 4, 5, and 6) 
 
During the meetings with the study therapists after the medication dosing session, 
participants will complete questionnaire assessment measures. During visit 4, study therapists 
will also complete questionnaires retrospectively rating various behaviors and experiences 
observed on the session day and reported by the participant during the meeting (using the Next-
Day Monitor Rating Form), and participants will be asked to discuss the narrative description of 
their medication session. 
 
The purpose of the integration sessions is to ensure psychological stability after the medication 
dosing session and provide an opportunity for the participant to discuss thoughts or feelings from the 
session. These post-medication integration sessions allow time for reflection, meaning-making and 
psychological change. Audio or video recordings (with coded id number) of this session will be made.  
 
6.2.5. Long-term follow-up 
 
A study therapist who conducted the integration, medication dosing and preparation 
sessions will contact the participant at 3 months post-psilocybin, and 6 months post-psilocybin 


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(note that this takes into account participants who receive psilocybin after the primary endpoint 
measures have been collected in the open label phase of the study (see below). The therapist 
will have a 30 min phone call or video call with the participant, and the participants will fill out 
measures using a secure online portal.  
 
6.2.6. Timing and Location of Meetings, Sessions, and Measures.  
 
Although much effort is put in to scheduling participants within the stated time 
frames, these are only estimates. Variables out of the study team’s control (e.g., participant 
availability, university closings, availability of study rooms, illness) may prevent the scheduling of 
volunteers within the stated time frame goals. There is no evidence to suggest that the 
difference in timing of sessions, meetings, and measures will adversely affect the volunteer or 
the validity of the study. On those occasions when the timing of meetings, sessions or measures 
deviate substantially from the time frames in the protocol, we will report these as deviations in 
the Continuing Review. 
 
6.3. 
Open Label Psilocybin Sessions.  
 
The participants who choose to receive open-label psilocybin will be re-screened after the 
blind is broken after primary endpoint measures are collected (week 4) to make sure they still meet 
study criteria. If they are eligible and stil choose to enroll in the open-label continuation, they may do so, 
undergoing a psilocybin-assisted session occurring within another seven to 14-day period. 
The open-label phase of the study will follow nearly identical procedures to those used in the 
randomized phase except that a single preparation psychotherapy session will be given (see Schedule 
below, Study day -1). Participants will be re-assessed on all study measures following the same schedule 
of the randomized phase.  
Participants need not complete any portion of the open-label phase or the several follow up 
support appointments for their participation in the study to be considered completed. 
Data will be collected from all subjects after open-label treatment for descriptive purposes and 
will be viewed not as part of our primary analysis plan but as part of a secondary analysis examining the 
impact of PAP on symptoms of depression and burnout. 
 
 
Schedule for Activities during Open Label Psilocybin Phase 
Purpose 
Prep 
Medi-
cation 
Inte- 
gration 
Inte-
gration 
Inte- 
gation 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Follow 
-up 
Study day (‘denotes open-label) 
-1’ 
0’ 
1’ 
7’ 
14’ 
21’ 
28’ 
56’ 
84’ 
180’ 
Visit number  
V7 
V8 
V9 
V10 
V11 
V12 
V13* 
V14* 
V15* 
V16* 
Research activity 
 
 
 
 
 
 
 
 
 
 
Psychiatric evaluation 
X 
 
 
 
 
 
 
 
 
 
Education re expectations 
X 
 
 
 
 
 
 
 
 
 
Preparation psychotherapy 
X 
 
 
 
 
 
 
 
 
 
Urine screen 
 
X 
 
 
 
 
 
 
 
 
Medication (psilocybin) 
 
X 
 
 
 
 
 
 
 
 
Medication dosing monitoring 
 
X 
 
 
 
 
 
 
 
 
Integration psychotherapy 
 
 
X 
X 
X 
 
 
 
 
 
Adverse event reporting 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measures 
 
 
 
 
 
 
 
 
 
 
Montgomery Asberg Depression 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Beck Depression Scale 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stanford Fulfillment Index 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Post-traumatic stress (PCL5) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 


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Likelihood to leave job 
X 
 
 
 
X 
 
 
 
 
 
Self-reported mystical exp 
 
X 
 
 
 
 
 
 
 
 
Moral injury symptom scale 
 
X 
 
 
 
 
 
X 
 
 
Psychedelic music questionnaire 
 
 
X 
 
 
 
 
 
 
 
Psychological flexibility (AAQII) 
X 
 
 
 
X 
X 
X 
X 
X 
 
Suicidality (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative interview 
 
 
 
 
 
X 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*Note that V13, V14, V15, and V16 are likely to be video or remote visits. 
 
6.4. 
Rescue Medications, Treatments, and Procedures 
 
The plan for managing psychiatric emergencies includes: 
• 
A detailed therapist manual, and training for all study therapists on procedures in the 
manual for handling potential adverse events including agitation, hallucinations, anxiety, 
and other intense psychological reactions. 
• 
The two-person therapist team that will be with the participant for the entire medication 
dosing session will include a licensed therapist or physician with training in psychiatric 
emergencies and adverse effects of psychedelics. 
• 
A psychiatrist team member will be involved in screening and evaluation of all 
participants. 
• 
A physician with training in psychiatric emergencies and adverse effects of psychedelics 
will be immediately available on site for the medication dosing days. 
• 
A psychiatrist team member will be immediately available to assess any participant noted 
by study staff to have a significant change in mood or suicidality. 
• 
In the event of a psychiatric emergency, the Harborview Medical Center Psychiatry 
Emergency Services in the next building is available 24 hours a day, with on-site 
psychiatrists and nurse practitioners. 
• 
The PI may prescribe a designated rescue medication in the event of symptoms that 
require it during or after the medication dosing session. Study therapists who have 
performed first-line and second-line interventions (that do not involve medications) will 
have the ability to contact the PI by phone, who is available to assess patients within 20 
min during every medication session. If a patient does have an adverse reaction that 
requires a rescue medication, participants will be monitored for up to 2 hours beyond the 
required 6 hour duration of the session. If at the end of that period that participant 
requires further, Dr Back (PI) will consult with the attending psychiatrist on call at 
Harborview Medical Center. 
If participants experience or report on any adverse effects or if the research staff feels 
that at the end of testing, that the participant has any adverse effects, participants will be able 
to remain until effects wear off (likely only for a short period) and medical assistance will be 
offered. Participants will be free to withdraw from the study whenever they wish. In addition, if 
any participant presents with an adverse reaction to the psychopharmacological agent as 
reported by them or assessed by a member of the research team, we will discontinue the study 
and call for medical assistance 
 
6.5. 
Safety Plan for Suicidality: 
During all study visits a study investigator with clinical training will assess the participant’s 
well- being – responses, intent, plan, etc. while administering the C-SSRS (Columbia Suicidality Severity 
Response Scale).  If these procedures result in any serious concerns on the part of the investigator, 
they will either ask the participant to meet with or call the PI or escort the participant to the 


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emergency room. If necessary, they will also call the participant’s treating clinician and/or their 
emergency contact. As part of the consent, participants are required to designate an emergency 
contact person and provide their treating clinician’s contact information. We will ask the treating 
clinician for their local plan for such emergencies so the study team can follow this plan should an 
emergency situation arise. 
 
7. 
Payments for Participation (Economic Considerations) 
Participants will not be paid for their participation. Expenses of participating in the study, such as 
parking will be covered by the study.  
 
8. 
Assessment of Safety  
8.1. 
Specification of Safety Parameters 
8.1.1. Definition of Adverse Events (AE) 
Adverse events (AEs) are defined any untoward, physical, social, economic, or 
psychological occurrence affecting human subjects in research. An AE can be any 
unfavorable or unintended event including abnormal laboratory finding, symptom, reaction, 
or disease. An AE does not necessarily have a causal relationship with the research, or any risk 
associated with the research, the research intervention, or the assessment. Adverse events 
involve subjects only. 
 
8.1.2. Definition of Serious Adverse Events (SAE) 
In addition to grading the adverse event, adverse events are evaluated to determine 
whether they meet the criteria for a Serious Adverse Event (SAE). An SAE is defined as 
death; a life threatening experience; inpatient hospitalization (for a person not already 
hospitalized); prolongation of hospitalization (for a patient already hospitalized); persistent or 
significant disability or incapacity; congenital anomaly and/or birth defects; or an event that 
jeopardizes the participant and may require medical, surgical, or other intervention to prevent 
one of the preceding conditions (FDA, 21 CFR Part 312). An adverse event is considered 
serious if it: 
• is life-threatening 
• results in in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• results in a congenital anomaly or birth defect OR 
• results in death 
• based upon appropriate medical judgment, may jeopardize the subject’s health, 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition, or 
• adversely affects the risk/benefit ratio of the study 
 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event. Similarly, an adverse event may be graded as moderate but still meet the criteria for 
an SAE. It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRBs and the Medical Monitor is necessary. 
 
8.1.3. Definition of Unanticipated Problems (UP) 
An unexpected adverse event is one that is not listed in the current Investigators 
Brochure for Psilocybin, assisted psychotherapy produced by MAPS or an event that is by 
nature more specific or more severe than a listed event. 


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Such an event is unlikely because as of 01 December 2016, with over 1000 
individuals exposed to Psilocybin in controlled research settings, there have been no 
unexpected drug- related SAEs to date and expected SAEs have been rare and non-life 
threatening. 
 
8.1.4. Classification of an Adverse Event 
The following scale will be used in grading the severity of adverse events noted during 
the study: 
1. Mild adverse event (does not affect patient activity) 
2. Moderate adverse event (mild disruption in usual activity) 
3. Severe (major disruption in usual activity) 
 
8.2. 
Time Period and Frequency for Event Assessment and Follow-Up 
Adverse events will be reviewed with subjects weekly from the time of preparation 
visit 1 through primary outcome collect at 4 weeks. Information will be assessed in-person 
and during weekly phone calls.  Adverse events or unanticipated problems involving risks to 
subjects or others will be reported to the HIC or HSC within 48 hours of it becoming known to 
the investigator, using the appropriate forms found on the website. 
 
8.3. 
Reporting Procedure (Adverse Events) 
The investigator will report the following types of adverse events: 
a. serious and unanticipated and possibly, probably, or definitely related events; 
b. anticipated adverse events occurring with a greater frequency than expected; 
c. other unanticipated problems involving risks to subjects or others. 
 
8.4. 
Study Halting Rules 
The Medical Monitor or the Principal Investigator has the right to discontinue this study 
at any time. If the trial is prematurely terminated, the Primary Investigator is to promptly 
inform the study participants and will assure appropriate therapy and follow- up. If the trial or 
study is prematurely discontinued, all procedures and requirements pertaining to retention and 
storage of documents will be observed. All other study materials will be treated in accordance 
with federal and state regulations. 
 
8.5. 
Attribution of Adverse Events 
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator according to the 
following categories: 
a. Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b. Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c. Possible: Adverse event may be related to investigational procedures(s)/agent(s).  
d. Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e. Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
8.7. 
Plan for Grading Adverse Events: The following scale will be used in grading the 
severity of adverse events noted during the study: 
 a. Mild adverse event 
 b. Moderate adverse event 


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c. Severe 
 
8.8. 
Plan for Determining Seriousness of Adverse Events: 
Serious Adverse Events: In addition to grading the adverse event, the PI will determine 
whether the adverse event meets the criteria for a Serious Adverse Event (SAE). An adverse 
event is considered serious if it results in any of the following outcomes: 
 
a. Death; 
b. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
c. A persistent or significant disability or incapacity; 
d. Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health, and may require medical or surgical intervention 
to prevent one of the other outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet the 
criteria for an SAE. It is important for the PI to consider the grade of the event as well as its 
“seriousness” when determining whether reporting to the IRB is necessary. 
 
8.9. 
Plan for reporting UPIRSOs (including Adverse Events) to the IRB. 
The Principal Investigator will report the following types of events to the IRB: Any 
incident, experience or outcome that meets ALL 3 of the following criteria: 
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB- 
approved protocol and informed consent document and (b) the characteristics of 
the subject population being studied; AND 
2. Is related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized. 
 
8.10. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be 
medical or non-medical in nature and include – but are not limited to – serious, unexpected, 
and related adverse events and unanticipated adverse device effects. Please note that 
adverse events are reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed 
above. 
These UPIRSOs/SAEs will be reported to the IRB using the appropriate forms. In the 
event that such events occur, Reportable Events (which are serious or life- threatening and 
unanticipated, or anticipated but occurring with a greater frequency than expected, and 
possibly, probably, or definitely related) or Unanticipated Problems Involving Risks to Subjects 
or Others that may require a temporary or permanent interruption of study activities will be 
reported immediately (if possible), followed by a written report to the IRB within 5 calendar 
days (in accordance with IRB Policy 710) of the Principal Investigator becoming aware of the 
event (using the appropriate forms) and to any appropriate funding and regulatory 
agencies. 
All related events involving risk but not meeting the prompt reporting requirements 


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should be reported to the IRB in summary form at the time of continuing review. If 
appropriate, such summary may be a simple brief statement that events have occurred at the 
expected frequency and level of severity as previously documented. 
 
8.11. 
Plan for reporting adverse events to co-investigators on the study, research monitor(s), e.g., 
Protocol Review Committee (PRC), study sponsors, funding and regulatory agencies, and regulatory 
and decision-making bodies. 
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified: 
a. All Co-Investigators listed on the protocol. 
b. Food and Drug Administration  
c. Study Funding and Sponsors 
The investigator will apprise fellow investigators and study personnel of all UPIRSOs 
and adverse events that occur during the conduct of this research project through regular 
study meetings, or via email as they are reviewed by the principal investigator. 
The protocol’s research study sponsors, funding and regulatory agencies, and 
regulatory and decision-making bodies will be informed of any Serious, Unanticipated and 
Related adverse events within 5 days (or within any contract or policy designated time 
period) of the event becoming known to the principal investigator. 
 
The principal investigator will conduct a review of all adverse events upon completion 
of every study subject. The principal investigator will evaluate the frequency and severity of 
the adverse events and determine if modifications to the protocol or consent form are 
required. 
 
8.12. 
Safety Oversight 
The principal investigator in conjunction with the Medical Monitor will be 
responsible for monitoring the data, assuring protocol compliance, and conducting the 
safety reviews at the specified frequency, which must be conducted at a minimum of every 
6 months (including when reapproval of the protocol is sought). 
During the review process, the principal investigator (in collaboration with the 
Medical Monitor) will evaluate whether the study should continue unchanged, require 
modification or amendment, continue or close to enrollment. Either the principal 
investigator, the HIC, or the Medical Monitor have the authority to stop or suspend the 
study or require modifications. Likewise, the principal investigator will periodically review 
the collection, storage, and distribution practices associated with clinical data bank, and 
determine whether changes to enhance confidentiality and privacy are required. The 
research team will follow the University of Washington guidelines for attribution of 
adverse events and grading the severity of adverse events (including determining whether 
the adverse event meets criteria for a Serious Adverse Event). 
 
8.13. 
Clinical Monitoring 
After administration of Psilocybin/placebo, participants will be checked 
regularly. A research team member will accompany the participants and be available 
at all times to call for medical assistance if required. Procedures will be immediately 
stopped if participants request to stop or exhibit any sign of significant distress. The 
study therapists will have immediate access to the PI or a designated physician to 


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assess any problems, or to clear a participant for discharge from the research facility. 
 
9. 
Statistical Considerations 
9.1. 
Measures to Minimize Bias 
9.1.1. Enrollment/Randomization/Masking Procedures 
The necessary strict exclusion criteria for psilocybin interventions may limit 
generalizability of the findings. The influence of repeated testing in the crossover design 
will be minimized by modeling order effects in analyses, but some effects of practice may 
persist.  
 
9.1.2. Evaluation of Success of Blinding 
At the end of the randomized treatment, participants will be asked to fill out a 5 point 
Likert scale with the following options: 
--I am positive I received psilocybin 
--I think I received psilocybin 
--I cannot tell whether I received psilocybin or niacin (placebo) 
--I think I received niacin (placebo) 
--I am positive I received niacin (placebo) 
 
9.1.3. Source Documents and Access to Source Data/Documents 
Paper source documents and research case books will be housed in restricted access files. 
Personally-identified information will be restricted to name, address, phone number, birth-
date, social security numbers, dates of care, and will be kept by investigators in a separate 
file from the research data which will be coded using a unique subject identification. 
 
 
9.1.4. Quality Assurance and Quality Control 
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews yearly. During the review process, the 
principal investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment.  Either the principal investigator 
or the IRB have the authority to stop or suspend the study or 
require modifications. 
 
9.2. 
Statistical approach  
The primary objective of this randomized trial is to compare the mean change from baseline 
MADRS among patients randomized to receive psilocybin to that among patients randomized to receive 
niacin.  The time point of primary interest at which change will be assessed will be 4 weeks.  Mean change 
between the two groups will be assessed with the two-sample t-test, or the Wilcoxon rank-sum test if 
distributional assumptions for the t-test are violated.  The table below shows the minimum detectable 
assumed-true effect size (represented in standard-deviation units, or the difference in mean change 
divided by the common standard deviation) to observe a statistically significant difference (at the two-
sided significance level of .05) with 80% and 90% power for a variety of total sample sizes. 
  
Sample size 
80% Power 
90% Power 
N=30 
1.06 SD units 
1.23 SD units 
N=40 
0.91 SD units 
1.05 SD units 
N=50 
0.81 SD units 
0.94 SD units 


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Based on the values in the above table, we will randomize 30 patients, as we hypothesize that an 
assumed-true effect size of 1.06 – 1.23 is achievable based on previous studies by Ross and Davis  and 
achieved effect sizes of 1.46 at 2 weeks at 1.69 at 6 weeks19 or 2.2 at 5 weeks.18 A sample size of N=30 will 
provide >90% power to detect a significant difference in the primary outcome between the psilocybin 25 
mg vs niacin groups.  Assuming a 15% drop-out rate of subjects in this study, we will enroll 36 subjects and 
assume 6 will not complete the study, so full enrollment in this study will be 36 with a target of 30 subjects 
completing the study. 
The primary analysis will be done using the intent-to-treat principle.  Randomization will be done 
using a permuted block design with randomly selected block sizes. 
Key secondary endpoints include those listed below, and a hierarchical approach will be taken to 
the potential analysis of these endpoints.  If the primary endpoint is statistically significant, then these 
secondary endpoints will be (potentially) formally compared in a hierarchical manner in the order listed 
below.  
1.     Mean change in burnout (Stanford Fulfillment index) from baseline to 4 weeks between the two 
groups 
2.     Mean change in symptoms of PTSD (PCL5) from baseline to 1 week and 4 weeks between the two 
groups. 
These secondary endpoints will be compared between groups as described above. At the first endpoint 
that is not statistically significant (at the two-sided significance level of .05), all subsequent endpoints will 
be evaluated descriptively and not formally assessed in order to maintain the overall type I error rate of 
.05. 
 
10. 
Ethics/Protection of Human Subjects 
10.1. 
Ethical Standards 
The research will be performed according to ethical principles and in compliance with 
all federal, state, and local laws, as well as institutional regulations and policies regarding the 
protection of human subjects. 
 
10.2. 
Informed Consent Process 
After an initial phone screen to determine obvious exclusions from the study 
protocol, potential subjects will be invited for an in-office visit. During the screening visit, the 
study procedures will be described, and the subject’s questions will be answered prior to 
obtaining an informed consent. The person obtaining the consent will ask the participant to 
provide a brief summary of the study to ensure they understand what is being asked of them 
and any potential risks and benefits. For participants who are out of the area, informed 
consent will be obtained via video conference and written consent documented using 
REDCap.  
 
10.3. 
Participant and Data Confidentiality 
Participant study identification numbers (which cannot be linked to participant), 
names, and other demographic information, contact information, and previous medical 
history will be kept in a locked filing cabinet located in a locked room. Secure research files 
will be used to store assessment and data forms derived from the research data 
collection. Each participant is assigned a numeric code to conceal identity. This coding will 
carefully safeguard confidentiality on encrypted computer hard disks used for analysis. No 
personal identifying data will appear in the computer files or other papers (e.g., 
questionnaires, laboratory raw data). 


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Care will be taken to conceal other possible sources of identification, including 
addresses or occupations. A list of participant numbers, names, and other demographic 
information will be kept in a locked cabinet located in a locked room. Cross-referenced 
names and code numbers will be included in a master list that will be stored in a locked file 
cabinet that will be accessible only to the research staff. The identities of participants will 
not be revealed in any description or publications resulting from this research. The 
granting agency, the research monitors, the PI’s laboratory, and collaborators will have 
access to de-identified study data. All electronic data is double password-protected and 
follows IRB standards at the University of Washington. Digital data will be stored on a 
secured server and on secured desktop computers. 
 
10.4. 
Research Use of Stored Human Data 
The investigators understand the importance of communicating research findings 
from studies. Results from this study may be presented at conferences and meetings or 
published 
in academic journals. All data would be deidentified and participant identity would never be 
disclosed when presenting results of the study. 
 
10.5. 
Future Use of Stored Data 
De-identified data may be stored indefinitely and used for publications, research 
presentations and meetings. 
 
 
11. 
Data Handling and Record Keeping 
11.1. 
Data Collection and Management Responsibilities 
The principal investigator, Anthony Back MD, will be responsible for monitoring 
the data, assuring protocol compliance, and conducting the safety reviews at the 
specified frequency, which must be conducted at a minimum of every 6 months. Dr. 
Back will confer and discuss any issues with the research and oversight team that 
have been brought to light and will discuss what alterations might be needed if any, 
in weekly rounds meetings (as is the clinic standard research practice). Any adverse 
events will be reported in accordance with University of Washington policies. 
During the review process, the principal investigator and the Medical Monitor 
will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. Either the principal investigator, the 
IRB, or University of Washington administrators have the authority to stop or suspend 
the study or require modifications. 
Research personnel will collect research data via direct interview after 
potential subjects’ sign release of information for available informants. This data will 
be recorded in both written and/or electronic formats, and all confidential research 
data will be separated and stored in locked and secured files. 
 
11.2. 
Study Records Retention 
All electronic research records will continue to be encrypted and password-protected 
after subject participation. Both written and electronic records will be destroyed 10 years 
after the protocol is completed. 
 


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12. 
Publication and Data Sharing Policy 
The identities of participants will not be revealed in any description or publications 
resulting from this research. The granting agency, the research monitors, the PI’s 
laboratory, and collaborators will have access to de-identified study data. 
 
13. 
Study Administration and Leadership 
13.1. 
Principal Investigator 
 
Anthony Back MD 
 
14. 
Conflict of Interest Policy 
There is no conflict of interest to report from any of the study staff. 
 
15.  
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