Clinical trial NCT02950467
Conditions: Distress Depression Grief
Keywords: HIV/AIDS Demoralization Psilocybin Group therapy
Sponsor: Joshua Woolley
Start date: 2018-01-05; Completion date: 2019-12-31
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether psilocybin-assisted group psychotherapy is a safe and feasible treatment for demoralization in long-term AIDS survivors (LTAS).

Detailed description:
This study is an open-label mixed-methods pilot study of an individual oral psilocybin drug session combined with ten sessions of an evidence-based, manualized brief group psychotherapy for existential distress in palliative care patients.

Arms: arm 1: Modified brief Supportive-Expressive Group Therapy will be administered as ten twice-weekly sessions. Oral psilocybin will be administered once in a clinical setting.
Interventions: intervention 1: Psilocybin intervention 2: Modified brief Supportive Expressive Group Therapy
Intervention descriptions: intervention 1: One individual oral psilocybin treatment session intervention 2: Ten sessions of twice-weekly manualized group therapy

Protocol documents:
Prot_SAP_003.pdf: 
Cover page 
 
Psilocybin-assisted Group Therapy for Demoralization  
in Long-term AIDS Survivors 
 
NCT02950467 
 
Protocol and SAP 
 
17 April 2018 
 
 


 
PSILOCYBIN-ASSISTED GROUP THERAPY FOR DEMORALIZATION IN 
LONG-TERM AIDS SURVIVORS 
 
Protocol Number: CHR#15-17825 
ClinicalTrials.gov: NCT02950467 
IND Number: 133326 
Research Advisory Panel of California: PR#1705H 
DEA: RW0519857 
Study Drug: Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) 
Study Psychotherapy: Supportive-Expressive Group Therapy 
Version Number: 1.3 
Version Date: 03 April 2018 
Principal Investigator (Sponsor-Investigator) 
Josh Woolley, MD, PhD 
University of California San Francisco 
401 Parnassus Ave San Francisco, CA 94143 
Telephone: 415-221-4810x24117 
Fax:  415-379-5667 
E-mail: josh.woolley@ucsf.edu 
Co-Investigators 
Brian Anderson, MD, MSc 
James Dilley, MD 
Christopher Stauffer, MD 
Statistician 
Matthew Boden, PhD 
Clinical Research Coordinator 
Brian Anderson, MD, MSc 
University of California San Francisco 
401 Parnassus Ave, Rm 263San Francisco, CA 94143 
brian.anderson@ucsf.edu 
Telephone: 415-476-7432 
Fax: 415-502-6361 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws. Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 


Abstract 
 
 
Title 
Psilocybin-Assisted Group Therapy for Demoralization in Long-term AIDS 
Survivors 
Patient 
population 
Gay-identified HIV-positive men ≥50 years old who were diagnosed with 
HIV prior to 1996. 
Rationale for 
Study 
Long-term AIDS Survivors (LTAS) are people living with HIV (PLH) who 
were diagnosed prior to the advent of combined antiretroviral therapy 
(ART) and, compared to their HIV seronegative peers, suffer higher rates 
of depression, anxiety, trauma exposure, substance use and risky sexual 
behaviors [1-6]. Prior to ART, people living with HIV were “end-of-life 
patients,” then with advent of ART they became “chronically ill,” and now 
many of them are re-approaching end-of-life status as their bodies age at 
an accelerated rate due to HIV infection, HIV therapies, HIV-associated 
non-AIDS conditions, or all of the above [7]. By 2014, 9,202 HIV-positive 
individuals living in San Francisco were older than 50 years old (58% of 
the city’s HIV-positive population) [8]. Like “cancer survivors,” AIDS 
survivors experience increased rates of psychological distress even long 
after their disease is controlled [9, 10]. LTAS are an emerging population 
whose mental health needs are under recognized and undertreated. 
Existential distress is a form of psychological suffering precipitated by the 
acute awareness of one’s mortality [11]. Demoralization is one type of 
existential distress [12], and it is characterized by a sense of 
hopelessness, helplessness and a loss of meaning in life [13]. 
Demoralization is a well-characterized clinical syndrome that captures the 
form of psychological distress suffered by many LTAS [1, 14]. 
Demoralization is also a clinical construct well-suited for investigation as a 
hypothesized therapeutic benefit of psilocybin-assisted psychotherapy in a 
population with chronic existential distress, like LTAS. Because it is 
experienced as a loss of meaning, demoralization should theoretically be 
treatable with interventions that enhance meaning-making [15]. An 
investigational pharmacotherapy that is thought to potently enhance 
meaning-making is psilocybin [16, 17]. Recent trials of individual 
psilocybin-assisted psychotherapy for anxiety and depression in cancer 
patients have shown this intervention to be safe [18-20], and have found 
significant improvements in anxiety and depression lasting months after a 
single treatment [19, 20]. Such impressive results are thought to be 
mediated by two mechanisms: 1) Having a complete “mystical-type” 
experience under the influence of psilocybin [21], and 2) Subsequent 
enhanced social support in the weeks following the mystical experience 
[22]. It remains unknown how these impressive results may translate into 
other palliative care populations. 
Since the beginning of the HIV/AIDS epidemic, many psychotherapies for 
people living with HIV have been preferentially delivered as groups 
because of enhanced cost-effectiveness and the group format’s unique 
clinical benefits with respect to the enhancement of social support in a 
population suffering high rates of isolation and loneliness [23]. This study 
will use the same standard psilocybin administration safety guidelines 
 


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Rationale for 
Study 
(continued) 
as prior trials [24], but the psychotherapy sessions will employ a modified 
form of Supportive-Expressive Group Therapy (SEGT) [25]. SEGT is a 
widely used, manualized, evidence-based group intervention for 
existential distress in patients with life-threatening disease [26]. The 
current study will be the first modern study of psilocybin-assisted group 
psychotherapy. 
In the current study, the group psychotherapy format functions as a 
standardized context in which patients’ experiences of social support can 
be objectively observed pre- and post-psilocybin. This is helpful because 
while prior trials of psilocybin-assisted psychotherapy evaluated clinical 
outcomes, they did not make use of validated measures of 
psychotherapeutic process. By administering psilocybin as an adjunct to 
SEGT, we will be able to explore quantitatively and qualitatively not only 
the intrapersonal, but also the interpersonal, therapeutic mechanisms 
catalyzed by psilocybin in LTAS suffering from demoralization. 
Primary 
Objective 
To demonstrate the safety and feasibility of Psilocybin-Assisted 
Supportive-Expressive Group Therapy (PA-SEGT) for demoralization in 
LTAS. 
Exploratory 
Objectives 
To explore the preliminary efficacy of PA-SEGT for improving 
demoralization, complicated grief, depression, anxiety, quality of life, 
functional social support, post-traumatic growth, openness to experience, 
mindfulness, social connection, nature relatedness and ART medication 
adherence in LTAS. 
To explore quantitatively and qualitatively the mechanisms through which 
PA-SEGT addresses existential distress in LTAS. 
Study Design 
Open-label mixed-methods pilot study of individual oral psilocybin drug 
sessions (with escalating dose) combined with an evidence-based, 
manualized brief group psychotherapy. 
Number of 
patients 
36 (maximum, with a minimum of 8) 
Duration of 
Therapy 
8 weeks after the initiation of the intervention. 
Duration of 
Follow up 
3 months after completion of the intervention. 
Duration of 
study 
2 years from the time the study opens to accrual. 
Study Therapy 
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) will be administered 
once at a moderate-to-high dose of 0.3mg/kg (or 0.36mg/kg) po during an 
individual medication visit to be held after 4 group therapy visits have 
been completed. Patients will undergo a total of 10  group psychotherapy 
sessions. 


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Safety 
Assessments 
Adverse events 
Vital signs 
Adverse Event Medication Session Form 
Columbia Suicide Severity Rating Scale  
Community Observer Rating Form 
Feasibility 
Assessments 
Rate of Patient Recruitment 
Rate of Patient Retention (Sessions Attended and Follow-ups Completed) 
Client Satisfaction Scale 
Individual Patient and Important Other/Caregiver Interviews 
Supportive-Expressive Group Therapy Topic Grid 
Focus Groups with Patients and Important Others/Caregivers 
Primary 
Outcomes 
Demoralization Scale-II 
Inventory of Complicated Grief 
Secondary 
Outcomes 
Antiretroviral Medication Adherence Scale 
Alcohol Use Disorders Identification Test 
Center for Epidemiologic Studies Depression Scale—Revised 
Challenging Experience Questionnaire 
Clinical Global Impressions Scale 
Credibility/Expectancy Questionnaire 
Duke/UNC Functional Social Support Questionnaire—5 
Drug Use Disorders Identification Test 
Experiences in Close Relationships scale—Modified 16 
Group Psychotherapy Intervention Rating Scale  
Group Questionnaire 
HIV and Abuse Related Shame Inventory 
Individual Group Member Interpersonal Process Scale 
International Personality Item Pool—Openness to Experience-20  
McGill Quality of Life Questionnaire—Revised-Short 
Multidimensional Assessment of Interoceptive Awareness—Revised 
Mystical Experience Questionnaire—30 
Nature Relatedness Scale, Short Form  
Post-traumatic Growth Inventory—Short Form 
PTSD Checklist-5 
Schedule of Attitudes towards Hastened Death 
Social Connectedness Scale-Revised 


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State-Trait Anxiety Inventory 
Qualitative analysis of therapy sessions, interviews & focus groups 
 
 
Unique Aspects 
of this Study 
This trial will be the first clinical trial of psilocybin-assisted psychotherapy 
for LTAS. It will also be the first modern trial of psilocybin-assisted group 
psychotherapy. It will be the first study of psilocybin-assisted 
psychotherapy for existential distress that will employ an evidence-based 
psychotherapy in the non-drug therapy sessions. The study will provide 
the first safety data for the use of this intervention in LTAS. It will not only 
yield preliminary data on the potential efficacy of this novel intervention, 
but it will also be the first study to employ both validated quantitative 
measures and qualitative methods in the analysis of the 
psychotherapeutic processes germane to psilocybin-assisted 
psychotherapy. It will also be the first clinical trial of psilocybin-assisted 
psychotherapy to assess the impact of the intervention on quality of life in 
partners/caregivers of LTAS. In anticipation of larger, better powered 
trials, clinical outcomes from this Phase I study will be used to produce 
the first estimates of effect size of this novel treatment for demoralization 
in palliative care patients. 


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Table of Contents 
1.0 Introduction 
1.1 
Background on Indication 
1.2 
Background on Psilocybin-assisted Psychotherapy 
1.3 
Rationale for the Proposed Study 
1.4 
Study Hypotheses 
 
2 
Objectives of the Study 
2.1 
Objectives 
2.1.1 Primary Objective 
2.1.2 Exploratory Objectives 
2.2 
Endpoints 
2.2.1 Primary Endpoints 
2.2.2 Exploratory Endpoints 
 
3 
Study Design 
3.1 
Characteristics 
3.2 
Number of Subjects 
3.3 
Eligibility Criteria 
3.3.1 Inclusion Criteria 
3.3.2 Exclusion Criteria 
3.4 
Duration of Therapy 
3.5 
Duration of Follow Up 
3.6 
Randomization Procedures 
3.7 
Study Timeline 
3.7.1 Primary Completion 
3.7.2 Study Completion 
 
4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug: Psilocybin 
4.2 
Drug Accountability 
4.3 
Drug Ordering 
4.4 
Packaging and Labeling of Study Drugs 
 
5 
Treatment Plan 
5.1 
Dosage and Administration 
5.1.1 Other Modalities 
5.2 
Monitoring and Toxicity Management 
 
6 
Study Procedures and Observations 
6.1 
Study Site 
6.2 
Selection of Measures 
6.3 
Qualitative Analyses 
6.4 
Schedule of Procedures and Observations 
6.4.1 Phone Screening 
6.4.2 In-person Screening and Enrollment 
6.4.3 Baseline Assessments 
6.4.3.1 Baseline Subject Assessments 
6.4.3.2 Baseline Caregiver/Important others Assessments 
6.4.4 Treatment Period 
6.4.4.1 Week 1-4 Group Therapy Sessions 


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6.4.4.2 Weeks 5-6 Individual Drug Sessions 
6.4.4.3 Weeks 7-10 Group Therapy Sessions 
6.4.5 Endpoint Assessments 
6.4.5.1 Endpoint (Week 10) Study Measures for Subject 
6.4.5.2 Endpoint (Week 10) Study Measures for Caregivers/Important others 
6.4.6 Post-treatment/Follow Up Assessments 
6.4.6.1 Focus Group 
6.4.6.2 3-Month Follow-up for Subject 
6.4.6.3 3-Month Patients for Caregivers/Important others 
6.4.6.4 3-Month Qualitative Interviews 
6.5 
Discontinuation of Therapy 
6.6 
Dietary Restrictions 
6.7 
Prohibited Medications 
6.8 
Study Clinicians 
 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Safety and Feasibility 
7.2 
Evaluation of Efficacy 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
7.3.2 Adverse reaction 
7.3.2.1 Suspected 
7.3.2.2 Unexpected 
7.3.2.3 Serious 
7.3.2.4 Life-threatening 
7.4 
Recording of an Adverse Event 
7.5 
Follow-up of Adverse Events 
7.6 
Adverse Events Monitoring 
7.7 
Expedited Reporting 
 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Design 
8.1.1 Randomization 
8.1.2 Stratification Factors 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
8.2.2 Replacement Policy 
8.2.3 Accrual estimates 
8.3 
Interim Analyses and Stopping Rules 
8.4 
Analyses Plans 
8.4.1 Analysis Population 
8.5 
Primary Analysis 
8.5.1 Exploratory Analyses 
8.6 
Study Results 
 
9 
Study Management 
9.1 
Pre-study Documentation 
9.2 
Institutional Review Board Approval 
9.3 
Informed Consent 
9.4 
Changes in the Protocol 
9.5 
Handling and Documentation of Clinical Supplies 
9.6 
Case Report Forms (CRFs) 
9.7 
Oversight and Monitoring Plan 
9.8 
Record Keeping and Record Retention 


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Abbreviations 
AGPA 
American Group Psychotherapy Association 
AHP 
Alliance Health Project 
AIDS 
Acquired Immune Deficiency Syndrome 
Albumin 
Alb 
AlkPhos 
Alkaline phosphatase 
Alt 
Alanine aminotransferase 
AMAS 
Antiretroviral Medication Adherence Scale 
AMAS 
ART Medication Adherence Scale 
ANOVA 
Analysis of Variance 
ART 
Antriretroviral Therapy 
Ast 
Aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BUN 
Blood Urine Nitrogen 
CBC 
Complete Blood Count 
ChEQ 
Challenging Experience Questionnaire 
CrEQ 
Credibility/Expectancy Questionnaire 
CESD-R 
Centers for Epidemiologic Studies Depression Scale—Revised 
CHR 
Committee on Human Research 
CMP 
Comprehensive Metabolic Panel 
CORF 
Community Observer Rating Form 
Cr 
Creatinine 
CSS 
Client Satisfaction Scale 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTC 
Concomitant Therapeutics Checklist 
DEA 
Drug Enforcement Agency 
DS-II 
Demoralization Scale—II 
DSM 
Data and Safety Monitor 
DUDIT 
Drug Use Disorders Identification Test 
DUFSS-5 
Duke UNC Functional Social Support Questionnaire-5 
ECG 
Electrocardiogram 
ECR-M16 
Experiences in Close Relationships scale—Modified 16 
ES 
Effect Size 
FDA 
Food and Drug Administration 
FT4 
Free thyroxine 
Gluc 
Glucose 
GPIRS 
Group Psychotherapy Intervention Rating Scale 
GQ 
Group Questionnaire 
HAART 
Highly Active Antiretroviral Therapy 
HANA 
HIV-Associated Non-AIDS 
HARSI 
HIV and Abuse Related Shame Inventory 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIM 
Hill Interaction Matrix 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICC 
Intraclass Correlation Coefficient 
ICF 
Informed Consent Form 
ICG 
Inventory of Complicated Grief 
IND 
Investigational New Drug 
IOS 
Inclusion of Other in the Self 
IPA 
Interpretive Phenomenological Analysis 
IPIP-OE-20 
International Personality Item Pool—Openness to Experience-20 
LPPI 
Langley Porter Psychiatric Institute 
LSD 
Lysergic acid diethylamide-25 


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LTAS 
Long-term AIDS Survivor 
MAIA 
Multidimensional Assessment of Interoceptive Awareness  
MAOI 
Monoamine Oxidase Inhibitors 
MEQ-30 
Mystical Experience Questionnaire—30 
MOCA 
Montreal Cognitive Assessment 
MQoL-RS 
McGill Quality of Life Questionnaire—Revised-Short  
NR 
Nature Relatedness Scale, Short Form 
NEO-PI-R 
Revised NEO Personality Inventory 
OPLH 
Older People Living with HIV 
PA-SEGT 
Psilocybin-assisted Supportive-Expressive Group Therapy  
PCL-5 
PTSD Checklist 
PEQ-S 
Persisting Effects Questionnaire—Spirituality 
PLH 
People Living with HIV 
Plt 
Platelet 
PPSv2 
Palliative Performance Scale version 2  
PTG 
Post-Traumatic Growth 
PTGI-SF 
Post-Traumatic Growth Inventory—Short Form 
PTSD 
Post-Traumatic Stress Disorder 
QoLLTI-Fv2 
Quality of Life in Life-Threatening Illness—Family Carer Version 2 
SAHD 
Schedule of Attitudes towards Hastened Death 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Personality Disorders 
SCID-5 
Structured Clinical Interview for DSM-5 
SCS-R 
Social Connectedness Scale-Revised 
SEGT 
Supportive-Expressive Group Therapy 
SEGT-TG 
Supportive-Expressive Group Therapy Topic Grid 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitors 
SSRI 
Serotonin Reuptake Inhibitors 
STAI 
State-Trait Anxiety Inventory 
Tbili 
Total bilirubin 
TCA 
Tricyclic Antidepressants 
TProt 
Total protein 
TSH 
Thyroid Stimulating Hormone 
WBC 
White Blood Cell 


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1 
Introduction 
We propose to conduct a clinical trial of psilocybin-assisted psychotherapy for 
demoralization in Long-term AIDS Survivors (LTAS). This will be the first trial of 
psilocybin-assisted psychotherapy specifically for people living with HIV (PLH) and it will 
be the first modern trial of psilocybin-assisted group psychotherapy for any indication. 
The study will consist of three groups of six gay-identified HIV-seropositive men ≥50 
years of age who were diagnosed with HIV prior to 1996 and who have moderate-to- 
severe demoralization [27] [13]. Each subject will undergo 8 weeks of a modified form of 
Supportive-Expressive Group Therapy [25] and one individual psilocybin treatment 
session [24] half-way through the intervention. Quantitative and qualitative measures of 
psychotherapeutic process will be used to explore the mechanisms by which this novel 
therapy seems to work, particularly on the interpersonal level. Quantitative and 
qualitative measures will assess changes in quality of life of the partners/caregivers of 
subjects undergoing the intervention. This study will contribute to the available data on 
the safety, feasibility and efficacy of psilocybin-assisted psychotherapy for existential 
distress in palliative care patients, and importantly will provide the first of such data on a 
palliative care population other than cancer patients [28]. 
 
 
Fig. 1 INTERVENTION TIMELINE 
 
 
 
 
 
 
 
1.1 
Background on Indication 
Existential Distress and Demoralization 
Existential distress is a form of psychological suffering that occurs when one is confronted 
with one’s own mortality [11]. Demoralization is a form of existential distress that is prevalent in 
the palliative care setting and is characterized by hopelessness and helplessness due to a loss 
of purpose and meaning in life [12, 13]. Demoralization is associated with, but distinct from, 
depression, anxiety, isolation, and the desire for hastened death [29]. In palliative care patients, 
demoralization has been shown to be more strongly associated with suicidal ideation than 
depression is [30]. In modern palliative care, the current standard is to address existential and 
spiritual issues in patients and their family members [31, 32]. Following the lead of innovators like 
Frankl [33] and Yalom [34], investigators have over the last two decades devised a number of 
existential psychotherapies [35-40] with varying impact on depression, anxiety and quality of life 


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[26, 41]. Arguably, what these therapies have in common is what Cassel [42] long ago prescribed 
for the relief of suffering—transcendence—an experience that is difficult to define medically and 
a challenge to provide consistently in clinical settings. Palliative care stands to benefit greatly from 
a time-limited intervention that enhances patients’ capacity to forge meaning, to transcend 
suffering, and to overcome social isolation and the fear of the unknown in a safe, immediate and 
reliable manner. This need is pronounced among LTAS. 
 
AIDS Survivors 
By 2004, there had been an estimated 929,985 cases of AIDS in the US, and 524,060 of 
them had died [43]. With the advent of combined antiretroviral therapy (ART) in 1996, HIV 
seropositive individuals began to accomplish what once was thought to be impossible—living into 
old age. Because of the decreased lifespan and the apparently accelerated aging experienced by 
PLH, “older” in HIV is defined as ≥50 years of age [44]. Many LTAS are therefore also considered 
older people living with HIV (OPLH). Despite recent gains in mortality, many of today’s LTAS are 
still grappling with having been, at one point, an “end-of-life” patient. Beyond being confronted by 
their own mortality at the time of diagnosis, LTAS frequently bore witness to the deaths of friends 
and loved-ones, and often served as informal caregivers to those dying of AIDS [45]. AIDS-related 
bereavement is associated with demoralization, depression, and problematic substance use [46]. 
Survivor’s guilt is common among LTAS, as is loneliness [47]. Isolation and loneliness are highly 
prevalent among LTAS not only because the gay community was decimated by AIDS in the 1980s 
and ‘90s, but also because many OPLH often lack traditional family support structures due to 
several possible causes that include protective withdrawal from one’s biological family, having 
been disowned by family or friends due to stigma, or not having children [1, 47]. Because of 
reduced social support networks, and therefore a relative lack of access to informal caregivers, 
OPLH are in general expected to be especially reliant on community-based services as they age 
[1]. 
 
Multimorbidities 
Compared to HIV seronegative demographically- and behaviorally-matched peers, OPLH 
are at increased risk of multimorbidities known as HIV-associated non-AIDS (HANA) conditions, 
such as cardiac disease, with PLH having a 50% increased risk of acute myocardial infarction 
compared to HIV seronegative matched controls [48]. PLH are also at higher risk of some HANA 
malignancies, having three times the cumulative incidence of liver cancer and thirty times the 
cumulative incidence of anal cancer [49]. PLH are also at increased risk of serious bone, liver and 
kidney disease [44, 50]. As the health of OPLH declines, HANA and other conditions can serve 
as continual reminders of one’s mortality. OPLH also suffer from high rates of mental health 
conditions such as depression (prevalence up to 50%), suicidal ideation, and anxiety (prevalence 
up to 20%) [1, 2]. AIDS patients have been found to have an increased desire for hastened death 
[51]. Among PLH (of all ages) PTSD has a prevalence that ranges 10-74% [3, 52]. Like PLH of 
other ages, OPLH have higher rates of substance use [4, 5, 53] and risky sexual behaviors [6] 
than the general population and these behaviors are associated with ART nonadherence and 
therefore disease progression and secondary HIV transmission [54]. The incidence of HIV in US 
adults over 50 years of age saw no improvement from 2010-2014 [55]. Comorbid depression, 
anxiety and PTSD are also associated with ART non-adherence in PLH [56-59]. Depression 
treatment has been shown to increase ART adherence in PLH [60], and possibly to decrease 
secondary transmission of HIV [61]. Data specific to OPLH and behavioral interventions that 
increase ART adherence, however, is limited to few studies that are wanting in methodological 
rigor [62]. 
 
Older People Living with HIV 
The CDC projected that people over the age of 50 years would constitute the majority of 
the HIV-positive population in the US by 2015 [63]. OPLH became the majority of the HIV-positive 
population in San Francisco in 2012, and their proportion of the population continues to rise [8]. 


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It is estimated that over 70% of the US HIV seropositive population will be ≥50 by 2020 [64]. The 
NIH Office of AIDS Research Working Group on HIV and Aging has highlighted as priority 
research areas, among others: Research on mental health in older adults with HIV and possible 
interventions; Research on substance use in older adults with HIV; Research on social networks 
and care giving of older adults with HIV [1]. The HIV community has responded to the 
demographic change by forming peer support groups and holding town halls on the issue across 
the country [65]. Organizational initiatives have sprung up around the issue, including patient 
advocacy groups like the Medius Institute and Let’s Kick AIDS Survivor Syndrome 
(www.letskickass.org), with “AIDS Survivor Syndrome” being a patient-promoted syndrome 
characterized by traumatic exposure, complicated grief, depression, self-destructive behavior and 
hopelessness. Also, many local government and non-profit efforts have emerged over the last 
half decade, including the AIDS Community Research Institute of America’s Center on HIV and 
Aging, the 50-Plus Program at San Francisco AIDS Foundation, and the San Francisco County 
Workgroup on HIV and Aging. Finally, the popular press has recently directed attention to the 
issue [66-68], and in 2016 the San Francisco Chronicle even made a feature-length documentary 
on the struggles of older HIV-positive gay men in San Francisco [69]. 
 
Treatment Needs 
Much of the recent literature on the mental health treatment needs of OPLH has focused 
on depression [7]. Despite the well-established relationship between depression, grief and 
demoralization in PLH [46], grief and demoralization have been less frequently studied since the 
advent of combined ART. Preliminary analysis of outcomes from support groups for OPLH at 
UCSF’s Alliance Health Project (AHP) indicates that depression and anxiety symptoms improve 
from participating in these groups, but trauma symptoms, particularly related to traumatic losses, 
tend to persist [70]. These AHP findings are supported by the literature that shows that 
coping/support groups for OPLH can improve depressive symptoms [71]. This is also supported 
by anecdotal evidence from the Director of the San Francisco AIDS Foundation’s 50-Plus 
program, who reports that members of this community need more access to treatments for 
psychological trauma [65]. Current literature suggests that PLH have difficulty finding therapies 
that adequately address traumatic loss and grief [72]. More specifically, the Director of the San 
Francisco AIDS Foundation’s 50-Plus program has stated “We need a treatment tailored to our 
community’s needs; not just recycled therapies for other people,” which again is supported by the 
literature which suggests that PLH respond better to therapies specifically targeted to grief and 
psychiatric distress (done in a group) than generic individual psychotherapy [73]. Whereas coping 
groups for bereavement in PLH have shown brief but unsustained improvements in grief, they 
have not proven to benefit general psychological distress or functioning [43]. Another recent study 
did demonstrate short-term reductions in traumatic stress from a coping group intervention in 
PLH, but no data are available on the durability of these benefits [74]. 
 
Group Therapy, Social Support, and Post-Traumatic Growth 
Spiegel and Yalom’s Supportive Expressive Group Therapy (SEGT) [34, 75] was originally 
designed as an intervention for advanced cancer patients, has since been modified to be used 
with a variety of palliative care patients, and has a robust evidence base for its efficacy [41]. SEGT 
emphasizes social support and increasing communication with caregivers. It also focuses on 
processing affect in the ‘here and now’ and ‘detoxifying death and dying’; it includes exposure to 
a therapeutic altered state of consciousness (self-hypnosis); and it encourages emotional 
expression and openness [25]. Manuals exist for traditional (1 year) [75] and brief (12-week) [76] 
SEGT, and SEGT has been shown to be teachable [77]. SEGT has also already been modified 
for and used with success in patients with advanced HIV [78]. A recent study of tele-SEGT for 
depressed OPLH found that therapeutic alliance did not predict clinical response, but group 
cohesion and perceived member similarity did [79]. Social support in PLH is related to improved 
mood, well-being and medication adherence [44]. Enhanced social support in PLH is also 
associated with enhanced post-traumatic growth (PTG) [80]. Whereas much of the literature on 


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the mental health of PLH focuses on coping, the concept of PTG goes beyond coping with the 
problems associated with living with HIV and includes improvement in one’s mental health. PTG 
comprises an increased appreciation for life, enhanced self-efficacy and ability to forge intimate 
relationships, and the increased expression of emotions and hope for the future [80]. PTG is 
associated with fewer depressive symptoms in PLH [81]. Currently, however, there is a dearth of 
literature specifically on PTG and HIV [3, 82], especially on interventions that enhance it. Of 
particular relevance to our study, PTG is associated with a heightened interest in spirituality [80]. 
 
Psychoneuroimmunology in HIV 
It seems that HIV remains a rich field of investigation of the mind-body connection, and 
perhaps especially among OPLH who may have greater mental and physical health needs 
compared to younger PLH. Earlier literature on psychoneuroimmunology and HIV regularly found 
associations between depression, traumatic exposure and disease progression and mortality in 
PLH, both before and soon after the advent of highly active antiretroviral therapy (HAART) [83, 
84]. It is unclear whether such associations remain with the improved ART regimens available 
today. Nevertheless, recent data have shown that spiritual coping in PLH is associated with 
increased survival [85]. And after controlling for ART use, depression, hopelessness, and 
avoidant coping have predicted the progression of viral load and CD4 count longitudinally [86]. 
Recent data from the NIH indicate that PTSD is associated with differential immune activation in 
PLH, even in those who are virally suppressed [52]. While spirituality and religiosity have been 
positively associated with enhanced mental health in PLH, the personality traits of 
conscientiousness, openness and agreeableness (measured with the NEO-PI-R) are more 
strongly positively associated with mental health in this population [87]. Openness has also been 
inversely associated with disease progression over 4 years [88]. Finally, in PLH dispositional 
mindfulness has been inversely related to depression, stress appraisal and negative affect, while 
it is positively associated with positive affect [89]. 
 
1.2 
Background on Psilocybin-assisted Psychotherapy 
Psilocybin is a natural product found in many species of psychoactive fungi around the world 
[90]. Modern scientific research with psilocybin began when the chemist Albert Hoffman first 
isolated psilocybin from Psilocybe mexicana mushrooms in 1957 [91]. Psilocybin (4- 
phosphoryloxy-N,N-dimethyltryptamine) is the prodrug of psilocin (4-hydroxy-N,N- 
dimethyltryptamine), an indoleamine that acts as an agonist of serotonin 5HT 1A, 2A and 2C 
receptors [92]. In humans, psilocybin is rapidly metabolized to psilocin after oral ingestion; 
psilocin has no known P450 interactions and is instead glucoronidated and renally excreted [91, 
93, 94]. Relative to other psychedelics (e.g., lysergic acid diethylamide-25, a.k.a. LSD), 
psilocybin has a simpler neurotransmitter receptor profile (it is known to act only at serotonin 
receptors) and a shorter duration of acute effects (4-5 hours) [91, 95]. Psilocybin is one of the 
“classic hallucinogens” (a.k.a. “classic psychedelics”) that were investigated in the mid-20th 
century for their potential as pharmacologic adjuncts to psychotherapy. By the mid-1960s, over 
1,000 clinical reports were published on the experiences of over 40,000 treatment sessions in 
which psychedelics had been legally administered to patients in clinical settings [96] such as at 
Harvard [97], UCLA [98], and UCSF [99]. 
This early research suggested that one of the most promising indications for psychedelic- 
assisted psychotherapy was the treatment of existential distress in patients with advanced 
disease, particularly cancer. This was first reported by Kast, an internist who administered LSD 
(without psychotherapy) to terminally-ill patients as an experimental analgesic. He found that a 
single dose of LSD decreased physical discomfort and improved mood, and that these effects 
lasted for about 10 days [100]. More systematic work later occurred at Spring Grove Hospital 
near Baltimore, Maryland where a team developed a protocol for psychedelic-assisted 
psychotherapy for the terminally ill. Their protocol included several non-drug preparatory 


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sessions designed to build trust and rapport between the participant and the therapists. Then, 
during the drug session itself, the therapists (usually a team of two) would sit beside the patient 
and mostly provided non-directive verbal reassurance. Afterward, several non-drug 
psychotherapy follow-up sessions took place over the next few weeks to psychologically 
“integrate” the drug experience into the patient’s life. One legacy of this work is the safety 
protocol recently developed at Johns Hopkins [24] for psychedelic drug administration, which 
has been adapted for this proposed study. 
 
In the 1970s, before rigorous and well-controlled trials of the Spring Grove protocol could be 
undertaken, clinical research with psychedelics in the US was abandoned due to increased 
regulatory requirements and an unfavorable political climate. Nevertheless, pharmacology and 
neuroscience studies continued, producing a clear understanding of psilocybin’s effects on 
neurotransmitter receptors and human physiology [91, 92, 101]. Unlike many other Schedule I 
controlled substances, the “classic psychedelics” are physiologically safe over a wide range of 
doses and have a low potential risk of addiction [92, 102]. The published case series of mid- 
Century psychedelic-assisted psychotherapy reveal an overall low rate of adverse events when 
administered in controlled clinical settings [103]. (For more clinical safety data, see Section 
4.1.1 below.) And while clinical research ceased in the US in the 1970s, psilocybin-assisted 
individual and group psychotherapy continued to be practiced legally in Germany and 
Switzerland into the 1990s [104]. 
Clinical research with psychedelics in the US reemerged in the 1990s when Strassman 
investigated the pharmacology of dimethyltryptamine in healthy volunteers [105]. He was followed 
by Griffiths et al who conducted a double-blinded RCT in which healthy volunteers were 
administered a single high dose of psilocybin (0.43mg/kg) vs active placebo (methylphenidate) 
and found that a significantly higher proportion of volunteers receiving psilocybin had “complete 
mystical experiences” [17]. Seventy-four percent of subjects rated the psilocybin experience as 
one of the five most spiritually significant experiences of their lives (compared to 8% of controls) 
[17]. Remarkably, subjects who received psilocybin also demonstrated significant increases in the 
personality trait of Openness on the NEO-Personality Inventory (e.g., aesthetic appreciation and 
sensitivity, imagination and fantasy, and tolerance of others’ views and values) 12 months after 
drug administration. No other discrete clinical intervention has ever been shown to cause 
significant and enduring changes in an adult’s personality structure [106]. 
 
The Griffiths et al. 2006 study was followed by Grob et al [18], who demonstrated in a double- 
blind cross-over RCT the safety and feasibility of psilocybin-assisted psychotherapy in 12 
advanced cancer patients with a DSM–IV anxiety diagnosis deemed to be secondary to their 
cancer diagnosis. This study utilized a single moderate dose of oral psilocybin (0.2mg/kg), and 
found improvements in anxiety and depression in the months following the intervention. The 
most recent data on psilocybin-assisted psychotherapy in existential distress in cancer patients 
come from two recently completed Phase II trials, whose results have not yet been published: 
Ross et al. conducted a double-blind cross-over RCT comparing an active placebo (niacin) to a 
single high dose of oral psilocybin (0.3mg/kg) in 29 cancer patients with moderate-to-severe 
anxiety and whose cancer was either active or in remission with a chance of recurrence. Their 
study found significantly greater reductions in anxiety and depression with psilocybin (versus 
placebo) lasting from hours after the drug session to up to 8 months later [19]. The second 
study, conducted by Griffiths et al, was a double-blind, cross-over RCT comparing a 
subthreshold dose (0.014) to a moderate-to-high dose (0.31) oral psilocybin in 51 cancer 
patients with depression and anxiety. They found reductions in anxiety and depression (both 
within-group and between groups) that were significant at 5 weeks post-treatment; the 
improvements in mood persisted at the 6 month follow-up time point [20]. 
Over the past 20 years psilocybin has shown to be safe and preliminarily effective in the 
treatment of not only existential distress in cancer patients [18-20], but also treatment-resistant 


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alcohol use disorder [107], treatment-resistant tobacco use disorder [108, 109], and obsessive- 
compulsive disorder [110]. 
 
 
1.3 
Rationale for the Proposed Study 
Rationale for Psilocybin-Assisted Psychotherapy for Demoralization in LTAS 
Per Section 1.1, above, there is a large unmet need for the treatment of existential distress in 
LTAS. Compared to classic examples of acute existential distress in end-of-life patients (e.g., 
cancer patients or advanced AIDS patients), the existential distress of LTAS is a more chronic 
condition complicated by severe grief and traumatic exposure. Like “cancer survivors,” AIDS 
survivors often experience increased rates of psychological distress long after their disease is 
controlled [9, 10]. While the existential distress of LTAS is multifaceted and complex, the well- 
characterized clinical syndrome of demoralization appears to capture the type of psychological 
distress suffered by many LTAS (6, 7). The concept of demoralization is predicated on the loss 
of one’s meaning-making ability in the face of distress. Enhancing meaning-making to address 
existential distress and complicated grief is a strategy that has been embraced not only by 
palliative speciatlists [36] and thanatologists [15], but also by the HIV community itself [65]. In 
general, the mental health needs of LTAS —an emerging, medically and psychosocially 
complex, and stigmatized population—remain under-recognized and undertreated, but in 
particular it seems LTAS could benefit from a brief intervention that would enhance meaning- 
making in order to better cope with, and transcend, years of loss and suffering. 
 
Modern studies of psilocybin-assisted psychotherapy for cancer patients and cancer survivors 
with existential distress provide promising preliminary evidence of this intervention in treating 
demoralization in palliative care patients [18-20]. These clinical improvements are thought to be 
mediated by having a complete “mystical-type” experience [21], which leads to an enhanced 
sense of meaning in one’s life [111], and an enhanced ability to engage with one’s social 
supports [22]. Moreover, psilocybin may also help improve patients’ relationships with love-ones 
who have already died: According to the most experienced clinician in the field of psilocybin- 
assisted psychotherapy, Dr. William Richards (who began treating palliative care patients with 
this method in the 1970s), psilocybin-assisted psychotherapy can be highly effective at treating 
protracted grief [112]—a rather difficult to treat symptom in LTAS (see above, Section 1.1 
Treatment Needs). 
 
LTAS – An Ideal Model for Studying Chronic Existential Distress in Palliative Care Patients 
Clinical trials in palliative care are fraught with many methodological challenges, especially 
subject recruitment given patients’ lack of interest in spending their limited time in research 
studies, or inability to comply with the physical demands of attending study visits and research 
protocols [113]. Attrition rates of up to 50% are not uncommon among psychotherapy trials with 
palliative care patients [77, 114, 115]. Recent trials of psilocybin-assisted psychotherapy for 
existential distress in cancer patients have struggled with recruitment [28]. The current proposed 
study of psilocybin-assisted psychotherapy in LTAS is unlikely to be hindered by these same 
recruitment challenges because the form of existential distress to be examined, demoralization, 
is thought to occur at high rates [65] among a largely ambulatory population that is known to 
avidly volunteer for medical research [116] and is desperately in search of treatment options 
[65]. Despite the fact that HIV is now considered a “chronic illness” and not an acutely life- 
threatening condition for most patients, PLH potentially face their mortality on a daily basis when 
they choose, or choose not, to adhere with their ART regimen, thus likely enhancing existential 
distress chronically. 
 
Rationale for using Psilocybin as a Psychotherapy Adjunct, and eschewing Psilocybin 
Monotherapy 


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This trial does not include a control arm of psilocybin without psychotherapy. When psilocybin 
and other psychedelics were investigated as pharmacologic adjuncts to psychotherapy in the 
1950s and 60s, clinical experience led to the principle of “drug, set and setting,” [117] which 
states that the clinical safety and outcomes of a psychedelic drug experience are highly 
influenced by the non-pharmacological variables of the patient’s mental state prior to drug 
administration (“set”) and their environment during the experience (“setting”). Unlike other 
modalities of drug-assisted psychotherapy (e.g., D-cycloserine-assisted cognitive behavioral 
therapy), in psychedelic-assisted psychotherapy, not only is the drug experience thought to 
deeply influence the content of the psychotherapy, but the content of the psychotherapy is 
likewise understood to intimately shape the drug experience itself. This consideration has led to 
the consensus that it is unethical for psychedelics to be administered to patients absent a 
supportive and therapeutic context. This context has typically been individual psychotherapy, 
but group therapy modalities have also been used. [96, 118] 
 
Rationale for Group Therapy 
Since the beginning of the HIV/AIDS epidemic, many psychotherapies for PLH have been 
preferentially delivered as groups because of enhanced cost-effectiveness and the group 
format’s unique clinical benefits with respect to the enhancement of social support in a 
population suffering high rates of isolation and loneliness [23]. 
 
The theoretical basis of the original Spring Grove approach to treating existential distress in 
palliative care patients was that patients suffer extreme isolation because of their disease, and 
that psychedelic-assisted psychotherapy could help relieve this isolation by facilitating: 1) living 
meaningfully in the present moment, and 2) reaching out and authentically connecting with 
loved ones [22]. Various clinical benefits were reported from their uncontrolled experimental 
sessions, including improvements in mood and anxiety, and increased openness to 
communication with loved ones [119]. These older findings are consistent with more recent 
social psychology findings that psilocybin decreases the subjective feeling of social exclusion 
[120] and another classic psychedelic, LSD, enhances emotional empathy and prosocial 
behavior [121]. 
 
The Spring Grove team concluded that optimal clinical outcomes were dependent upon 
attaining a “psychedelic peak experience,” which was conceived of as akin to William James’ 
“conversion experience,” [122] or Abraham Maslow’s “peak experience,” [123] —a transcendent 
state of unity, intense positive emotions, and ineffability that was experienced as deeply 
meaningful. [22] To describe this mental state, the current psilocybin literature has adopted the 
terminology of the “complete mystical experience,” which is defined by standard criteria using a 
validated psychometric measure, the Mystical Experience Questionnaire—30 item [124]. 
Because the Spring Grove team believed that the “transcendental nature of the experience 
[could] neutralize a sense of alienation…” they sought to facilitate such experiences in order “to 
maximize patients’ opportunities for living by lessening their sense of isolation and alienation, 
and in so doing, assist in their reaching out to those around them” [125]. One aspect of this 
model that has received little mention in the recent literature is that the original Spring Grove 
protocol included non-drug family therapy sessions conducted both before and after drug 
sessions [22]. The purpose of these sessions was to prepare the family to better help the 
patients integrate their psychedelic experience after the drug sessions, as well as to aid the 
family in their imminent grieving process. 
 
Spontaneous feedback from several subjects in the recent NYU psilocybin-assisted 
psychotherapy trial for existential distress in cancer patients included the request to be 
introduced to the other study subjects [19], apparently to share, process and integrate their 
experiences in a setting of mutual aid and understanding. Subjects from recent MDMA-assisted 
psychotherapy trials for PTSD have also spontaneously made this request, leading the study 


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sponsors to create a web forum for the patients to be in touch with each other after completing 
the trials [126]. It appears to be helpful to patients treated with psychedelic-assisted 
psychotherapy to spend time with peers in their attempt to integrate the “peak” experiences, the 
phenomenology of which can be rather uncanny and perhaps difficult for psychedelic-naïve 
family or friends to comprehend [127]. 
 
Conducting non-drug psychotherapy sessions in groups may shed light on possible key 
mechanisms of psilocybin-assisted psychotherapy for existential distress. Whereas therapeutic 
alliance is thought to be the most important mediator of clinical outcomes in individual 
psychotherapy, group cohesion is widely recognized as the analogous mechanism in group 
psychotherapy [128, 129]. Examining the change of group cohesion pre- and post-psilocybin 
with validated self-report [130] and observer-rated instruments [131] will provide a novel and 
standardized means of observing how psilocybin drug sessions may affect the interpersonal 
functioning of distressed palliative care patients. 
 
A significant limitation of group therapy clinical trials is that large sample sizes are required to 
demonstrate efficacy because of the likely interdependence of outcomes of members of the 
same group [132]. For this reason, qualitative (e.g. Interpretive Phenomenological Analysis) 
and/or sequential (e.g. the Hill Interaction Matrix) measures of psychotherapeutic process are 
often used to make inductive inferences about clinical change from group therapy over time 
[133]. Process is understood as the conglomeration of intrapersonal functions, interpersonal 
dynamics and group environment that leads to therapeutic change [134]. To improve the 
evidence base for group psychotherapy, the American Group Psychotherapy Association 
(AGPA) has developed clinical practice guidelines [135] and a standard set of measures and 
tools for creating and managing psychotherapy groups for clinical practice and research [136]. 
In developing the protocol for this proposed study, we have drawn not only from the literatures 
on psilocybin-assisted psychotherapy and palliative care, but also from these AGPA clinical and 
research guidelines, as well as on the consultation of local group psychotherapy experts [137]. 
 
Rationale for Dosing Regimen 
Griffiths et al [138] have characterized the dose-response relationship of oral psilocybin in 
healthy volunteers. They found that when considering the odds of attaining a complete mystical 
experience versus having a temporary anxiety reaction during the drug experience (lasting on 
the order of minutes), the optimal dose likely falls between 0.29mg/kg and 0.43mg/kg [138]. This 
dose range has been successfully used in studies of psilocybin-assisted psychotherapy for 
existential distress in cancer patients [19, 20], severe alcohol use disorder [107] and tobacco 
use disorder [108]. The current study will employ a dose of 0.3mg/kg po in the first group, and if 
this is well tolerated will then escalate to 0.36mg/kg po in subsequent groups. 
 
The dosing of the psychotherapy—8 weekly sessions—was chosen on the basis of comparison 
with similar group psychotherapies for existential distress in palliative care patients. The group 
psychotherapy with the best evidence-base for treating existential distress in palliative care 
patients, Meaning-Centered Group Psychotherapy, also employs 8 sessions [139]. The group 
psychotherapy with the best evidence-based for treating complicated grief has 16 weekly 
sessions [140]. Our protocol uses a modified course of Brief Supportive-Expressive Group 
Therapy, which was designed and tested as a 12-week course of treatment [76]. Empirical data 
suggest that group therapies lasting at least 12 sessions are shown to have greater correlations 
between group cohesion and clinical outcomes [129]. We hypothesize that psilocybin will 
catalyze group cohesion in a shorter period of time, thus making 12-16 weeks of group therapy 
unnecessary for detecting comparable results with regards to cohesion and clinical outcomes. 
 
Rationale for Supportive-Expressive Group Therapy 


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While prior trials of psilocybin-assisted psychotherapy for existential distress in palliative care 
patients have followed a standard drug administration safety protocol, they have not used 
manualized psychotherapies in the non-drug therapy sessions; our study will be the first to do 
this, which should enhance generalizability of the results. The format and content of SEGT are 
appropriately flexible for incorporating individual psilocybin sessions during the course of 
therapy, and including psychoeducation on psilocybin in the preparatory sessions. The focus of 
SEGT on expressing emotions and enhancing communication with caregivers is expected to be 
helpful in integrating psilocybin experiences [118]. Psilocybin has been shown to enhance 
access to positive emotional memories [141] and to increase the personality trait of openness 
[106], and this should support SEGT’s aim of increasing awareness of one’s emotions and 
openness to new experiences. Because the primary aim of this pilot trial is to assess safety and 
feasibility of this modality—and assessing efficacy is a secondary aim—no control group of 
traditional SEGT will be included in the study. For the rationale on why psilocybin monotherapy 
(without an adjunctive psychotherapy) will not be offered as control condition, see above. 
 
 
1.4 
Study Hypotheses 
Primary 
 
1. The study will recruit, consent and enroll at least 18 subjects (in 3 groups of 6 members) 
over 18 months; these subjects will complete all treatment and evaluation sessions and 
they will experience no treatment-emergent serious adverse events. 
 
 
Secondary 
 
1. The difference in pre- and post-treatment mean scores of demoralization, complicated 
grief, depression, PTSD, shame, anxiety, quality of life, functional social support, post-
traumatic growth, openness to experience, attachment security, mindfulness, global 
clinical impressions and ART medication adherence will trend toward significant 
improvement. These improvements will be sustained at 3-month follow-up. 
2. The difference in pre- and post-psilocybin rates of change of group cohesion and group 
process will trend toward significant improvement. 
3. Qualitative analyses of subject behavior and caregiver/important other reports will lead 
to greater understanding of the interpersonal mechanisms of action of psilocybin- 
assisted psychotherapy. 


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2 
Objectives of the Study 
2.1 
Objectives 
2.1.1 Primary Objective 
• 
To demonstrate the safety and feasibility of Psilocybin-Assisted Supportive-Expressive 
Group Psychotherapy (PA-SEGT) for demoralization in long-term AIDS survivors 
(LTAS). 
2.1.2 Exploratory Objectives 
• 
To explore the preliminary efficacy of PA-SEGT for improving demoralization, 
complicated grief, depression, PTSD, shame, anxiety, post-traumatic growth, quality 
of life, functional social support, openness to experience, attachment security, social 
connection, nature relatedness and ART medication adherence in LTAS. 
• 
To explore quantitatively and qualitatively the mechanisms (e.g. group cohesion) through 
which PA-SEGT addresses demoralization and other mental health outcomes in LTAS. 
2.2 
Endpoints 
2.2.1 Primary Endpoints 
• 
Safety will be defined based on the rate of adverse reactions (defined by the NIH 
Division of AIDS Table of Grading of Severity of Adult and Pediatric Adverse Events 
V2.0) (see Section 5 below). The safety of acute drug effects will be assessed by 
monitoring vital signs for tachycardia (HR>100bpm), bradycardia (HR<60bpm), 
hypertension (SBP>140mmHg or DBP>90mmHg) and hypotension (SBP<100mmHg or 
DBP<60mmHg). Drug-induced mental status changes will be assessed using the 
Adverse Event Medication Session Rating Form during drug sessions, pre and post 
measures with the Montreal Cognitive Assessment, and the Persisting Effects 
Questionnaire—Spirituality at study follow up. Suicidality will be assessed with the 
Columbia Suicide Severity Rating Scale. Follow-up safety data will be gathered for 3 
months. 
• 
Feasibility will partially be assessed in terms of the rates of patient recruitment and 
retention. Feedback on acceptability will also be gathered from subjects and 
caregivers/important others using the Client Satisfaction Scale. Patients and caregivers 
will also be invited to provide feedback during a focus group and patients will be invited 
to participate in individual interviews after the intervention. A SEGT Topic Grid will be 
used to evaluate video recordings of group therapy sessions in order to assess therapist 
adherence to the PA-SEGT model. 
2.2.2 Exploratory Endpoints 
Preliminary efficacy will be assessed with the primary clinical outcome measures: 
• 
Change in demoralization will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up scores of the Demoralization Scale-II. 
• 
Change in complicated grief will be defined by the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Inventory of Complicated Grief. 
Preliminary efficacy will also be explored with the following secondary endpoints (See Section 5 
for details on individual measures): 


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• 
Change in ART medication adherence will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of the ART Medication Adherence 
Scale. 
• 
Change in depression will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Center for Epidemiologic 
Studies Depression Scale—Revised.Change in subject quality of life will be defined by 
the difference in pre-treatment, post- treatment, and 3-month follow-up mean scores of 
the McGill Quality of Life Questionnaire—Revised. 
• 
Change in desire for hastened death will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of Schedule of Attitudes towards 
Hastened Death. 
• 
Change in anxiety will be defined as the difference in pre-treatment, post-treatment, and 
3-month follow-up mean scores of the State-Trait Anxiety Inventory. 
• 
Change in social support will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Duke/UNC Functional Social 
Support Questionnaire-5. 
• 
Post-traumatic growth due to the intervention will be defined by post-treatment and 3-
month follow-up mean scores of Post-Traumatic Growth Inventory—Short Form. 
• 
Change in PTSD symptoms will be defined as the difference in pre-treatment, 
post- treatment, and 3-month follow-up mean scores of the PTSD Checklist-5. 
• 
Change in global clinical status will be defined as the difference in pre-treatment and 
post- treatment mean scores of the Clinical Global Impressions Scale completed by an 
clinical rater. 
• 
Change in openness to experience will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of the International Personality Item 
Pool—Openness to Experience-20 scale. 
• 
Change in mindfulness will be defined as the difference in pre-treatment, post-treatment, 
and 3-month follow-up mean scores of subscales of the Multidimensional Assessment of 
Interoceptive Awareness. 
• 
Change in social connectedness will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Social Connectedness Scale—
Revised. 
• 
Change in Nature Relatedness will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Nature Relatedness Scale, Short 
Form Version. 
• 
Change in alcohol and drug use will be defined by different in the baseline and 3-month 
follow-up AUDIT and DUDIT scores 
 
Psychotherapeutic process and mechanisms will be explored with the following endpoints: 
• 
Change in group cohesion will be defined as the difference in rate of Group 
Questionnaire score change pre- and post-psilocybin. 
• 
Change in group process will be assessed as the difference in rate of progression of 


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the Hill Interaction Matrix score pre- and post-psilocybin. 
• 
Change in group process will be assessed as the change in the Individual Group 
Member Interpersonal Process Scale over time. 
• 
Expectancy effects will be estimated based on the pre-psilocybin total score of the 
Credibility/Expectancy Questionnaire. 
 
• 
Subjective experience of a psilocybin treatment session will be evaluated with the 
Mystical Experience Questionnaire—30 and the Challenging Experience Questionnaire. 
• 
Change in attachment security will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Experiences in Close 
Relationships scale—Modified 16. 
• 
Qualitative analysis of therapy session video footage, semi-structured patient 
interviews, focus groups and process notes written by study staff. 
• 
Change in inclusion of other in self will be defined by the difference in pre-
treatment, post-treatment, and 3-month follow-up results of the Inclusion of 
Other in Self measure. 
 


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3 
Study Design 
3.1 
Characteristics 
This is a Phase I open-label pilot mixed-methods study of the safety and feasibility of an 8-week 
group psychotherapy intervention that includes one individual drug session with oral synthetic 
psilocybin. This intervention is designed to treat demoralization in LTAS. Groups of 6 subjects 
will be run in sequence. Safety data will be gathered before, during, immediately after, and for 3 
months after the intervention. Subjects will complete self-report measures and semi-structured 
interviews related to acceptability and subjective experience. Exploratory analyses will be 
conducted of clinical outcomes. Exploratory analyses will also include quantitative and 
qualitative assessments of psychotherapeutic process mechanisms. 
3.2 
Number of Subjects 
We estimate that a total of 60 patients will be screened in-person for the study. We estimate that 
at least 18 patients will need to be enrolled given the high rate of drop outs seen in group 
psychotherapy studies in this population [114]. Patients who have been assigned to a group will 
be replaced only if they drop out prior to the first group therapy session (this avoids the possible 
symbolic message that if a subject were to die, that he would be easily replaced in the group). 
We aim for, at minimum, 8 subjects (two groups of at least 4 subjects each) will complete the 
study; at maximum, 36 subjects (six groups of six subjects each) will complete the study. (See 
Section 8.2.1 Sample Size and Power Estimate.) 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first group therapy session and 
must satisfy all inclusion and exclusion criteria. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed consent 
must be obtained from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
3.3.1 Inclusion Criteria 
1. Gay-identified men ≥50 years old who are able to understand a written informed consent 
document and who are willing to sign it. 
2. Laboratory confirmed HIV seropositive status; and diagnosed prior to 1996. 
3. Moderate-to-severe demoralization, determined by a score of 8 or higher on the 
Demoralization Scale-II [27]. 
3.3.2 Exclusion Criteria 
1. Life expectancy <6 months (determined by the patient’s non-study PMD) 
2. Poor functional status (Palliative Performance Scale-v2 <60%). 
3. Cognitive impairment (Montreal Cognitive Assessment ≤25)1 or diagnosis of a 
neurodegenerative disorder. 
 
 
1 See reference 142. 
Milanini, B., et al., The Montreal Cognitive Assessment (MoCA) to screen for cognitive 
impairment in HIV over age 60. Journal of acquired immune deficiency syndromes (1999), 2014. 67(1): p. 67. 


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4. The regular use of psychotropic medications within 2 weeks of study participation, 
including antidepressants (such as serotonin-reuptake inhibitors, tricyclic 
antidepressants and monoamine oxidase inhibitors), anxiolytics, stimulants,1 
antipsychotics, anti-epileptics, cannabis products and non-topical corticosteroids. Low 
dose (less than or equal to 50mg) TCAs prescribed for neuropathic pain are not considered 
psychotropic. Participants are prohibited from using these medications during the study, but do not need 
to demonstrate a period of psychiatric stability for 2 weeks prior to enrollment. Patients will be asked 
to refrain from consuming prescription analgesics or alcohol the day before, of, and 
after psilocybin sessions. 
5. History of a psychotic disorder or a bipolar disorder (determined by SCID-5). 
6. Family history of psychotic disorder or bipolar disorder (first or second degree relative). 
7. Current, severe Major Depressive Episode (These individuals will be referred to 
standard-of-care treatment in the community). 
8. History of active suicidal ideation with intent in the last 6 months (Suicidal ideation 
score >3and Reason for ideation >1 on C-SSRS); or a history of suicide attempt in 
the last 5 years with Actual lethality/Medical damage >0 or Potential lethality >0 (on 
C-SSRS). 
9. Narcissistic personality disorder, moderate-to-severe (determined by SCID-5-PD). 
10. History of Hallucinogen Use Disorder (Moderate or Severe) or Hallucinogen 
Persisting Perception Disorder (determined by SCID-5). 
11. History of a seizure disorder. 
12. CNS metastases or symptomatic CNS infection. 
13. Clinically significant cardiovascular disease (CAD, CHF, arrhythmia); baseline 
QTc>450msec; uncontrolled hypertension (SBP>139mmHG or DBP>89mmHG if over 65 
years old) or tachycardia (average HR>90bpm if over 65 years old) averaged over at least 
two measurements. 
14. Supplemental oxygen requirement. 
15. Insulin-dependent diabetes mellitus or poorly controlled non-insulin dependent diabetes 
mellitus (e.g., history of an episode of hypoglycemia or hospitalization for hyperglycemia 
on the current regimen). 
16. Inadequate hepatic function (Total bilirubin > normal institutional limits, OR AST >3 
upper institutional upper limit of normal, OR AST >3 upper institutional upper limit of 
normal), as determined by most recent laboratory tests. 
17. Inadequate renal function as determined by eGFR < 30 mL/min/1.73 m2 (based on the 
MDRD equation) or  CrCl < 30 mL/min (based on the C-G equation). 
18. Concomitant dosing of psilocybin with known UGT1A10 and UGT1A9 inhibitors (e.g., 
diclofenac and probenecid) will be avoided. There is no exclusion criterion based on the 
use of medications or substances that are inhibitors or inducers of CYP450 enzymes. 
19. The use of efavirenz (a.k.a, Sustiva or Atripla). 
20. If deemed by clinical judgment of the study investigators to be unsafe for undergoing the 
intervention and/or inappropriate for participating in a therapy group. 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 8 weeks 
or until: 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
                                               
1 Individuals taking antidepressants, anxiolytics and stimulants will be presented with the option of tapering off, 
and remaining off, of their medication for the duration of the study, if their prescribing physician agrees with this 
course of treatment. 
 


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• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
3.5 
Duration of Follow Up 
Patients will be followed for 3 months after completion of treatment or removal from study, or 
until death, whichever occurs first. Patients removed from study for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization of all treatment related 
adverse events. 
3.6 
Randomization Procedures 
Patients will not be randomized; this is an open-label pilot trial with one treatment arm. 
3.7 
Study Timeline 
3.7.1 Primary Completion 
The study will reach primary completion 36 months from the time the study opens to accrual. 
3.7.2 Study Completion 
The study will reach study completion 48 months from the time the study opens to accrual. 


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4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug: Psilocybin 
Psilocybin is available as a powder that can be encapsulated for oral administration. 
Classification 
Psilocybin is an indoleamine psychedelic and is one of the “classic psychedelics.” It has a 
chemical structure similar to that of the neurotransmitter serotonin. 
Mechanism of Action 
Psilocybin is an agonist of serotonin 5HT2A, 2C and 1A receptors [92, 101]. 
Metabolism 
After ingestion, psilocybin is rapidly dephosphorylated to psilocin, which is metabolized via 
oxidation and glucuronidation in the small intestine and the liver, and subsequently excreted 
renally [91, 93, 94]. 
Contraindications 
Current safety standards for experimental psilocybin administration [24, 143] include providing a 
comfortable environment, the presence of supportive and non-directive therapists or research 
staff, and strict exclusion criteria. Beyond this basic principle, psilocybin should generally not be 
administered to individuals with a personal or family history of psychosis or bipolar disease, or 
individuals who are acutely suicidal. It should also not be administered to individuals with severe 
cardiovascular disease or CNS disease (metastases, a seizure disorder, or traumatic brain 
injury). Co-administration with medications associated with the serotonin syndrome [144] should 
be avoided. 
Availability 
Psilocybin is a Schedule I compound, and so requires a DEA Schedule I license to handle. For 
the purposes of this study, psilocybin is available from the laboratory of Dr. Roland Griffiths at 
Johns Hopkins University (IND#133202). 
Storage and handling 
Psilocybin is stored at 15-30°C. Each subject’s dose will be, to the nearest milligram, as close 
as possible to that indicated by their actual bodyweight (e.g., 0.30mg/kg or 0.36mg/kg), with a 
maximum dose not to exceed that calculated for a BMI of 35 at that participant’s height. The 
psilocybin will be provided to UCSF in powder form, and the UCSF Investigational Drug Service 
of the UCSF Department of Pharmacy Services will encapsulate the drug. The study drug will 
be stored in a secure vault in the Investigational Drug Service in the Inpatient Pharmacy in 
Moffitt-Long Hospital (505 Parnassus Ave, San Francisco). 
Side Effects 
Psilocybin is known to be physiologically safe at the doses proposed for this study, and is not 
addictive [92, 102]. Safe administration is dependent on using a supportive and structured 
administration protocol [24]. Psilocybin is known to possibly cause the following transient side 
effects: Anxiety, thought disorder, nausea, emesis, increase or decrease in heart rate, increase 
or decrease in blood pressure, and headache [18, 24, 91, 95, 145, 146]. Anxiety and thought 
disorder reactions appear to be dose-dependent, with higher doses associated with greater 
frequency of temporary anxiety and thought disorder reactions [138]. 


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Clinical Safety Data 
Psilocybin, in the form of psilocybe mushrooms, has been consumed by humans for ritual and 
healing purposes for at least hundreds of years [147]. The most extensive review of mid- 
Century reports of the safety of the controlled, clinical uses of psychedelics, including psilocybin, 
found an overall low incidence of adverse events [103]. After clinical research with psilocybin in 
North America stopped in the 1970s, psilocybin continued to be used legally as a psychotherapy 
adjunct in Germany and Switzerland in the 1980s and 90s, but no comprehensive safety data 
are available from this period [104, 148]. 
 
Since the 1990s, hundreds of doses of psilocybin have been administered to humans in clinical 
trials and research laboratories across North America and Europe. Gouzoulis-Mayfrank et al 
found negligible acute effects on vital signs (heart rate, blood pressure, temperature) and 
neuroendocrine levels (cortisol, prolactin, growth hormone), but did find significant transient 
mental status changes in eight healthy volunteers administered a moderate dose 
(0.2mg/kg, with total dose <15mg) of oral psilocybin [149]. A review of results from the 
Vollenweider laboratory in Zurich, Switzerland found that in 110 subjects administered 1-4 low- 
to-high doses of oral psilocybin there were no detectable persisting adverse effects, and all 
acute adverse reactions (e.g., dysphoria or anxiety) were controlled with interpersonal support 
alone, meaning no pharmacologic or other medical interventions were necessary [143]. 
Moreover, several subjects who did report acutely distressful experiences later claimed in long- 
term follow up that these experiences had been “enriching”. [143] A subsequent review from 
that laboratory found that among 261 subjects who received low-to-high doses of oral 
psilocybin, both mystical-type experiences and acute anxious reactions were strongly positively 
correlated with drug dose [150]. Importantly, anxious reactions were also strongly correlated 
with the experimental setting (more anxiety was reported if the subject underwent a PET scan 
during the experiment), which argues in favor of the idea that the risk of adverse events can be 
mitigated by providing a comfortable and supportive setting for drug administration. This 
laboratory’s recent findings from 50 subjects [151], and another 25 subjects [152] receiving a 
moderate oral dose of psilocybin (0.16mg/kg po or 0.215mg/kg po) reported no adverse events, 
and found improvement in mood. In contrast to the PET study above, another laboratory in 
London found no adverse events when they administered moderate dose iv psilocybin to 15 
healthy subjects with prior psychedelic experience while undergoing brain fMRI; these subjects 
reported improved well-being on 2-week follow up [141]. 
 
Grob et al conducted the first modern study on the use of psilocybin in subjects with advanced- 
stage cancer [18]. Subjects received a single moderate dose (0.2mg/kg) of oral psilocybin with 
pre- and post-drug supportive psychotherapy. This was well-tolerated with subjects showing 
only mild transient increases in blood pressure and heart rate compared to active placebo; no 
subjects experienced acute anxiety during the experience; and subjects spontaneously 
requested that a second dosing session be added to the protocol. Since the Grob et al. study, 
two larger double-blind RCTs of psilocybin-assisted psychotherapy in cancer patients with 
anxiety or depression, conducted at NYU and Johns Hopkins, were published; they both 
reported no adverse reactions (e.g., headache, anxiety or psychosis-like symptoms) lasting 
longer than 24 hours [19, 20]. Separately, the Johns Hopkins laboratory has reported zero 
persisting psychological problems among the 54 subjects to whom they had administered high 
dose (>25mg po) oral psilocybin to by 2008 [24]. By October 2016, the Johns Hopkins team has 
had no significant adverse events after administering psilocybin to approximately 270 subjects 
over 560 drug treatment sessions, and emergent medications have never been needed to 
maintain the safety of the subjects nor the study therapists (Griffiths, personal communication 
2016). 
 
Oral psilocybin has also been administered to other clinical populations in modern controlled 
clinical settings with good safety outcomes. Of 9 subjects with OCD who were administered low- 


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to-high doses of oral psilocybin, the only adverse event reported was transient hypertension 
[110]. Of 15 nicotine-dependent smokers receiving moderate-to-high doses of oral psilocybin, 
adverse events included acute anxiety, mild transient increases in hypertension and heart rate, 
and mild headaches [108]. Of 10 subjects with alcohol dependence administered moderate-to- 
high doses of oral psilocybin, the only adverse event reported was mild transient hypertension 
[107]. A recent open-label pilot study of 12 subjects with treatment-resistant depression, each 
receiving a low oral dose (10mg) followed one week later by a high dose (25mg) found transient 
anxiety, thought disorder, nausea and headache, but no severe or unexpected adverse events 
when followed for up to 3 months after the high dose session [153]. Finally, recent 
epidemiological data argue for a positive correlation between lifetime classic psychedelic use 
(including psilocybin) in the US population and reduced rates of past month psychological 
distress, past year suicidal ideation and past year suicidal attempt [154]. 
4.2 
Drug Accountability 
Each UCSF campus investigator using Schedule I substances in research must obtain their own 
Schedule I registration with the DEA and is responsible for the ordering, security, accountability 
and disposition of all product ordered under their registration. Psilocybin will be obtained from 
the laboratory of Dr. Roland Griffiths at Johns Hopkins University, and the drug will be shipped 
to the Investigational Drug Service of the Department of Pharmaceutical Services at UCSF 
Medical Center (505 Parnasssus Ave, Room M39C, San Francisco, CA 94143; Phone 
415.353.1798). The pharmacy has been used for the storage and preparation of Schedule I 
controlled substances for individual campus Schedule I registrants for many years. 
 
Storage: Schedule I substances will be stored in one of two large combination lock safes 
located in the investigational drug storage room of the UCSF Inpatient Pharmacy. The 
investigational drug storage room is a limited access storage room located in the basement of 
Moffitt Hospital on the UCSF Parnassus Campus (505 Parnassus Avenue). The room bears a 
security lock, accessible to the investigational pharmacy staff. The combination of the safe is 
known only to the investigational drug pharmacy staff. 
 
Upon receipt of a medication order from the investigator, the drug supply will be accessed by 
the investigational pharmacy staff. The ordered dose will be obtained, placed in appropriate 
pharmacy dispensing container and labeled for the research subject. The dose contained will 
be sealed with a tamper evident seal. Research staff will escort the patient to the Inpatient 
Pharmacy on the day of dosing. Drug will be dispensed directly to the research subject by the 
pharmacy staff after confirming patient identification and acquiring the patient’s signature on the 
pharmacy’s chain of custody documentation. The subject will then be escorted by study staff 
from the Inpatient Pharmacy through indoor hallways that connect the Moffitt Hospital (where 
the pharmacy is located) to the Langley Porter Psychiatric Institute (where the drug 
administration will take place). 
 
Dispensing: Psilocybin was shipped from Dr. Roland Griffiths in powder form and will need to 
be allocated into gelcaps by the UCSF Investigational Drug Service. Subjects will be dispensed 
one gelcap with their dose based on weight, as measured prior to the drug treatment day by 
study staff. Psilocybin will be ingested by study subjects in the testing area (Room A-310) of the 
third floor annex of Langley Porter Psychiatric Institute. 
 
Records: Record keeping will be in accordance with federal and state regulations for Schedule 
I controlled substances. Inventory will be taken at least every two years at end of the business 
day and maintained in a printed form. 


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4.3 
Drug Ordering 
UCSF has obtained psilocybin directly from Dr. Roland Griffiths at Johns Hopkins University. 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 


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5 
Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an outpatient basis. 
Table 5.1 Regimen Description 
 
 
 
 
Study 
Drug 
Premedication 
/ precautions 
Dose 
Route 
Schedule 
Psilocybin 
Avoid all other 
psychotropic agents 
within 48hr of each 
dose 
0.3mg/kg 
or    
0.36mg/kg 
(moderate- 
to-high) 
Oral 
After 4 
group 
therapy 
visits 
 
Psilocybin is not physiologically toxic at the doses being used in this study. No human data 
exists that suggest what a toxic dose of psilocybin might be, but experiments in animals 
suggest that the LD50 of psilocybin in humans may be in the range of grams [91], which is 
two orders of magnitude higher than the highest dose to be used in this study. Patients 
could have short-term (<24hr) challenging psychological reactions. Patients who have a 
serious adverse event consisting of a negative psychological reaction lasting >24hr will be 
followed by a study physician until the resolution of the event and, at the discretion of the 
PI, may be removed from the study. There is reason to believe that participating in the 
integration group therapy sessions after a negative psychological reaction may help in 
recovering from such an event, and so participants will not automatically be removed from 
the study merely for having a prolonged negative psychological reaction to the psilocybin 
session (See Section 7.3 for definitions of Adverse Event.) 
 
5.1.1 Other Modalities 
Patients will participate in group therapy sessions following a modified manual of Brief 
Supportive-Expressive Group Therapy (SEGT) [76]. SEGT emphasizes therapeutic goals that 
include enhancing mutual support, openness and emotional expression, improved social and 
family support, and detoxifying death and dying. The weekly sessions will last 90 minutes and 
be conducted by 2 co-facilitators with experience leading psychotherapy groups. 
5.2 
Monitoring and Toxicity Management 
Of the hundreds of subjects administered psilocybin in clinical or research settings over the last 
two decades, none have required emergent psychiatric medications or emergency department 
care [24, 143, 154]. Each subject receiving psilocybin will be evaluable for safety. The safety 
parameters include physical findings and spontaneous reports of adverse events reported to the 
investigator by subjects and primary caregivers. Each subject will be assessed periodically for 
the development of any toxicity as outlined in Section 6 Study Procedures and Observations. 
Toxicity will be assessed according to the NIH Division of AIDS Table of Grading of Severity of 
Adult and Pediatric Adverse Events V2.0 (http://rsc.tech- 
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. We will monitor specifically for hypertension, hypotension, tachycardia, nausea, emesis, 
headache, anxiety, dysphoria, mania, suicidality and psychosis during drug sessions using 
the Adverse Event Medication Session Rating Form (see Appendix). Acute physical adverse 
events (e.g., nausea or hypertension) will trigger increased frequency of monitoring. Acute 
psychological adverse events will be managed by supportive reassurance and, if needed, 
medications such as lorazepam or olanzapine. Further management of physical or 
psychiatric adverse events will depend upon the judgment of the on-call study physician and 
may include, if necessary, transportation to the UCSF Parnassus Emergency Department, 
which is located immediately adjacent to the Langley Porter Psychiatric Institute. 


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See Appendix A for a timeline of all assessments 
 
6 
Study Procedures and Observations 
 
 
 
 
 
6.1 
Study Site 
All in-person pre-treatment and treatment patient contact will occur at the Langley Porter 
Psychiatric Institute (LPPI) at 401 Parnassus Ave, San Francisco. LPPI is a psychiatric hospital 
within the UCSF Medical Center Parnassus Campus and is immediately adjacent to the UCSF 
Parnassus Emergency Department. 
 
6.2 
Selection of Measures 
Antiretroviral Medication Adherence Scale (AMAS)—A single item 11-point Likert scale (0%- 
100%) of ART medication adherence percentage over the past week. This scale was invented 
for this study. 
Alcohol Use Disorders Identification Test (AUDIT) – A 10-item screening tool developed by 
the World Health Organization to assess alcohol consumption, drinking behaviors, and 
alcohol-related problems. 
 
Center for Epidemiologic Studies Depression Scale-Revised (CES-D-R)—A 20-item validated 5- 
point Likert scale self-report scale for the detection of depression [155] that has been shown to 
be sensitive to change in symptoms in palliative care patients. [156]. 
 
Client Satisfaction Scale (CSS)—A 4-item 10-point Likert scale (“very dissatisfied” to “very 
satisfied”) designed for this study assessing satisfaction with the intervention. 
 
Clinical Global Impressions scale (CGI)—A widely-used 3-item clinician-administered 
assessment developed by the NIMH to assess change in patients in psychopharmacology 
trials[157]. 
 
Challenging Experiences Questionnaire (ChEQ)—A validated 26-item 6-point Likert scale of the 
extent to which subjects experienced challenging experiences during a psychedelic drug 
treatment session[158]. The scale has 7 factors: fear, grief, physical distress, insanity, isolation, 
death and paranoia. 
 
Columbia Suicide Severity Rating Scale (C-SSRS)—A validated 17-item scale that assesses 
suicidal ideation and behavior (www.cssrs.columbia.edu) according to the Columbia 
Classification Algorithm for Suicide Assessment (C-CASA), which the FDA Division of 
Psychiatric Products requires be used in clinical trials it oversees. 
 
Community Observer Rating Form (CORF)—A 13-item 10-point Likert scale developed by 
Griffiths et al to triangulate behavioral observations of individuals administered psilocybin [17]. 
 
Concomitant Therapeutics Checklist (CTC)—A checklist designed for this study to assess the 
following categories of mental health therapies used over the last week: Prescription 
medications, non-prescription medications, psychotherapy, mutual aid groups, self-help 


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techniques, integrative medicine modalities, other. 
Credibility/Expectancy Questionnaire (CrEQ)—A 6-item self-report measure of cognitive and 
affective assessments of a mental health therapy with high internal consistency and good test- 
retest reliability [159] that we have adapted for psychological distress. 
 
Demoralization Scale-II (DS-II)—An abbreviated, 16-item and 3-point version of the well- 
validated original 24-item Demoralization Scale [160], which is the most widely used self-report 
measure of demoralization in palliative care patients [29]. The DS-II has two subscales: 
Meaning and Purpose, and Distress and Coping Ability, and shows both good internal and 
external validity in palliative care patients [27, 161]. 
 
Drug Use Disorders Identification Test (DUDIT) – An 11-item screening tool developed as a 
parallel to the AUDIT to assess drug consumption, drug use behaviors, and drug-related 
problems. 
 
Duke UNC Functional Social Support Questionnaire-5 (DUFSS-5)—A 5-item, 3-point Likert, 
self-report measure of perceived functional social support. The abbreviated 5-item scale has 
been validated in patients with severe medical illness (advanced cancer or AIDS) [162]. 
 
Experiences in Close Relationships scale—Modified 16 (ECR-M16)—A 16-item, 7-point Likert 
self-report measure of attachment security. The abbreviated 16-item version is reliable and has 
been validated in patients with severe medical illness (metastatic cancer)[163]. 
 
Group Questionnaire (GQ)—A validated self-report 30-item 7-point Likert questionnaire of 
therapeutic relationships in group therapy [130]. GQ has a three-factor model of group 
cohesion: Positive Bonding, Positive Working, Negative Relationships, all of which manifest in 
both member-member and member-leader relationships [164].  GQ was empirically-derived 
from measures in the AGPA CORE-R Battery [136] that assess therapeutic alliance and 
cohesion—the two factors known to best predict clinical outcomes of group psychotherapy trials 
[129]. 
 
Group Psychotherapy Intervention Rating Scale (GPIRS)—An empirically-derived observer- 
rated 48-item instrument that assesses group therapist behaviors that help create and maintain 
group cohesion [165]. 
 
HIV and Abuse Related Shame Inventory (HARSI)—A validated 22-item 5-point Likert scale(“Not 
at All” to “Very Much”) (Neufeld et al 2012, AIDS Behavior, 16:1063-1074). 
 
Hill Interaction Matrix (HIM)—The gold standard in group therapy process measures [166], the 
HIM is an observer-rated instrument that assesses group therapy sessions using a 4x4 matrix of 
style categories (conventional, assertive, speculative and confrontational) and content 
categories (general, group, personal, relationship). The HIM has been used since the 1960s 
and there exists an extensive database of normative data against which to compare outcomes 
[131]. 
 
International Personality Item Pool-Openness to Experience-20 (IPIP-OE-20)—A 20-item self- 
report measure that uses items in the public domain to evaluate a construct approximately 
equivalent to Openness, which is evaluated by the NEO-PI-R [167]. 
 
Inventory of Complicated Grief (ICG)—A well-validated 19-item 5-point Likert scale (“never” to 
“always”) that is the gold standard self-report instrument for measuring complicated grief [168, 
169]. 
 
McGill Quality of Life Questionnaire-Revised-Short (MQoL-RS)—A well-validated 15-item 11- 
point Likert scale that assess quality of life in palliative care patients by assessing the following 


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domains: Overall quality of life, Physical well-being, Psychological well-being, Social support 
and Existential well-being. We will only use 4 items, which are Parts A (Overall quality of life) 
and B (Physical symptoms). 
 
Multidimensional Assessment of Interoceptive Awareness-Revised (MAIA-R)—A well-validated 
32-item 6-point Likert scale of bodily and mental awareness that measures the following 8 
domains: Noticing, Not-distracting, Not-worrying, Attention regulation, Emotional awareness, 
Self-regulation, Body listening and Trusting [170]. If this study, we will use the Emotional 
awareness (5-tiems), Self-regulation (4-items) and Trusting (3-items) subscales. 
 
Mystical Experience Questionnaire-30 (MEQ-30)—A well-validated 30-item 6-point Likert scale 
(“none; not at all” to “extreme [more than any other time in my life]”) self-report measure of 
mystical-type experiences [124], derived from the earlier work of Pahnke et al. [119]. 
 
Nature Relatedness Scale, Short-Form Version (NR-6)—A 6-item version of a well-validated 
5-point Likert scale self-report measure of environmental connectedness (Nisbet, E. K., & 
Zelenski, J. M. (2013). The NR-6: a new brief measure of nature relatedness. Frontiers in 
Psychology, 4, 11. doi:10.3389/fpsyg.2013.00813) 
 
Palliative Performance Scale version 2 (PPSv2)—A validated clinician-administered tool based 
on the Karnovsky Performance Scale but adapted for a palliative care population [113, 171]. 
 
Persisting Effects Questionnaire—Spirituality (PEQ-S)—An instrument developed by Griffiths et 
al for subjects who have been administered psilocybin to assess enduring changes in attitudes 
about life, attitudes about self, mood changes, relationships, behavioral changes, and spirituality 
[138]. The measure also includes 4 questions about the drug experience itself concerning 
personal meaningfulness, spiritual significance, how psychologically challenging it was, and 
personal psychological insights gained. We will only use the Spirituality subscale (59-item, 6 
point Likert scale [“none; not at all” to “extreme”]), and the four questions about the psilocybin 
experience. 
 
Post-traumatic Growth Inventory-Short Form (PTGI-SF)—A validated 10-item 6-point Likert 
scale meant to assess the following psychological factors in populations that have suffered a 
traumatic event or major crisis: quality of relationships with others, openness to new 
possibilities, personal strengths, spiritual change, and appreciation of life [172]. 
 
PTSD Checklist (PCL-5): A validated 20-item, 5-point Likert scale (from “Not at All” to 
“Extremely”) to measure symptom criteria for PTSD from the DSM-5. [Weathers, F.W., Litz, 
B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & Schnurr, P.P. (2013). The PTSD Checklist 
for DSM-5 (PCL-5)] 
 
 
Quality of Life in Life Threatening Illness Family Caregiver version 2 (QoLLTI-Fv2)—A validated 
17-item 11-point Likert scale (0-10) self-report measure that assesses seven domains of quality 
of life in caregivers for patients with life-threatening illness: state of carer, patient well-being, 
quality of care, outlook, environment, finances and relationships. This instrument was developed 
by the same laboratory that developed the McGill Quality of Life scale [173]. 
 
Schedule of Attitudes towards Hastened Death (SAHD)—A 20-item True/False self- report 
measure of the desire for hastened death validated in patients with HIV/AIDS and other 
palliative care conditions [174]. 
 
Social Connectedness Scale-Revised (SCS-R)—A well-validated 8-item 6-point Likert scale 
(negatively-worded items rated from "strongly agree" to "strongly disagree") self-report measure 
which has shown strong construct, convergent and discriminant validity as well as reliability (α > 


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.92) for assessing the degree to which subjects feel connected to their social environment (Lee, 
R. M., & Robbins, S. B. (1995). Measuring Belongingness: The Social Connectedness and 
Social Assurance Scales. Journal of Counseling Psychology, 42(2), 
232-241. doi:10.1037//0022-0167.42.2.232) 
 
State-Trait Anxiety Inventory (STAI)—A 40-item 4-point Likert scale that is the gold standard in 
self-report measures for state and trait anxiety [175, 176]. 
 
Supportive-Expressive Group Therapy Topic Grid (SEGT-TG)—A measure developed by  
Spiegel and Spira for the original studies of SEGT[75]. Independent raters watch video of 
therapy sessions and document the number of minutes in which particular target discussion 
topics are handled in the session. 
Structured Clinical Interview for DSM-5 (SCID-5)—The gold standard structured clinical 
interview for DSM-5 criteria for major psychopathology. We will use portions of the SCID to 
screen for lifetime Depressive, Psychotic, Bipolar and Hallucinogen-related disorders. 
 
Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD)—A self-report 
questionnaire based on DSM-5 criteria for personality disorders. We will use this to screen for 
Cluster B personality disorders. 
 
6.3 
Qualitative Analyses 
Qualitative analyses be grounded in Interpretive Phenomenological Analysis (IPA) [177]. Data 
for qualitative analysis will include transcripts from a convenience sample of group therapy 
sessions and psilocybin drug sessions, therapist process notes, patients’ written accounts of 
their psilocybin experiences, verbal feedback elicited from patients throughout the study, 
transcripts from focus groups conducted after the study endpoint, and transcripts from 30-60 
minute semi-structured interviews conducted with selected patients after the 6-month follow-up. 
IPA is widely used in studies of psychological interventions to better understand a patient’s 
experience of their treatment, and is typically used to elicit convergent and divergent themes in 
studies with small sample sizes [177]. Two investigators with experience in qualitative analysis 
will at first independently code the same transcripts for prominent themes, followed by 
comparison of their codes until a consensus is reached on an appropriate coding scheme. A 
code book will be established which will be used to code further sources. Consensus will be re- 
established on an iterative basis according to the criteria of the coders and the PI. 
 
 
6.4 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments. Screening assessments will be performed on 
enrollment. Any results falling outside of the reference ranges may be repeated at the 
discretion of the investigator. All on-study visit procedures are allowed a window of ± 7 days 
unless otherwise noted. Treatment or visit delays for public holidays or weather conditions do 
not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records. 
6.4.1 Phone Screening 


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Potential subjects will be screened over the phone to assure that they understand the time 
requirements of the study, they identify as a gay man, they are at least 50 years old, they were 
diagnosed with HIV prior to 1996, they report experiencing moderate-to-severe symptoms of 
demoralization on the DS-II and that they report complicated grief on the ICG, and that they do 
not meet any major exclusion criteria (e.g., history of psychosis or bipolar disorder; recent active 
suicidal ideation). A brief orientation to the study protocol, including psychoeducation on 
psilocybin, will be provided to patients who are not excluded. The patient will then be scheduled 
for an in-person screening and enrollment visit. 
 
 
6.4.2 In-person Screening and Enrollment 
Screening procedures and assessments to be completed on day of Enrollment (prior laboratory 
results from UCSF clinics may be considered instead of performing labs at enrollment if the 
results are less than 6 months old): 
• 
Demographics questionnaire (Age, ethnicity/race, civil status, years of education, 
income) 
• 
Vital signs; Physical examination; Complete medical and psychiatric history, including 
current medication list; Performance status (PPSv2); Mental Status Exam; Cognitive 
Status (Montreal Cognitive Assessment) 
• 
Complete blood count (WBC, Hgb, Hct, Plt) 
• 
Comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Cr, Gluc, Tbili, Ast, Alt, AlkPhos, 
TProt, Alb) 
• 
TSH, FT4 
• 
Urinalysis 
• 
Urine toxicology (must be completed on day of Enrollment) 
• 
HIV viral load, CD4 count, CD8 count 
• 
RPR or Treponemal Antibody 
• 
Electrocardiogram (ECG) 
• 
Selected screening portions of Structured Clinical Interview for DSM-5 Clinical Trials 
Version (SCID-5); sections on current Depressive disorders; lifetime Psychotic disorders, 
Bipolar disorders and Hallucinogen-related disorders), Structured Clinical Interview for 
DSM-5 Personality Disorders, self-report version (SCID-5-PD; section on Cluster B 
disorders) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS): Baseline/Screening (last 12 months) 
• 
ART Medication Adherence Scale (AMAS), Centers for Epidemiologic Studies 
Depression Scale—Revised (CESD-R), Demoralization Scale—II (DS-II), Inventory of 
Complicated Grief (ICG), McGill Quality of Life Questionnaire-Revised-Short (MQoL- 
RS), PTSD Checklist-5 (PCL-5), Schedule of Attitudes towards Hastened Death 
(SAHD), State-Trait Anxiety Inventory (STAI). 
Upon completing a successful in-person screening, subjects will also meet individually with one 
of the study therapists for 30 minutes to develop rapport and to discuss details about the 
subject’s personal life, such as past and current relationships, family dynamics, and concerns 
about their disease. Finally, the subject will be placed on the waitlist until 6 subjects are 
available to start a group. 
 
 
6.4.3 Baseline Assessments (Week 1) 


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6.4.3.1 Baseline Subject Assessments 
Baseline assessments will be filled out during an individual therapy session wherein the subject 
will meet one or both of the group therapists in the week prior to the first group therapy session. 
Separately, the subject’s caregiver/important other will be invited to meet with study staff for a 
brief interview on their relationship with the subject [see Appendix C for interview guides]. The 
individual session for the study subject is meant to build trust and rapport with the group 
therapists, to learn more about the subject’s life history and struggles with his health, to elicit the 
subject’s preferences and intentions for the treatment sessions, and to orient the subject further 
to the intervention protocol. If screening/enrollment measures were completed within 1 week of 
the baseline assessment, those measures will not need to be repeated. 
 
• 
AMAS, AUDIT, CESD-R, CTC, DS-II, DUDIT, DUFSS-5, ECR-M16, ICG, IOS, IPIP-OE-
20, MAIA-R, MQoL- RS, NR-6, PCL-5, PTGI-SF, SAHD, SCS-R, and STAI. A clinical 
rater will perform a CGI and C-SSRS(Interval) for each subject. 
6.4.3.2 Baseline Caregiver/Important Other Assessments 
• 
CORF 
 
6.4.4 Treatment Period 
6.4.4.1 Group Therapy Sessions #1-4 (Weeks 2-3) 
Patients will undergo four 90-minute group therapy preparatory sessions (2 per week) that will 
be audio and video recorded. Video footage of a random sampling of sessions will be analyzed 
with the HIM, SEGT-TG and the GPIRS. Patients will fill out the GQ after the sessions in Week 
2 and 4. A clinical rater will administer the C- SSRS(Interval) to each subject at each weekly 
study visit. 
 
 
6.4.4.2 Individual Drug Sessions (Weeks 4-5) 
Patients will undergo individual drug sessions in which they are administered psilocybin 
0.30mg/kg (or 0.36mg/kg) po, with a maximum dose not to exceed that calculated for a BMI of 
35 at their height. The drug will be administered following the safety guidelines outlined by 
Johnson et al [24].  
 
The day prior to the session, patients will be screened over the phone for contraindicated 
medications and reminded about procedures for the medication visit. Specifically, 
participants will be reminded that they cannot drive an automobile for the rest of the 
day after their medication visit, and they will be advised that if they will take the BART, 
they should not drive their car to the BART station.  
 
On the day of the medication visit, patients will arrive at the Langley Porter Psychiatric Institute 
by 08:00 and be oriented to the drug session room, which will contain a couch for the patient to 
lie on and aesthetically pleasing décor. Before the medication session starts, participants will 
complete a urine drug screen and the CrEQ. Participants will then hand over their shoes, keys, 
wallet and phones to the study therapists for safe keeping; these will all be returned to the 
patient upon completion of the treatment session. 
The entire session will be audio and video recorded for subsequent behavioral analysis and 
rating of therapist adherence to the therapy protocol. The patient will ingest the psilocybin 
capsules with 4 ounces of water and then be instructed to lie down on the couch wearing 


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eyeshades and listening to a preselected music soundtrack via headphones. The subject will be 
instructed to focus their attention internally and to attempt to interact minimally with the two 
therapists who will be present in the room throughout the drug session, but will be as non- 
directive as possible in their interactions with the patient. In the event of a psychologically 
challenging experience such as significant anxiety or confusion, the therapists will provide 
verbal reassurance. Patients will have been instructed in the preparatory therapy session to 
notify the study therapists if during the treatment they feel anxiety or fear. 
In the event of a psychiatric emergency, verbal de-escalation and physical and/or chemical 
restraint will be used to maintain the safety of the subject and the therapists, according to the 
clinical judgment of the on-call study physician. All possible efforts will be made to avoid using 
restraints of any kind. Subjects will not be allowed to leave the premises until the drug effects 
have worn off. 
 
During the drug session, vital signs (heart rate and blood pressure) will be recorded at 10 
minutes prior to drug ingestion, and then 30, 60, 90, 120, 180, 240, 300, and 360 minutes after 
drug ingestion.  
In the event of a medical emergency, subjects will be evaluated by the on-call study physician 
who will be on-site for all drug administrations. At least one ACLS-certified study clinician will be 
on-site for all drug administrations. While expected to be rare, the most likely serious adverse 
event to occur would be a hypertensive crisis. If a subject’s blood pressure becomes grossly 
elevated (SBP >180mmHg, DBP >110mmHG) or unsafe (BP elevations with associated 
symptoms such as chest pain or shortness of breath), blood pressure will be rechecked 
immediately in both arms and the on-call physician will be notified if s/he is not already in the 
treatment room. If the subject is clinically suspected of being in hypertensive emergency (with 
signs of end-organ damage), then the subject will be transported to the UCSF Emergency 
Department for further evaluation and treatment. The Emergency Department’s door is less than 
a 1 minute walk from the Langley Porter Psychiatric Institute. If the patient if determined to be in 
hypertensive urgency (without clinical signs of end-organ damage), then blood pressure will 
be re-assessed every 5 minutes while the study physician continues to her/his evaluation for 
signs of clinical instability, and the study physician may attempt to calm the subject with verbal 
de-escalation or an anxiolytic (e.g. lorazepam) as transient hypertension is most likely to be due 
to a challenging psychological experience. If after 20 minutes the hypertensive urgency has not 
improved, the study physician will evaluate the need for transporting the subject to the 
Emergency Department for further evaluation and treatment. In the case of acute chest pain, 
the on-call study physician will have available sublingual nitroglycerin to administer to the 
subject and an electrocardiogram machine. A crash cart is located in the building, but the goal 
will be to transport a decompensating patient to the Emergency Department prior to the crash 
cart becoming imminently necessary. In the event of a suspected hypoglycemic episode in a 
subject with diabetes mellitus, a finger stick blood glucose will be checked on an as needed 
basis, and fruit or oral glucose tablets will be available. 
As the drug effects begin to wear off at the 5-6 hour mark, the therapists will engage the patient 
in a therapeutic interview to explore the experience (see Appendix C for interview guide); this 
discussion will also be videotaped. A clinical rater will administer the C-SSRS(Interval). Only 
once patients are deemed to be free of the acute effects of the drug, and after at least 7 hours 
have passed since ingestion of the drug, will the participant be allowed to leave the premise in 
the company of a caregiver who has been instructed on how best to support the patient over 
the coming days.  
The patient and caregiver will be given a study clinician’s pager number in case of any clinical 
event off-site that needs further assessment. Patients must agree not to drive themselves home, 
nor to drive later that same day after they arrive home. Patients will be instructed to write a 
detailed account of their experience during the drug session at some point over the next week. 
In the event that a participant did not arrange a friend/family member to accompany 
them home, the participant will be required to stay with the study clinicians longer, will be 


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encouraged to eat, and then the participant will be escorted to the curb by study staff and seen 
into a taxi/Lyft/Uber that will be instructed to take them home. The participant will also be 
instructed to call the study MD when they arrive home. All efforts will be made to avoid this 
situation. In the weeks prior to the medication session, participants will be regularly reminded to 
arrange for someone to accompany them home. 
The following day patients will return to the study site to meet with a study therapist and engage 
in a therapeutic discussion of their experience for 90 minutes. Patients will complete the MEQ-
30, ChEQ, STAI, SAHD, MQoL, and the C-SSRS(Interval) at this visit. Patients may again meet 
with study staff in person prior to the next group therapy session if they request this or if study 
clinicians deem it clinically warranted. 
 
 
6.4.4.3 Group Therapy Sessions #5-10 (Weeks 6-8) 
Patients will undergo six group therapy sessions each  90-minutes long. Video footage of a 
random sampling of sessions will be analyzed with the HIM, SEGT-TG, IGMIPS and the 
GPIRS. Prior to each session, patients will be screened for adverse events and evaluated with the 
CSSR-S. Prior to sessions 5, 7 and 9, participants will fill out the CTC. After sessions 6, 8 and 
10, participants will fill out the GQ. At the end of session 5, participants will fill out these 
questionnaires: CESD-R, DS-II, ICG, PCL-5, HARSI. After sessions 7 and 10, participants will fill 
out the DS-II and ICG. 
 
6.4.5 Endpoint Assessments 
6.4.5.1 Endpoint (Week 8) Study Measures for Subjects 
Immediately after the last group therapy session (Week 8), patients will complete the AMAS, 
CESD-R, DS-II, DUFSS-5, ECR-M16, ICG, IOS, MQoL-RS, NR-6, PCL-5 SAHD, SCS-R, 
STAI, PTGI-SF, IPIP-OE-20, MAIA-R, HARSI, CTC, and CSS. A clinical rater will perform a 
MoCA and CGI for each subject. 
6.4.5.2 Endpoint (Week 8) Study Measures for Caregivers/Important 
Others 
Patients’ primary caregivers/important others will complete the CORF and CSS. 
6.4.6 Post-treatment/Follow Up Assessments 
6.4.6.1 Focus Group (Week 10) 
Two weeks after the last group therapy session, subjects and their caregivers/important others 
will be invited to participate in a focus group wherein they will be asked to give feedback 
regarding their experiences in the study. Effort will be made to get both responders and non- 
responders to attend the focus groups. A clinical rater will administer the C-SSRS(Interval) to 
each subject. Prior to the focus group each participant will fill out the DS-II and ICG. This will 
be video-recorded for subsequent qualitative analysis. See Appendix C for focus group guide. 
 
6.4.6.2 3-Month Follow-up for Subjects 
At 3 Months, patients will be mailed a packet with the following measures to be completed: 
AMAS, AUDIT, CESD-R, DS-II, DUDIT, DUFSS-5, ECR-M16, HARSI, ICG, MQoL-RS, NR-6, 
PCL-5, SAHD, SCS-R, STAI, PTGI-SF, IPIP-OE-20, MAIA-R, CTC, and the CSS. They will be 
called and encouraged to complete the packet. 
 


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6.4.6.3 3-Month Patients for Caregivers/Important Others 
At 3 Months, primary caregivers/important others will be mailed a packet with the following 
measures: CORF and CSS. They will be called and encouraged to complete the packet. 
6.4.6.4 3-Month Qualitative Interviews 
Between the Focus Group and the 3-month follow-up, subjects and caregivers/important others 
will be invited to participate in a semi-structured interview of their experience in the study. These 
interviews will be analyzed to detect potential mechanisms of the intervention as well as 
outcomes not addressed by the study measures. See Appendix C for interview guide. 
6.5 
Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interest. Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s non-compliance or simply significant uncertainty on 
the part of the Investigator that continued participation is prudent. There may also be 
administrative reasons to terminate participation, such as concern about a patient’s 
compliance with the prescribed treatment regimen. 
6.6 
Dietary Restrictions 
No dietary restrictions are included in the protocol. 
6.7 
Prohibited Medications 
Patients are prohibited from using medications from the following classes while enrolled in the 
study: 
 
• 
Serotonin Reuptake Inhibitors (SSRIs and SNRIs) 
• 
Tricyclic Antidepressants (TCAs) 
• 
Monoamine Oxidase Inhibitors (MAOIs) 
• 
Atypical antidepressants (e.g., mirtazapine, nefazodone) 
• 
Antipsychotics/Neuroleptics (typical and atypical) 
• 
Anti-epileptics or mood stabilizers (e.g., lithium, valproate) 
• 
Stimulants (e.g., methylphenidate, modafinil) 
• 
Efavirenz (Sustiva, in Atripla) 
• 
Insulin 
• 
Non-topical corticosteroids 
• 
Herbal supplements intended to affect mood or anxiety. 
 
Conditional medication restrictions 
• 
Trazodone 
o Trazodone ≤50mg/24hr for insomnia is allowed, but not within 48hr of psilocybin 
session 
• 
Benzodiazepines 
o PRNs are allowed, but not within 48hr of psilocybin session 
o “z-drugs” (e.g., zolpidem) are not allowed within 48hr of psilocybin session 
• 
Non-benzodiazepine anxiolytics (e.g. gabapentin, buspar) 
o Gabapentin for neuropathic pain is allowed, but not within 48hr of psilocybin 
session 
 
Individuals who at screening are excluded for taking contraindicated antidepressants, anxiolytics, 


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stimulants or herbal supplements can be re-screened for the study if—under the guidance of their 
usual physician—they successfully taper off these medications and demonstrate a period of 
psychiatric stability lasting at least 2 weeks. One exception to the required 2 week period is for 
individuals taking low dose TCAs (≤50mg imipramine equivalent) for reasons other than 
depression or anxiety (e.g., peripheral neuropathy or insomnia). These individuals may, under the 
guidance of their usual physician, taper off these medications and then be enrolled in the study 
once they are no longer taking the TCA. 
 
6.8 
Study Clinicians 
Study clinicians (group therapists and treatment session guides) will be approved by a panel 
consisting of: Dr. Josh Woolley (PI), Dr. Alicia Danforth (UCLA psilocybin team, and lead 
clinical supervisor for UCSF the team), Dr. Brian Anderson (UCSF psilocybin team), and Robert 
Jesse (Johns Hopkins psilocybin team). Group therapists and treatment session guides will all be 
licensed clinicians (MD, RN, NP, MFT, LCSW, PhD, PsyD, Chaplain, etc) in the state of 
California; an exception will be made if the person is unlicensed but currently enrolled in a 
clinical training program and has had sufficient clinical exposure, according to the judgment of the 
above-mentioned panel. The selection of therapists/guides will give preference to those who have: 
1) prior clinical experience working with the study population; 2) have demographic similarities to 
the study population (age, gender, sexual orientation); 3) prior experience conducting group 
therapy; 4) prior experience working with individuals under the influence of psychedelics either in 
research settings or harm-reduction settings (such as the Zendo Project); 5) have completed the 
CIIS certificate program in Psychedelic-assisted Psychotherapy and research; 
6) must have completed CITI training and have been added to the study IRB. 
 
Group therapist pairs will consist of one lead and one secondary therapist. The lead must have 
had significant experience as a group therapy leader; the secondary must have some experience 
as a group therapy leader. Group therapists will undergo at least 16 hours of training in 
Supportive-Expressive Group Therapy (SEGT) by studying SEGT training videos, the SEGT 
adherence rating scales that will be used in the study, and the 3 following SEGT manuals: the 
original manual for metastatic breast cancer patients [75], the manual for brief SEGT in newly 
diagnosed breast cancer patients [76], and the adaptation by Maldonado et al for patients with 
AIDS [78]. All group therapists will undergo at least one 'dry run' session of the SEGT method 
prior to starting a group. 
 
Each subject will have 2 guides working with them in their drug treatment day (not necessarily 
one male and one female). At least one of the treatment session guides will be one of the 
subject's group therapy co-therapists. Treatment session guides will undergo instruction by Dr. 
Alicia Danforth and/or Dr. Anderson. Overall clinical supervision will be a responsibility shared 
by Dr. Josh Woolley (PI), Dr. Brian Anderson (lead medical supervisor) and Dr. Danforth (lead 
psychotherapy supervisor). Clinical consultation will be available from others involved in the 
study, such as Dr. Jim Dilley, Co-Investigator of this study and founder and of the UCSF 
Alliance Health Project, as well as Dr. Rob Daroff, a study clinician who is a staff psychiatrist at 
the SFVA with many years experiencing running psychotherapy groups for gay men in San 
Francisco. 
 
Clinical supervision specifically related to psilocybin, and SEGT, will happen in the form of 
debriefing sessions after every study visit. Dr. Anderson will be an in-the-room observer of the 
group therapy sessions to take notes and later discuss with the group therapists their adherence to 
the SEGT method and its current adaptation to the psilocybin trial. Dr. Anderson and Dr. 
Danforth will review video of treatment sessions and discuss the technique observed with the 


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individual session guides on an as needed basis. Video segments of group therapy sessions and 
psilocybin treatment sessions will be used for discussion in a periodic supervision workshop to 
be held after the completion of each group therapy cohort and which all study clinicians will be 
highly encouraged to attend. The number of supervision sessions a study clinician is required to 
attend to maintain eligibility to work on the study will be up to the discretion of the clinical 
supervisors. 


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7 
Reporting and Documentation of Results 
7.1 
Evaluation of Safety and Feasibility 
The assessment of safety and feasibility will be informed by surveillance of adverse events in all 
patients who enroll in the study. The study will use the NIH Division of AIDS Table of Grading of 
Severity of Adult and Pediatric Adverse Events V2.0 for reporting of adverse events. Analyses 
of feasibility and acceptability will also be informed by rates of patient recruitment and retention, 
therapist protocol adherence, self-report measures (CrEQ and CSS), and spontaneous 
feedback from subjects, caregivers/important others, and study therapists. 
7.2 
Evaluation of Efficacy 
We will evaluate for trends in changes of group mean measures of demoralization, complicated 
grief, depression, anxiety, and other constructs mentioned above. These evaluations will consist 
of self-report measures (e.g., DS-II) and observations from caregivers/important others and 
clinical raters (e.g., CORF and CGI). 
 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality. An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 


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as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.4 
Recording of an Adverse Event 
All adverse events will be entered into UCSF REDCap, whether or not the event is believed to 
be associated with use of the study drug. Data about these events and their severity will be 
recorded using the NIH Division of AIDS Table of Grading of Severity of Adult and Pediatric 
Adverse Events V2.0. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into UCSF REDCap using the 
classification system listed below: 


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Relationship 
Attribution Description 
Unrelated to 
investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to 
the intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Possible 
The AE may be related to the 
intervention 
Related to 
investigational 
drug/intervention 
Probable 
The AE is likely related to the 
intervention 
The AE is clearly related to the 
intervention 
Definite 
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator. 
When specific adverse events are not listed in the above NIH DAIDS Table of Grading of 
Severity, they will be graded by the Investigator as none, mild, moderate or severe according to 
the following grades and definitions: 
 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild: Mild symptoms causing no or minimal interference with usual social & 
functional activities with intervention not indicated 
Grade 2 
Moderate: Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated 
Grade 3 
Severe: Severe symptoms causing inability to perform usual social & functional 
activities with intervention or hospitalization indicated 
Grade 4 
Potentially life-threatening: Potentially life-threatening symptoms causing 
inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death 
Grade 5 
Death related to AE 
 
7.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
7.6 
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into UCSF REDCap, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
Data and Safety Monitor (DSM) and UCSF’s Institutional Review Board, the Committee on 
Human Research (CHR); and, when the study is conducted under an Investigational New Drug 
Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA reporting 
criteria. 
In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into UCSF REDCap will be reviewed and monitored by the Data and Safety Monitor on an 


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ongoing basis, discussed at DSM meetings which take place after each therapy group 
completes the 8-week intervention. 
7.7 
Expedited Reporting 
Reporting to the Data and Safety Monitor 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSM within 1 
business day of knowledge of the event. The contact may be by phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional 
Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
• 
Suspected adverse reaction (as defined in 7.3.2.1) 
• 
Unexpected (as defined in 7.3.2.2) 
• 
Serious (as defined in 7.2.3.3) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug 
Serious adverse reactions will be reported to the Heffter Research Institute and the Usona 
Institute, which are consultants for this study. 


Phase I – Study drug(s) 
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Protocol CHR#15-17825 
 
 
 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Design 
This open-label single-arm mixed-methods pilot study will use descriptive statistics and 
qualitative methods to evaluate safety and feasibility in terms of rates of adverse events, patient 
recruitment and retention, and feedback on the intervention’s utility, content and duration. Given 
the small sample size of this study, small-to-medium effect sizes will likely be undetectable; and 
so descriptive statistics will be used to report changes in mean measures at baseline compared 
to the endpoint, and again at the 3-month follow-up. Exploratory ANOVAs will also be done to 
model changes in therapeutic process values (e.g., group cohesion) over time. Qualitative 
thematic analysis will also be used to evaluate verbal and written reports of patient and 
caregiver/important other experiences with the study in order to optimize implementation of the 
intervention in larger, future trials. 
 
8.1.1 Randomization 
No randomization procedures will be used. 
8.1.2 Stratification Factors 
No stratification procedures will be used. 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
This pilot study of the safety and feasibility of psilocybin-assisted group therapy aims to enroll at 
least 18 subjects, and will have a maximum total sample size of 36. We estimate needing to 
enroll 18 subjects given attrition rates of up to 45% reported in trials of other group therapies for 
existential distress in palliative care patients [114]. For comparison, four different safety and 
feasibility pilot studies of psilocybin-assisted psychotherapy have been conducted over the last 
two decades, and have included 9, 10, 12 and 15 patients each [18, 107, 108, 110]. Four 
recently published feasibility pilot studies of meaning-focused group psychotherapies for 
palliative care patients have included 5, 11, 11, and 16 patients each [40, 178-180]. 
 
Group therapy studies should include at least 2 groups of at least 4-6 members [135], so we 
plan to have at least 8 subjects complete the intervention. We expect to be able to enroll at least 
6 subjects every 6 months. 
 
Because the proposed study is a pilot focused on investigating safety and feasibility, power 
calculations for efficacy measures are not indicated. Pilot studies are often used to estimate 
values that are then utilized in power calculations for full-scale trials. Indeed, we will estimate 
effect size (ES) and the intraclass correlation coefficient (ICC) [132] for the intervention based 
on our preliminary efficacy results. Group psychotherapy trials generally require large sample 
sizes to demonstrate statistical significance in change in efficacy measures given the likely 
interdependence of clinical outcomes when interventions are delivered in groups [132, 133]. 
Thus, future full-scale trials can utilize our estimates to derive adequate, and likely large, sample 
sizes. 


Phase I – Study drug(s) 
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Protocol CHR#15-17825 
 
 
 
8.2.2 Replacement Policy 
Study subjects who have been assigned to a group and drop out prior to the first group session 
can be replaced by a new subject who will be assigned to the same group. Subjects who drop 
out after the first group therapy session will not be replaced. 
8.2.3 Accrual estimates 
The annual number of eligible patients is high given the size of the population of HIV- 
seropositive gay-identified men in the San Francisco Bay Area. In 2014, San Francisco reported 
15,979 people living with HIV, 14,221 of whom were men who have sex with men, and 9,202 of 
whom are 50 and older [8]. If accrual falls short of expectations, advertising and recruitment 
efforts will be expanded. 
 
8.3 
Interim Analyses and Stopping Rules 
After the occurrence of one Adverse Event judged to be Severe and potentially related to the 
drug/intervention, enrollment will be stopped until a Safety Review has been completed and the 
appropriate protocol amendments implemented. 
 
8.4 
Analyses Plans 
The study’s biostatistician is Matthew Boden, Ph.D. Alongside the PI, Dr. Boden will be co- 
responsible for assuring that clinical data are correctly collected, stored and analyzed. He will 
work directly with the PI to assure that interpretations of these data are coherent and justified. 
Dr. Boden’s professional interests are rooted in the research, evaluation and implementation of 
evidence-based treatments for complex and severe mental disorders. As a Health Science 
Specialist at the Center for Innovation to Implementation (Ci2i), Veterans Affairs (VA) Palo Alto 
Health Care System, Dr. Boden investigates the clinical effects and implementation of evidence- 
based psychosocial treatments for psychotic, anxiety, and substance use disorders. His 
research utilizes a variety of assessment (e.g., structured clinical interviews, biological assays) 
and statistical (e.g., linear mixed models, exploratory structural equation modeling) techniques. 
As a Senior Evaluator at the Program Evaluation and Resource Center (PERC), VA Office of 
Mental Health Operations (OMHO), Dr. Boden supports OMHO’s nationwide program 
evaluation and quality improvement efforts. 
 
 
8.4.1 Analysis Population 
All patients who enroll in the study will be included in analyses of safety and tolerability. 
 
All patients who make any contact at all with the study (including those who are screened out 
over the phone) will be included in analyses of feasibility. 
 
All patients who enroll in the trial will be included in analyses of efficacy. Repeated efficacy 
measures will be gathered and trended, regardless of missing data or protocol non-adherence. 
 
All patients who participate in at least one group therapy session will be included in analyses of 
psychotherapeutic process. 
 
8.5 
Primary Analysis 
Safety analyses will be performed for all patients who enroll in the study. The study will use the 
NIH Division of AIDS Table of Grading of Severity of Adult and Pediatric Adverse Events V2.0 to 


Phase I – Study drug(s) 
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Protocol CHR#15-17825 
 
 
 
classify adverse events. Descriptive statistics (percentages) will be reported for the incidence of 
any Adverse Events reported, including suicidality as measured by the C-SSRS. Median scores 
will also be calculated for total scores of the feasibility measures: CSS, CrEQ, and PEQ-S. The 
differences of mean pre- and post-treatment scores on the CORF will be calculated. Differences 
in individual pre- and post-treatment MoCA scores will be assessed for each individual. 
Therapist protocol adherence will be reported as a rate of discussion topic deviations from the 
protocol. 
8.5.1 Exploratory Analyses 
Change in efficacy measures from pre-treatment to post-treatment to 3-month follow-up will be 
analyzed with descriptive statistics to represent trends in mean levels. Recognizing that the 
calculations will likely be underpowered, we will also perform ANOVAs of the secondary 
outcome measures. To assist in gauging the clinical relevance of these data relative to 
measurement error, and to overcome some of the limitations of the study’s small sample size, 
Reliable Change Indices (RCI) will be calculated [181]. Data from efficacy measures will also be 
used to estimate effect sizes and intraclass correlation coefficients for use in larger, future 
studies. 
Change in process measures (e.g., the HIM, QPIRS and GQ) over time will be analyzed with 
ANOVAs to assess the slopes of individual participants and of the whole sample. 
Qualitative thematic analyses will be conducted according to the methods outlined in Section 
6.3. Iterative inductive analyses will be performed with the aid of NVivo analytical software. 
 
 
8.6 
Study Results 
Study results will be reported following the guidelines of the TREND Statement for reporting of 
results from non-randomized interventions [182]. The study biostatistician will oversee or review 
the interpretation of all the above analyses and descriptive statistics. 


Phase I – Study drug(s) 
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Version date: 24 August 2017 
Protocol CHR#15-17825 
 
 
 
9 
Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects. 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board). The initial protocol and all 
protocol amendments must be approved by the IRB prior to implementation. 
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. 
The original signed copy of the consent document must be retained in the medical record or 
research file. 
During enrollment, patients will be consented for participation in the study, including having the 
various aspects of their participation video-recorded. They will also sign a Release of 
Information for study staff to speak to the patients’ primary caregivers and primary physicians. 
Primary caregivers/important others will also be consented during enrollment. 
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by the CHR prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval. In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation. The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 


Phase I – Study drug(s) 
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Protocol CHR#15-17825 
 
 
 
9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included. The sponsor- 
investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients. Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into UCSF REDCap via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry with a 
secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as 
soon as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
UCSF personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The DSM will routinely review all adverse events and suspected adverse reactions considered 
“serious”. The DSM will audit study-related activities to ensure that the study is conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP). Significant results of the DSM audit will be communicated to the IRB 
and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as applicable. See Appendix for Data and Safety Monitoring Plan for additional 
information. 


Phase I – Study drug(s) 
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Protocol CHR#15-17825 
 
 
 
9.8 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 






















WEEK 1
WEEK 2
WEEK 2 WEEK 3 WEEK 3 WEEK 4‐5 WEEK 4‐5
WEEK 4‐5
WEEK 6 WEEK 6
WEEK 7
WEEK 7
WEEK 8 WEEK 8
FU:2WeekFU:3Month
Phone Screen Enrollment Baseline + Meet Thrpsts
G1
G2
G3
G4
PSY‐1day PSY
PSY+1day
G5
G6
G7
G8
G9
G10 + Endpoin F/U
F/U
Medical screening
History & Physical
x
History & Physical
Labs
x
Labs
ECG
x
ECG
Urine drug screen
x
x (pre)
Urine drug screen
Phone Rx screen
x
Phone Rx screen
CLINICAL RATERS
CLINICAL RATERS
MoCA
x
x
MoCA
PPSv2
x
PPSv2
SCID‐5
x
SCID‐5
SCID‐5‐PD‐B
x
SCID‐5‐PD‐B
ASI‐Lite
x
ASI‐Lite
AE Screen
x
x
x
x
x
x
x (during)
x
x
x
x
x
x
x
x
x
AE Screen
C‐SSRS
x
x
x
x
x
x
x
x(post)
x
x
x
x
x
x
x
x
x
C‐SSRS
HIM
x
x
x
x
x
x
x
x
HIM
GPIRS
x
x
x
x
x
x
x
x
GPIRS
SEGT‐TG
x
x
x
x
x
x
x
x
SEGT‐TG
STUDY THERAPISTS
STUDY THERAPISTS
BP/HR
x (during)
BP/HR
CGI
x
x
CGI
Process Notes
x
x
x
x
x
x
x
x
x
x
x
Process Notes
SUBJECTS
Measure
Demographics
x
Demographics
GQ
x
x
x
x
x
GQ
CTC
x
x
x
x
x (pre)
x
x
x
x
CTC
AMAS
x
x
x
x
AMAS
CESD‐R
x
x
x
x
x
x
CESD‐R
DS‐II
x
x
x
x
x
x
x
x
x
DS‐II
ICG
x
x
x
x
x
x
x
x
x
ICG
PCL‐5
x
x
x
x
x
x
PCL‐5
HARSI
x
x
x
x
x
x
HARSI
MQOL‐RS
x
x
x
x
x
x
MQOL‐RS
SAHD
x
x
x
x
x
x
SAHD
STAI
x
x
x
x
x
x
STAI
ECR‐M16
x
x
x
ECR‐M16
AUDIT/DUDIT
X
X
AUDIT/DUDIT
DUFSS‐5
x
x
x
DUFSS‐5
IPIP‐Openness‐20
x
x
x
IPIP‐Openness‐20
PTGI‐SF
X
x
x
PTGI‐SF
MAIA‐R
x
x
MAIA‐R
SCS‐R
x
x
x
SCS‐R
NR‐6
x
x
x
NR‐6
CrEQ
x (pre)
CrEQ
ChEQ
x
ChEQ
MEQ‐30
x
MEQ‐30
CSS
x
x
CSS
Qualitative Interview
x
x
Qualitative Interview
Focus Group
x
Focus Group
CAREGIVER/IMPORTANT OTHER
CAREGIVER/IMPORT OTHER
CORF
x
x
x
CORF
CSS
x
x
CSS
Qualitative Interview
x
x
Qualitative Interview
Focus Group
x
Focus Group

ICF_002.pdf: 
Cover page 
 
Psilocybin-assisted Group Therapy for Demoralization  
in Long-term AIDS Survivors 
 
NCT02950467 
 
Informed Consent Form 
 
17 April 2018 
 



















Prot_SAP_000.pdf: 
Cover page 
 
Psilocybin-assisted Group Therapy for Demoralization  
in Long-term AIDS Survivors 
 
NCT02950467 
 
Protocol and SAP 
 
20 February 2019 
 


 
PSILOCYBIN-ASSISTED GROUP THERAPY FOR DEMORALIZATION IN 
LONG-TERM AIDS SURVIVORS 
 
Protocol Number: CHR#15-17825 
ClinicalTrials.gov: NCT02950467 
IND Number: 133326 
Research Advisory Panel of California: PR#1705H 
DEA: RW0519857 
Study Drug: Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) 
Version Number: 2.0 
Version Date: 27 January 2019 
 
Principal Investigator (Sponsor-Investigator) 
Brian Anderson, MD, MSc 
University of California San Francisco 
401 Parnassus Ave, Rm 309 
San Francisco, CA 94143 
E-mail: brian.anderson@ucsf.edu  
Telephone: 415-476-7432 
Co-Principal Investigator 
Josh Woolley, MD, PhD 
University of California San Francisco 
401 Parnassus Ave  
San Francisco, CA 94143  
E-mail: josh.woolley@ucsf.edu 
Telephone: 415-221-4810x24117   Fax:  415-379-5667 
Co-Investigators 
James Dilley, MD 
Christopher Stauffer, MD 
Statistician 
Matthew Boden, PhD 
Clinical Research Coordinator 
Phillip Perl, MA 
E-mail: phillip.perl@ucsf.edu  
Telephone: 415-476-7432   Fax: 415-502-6361 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws. Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 


Abstract 
 
 
Title 
Psilocybin-Assisted Group Therapy for Demoralization in Long-term AIDS 
Survivors 
Patient 
population 
HIV-positive people ≥50 years old who were diagnosed with HIV prior to 
the clinical availability of combination antiretroviral therapy (~1996). 
Rationale for 
Study 
Long-term AIDS Survivors (LTAS) are people living with HIV (PLH) who 
were diagnosed prior to the advent of combination antiretroviral therapy 
(ART) and, compared to their HIV seronegative peers, suffer higher rates 
of depression, anxiety, trauma exposure, substance use and risky sexual 
behaviors [1-6]. Prior to ART, people living with HIV were “end-of-life 
patients,” then with advent of ART they became “chronically ill,” and now 
many of them are re-approaching end-of-life status as their bodies age at 
an accelerated rate due to HIV infection, HIV therapies, HIV-associated 
non-AIDS conditions, or all of the above [7]. By 2014, 9,202 HIV-positive 
individuals living in San Francisco were older than 50 years old (58% of 
the city’s HIV-positive population) [8]. Like “cancer survivors,” AIDS 
survivors experience increased rates of psychological distress even long 
after their disease is controlled [9, 10]. LTAS are an emerging population 
whose mental health needs are under recognized and undertreated. 
Existential distress is a form of psychological suffering precipitated by the 
acute awareness of one’s mortality [11]. Demoralization is one type of 
existential distress [12], and it is characterized by a sense of 
hopelessness, helplessness and a loss of meaning in life [13]. 
Demoralization is a well-characterized clinical syndrome that captures the 
form of psychological distress suffered by many LTAS [1, 14]. 
Demoralization is also a clinical construct well-suited for investigation as a 
hypothesized therapeutic benefit of psilocybin-assisted psychotherapy in a 
population with chronic existential distress, like LTAS. Because it is 
experienced as a loss of meaning, demoralization should theoretically be 
treatable with interventions that enhance meaning-making [15]. An 
investigational pharmacotherapy that is thought to potently enhance 
meaning-making is psilocybin [16, 17]. Recent trials of individual 
psilocybin-assisted psychotherapy for anxiety and depression in cancer 
patients have shown this intervention to be safe [18-20], and have found 
significant improvements in anxiety and depression lasting months after a 
single treatment [19, 20]. Such impressive results are thought to be 
mediated by two mechanisms: 1) Having a complete “mystical-type” 
experience under the influence of psilocybin [21], and 2) Subsequent 
enhanced social support in the weeks following the mystical experience 
[22]. It remains unknown how these impressive results may translate into 
other palliative care populations. 
Since the beginning of the HIV/AIDS epidemic, many psychotherapies for 
people living with HIV have been preferentially delivered as groups 
because of enhanced cost-effectiveness and the group format’s unique 
clinical benefits with respect to the enhancement of social support in a 
population suffering high rates of isolation and loneliness [23]. This study 
will use the same standard psilocybin administration safety guidelines 
 


Protocol CHR#15-17825 
Phase I – Study drug(s) 
Page 3 of 61 
Version date: 27 January 2019 
 
 
 
 
Rationale for 
Study 
(continued) 
as prior trials [24], but the psychotherapy sessions will employ a modified 
form of Supportive-Expressive Group Therapy (SEGT) [25]. SEGT is a 
widely used, manualized, evidence-based group intervention for 
existential distress in patients with life-threatening disease [26]. The 
current study will be the first modern study of psilocybin-assisted group 
psychotherapy. 
In the current study, the group psychotherapy format functions as a 
standardized context in which patients’ experiences of social support can 
be objectively observed pre- and post-psilocybin. This is helpful because 
while prior trials of psilocybin-assisted psychotherapy evaluated clinical 
outcomes, they did not make use of validated measures of 
psychotherapeutic process. By administering psilocybin as an adjunct to 
SEGT, we will be able to explore quantitatively and qualitatively not only 
the intrapersonal, but also the interpersonal, therapeutic mechanisms 
catalyzed by psilocybin in LTAS suffering from demoralization. 
Primary 
Objective 
To demonstrate the safety and feasibility of Psilocybin-Assisted 
Supportive-Expressive Group Therapy (PA-SEGT) for demoralization in 
LTAS. 
Exploratory 
Objectives 
To explore the preliminary efficacy of PA-SEGT for improving 
demoralization, complicated grief, depression, anxiety, quality of life, 
functional social support, post-traumatic growth, openness to experience, 
mindfulness, social connection, nature relatedness and ART medication 
adherence in LTAS. 
To explore quantitatively and qualitatively the mechanisms through which 
PA-SEGT addresses existential distress in LTAS. 
Study Design 
Open-label mixed-methods pilot study of individual oral psilocybin drug 
sessions (with escalating dose) combined with an evidence-based, 
manualized brief group psychotherapy. 
Number of 
patients 
A maximum of 36 patients will receive the intervention and complete the 
study. 
A minimum of 8 patients will receive the intervention and complete the 
study. 
Duration of 
Therapy 
8 weeks after the initiation of the intervention. 
Duration of 
Follow up 
3 months after completion of the intervention. 
Duration of 
study 
2 years from the time the study opens to accrual. 
Study Therapy 
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) will be administered 
once at a moderate-to-high dose of 0.3mg/kg (or 0.36mg/kg) po during an 
individual medication visit to be held after 4 group therapy visits have 
been completed. Patients will undergo a total of 10 group psychotherapy 
sessions. 


Protocol CHR#15-17825 
Phase I – Study drug(s) 
Page 4 of 61 
Version date: 27 January 2019 
 
 
 
 
Safety 
Assessments 
Adverse events 
Vital signs 
Adverse Event Medication Session Form 
Columbia Suicide Severity Rating Scale  
Community Observer Rating Form 
Feasibility 
Assessments 
Rate of Patient Recruitment 
Rate of Patient Retention (Sessions Attended and Follow-ups Completed) 
Client Satisfaction Scale 
Individual Patient and Important Other/Caregiver Interviews 
Supportive-Expressive Group Therapy Topic Grid 
Focus Groups with Patients and Important Others/Caregivers 
Primary 
Outcomes 
Demoralization Scale-II 
Inventory of Complicated Grief 
Secondary 
Outcomes 
Antiretroviral Medication Adherence Scale 
Alcohol Use Disorders Identification Test 
Center for Epidemiologic Studies Depression Scale—Revised 
Challenging Experience Questionnaire 
Clinical Global Impressions Scale 
Credibility/Expectancy Questionnaire 
Duke/UNC Functional Social Support Questionnaire—5 
Drug Use Disorders Identification Test 
Experiences in Close Relationships scale—Modified 16 
Group Psychotherapy Intervention Rating Scale  
Group Questionnaire 
HIV and Abuse Related Shame Inventory 
Individual Group Member Interpersonal Process Scale 
International Personality Item Pool—Openness to Experience-20 
Life Events Checklist - 5 
McGill Quality of Life Questionnaire—Revised-Short 
Multidimensional Assessment of Interoceptive Awareness—Revised 
Mystical Experience Questionnaire—30 
Nature Relatedness Scale, Short Form  
Post-traumatic Growth Inventory—Short Form 
PTSD Checklist-5 
Schedule of Attitudes towards Hastened Death 
Social Connectedness Scale-Revised 


Protocol CHR#15-17825 
Phase I – Study drug(s) 
Page 5 of 61 
Version date: 27 January 2019 
 
 
State-Trait Anxiety Inventory 
Qualitative analysis of therapy sessions, interviews & focus groups 
Unique Aspects 
of this Study 
This trial will be the first clinical trial of psilocybin-assisted psychotherapy 
for LTAS. It will also be the first modern trial of psilocybin-assisted group 
psychotherapy. It will be the first study of psilocybin-assisted 
psychotherapy for existential distress that will employ an evidence-based 
psychotherapy in the non-drug therapy sessions. The study will provide 
the first safety data for the use of this intervention in LTAS. It will not only 
yield preliminary data on the potential efficacy of this novel intervention, 
but it will also be the first study to employ both validated quantitative 
measures and qualitative methods in the analysis of the 
psychotherapeutic processes germane to psilocybin-assisted 
psychotherapy. It will also be the first clinical trial of psilocybin-assisted 
psychotherapy to assess the impact of the intervention on quality of life in 
partners/caregivers of LTAS. In anticipation of larger, better powered 
trials, clinical outcomes from this Phase I study will be used to produce 
the first estimates of effect size of this novel treatment for demoralization 
in palliative care patients. 


Protocol CHR#15-17825 
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Table of Contents 
1.0 Introduction 
1.1 
Background on Indication 
1.2 
Background on Psilocybin-assisted Psychotherapy 
1.3 
Rationale for the Proposed Study 
1.4 
Study Hypotheses 
 
2 
Objectives of the Study 
2.1 
Objectives 
2.1.1 Primary Objective 
2.1.2 Exploratory Objectives 
2.2 
Endpoints 
2.2.1 Primary Endpoints 
2.2.2 Exploratory Endpoints 
 
3 
Study Design 
3.1 
Characteristics 
3.2 
Number of Subjects 
3.3 
Eligibility Criteria 
3.3.1 Inclusion Criteria 
3.3.2 Exclusion Criteria 
3.4 
Duration of Therapy 
3.5 
Duration of Follow Up 
3.6 
Randomization Procedures 
3.7 
Study Timeline 
3.7.1 Primary Completion 
3.7.2 Study Completion 
 
4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug: Psilocybin 
4.2 
Drug Accountability 
4.3 
Drug Ordering 
4.4 
Packaging and Labeling of Study Drugs 
 
5 
Treatment Plan 
5.1 
Dosage and Administration 
5.1.1 Other Modalities 
5.2 
Monitoring and Toxicity Management 
5.3 
Pregnancy 
 
6 
Study Procedures and Observations 
6.1 
Study Site 
6.2 
Selection of Measures 
6.3 
Qualitative Analyses 
6.4 
Schedule of Procedures and Observations 
6.4.1 Phone Screening 
6.4.2 In-person Screening and Enrollment 
6.4.3 Baseline Assessments 
6.4.3.1 Baseline Subject Assessments 
6.4.3.2 Baseline Caregiver/Important others Assessments 
6.4.4 Treatment Period 
6.4.4.1 Group Therapy Sessions 1-4


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6.4.4.2 Individual Drug Sessions 
6.4.4.3 Group Therapy Sessions 5-10 
6.4.5 Endpoint Assessments 
6.4.5.1 Endpoint (Group 10) Study Measures for Subject 
6.4.5.2 Endpoint (Group 10) Study Measures for Caregivers/Important others 
6.4.6 Post-treatment/Follow Up Assessments 
6.4.6.1 Focus Group 
6.4.6.2 3-Month Follow-up for Subject 
6.4.6.3 3-Month Patients for Caregivers/Important others 
6.4.6.4 3-Month Qualitative Interviews 
6.5 
Discontinuation of Therapy 
6.6 
Dietary Restrictions 
6.7 
Prohibited Medications 
6.8 
Study Clinicians 
 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Safety and Feasibility 
7.2 
Evaluation of Efficacy 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
7.3.2 Adverse reaction 
7.3.2.1 Suspected 
7.3.2.2 Unexpected 
7.3.2.3 Serious 
7.3.2.4 Life-threatening 
7.4 
Recording of an Adverse Event 
7.5 
Follow-up of Adverse Events 
7.6 
Adverse Events Monitoring 
7.7 
Expedited Reporting 
 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Design 
8.1.1 Randomization 
8.1.2 Stratification Factors 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
8.2.2 Replacement Policy 
8.2.3 Accrual estimates 
8.3 
Interim Analyses and Stopping Rules 
8.4 
Analyses Plans 
8.4.1 Analysis Population 
8.5 
Primary Analysis 
8.5.1 Exploratory Analyses 
8.6 
Study Results 
 
9 
Study Management 
9.1 
Pre-study Documentation 
9.2 
Institutional Review Board Approval 
9.3 
Informed Consent 
9.4 
Changes in the Protocol 
9.5 
Handling and Documentation of Clinical Supplies 
9.6 
Case Report Forms (CRFs) 
9.7 
Oversight and Monitoring Plan 
9.8 
Record Keeping and Record Retention 


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Abbreviations 
AGPA 
American Group Psychotherapy Association 
AHP 
Alliance Health Project 
AIDS 
Acquired Immune Deficiency Syndrome 
Albumin 
Alb 
AlkPhos 
Alkaline phosphatase 
Alt 
Alanine aminotransferase 
AMAS 
Antiretroviral Medication Adherence Scale 
AMAS 
ART Medication Adherence Scale 
ANOVA 
Analysis of Variance 
ART 
combination Antiretroviral Therapy 
Ast 
Aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BUN 
Blood Urine Nitrogen 
CBC 
Complete Blood Count 
ChEQ 
Challenging Experience Questionnaire 
CrEQ 
Credibility/Expectancy Questionnaire 
CESD-R 
Centers for Epidemiologic Studies Depression Scale—Revised 
CHR 
Committee on Human Research 
CMP 
Comprehensive Metabolic Panel 
CORF 
Community Observer Rating Form 
Cr 
Creatinine 
CSS 
Client Satisfaction Scale 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTC 
Concomitant Therapeutics Checklist 
DEA 
Drug Enforcement Agency 
DS-II 
Demoralization Scale—II 
DSM 
Data and Safety Monitor 
DUDIT 
Drug Use Disorders Identification Test 
DUFSS-5 
Duke UNC Functional Social Support Questionnaire-5 
ECG 
Electrocardiogram 
ECR-M16 
Experiences in Close Relationships scale—Modified 16 
ES 
Effect Size 
FDA 
Food and Drug Administration 
FT4 
Free thyroxine 
Gluc 
Glucose 
GPIRS 
Group Psychotherapy Intervention Rating Scale 
GQ 
Group Questionnaire 
HAART 
Highly Active Antiretroviral Therapy 
HANA 
HIV-Associated Non-AIDS 
HARSI 
HIV and Abuse Related Shame Inventory 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIM 
Hill Interaction Matrix 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICC 
Intraclass Correlation Coefficient 
ICF 
Informed Consent Form 
ICG 
Inventory of Complicated Grief 
IND 
Investigational New Drug 
IPA 
Interpretive Phenomenological Analysis 
IPIP-OE-20 
International Personality Item Pool—Openness to Experience-20 
LEC-5 
Life Events Checklist-5 
LPPI 
Langley Porter Psychiatric Institute 
LSD 
Lysergic acid diethylamide-25 


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LTAS 
Long-term AIDS Survivor 
 MAIA 
Multidimensional Assessment of Interoceptive Awareness  
MAOI 
Monoamine Oxidase Inhibitors 
MEQ-30 
Mystical Experience Questionnaire—30 
MOCA 
Montreal Cognitive Assessment 
MQoL-RS 
McGill Quality of Life Questionnaire—Revised-Short  
NR 
Nature Relatedness Scale, Short Form 
NEO-PI-R 
Revised NEO Personality Inventory 
OPLH 
Older People Living with HIV 
PA-SEGT 
Psilocybin-assisted Supportive-Expressive Group Therapy  
PCL-5 
PTSD Checklist 
PEQ-S 
Persisting Effects Questionnaire—Spirituality 
PLH 
People Living with HIV 
Plt 
Platelet 
PPSv2 
Palliative Performance Scale version 2  
PTG 
Post-Traumatic Growth 
PTGI-SF 
Post-Traumatic Growth Inventory—Short Form 
PTSD 
Post-Traumatic Stress Disorder 
QoLLTI-Fv2 
Quality of Life in Life-Threatening Illness—Family Carer Version 2 
SAHD 
Schedule of Attitudes towards Hastened Death 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Personality Disorders 
SCID-5 
Structured Clinical Interview for DSM-5 
SCS-R 
Social Connectedness Scale-Revised 
SEGT 
Supportive-Expressive Group Therapy 
SEGT-TG 
Supportive-Expressive Group Therapy Topic Grid 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitors 
SSRI 
Serotonin Reuptake Inhibitors 
STAI 
State-Trait Anxiety Inventory 
Tbili 
Total bilirubin 
TCA 
Tricyclic Antidepressants 
TProt 
Total protein 
TSH 
Thyroid Stimulating Hormone 
WBC 
White Blood Cell 


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1 
Introduction 
We propose to conduct a clinical trial of psilocybin-assisted psychotherapy for 
demoralization in Long-term AIDS Survivors (LTAS). This will be the first trial of 
psilocybin-assisted psychotherapy specifically for people living with HIV (PLH) and it will 
be the first modern trial of psilocybin-assisted group psychotherapy for any indication. 
The study will consist of up to six groups of six gay-identified HIV-seropositive people 
≥50 years of age who were diagnosed with HIV prior to the clinical availability of 
combination antiretroviral therapy (~1996) and who have moderate-to- severe 
demoralization [13, 27]. Psychotherapy groups may be organized based on gender 
identity and sexual orientation to create homogenous groups. Each subject will undergo 
10 sessions of a modified form of Supportive-Expressive Group Therapy [25] and one 
individual psilocybin treatment session [24] after group four of the intervention. 
Quantitative and qualitative measures of psychotherapeutic process will be used to 
explore the mechanisms by which this novel therapy seems to work, particularly on the 
interpersonal level. Quantitative and qualitative measures will assess changes in quality 
of life of the partners/caregivers of subjects undergoing the intervention. This study will 
contribute to the available data on the safety, feasibility and efficacy of psilocybin-
assisted psychotherapy for existential distress in palliative care patients, and 
importantly will provide the first of such data on a palliative care population other than 
cancer patients [28]. 
 
 
Fig. 1 INTERVENTION TIMELINE 
 
 
 
1.1 
Background on Indication 
Existential Distress and Demoralization 
Existential distress is a form of psychological suffering that occurs when one is confronted with 
one’s own mortality [11]. Demoralization is a form of existential distress that is prevalent in the 
palliative care setting and is characterized by hopelessness and helplessness due to a loss of 
purpose and meaning in life [12, 13]. Demoralization is associated with, but distinct from, 
depression, anxiety, isolation, and the desire for hastened death [29]. In palliative care patients, 
demoralization has been shown to be more strongly associated with suicidal ideation than 
depression is [30]. In modern palliative care, the current standard is to address existential and 
spiritual issues in patients and their family members [31, 32]. Following the lead of innovators like 
Frankl [33] and Yalom [34], investigators have over the last two decades devised a number of 
existential psychotherapies [35-40] with varying impact on depression, anxiety and quality of life 
[26, 41]. Arguably, what these therapies have in common is what Cassel [42] long ago prescribed 


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for the relief of suffering—transcendence—an experience that is difficult to define medically and a 
challenge to provide consistently in clinical settings. Palliative care stands to benefit greatly from a 
time-limited intervention that enhances patients’ capacity to forge meaning, to transcend 
suffering, and to overcome social isolation and the fear of the unknown in a safe, immediate and 
reliable manner. This need is pronounced among LTAS. 
 
AIDS Survivors 
By 2004, there had been an estimated 929,985 cases of AIDS in the US, and 524,060 of 
them had died [43]. With the advent of combination antiretroviral therapy (ART) in 1996, HIV 
seropositive individuals began to accomplish what once was thought to be impossible—living into 
old age. Because of the decreased lifespan and the apparently accelerated aging experienced by 
PLH, “older” in HIV is defined as ≥50 years of age [44]. Many LTAS are therefore also considered 
older people living with HIV (OPLH). Despite recent gains in mortality, many of today’s LTAS are 
still grappling with having been, at one point, an “end-of-life” patient. Beyond being confronted by 
their own mortality at the time of diagnosis, LTAS frequently bore witness to the deaths of friends 
and loved-ones, and often served as informal caregivers to those dying of AIDS [45]. AIDS-related 
bereavement is associated with demoralization, depression, and problematic substance use [46]. 
Survivor’s guilt is common among LTAS, as is loneliness [47]. Isolation and loneliness are highly 
prevalent among LTAS not only because affected communities were decimated by AIDS in the 
1980s and ‘90s, but also because many OPLH often lack traditional family support structures 
due to several possible causes that include protective withdrawal from one’s biological family, 
having been disowned by family or friends due to stigma, or not having children [1, 47]. Because 
of reduced social support networks, and therefore a relative lack of access to informal 
caregivers, OPLH are in general expected to be especially reliant on community-based services 
as they age [1]. 
 
Multimorbidities 
Compared to HIV seronegative demographically- and behaviorally-matched peers, OPLH 
are at increased risk of multimorbidities known as HIV-associated non-AIDS (HANA) conditions, 
such as cardiac disease, with PLH having a 50% increased risk of acute myocardial infarction 
compared to HIV seronegative matched controls [48]. PLH are also at higher risk of some HANA 
malignancies, having three times the cumulative incidence of liver cancer and thirty times the 
cumulative incidence of anal cancer [49]. PLH are also at increased risk of serious bone, liver and 
kidney disease [44, 50]. As the health of OPLH declines, HANA and other conditions can serve 
as continual reminders of one’s mortality. OPLH also suffer from high rates of mental health 
conditions such as depression (prevalence up to 50%), suicidal ideation, and anxiety (prevalence 
up to 20%) [ 1 ,  2 ] .  AIDS patients have been found to have an increased desire for hastened 
death [51]. Among PLH (of all ages) PTSD has a prevalence that ranges 10-74% [3, 52]. Like 
PLH of other ages, OPLH have higher rates of substance use [4, 5, 53] and risky sexual 
behaviors [6] than the general population and these behaviors are associated with ART 
nonadherence and therefore disease progression and secondary HIV transmission [54]. The 
incidence of HIV in US adults over 50 years of age saw no improvement from 2010-2014 [55]. 
Comorbid depression, anxiety and PTSD are also associated with ART non-adherence in PLH 
[56-59]. Depression treatment has been shown to increase ART adherence in PLH [60], and 
possibly to decrease secondary transmission of HIV [61]. Data specific to OPLH and behavioral 
interventions that increase ART adherence, however, is limited to few studies that are wanting in 
methodological rigor [62]. 
 
Older People Living with HIV 
The CDC projected that people over the age of 50 years would constitute the majority of 
the HIV-positive population in the US by 2015 [63]. OPLH became the majority of the HIV-positive 
population in San Francisco in 2012, and their proportion of the population continues to rise [8]. 


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It is estimated that over 70% of the US HIV seropositive population will be ≥50 by 2020 [64]. The 
NIH Office of AIDS Research Working Group on HIV and Aging has highlighted as priority 
research areas, among others: Research on mental health in older adults with HIV and possible 
interventions; Research on substance use in older adults with HIV; Research on social networks 
and care giving of older adults with HIV [1]. The HIV community has responded to the 
demographic change by forming peer support groups and holding town halls on the issue across 
the country [65]. Organizational initiatives have sprung up around the issue, including patient 
advocacy groups like the Medius Institute and Let’s Kick AIDS Survivor Syndrome 
(www.letskickass.org), with “AIDS Survivor Syndrome” being a patient-promoted syndrome 
characterized by traumatic exposure, complicated grief, depression, self-destructive behavior and 
hopelessness. Also, many local government and non-profit efforts have emerged over the last 
half decade, including the AIDS Community Research Institute of America’s Center on HIV and 
Aging, the 50-Plus Program at San Francisco AIDS Foundation, and the San Francisco County 
Workgroup on HIV and Aging. Finally, the popular press has recently directed attention to the 
issue [66-68], and in 2016 the San Francisco Chronicle even made a feature-length documentary 
on the struggles of older HIV-positive gay men in San Francisco [69]. 
 
Treatment Needs 
Much of the recent literature on the mental health treatment needs of OPLH has focused 
on depression [7]. Despite the well-established relationship between depression, grief and 
demoralization in PLH [46], grief and demoralization have been less frequently studied since the 
advent of ART. Preliminary analysis of outcomes from support groups for OPLH at UCSF’s 
Alliance Health Project (AHP) indicates that depression and anxiety symptoms improve from 
participating in these groups, but trauma symptoms, particularly related to traumatic losses, tend 
to persist [70]. These AHP findings are supported by the literature that shows that 
coping/support groups for OPLH can improve depressive symptoms [71]. This is also supported 
by anecdotal evidence from the Director of the San Francisco AIDS Foundation’s 50-Plus 
program, who reports that members of this community need more access to treatments for 
psychological trauma [65]. Current literature suggests that PLH have difficulty finding therapies 
that adequately address traumatic loss and grief [72]. More specifically, the Director of the San 
Francisco AIDS Foundation’s 50-Plus program has stated “We need a treatment tailored to our 
community’s needs; not just recycled therapies for other people,” which again is supported by the 
literature which suggests that PLH respond better to therapies specifically targeted to grief and 
psychiatric distress (done in a group) than generic individual psychotherapy [73]. Whereas coping 
groups for bereavement in PLH have shown brief but unsustained improvements in grief, they 
have not proven to benefit general psychological distress or functioning [43]. Another recent study 
did demonstrate short-term reductions in traumatic stress from a coping group intervention in 
PLH, but no data are available on the durability of these benefits [74]. 
 
Group Therapy, Social Support, and Post-Traumatic Growth 
Spiegel and Yalom’s Supportive Expressive Group Therapy (SEGT) [34, 75] was originally 
designed as an intervention for advanced cancer patients, has since been modified to be used 
with a variety of palliative care patients, and has a robust evidence base for its efficacy [41]. SEGT 
emphasizes social support and increasing communication with caregivers. It also focuses on 
processing affect in the ‘here and now’ and ‘detoxifying death and dying’; it includes exposure to 
a therapeutic altered state of consciousness (self-hypnosis); and it encourages emotional 
expression and openness [25]. Manuals exist for traditional (1 year) [75] and brief (12-week) [76] 
SEGT, and SEGT has been shown to be teachable [77]. SEGT has also already been modified 
for and used with success in patients with advanced HIV [78]. A recent study of tele-SEGT for 
depressed OPLH found that therapeutic alliance did not predict clinical response, but group 
cohesion and perceived member similarity did [79]. Social support in PLH is related to improved 
mood, well-being and medication adherence [44]. Enhanced social support in PLH is also 
associated with enhanced post-traumatic growth (PTG) [80]. Whereas much of the literature on 


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the mental health of PLH focuses on coping, the concept of PTG goes beyond coping with the 
problems associated with living with HIV and includes improvement in one’s mental health. PTG 
comprises an increased appreciation for life, enhanced self-efficacy and ability to forge intimate 
relationships, and the increased expression of emotions and hope for the future [80]. PTG is 
associated with fewer depressive symptoms in PLH [81]. Currently, however, there is a dearth of 
literature specifically on PTG and HIV [3, 82], especially on interventions that enhance it. Of 
particular relevance to our study, PTG is associated with a heightened interest in spirituality [80]. 
 
Psychoneuroimmunology in HIV 
It seems that HIV remains a rich field of investigation of the mind-body connection, and 
perhaps especially among OPLH who may have greater mental and physical health needs 
compared to younger PLH. Earlier literature on psychoneuroimmunology and HIV regularly found 
associations between depression, traumatic exposure and disease progression and mortality in 
PLH, both before and soon after the advent of ART [83, 84]. It is unclear whether such 
associations remain with the improved ART regimens available today. Nevertheless, recent data 
have shown that spiritual coping in PLH is associated with increased survival [85]. And after 
controlling for ART use, depression, hopelessness, and avoidant coping have predicted the 
progression of viral load and CD4 count longitudinally [86]. Recent data from the NIH indicate 
that PTSD is associated with differential immune activation in PLH, even in those who are virally 
suppressed [52]. While spirituality and religiosity have been positively associated with enhanced 
mental health in PLH, the personality traits of conscientiousness, openness and agreeableness 
(measured with the NEO-PI-R) are more strongly positively associated with mental health in this 
population [87]. Openness has also been inversely associated with disease progression over 4 
years [88]. Finally, in PLH dispositional mindfulness has been inversely related to depression, 
stress appraisal and negative affect, while it is positively associated with positive affect [89]. 
 
1.2 
Background on Psilocybin-assisted Psychotherapy 
Psilocybin is a natural product found in many species of psychoactive fungi around the world 
[90]. Modern scientific research with psilocybin began when the chemist Albert Hoffman first 
isolated psilocybin from Psilocybe mexicana mushrooms in 1957 [91]. Psilocybin (4- 
phosphoryloxy-N,N-dimethyltryptamine) is the prodrug of psilocin (4-hydroxy-N,N- 
dimethyltryptamine), an indoleamine that acts as an agonist of serotonin 5HT 1A, 2A and 2C 
receptors [92]. In humans, psilocybin is rapidly metabolized to psilocin after oral ingestion, 
where it demonstrates linear pharmacokinetics over the 0.3-0.6 mg/kg dose range [93].  
Psilocin has no known P450 interactions and is instead glucoronidated and renally excreted 
[91, 94, 95]; less than 2% of plasma psilocin is excreted in the urine in that form, suggesting no 
need for dose adjustment in patients with mild-moderate renal impairment [93]. Relative to 
other psychedelics (e.g., lysergic acid diethylamide-25, a.k.a. LSD), psilocybin has a simpler 
neurotransmitter receptor profile (it is known to act only at serotonin receptors) and a shorter 
duration of acute effects (4-5 hours) [91, 96]. Psilocybin is one of the “classic hallucinogens” 
(a.k.a. “classic psychedelics”) that were investigated in the mid-20th century for their potential as 
pharmacologic adjuncts to psychotherapy. By the mid-1960s, over 1,000 clinical reports were 
published on the experiences of over 40,000 treatment sessions in which psychedelics had 
been legally administered to patients in clinical settings [97] such as at Harvard [98], UCLA [99], 
and UCSF [100]. 
This early research suggested that one of the most promising indications for psychedelic- 
assisted psychotherapy was the treatment of existential distress in patients with advanced 
disease, particularly cancer. This was first reported by Kast, an internist who administered LSD 
(without psychotherapy) to terminally-ill patients as an experimental analgesic. He found that a 
single dose of LSD decreased physical discomfort and improved mood, and that these effects 
lasted for about 10 days [101]. More systematic work later occurred at Spring Grove Hospital 


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near Baltimore, Maryland where a team developed a protocol for psychedelic-assisted 
psychotherapy for the terminally ill. Their protocol included several non-drug preparatory 
sessions designed to build trust and rapport between the participant and the therapists. Then, 
during the drug session itself, the therapists (usually a team of two) would sit beside the patient 
and mostly provided non-directive verbal reassurance. Afterward, several non-drug 
psychotherapy follow-up sessions took place over the next few weeks to psychologically 
“integrate” the drug experience into the patient’s life. One legacy of this work is the safety 
protocol recently developed at Johns Hopkins [24] for psychedelic drug administration, which 
has been adapted for this proposed study. 
 
In the 1970s, before rigorous and well-controlled trials of the Spring Grove protocol could be 
undertaken, clinical research with psychedelics in the US was abandoned due to increased 
regulatory requirements and an unfavorable political climate. Nevertheless, pharmacology and 
neuroscience studies continued, producing a clear understanding of psilocybin’s effects on 
neurotransmitter receptors and human physiology [91, 92, 102]. Unlike many other Schedule I 
controlled substances, the “classic psychedelics” are physiologically safe over a wide range of 
doses and have a low potential risk of addiction [92, 103]. The published case series of mid- 
Century psychedelic-assisted psychotherapy reveal an overall low rate of adverse events when 
administered in controlled clinical settings [104]. (For more clinical safety data, see Section 
4.1.1 below.) And while clinical research ceased in the US in the 1970s, psilocybin-assisted 
individual and group psychotherapy continued to be practiced legally in Germany and 
Switzerland into the 1990s [105]. 
Clinical research with psychedelics in the US reemerged in the 1990s when Strassman 
investigated the pharmacology of dimethyltryptamine in healthy volunteers [106]. He was followed 
by Griffiths et al who conducted a double-blinded RCT in which healthy volunteers were 
administered a single high dose of psilocybin (0.43mg/kg) vs active placebo (methylphenidate) 
and found that a significantly higher proportion of volunteers receiving psilocybin had “complete 
mystical experiences” [17]. Seventy-four percent of subjects rated the psilocybin experience as 
one of the five most spiritually significant experiences of their lives (compared to 8% of controls) 
[17]. Remarkably, subjects who received psilocybin also demonstrated significant increases in the 
personality trait of Openness on the NEO-Personality Inventory (e.g., aesthetic appreciation and 
sensitivity, imagination and fantasy, and tolerance of others’ views and values) 12 months after 
drug administration. No other discrete clinical intervention has ever been shown to cause 
significant and enduring changes in an adult’s personality structure [107]. 
 
This was followed by three double-blind, cross-over RCT studies investigating psilocybin-
assisted psychotherapy for cancer patients with DSM-IV diagnoses that included symptoms of 
anxiety and/or depression. First, in 2011, Grob et al [18] demonstrated the safety and 
feasibility of psilocybin-assisted psychotherapy in 12 advanced cancer patients with a DSM–IV 
anxiety diagnosis deemed to be secondary to their cancer diagnosis. This study utilized a 
single moderate dose of oral psilocybin (0.2mg/kg), and found positive trends toward 
improvements in anxiety and depression in the months following the intervention [18]. Next, in 
2016, Ross et al. compared an active placebo (niacin) to a single high dose of oral psilocybin 
(0.3mg/kg), both paired with psychotherapy, in 29 cancer patients with moderate-to-severe 
anxiety and whose cancer was either active or in remission with a chance of recurrence. They 
found significant within- and between-group reductions in anxiety and depression measured at 
three different time points and persisting for up to eight months. They also found significant 
reductions in demoralization and hopelessness [19]. Also in 2016, Griffiths et al compared a 
placebo-like dose (0.014 or 0.043mg/kg) to a high dose (0.314 or 0.429mg/kg) of oral 
psilocybin in 51 cancer patients with depression and anxiety [108]. They found significant 
within- and between-group reductions in anxiety and depression at 5 weeks; the within-group 
improvement persisted at the 6 month follow-up [20]. 
 
Both Ross et al. and Griffiths et al. found rates of clinical response to a single dose of 
psilocybin at the long-term follow-up (>=6 months) to be approximately 60-80% for measures 


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of anxiety and depression [108, 109]. These studies were followed by Carhart-Harris et al., an 
open-label feasibility study in which 20 patients with unipolar treatment-resistant major 
depression received two doses of oral psilocybin (10 and 25 mg) along with psychological 
support [110]. They found significant reductions in depression at all six time points measured 
after the drug sessions, persisting out to 6 months. Notably, the patients in this study had more 
severe baseline depression on average than those in the Ross et al. and Griffiths et al. studies, 
and they had all previously failed to respond to at least two pharmacologically distinct 
antidepressant drugs. While only suggestive because of the open-label design, these data are 
promising given the treatment-resistant group. 
Over the past 20 years psilocybin has been shown to be safe and preliminarily effective in the 
treatment of not only anxiety and depression in cancer patients [18-20], but also treatment-
resistant alcohol use disorder [111], treatment-resistant tobacco use disorder [112, 113], and 
obsessive- compulsive disorder [114]. 
 
1.3 
Rationale for the Proposed Study 
Rationale for Psilocybin-Assisted Psychotherapy for Demoralization in LTAS 
Per Section 1.1, above, there is a large unmet need for the treatment of existential distress in 
LTAS. Compared to classic examples of acute existential distress in end-of-life patients (e.g., 
cancer patients or advanced AIDS patients), the existential distress of LTAS is a more chronic 
condition complicated by severe grief and traumatic exposure. Like “cancer survivors,” AIDS 
survivors often experience increased rates of psychological distress long after their disease is 
controlled [9, 10]. While the existential distress of LTAS is multifaceted and complex, the well- 
characterized clinical syndrome of demoralization appears to capture the type of psychological 
distress suffered by many LTAS [6, 7]. The concept of demoralization is predicated on the loss 
of one’s meaning-making ability in the face of distress. Enhancing meaning-making to address 
existential distress and complicated grief is a strategy that has been embraced not only by 
palliative specialists [36] and thanatologists [15], but also by the HIV community itself [65]. In 
general, the mental health needs of LTAS —an emerging, medically and psychosocially 
complex, and stigmatized population—remain under-recognized and undertreated, but in 
particular it seems LTAS could benefit from a brief intervention that would enhance meaning- 
making in order to better cope with, and transcend, years of loss and suffering. 
 
Modern studies of psilocybin-assisted psychotherapy for cancer patients and cancer survivors 
with existential distress provide promising preliminary evidence of this intervention in treating 
demoralization in palliative care patients [18-20]. These clinical improvements are thought to be 
mediated by having a complete “mystical-type” experience [21], which leads to an enhanced 
sense of meaning in one’s life [115], and an enhanced ability to engage with one’s social 
supports [22]. Moreover, psilocybin may also help improve patients’ relationships with love-ones 
who have already died: According to the most experienced clinician in the field of psilocybin- 
assisted psychotherapy, Dr. William Richards (who began treating palliative care patients with 
this method in the 1970s), psilocybin-assisted psychotherapy can be highly effective at treating 
protracted grief [116]—a rather difficult to treat symptom in LTAS (see above, Section 1.1 
Treatment Needs). 
 
LTAS – An Ideal Model for Studying Chronic Existential Distress in Palliative Care Patients 
Clinical trials in palliative care are fraught with many methodological challenges, especially 
subject recruitment given patients’ lack of interest in spending their limited time in research 
studies, or inability to comply with the physical demands of attending study visits and research 
protocols [117]. Attrition rates of up to 50% are not uncommon among psychotherapy trials with 
palliative care patients [36, 77, 118]. Recent trials of psilocybin-assisted psychotherapy for 
existential distress in cancer patients have struggled with recruitment [28]. The current proposed 
study of psilocybin-assisted psychotherapy in LTAS is unlikely to be hindered by these same 
recruitment challenges because the form of existential distress to be examined, demoralization, 


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is thought to occur at high rates [65] among a largely ambulatory population that is known to 
avidly volunteer for medical research [119] and is desperately in search of treatment options 
[65]. Despite the fact that HIV is now considered a “chronic illness” and not an acutely life- 
threatening condition for most patients, PLH potentially face their mortality on a daily basis when 
they choose, or choose not, to adhere with their ART regimen, thus likely enhancing existential 
distress chronically. 
 
Rationale for using Psilocybin as a Psychotherapy Adjunct, and eschewing Psilocybin 
Monotherapy 
This trial does not include a control arm of psilocybin without psychotherapy. When psilocybin 
and other psychedelics were investigated as pharmacologic adjuncts to psychotherapy in the 
1950s and 60s, clinical experience led to the principle of “drug, set and setting,” [120] which 
states that the clinical safety and outcomes of a psychedelic drug experience are highly 
influenced by the non-pharmacological variables of the patient’s mental state prior to drug 
administration (“set”) and their environment during the experience (“setting”). Unlike other 
modalities of drug-assisted psychotherapy (e.g., D-cycloserine-assisted cognitive behavioral 
therapy), in psychedelic-assisted psychotherapy, not only is the drug experience thought to 
deeply influence the content of the psychotherapy, but the content of the psychotherapy is 
likewise understood to intimately shape the drug experience itself. This consideration has led to 
the consensus that it is unethical for psychedelics to be administered to patients absent a 
supportive and therapeutic context. This context has typically been individual psychotherapy, 
but group therapy modalities have also been used. [97, 121] 
 
Rationale for Group Therapy 
Since the beginning of the HIV/AIDS epidemic, many psychotherapies for PLH have been 
preferentially delivered as groups because of enhanced cost-effectiveness and the group 
format’s unique clinical benefits with respect to the enhancement of social support in a 
population suffering high rates of isolation and loneliness [23]. 
 
The theoretical basis of the original Spring Grove approach to treating existential distress in 
palliative care patients was that patients suffer extreme isolation because of their disease, and 
that psychedelic-assisted psychotherapy could help relieve this isolation by facilitating: 1) living 
meaningfully in the present moment, and 2) reaching out and authentically connecting with 
loved ones [22]. Various clinical benefits were reported from their uncontrolled experimental 
sessions, including improvements in mood and anxiety, and increased openness to 
communication with loved ones [122]. These older findings are consistent with more recent 
social psychology findings that psilocybin decreases the subjective feeling of social exclusion 
[123] and another classic psychedelic, LSD, enhances emotional empathy and prosocial 
behavior [124]. 
 
The Spring Grove team concluded that optimal clinical outcomes were dependent upon 
attaining a “psychedelic peak experience,” which was conceived of as akin to William James’ 
“conversion experience,” [125] or Abraham Maslow’s “peak experience,” [126]—a transcendent 
state of unity, intense positive emotions, and ineffability that was experienced as deeply 
meaningful. [22] To describe this mental state, the current psilocybin literature has adopted the 
terminology of the “complete mystical experience,” which is defined by standard criteria using a 
validated psychometric measure, the Mystical Experience Questionnaire—30 item [127]. 
Because the Spring Grove team believed that the “transcendental nature of the experience 
[could] neutralize a sense of alienation…” they sought to facilitate such experiences in order “to 
maximize patients’ opportunities for living by lessening their sense of isolation and alienation, 
and in so doing, assist in their reaching out to those around them” [128]. One aspect of this 
model that has received little mention in the recent literature is that the original Spring Grove 
protocol included non-drug family therapy sessions conducted both before and after drug 
sessions [22]. The purpose of these sessions was to prepare the family to better help the 
patients integrate their psychedelic experience after the drug sessions, as well as to aid the 


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family in their imminent grieving process. 
 
Spontaneous feedback from several subjects in the recent NYU psilocybin-assisted 
psychotherapy trial for existential distress in cancer patients included the request to be 
introduced to the other study subjects [19], apparently to share, process and integrate their 
experiences in a setting of mutual aid and understanding. Subjects from recent MDMA-assisted 
psychotherapy trials for PTSD have also spontaneously made this request, leading the study 
sponsors to create a web forum for the patients to be in touch with each other after completing 
the trials [129]. It appears to be helpful to patients treated with psychedelic-assisted 
psychotherapy to spend time with peers in their attempt to integrate the “peak” experiences, the 
phenomenology of which can be rather uncanny and perhaps difficult for psychedelic-naïve 
family or friends to comprehend [130]. 
 
Conducting non-drug psychotherapy sessions in groups may shed light on possible key 
mechanisms of psilocybin-assisted psychotherapy for existential distress. Whereas therapeutic 
alliance is thought to be the most important mediator of clinical outcomes in individual 
psychotherapy, group cohesion is widely recognized as the analogous mechanism in group 
psychotherapy [131, 132]. Examining the change of group cohesion pre- and post-psilocybin 
with validated self-report [133] and observer-rated instruments [134] will provide a novel and 
standardized means of observing how psilocybin drug sessions may affect the interpersonal 
functioning of distressed palliative care patients. 
 
A significant limitation of group therapy clinical trials is that large sample sizes are required to 
demonstrate efficacy because of the likely interdependence of outcomes of members of the 
same group [135]. For this reason, qualitative (e.g. Interpretive Phenomenological Analysis) 
and/or sequential (e.g. the Hill Interaction Matrix) measures of psychotherapeutic process are 
often used to make inductive inferences about clinical change from group therapy over time 
[136]. Process is understood as the conglomeration of intrapersonal functions, interpersonal 
dynamics and group environment that leads to therapeutic change [137]. To improve the 
evidence base for group psychotherapy, the American Group Psychotherapy Association 
(AGPA) has developed clinical practice guidelines [138] and a standard set of measures and 
tools for creating and managing psychotherapy groups for clinical practice and research [139]. 
In developing the protocol for this proposed study, we have drawn not only from the literatures 
on psilocybin-assisted psychotherapy and palliative care, but also from these AGPA clinical and 
research guidelines, as well as on the consultation of local group psychotherapy experts [140]. 
 
Rationale for Dosing Regimen 
Griffiths et al [141] have characterized the dose-response relationship of oral psilocybin in 
healthy volunteers. They found that when considering the odds of attaining a complete mystical 
experience versus having a temporary anxiety reaction during the drug experience (lasting on 
the order of minutes), the optimal dose likely falls between 0.29mg/kg and 0.43mg/kg [141]. This 
dose range has been successfully used in studies of psilocybin-assisted psychotherapy for 
existential distress in cancer patients [19, 20], severe alcohol use disorder [111] and tobacco 
use disorder [112]. The current study will employ a dose of 0.3mg/kg po in the first group, and if 
this is well tolerated will then escalate to 0.36mg/kg po in subsequent groups. 
 
The dosing of the psychotherapy—10 sessions occurring at a frequency of 1-2 times per 
week—was chosen on the basis of comparison with similar group psychotherapies for 
existential distress in palliative care patients. The group psychotherapy with the best evidence-
base for treating existential distress in palliative care patients, Meaning-Centered Group 
Psychotherapy, employs 8 sessions [142]. The group psychotherapy with the best evidence-
based for treating complicated grief has 16 weekly sessions [143]. Our protocol uses a modified 
course of Brief Supportive-Expressive Group Therapy, which was designed and tested as a 12-
week course of treatment [76]. Empirical data suggest that group therapies lasting at least 12 
sessions are shown to have greater correlations between group cohesion and clinical outcomes 


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[132]. We hypothesize that psilocybin will catalyze group cohesion in a shorter period of time, 
thus making 12-16 weeks of group therapy unnecessary for detecting comparable results with 
regards to cohesion and clinical outcomes. 
 
Rationale for Supportive-Expressive Group Therapy 
While prior trials of psilocybin-assisted psychotherapy for existential distress in palliative care 
patients have followed a standard drug administration safety protocol, they have not used 
manualized psychotherapies in the non-drug therapy sessions; our study will be the first to do 
this, which should enhance generalizability of the results. The format and content of SEGT are 
appropriately flexible for incorporating individual psilocybin sessions during the course of 
therapy, and including psychoeducation on psilocybin in the preparatory sessions. The focus of 
SEGT on expressing emotions and enhancing communication with caregivers is expected to be 
helpful in integrating psilocybin experiences [121]. Psilocybin has been shown to enhance 
access to positive emotional memories [144] and to increase the personality trait of openness 
[107], and this should support SEGT’s aim of increasing awareness of one’s emotions and 
openness to new experiences. Because the primary aim of this pilot trial is to assess safety and 
feasibility of this modality—and assessing efficacy is a secondary aim—no control group of 
traditional SEGT will be included in the study. For the rationale on why psilocybin monotherapy 
(without an adjunctive psychotherapy) will not be offered as control condition, see above. 
 
 
1.4 
Study Hypotheses 
Primary 
 
1. The study will recruit, consent and enroll 18 subjects (in 3 groups of 6 members) over 
18 months; these subjects will complete all treatment and evaluation sessions and they 
will experience no treatment-emergent serious adverse events. 
 
 
Secondary 
 
1. The difference in pre- and post-treatment mean scores of demoralization, complicated 
grief, depression, PTSD, shame, anxiety, quality of life, functional social support, post-
traumatic growth, openness to experience, attachment security, mindfulness, global 
clinical impressions and ART medication adherence will trend toward significant 
improvement. These improvements will be sustained at 3-month follow-up. 
2. The difference in pre- and post-psilocybin rates of change of group cohesion and group 
process will trend toward significant improvement. 
3. Qualitative analyses of subject behavior and caregiver/important other reports will lead 
to greater understanding of the interpersonal mechanisms of action of psilocybin- 
assisted psychotherapy. 


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2 
Objectives of the Study 
2.1 
Objectives 
2.1.1 Primary Objective 
• 
To demonstrate the safety and feasibility of Psilocybin-Assisted Supportive-Expressive 
Group Psychotherapy (PA-SEGT) for demoralization in long-term AIDS survivors 
(LTAS). 
2.1.2 Exploratory Objectives 
• 
To explore the preliminary efficacy of PA-SEGT for improving demoralization, 
complicated grief, depression, PTSD, shame, anxiety, post-traumatic growth, quality 
of life, functional social support, openness to experience, attachment security, social 
connection, nature relatedness and ART medication adherence in LTAS. 
• 
To explore quantitatively and qualitatively the mechanisms (e.g. group cohesion) through 
which PA-SEGT addresses demoralization and other mental health outcomes in LTAS. 
2.2 
Endpoints 
2.2.1 Primary Endpoints 
• 
Safety will be defined based on the rate of adverse reactions (defined by the NIH 
Division of AIDS Table of Grading of Severity of Adult and Pediatric Adverse Events 
V2.0) (see Section 5 below). The safety of acute drug effects will be assessed by 
monitoring vital signs for tachycardia (HR>100bpm), bradycardia (HR<60bpm), 
hypertension (SBP>140mmHg or DBP>90mmHg) and hypotension (SBP<100mmHg or 
DBP<60mmHg). Drug-induced mental status changes will be assessed using the 
Adverse Event Medication Session Rating Form during drug sessions, pre and post 
measures with the Montreal Cognitive Assessment, and the Persisting Effects 
Questionnaire—Spirituality at study follow up. Suicidality will be assessed with the 
Columbia Suicide Severity Rating Scale. Follow-up safety data will be gathered for 3 
months. 
• 
Feasibility will partially be assessed in terms of the rates of patient recruitment and 
retention. Feedback on acceptability will also be gathered from subjects and 
caregivers/important others using the Client Satisfaction Scale. Patients and caregivers 
will also be invited to provide feedback during a focus group and patients will be invited 
to participate in individual interviews after the intervention. A SEGT Topic Grid will be 
used to evaluate video recordings of group therapy sessions in order to assess therapist 
adherence to the PA-SEGT model. 
2.2.2 Exploratory Endpoints 
Preliminary efficacy will be assessed with the primary clinical outcome measures: 
• 
Change in demoralization will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up scores of the Demoralization Scale-II. 
• 
Change in complicated grief will be defined by the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Inventory of Complicated Grief. 
Preliminary efficacy will also be explored with the following secondary endpoints (See Section 5 
for details on individual measures): 


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• 
Change in ART medication adherence will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of the ART Medication Adherence 
Scale. 
• 
Change in depression will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Center for Epidemiologic 
Studies Depression Scale—Revised. 
• 
Change in subject quality of life will be defined by the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the McGill Quality of Life 
Questionnaire—Revised. 
• 
Change in desire for hastened death will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of Schedule of Attitudes towards 
Hastened Death. 
• 
Change in anxiety will be defined as the difference in pre-treatment, post-treatment, and 
3-month follow-up mean scores of the State-Trait Anxiety Inventory. 
• 
Change in social support will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Duke/UNC Functional Social 
Support Questionnaire-5. 
• 
Post-traumatic growth due to the intervention will be defined by post-treatment and 3-
month follow-up mean scores of Post-Traumatic Growth Inventory—Short Form. 
• 
Change in PTSD symptoms will be defined as the difference in pre-treatment, 
post- treatment, and 3-month follow-up mean scores of the PTSD Checklist-5. 
• 
Change in global clinical status will be defined as the difference in pre-treatment and 
post- treatment mean scores of the Clinical Global Impressions Scale completed by a 
clinical rater. 
• 
Change in openness to experience will be defined as the difference in pre-treatment, 
post-treatment, and 3-month follow-up mean scores of the International Personality Item 
Pool—Openness to Experience-20 scale. 
• 
Change in mindfulness will be defined as the difference in pre-treatment, post-treatment, 
and 3-month follow-up mean scores of subscales of the Multidimensional Assessment of 
Interoceptive Awareness. 
• 
Change in social connectedness will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Social Connectedness Scale—
Revised. 
• 
Change in Nature Relatedness will be defined by the difference in pre-treatment, post-
treatment, and 3-month follow-up mean scores of the Nature Relatedness Scale, Short 
Form Version. 
• 
Change in alcohol and drug use will be defined by different in the baseline and 3-month 
follow-up AUDIT and DUDIT scores 
 
Psychotherapeutic process and mechanisms will be explored with the following endpoints: 
• 
Change in group cohesion will be defined as the difference in rate of Group 
Questionnaire score change pre- and post-psilocybin. 


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• 
Change in group process will be assessed as the difference in rate of progression of 
the Hill Interaction Matrix score pre- and post-psilocybin. 
• 
Change in group process will be assessed as the change in the Individual Group 
Member Interpersonal Process Scale over time. 
• 
Expectancy effects will be estimated based on the pre-psilocybin total score of the 
Credibility/Expectancy Questionnaire. 
 
• 
Subjective experience of a psilocybin treatment session will be evaluated with the 
Mystical Experience Questionnaire—30 and the Challenging Experience Questionnaire. 
• 
Change in attachment security will be defined as the difference in pre-treatment, post- 
treatment, and 3-month follow-up mean scores of the Experiences in Close 
Relationships scale—Modified 16. 
• 
Qualitative analysis of therapy session video footage, semi-structured patient 
interviews, focus groups and process notes written by study staff. 
• 
Change in inclusion of other in self will be defined by the difference in pre-
treatment, post-treatment, and 3-month follow-up results of the Inclusion of 
Other in Self measure. 
 


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3 
Study Design 
3.1 
Characteristics 
This is a Phase I open-label pilot mixed-methods study of the safety and feasibility of an 8-week 
group psychotherapy intervention that includes one individual drug session with oral synthetic 
psilocybin. This intervention is designed to treat demoralization in LTAS. Groups of 6 subjects 
will be run in sequence. Safety data will be gathered before, during, immediately after, and for 3 
months after the intervention. Subjects will complete self-report measures and semi-structured 
interviews related to acceptability and subjective experience. Exploratory analyses will be 
conducted of clinical outcomes. Exploratory analyses will also include quantitative and 
qualitative assessments of psychotherapeutic process mechanisms. 
3.2 
Number of Subjects 
We estimate that a total of 72 patients will be consented and screened in-person for the study in 
order to enroll 6 therapy groups of 6 members each. Patients who have been assigned to a 
group will be replaced only if they drop out prior to the first group therapy session. (See Section 
8.2.1 Sample Size and Power Estimate.) 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first group therapy session and 
must satisfy all inclusion and exclusion criteria. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed consent 
must be obtained from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
3.3.1 Inclusion Criteria 
1. HIV-positive persons (laboratory-confirmed) ≥50 years old who are able to understand a 
written informed consent document and who are willing to sign it. 
2. Participant-reported diagnosis of HIV or AIDS prior to the clinical availability of protease 
inhibitors (mid-1996).1  
3. Moderate-to-severe demoralization, determined by a score of 8 or higher on the 
Demoralization Scale-II [27]. 
3.3.2 Exclusion Criteria 
1. Life expectancy <6 months (determined by the patient’s non-study PMD) 
2. Current pregnancy, or the intention of becoming pregnant within 3 months of enrollment 
3. Being of childbearing potential, and refraining from dual-method contraception 
4. Poor functional status (Palliative Performance Scale-v2 <60%). 
5. Major cognitive impairment (Montreal Cognitive Assessment <23).  
6. The regular use of psychotropic medications within 2 weeks of study participation, 
including antidepressants (such as serotonin-reuptake inhibitors, tricyclic 
antidepressants and monoamine oxidase inhibitors),2 antipsychotics, and mood 
                                               
1 This includes participants who at a later timepoint had laboratory-confirmed HIV but prior to mid-1996 had 
refused or not accessed testing, yet they believed themselves to be HIV+ and by clinical reasoning were 
likely to have seroconverted by this timepoint. 
2 Individuals taking antidepressants will be presented with the option of tapering off, and remaining off, of their 
medication for the duration of the study, if their prescribing physician agrees with this course of treatment. 
 


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stabilizers. Low dose (≤50mg) TCAs prescribed for neuropathic pain are not 
considered psychotropic; participants are prohibited from using these medications 
during the study, but do not need to demonstrate a period of psychiatric stability for 2 
weeks prior to enrollment. Patients will be asked to refrain from consuming alcohol, 
prescription analgesics, PRN anxiolytics and PRN stimulants the day before and of a 
psilocybin session. 
7. History of a psychotic disorder or Bipolar disorder I or II (determined by SCID-5). 
8. Family history of primary psychotic disorder or primary bipolar disorder (first or second 
degree relative). 
9. Current, severe Major Depressive Episode (These individuals will be referred to 
standard-of-care treatment in the community). 
10. History of active suicidal ideation with intent in the last 3 months (Suicidal ideation 
score >3 and Reason for ideation >1 on C-SSRS); or a history of suicide attempt in 
the last 2 years with Actual lethality/Medical damage >0 or Potential lethality >0 (on 
C-SSRS). 
11. Narcissistic personality disorder, moderate-to-severe (determined by SCID-5-PD). 
12. History of Hallucinogen Use Disorder (Moderate or Severe) or Hallucinogen 
Persisting Perception Disorder (determined by SCID-5). 
13. History of a seizure disorder in adulthood. 
14. CNS metastases or symptomatic CNS infection. 
15. Clinically significant cardiovascular disease (CAD, CHF, arrhythmia); or baseline 
QT/QTc>500msec; or baseline QT/QTc 451-500msec with repeat QT/QTc >500msec. 
16. Uncontrolled hypertension (SBP>139mmHG or DBP>89mmHG if over 65 years old) or 
tachycardia (average HR>90bpm if over 65 years old) averaged over at least two 
measurements. 
17. Supplemental oxygen requirement. 
18. Poorly controlled diabetes mellitus (e.g., history of an episode of hypoglycemia or 
hospitalization for hyperglycemia on the current diabetes regimen). 
19. Inadequate hepatic function (Total bilirubin >2mg/dL, OR AST >6 upper institutional 
upper limit of normal, OR AST >6 upper institutional upper limit of normal), as 
determined by most recent laboratory tests. 
20. Inadequate renal function as determined by eGFR < 30 mL/min/1.73 m2 (based on the 
MDRD equation) or CrCl < 30 mL/min (based on the C-G equation). 
21. Concomitant dosing of psilocybin with known UGT1A10 and UGT1A9 inhibitors (e.g., 
diclofenac and probenecid) will be avoided. There is no exclusion criterion based on the 
use of medications or substances that are inhibitors or inducers of CYP450 enzymes. 
22. The use of efavirenz (a.k.a, Sustiva or Atripla). 
23. If deemed by clinical judgment of the study investigators to be unsafe for undergoing 
the intervention and/or inappropriate for participating in a therapy group. 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 8 weeks 
or until: 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
3.5 
Duration of Follow Up 
Patients will be followed for 3 months after completion of treatment or removal from study, or 


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until death, whichever occurs first. Patients removed from study for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization of all treatment related 
adverse events. 
3.6 
Randomization Procedures 
Patients will not be randomized; this is an open-label pilot trial with one treatment arm. 
3.7 
Study Timeline 
3.7.1 Primary Completion 
The study will reach primary completion 36 months from the time the study opens to accrual. 
3.7.2 Study Completion 
The study will reach study completion 48 months from the time the study opens to accrual. 


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4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug: Psilocybin 
Psilocybin is available as a powder that can be encapsulated for oral administration. 
Classification 
Psilocybin is an indoleamine psychedelic and is one of the “classic psychedelics.” It has a 
chemical structure similar to that of the neurotransmitter serotonin. 
Mechanism of Action 
Psilocybin is an agonist of serotonin 5HT2A, 2C and 1A receptors [92, 102]. 
Metabolism 
After ingestion, psilocybin is rapidly dephosphorylated to psilocin, which is metabolized via 
oxidation and glucuronidation in the small intestine and the liver, and subsequently excreted 
renally [91, 94, 95]. 
Contraindications 
Current safety standards for experimental psilocybin administration [24, 145] include providing a 
comfortable environment, the presence of supportive and non-directive therapists or research 
staff, and strict exclusion criteria. Beyond this basic principle, psilocybin should generally not be 
administered to individuals with a personal or family history of psychosis or bipolar disease, or 
individuals who are acutely suicidal. It should also not be administered to individuals with severe 
cardiovascular disease. Co-administration with medications associated with the serotonin 
syndrome [146] should be avoided. 
There have been no rigorous studies of the effects of psilocybin on pregnancy. We are aware of 
only one published care report from a research study in which a woman consumed pure 
psilocybin about every 2 weeks throughout her pregnancy to no apparent detriment to the child, 
who was followed for 1 year postnatally [120]. It is recommended that women who are pregnant 
avoid using psilocybin. Non-clinical and clinical data describing the effects of oral psilocybin on 
lactation, sperm, and teratogenicity are not available. 
Availability 
Psilocybin is a Schedule I compound, and so requires a DEA Schedule I license to handle. For 
the purposes of this study, psilocybin is available from the laboratory of Dr. Roland Griffiths at 
Johns Hopkins University (IND#133202) and from Usona Institute (Madison, WI). 
Storage and handling 
Psilocybin is stored at 15-30°C. Each subject’s dose will be, to the nearest milligram, as close 
as possible to that indicated by their actual bodyweight (e.g., 0.30mg/kg or 0.36mg/kg), with a 
maximum dose not to exceed that calculated for a BMI of 35 at that participant’s height. The 
psilocybin will be provided to UCSF in powder form, and the UCSF Investigational Drug Service 
of the UCSF Department of Pharmacy Services will encapsulate the drug. The study drug will 
be stored in a secure vault in the Investigational Drug Service in the Inpatient Pharmacy in 
Moffitt-Long Hospital (505 Parnassus Ave, San Francisco). 
Side Effects 
Psilocybin is known to be physiologically safe at the doses proposed for this study, and is not 
addictive [92, 103]. Safe administration is dependent on using a supportive and structured 
administration protocol [24]. Psilocybin is known to possibly cause the following transient side 
effects: Anxiety, thought disorder, nausea, emesis, increase or decrease in heart rate, increase or 


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decrease in blood pressure, and headache [18, 24, 91, 96, 147, 148]. Anxiety and thought 
disorder reactions appear to be dose-dependent, with higher doses associated with greater 
frequency of temporary anxiety and thought disorder reactions [141]. 
Clinical Safety Data 
Psilocybin, in the form of psilocybe mushrooms, has been consumed by humans for ritual and 
healing purposes for at least hundreds of years [149]. The most extensive review of mid- 
Century reports of the safety of the controlled, clinical uses of psychedelics, including psilocybin, 
found an overall low incidence of adverse events [104]. After clinical research with psilocybin in 
North America stopped in the 1970s, psilocybin continued to be used legally as a psychotherapy 
adjunct in Germany and Switzerland in the 1980s and 90s, but no comprehensive safety data 
are available from this period [105, 150]. 
 
Since the 1990s, hundreds of doses of psilocybin have been administered to humans in clinical 
trials and research laboratories across North America and Europe. Gouzoulis-Mayfrank et al 
found negligible acute effects on vital signs (heart rate, blood pressure, temperature) and 
neuroendocrine levels (cortisol, prolactin, growth hormone), but did find significant transient 
mental status changes in eight healthy volunteers administered a moderate dose 
(0.2mg/kg, with total dose <15mg) of oral psilocybin [151]. A review of results from the 
Vollenweider laboratory in Zurich, Switzerland found that in 110 subjects administered 1-4 low- 
to-high doses of oral psilocybin there were no detectable persisting adverse effects, and all 
acute adverse reactions (e.g., dysphoria or anxiety) were controlled with interpersonal support 
alone, meaning no pharmacologic or other medical interventions were necessary [145]. 
Moreover, several subjects who did report acutely distressful experiences later claimed in long- 
term follow up that these experiences had been “enriching”. [145] A subsequent review from 
that laboratory found that among 261 subjects who received low-to-high doses of oral 
psilocybin, both mystical-type experiences and acute anxious reactions were strongly positively 
correlated with drug dose [152]. Importantly, anxious reactions were also strongly correlated 
with the experimental setting (more anxiety was reported if the subject underwent a PET scan 
during the experiment), which argues in favor of the idea that the risk of adverse events can be 
mitigated by providing a comfortable and supportive setting for drug administration. This 
laboratory’s recent findings from 50 subjects [153], and another 25 subjects [154] receiving a 
moderate oral dose of psilocybin (0.16mg/kg po or 0.215mg/kg po) reported no adverse events, 
and found improvement in mood. In contrast to the PET study above, another laboratory in 
London found no adverse events when they administered moderate dose iv psilocybin to 15 
healthy subjects with prior psychedelic experience while undergoing brain fMRI; these subjects 
reported improved well-being on 2-week follow up [144]. 
 
Grob et al conducted the first modern study on the use of psilocybin in subjects with advanced- 
stage cancer [18]. Subjects received a single moderate dose (0.2mg/kg) of oral psilocybin with 
pre- and post-drug supportive psychotherapy. This was well-tolerated with subjects showing 
only mild transient increases in blood pressure and heart rate compared to active placebo; no 
subjects experienced acute anxiety during the experience; and subjects spontaneously 
requested that a second dosing session be added to the protocol. Since the Grob et al. study, 
two larger double-blind RCTs of psilocybin-assisted psychotherapy in cancer patients with 
anxiety or depression, conducted at NYU and Johns Hopkins, were published; they both 
reported no adverse reactions (e.g., headache, anxiety or psychosis-like symptoms) lasting 
longer than 24 hours [19, 20]. Separately, the Johns Hopkins laboratory has reported zero 
persisting psychological problems among the 54 subjects to whom they had administered high 
dose (>25mg po) oral psilocybin to by 2008 [24]. By October 2016, the Johns Hopkins team has 
had no significant adverse events after administering psilocybin to approximately 270 subjects 
over 560 drug treatment sessions, and emergent medications have never been needed to 
maintain the safety of the subjects nor the study therapists [155]. 
 
Oral psilocybin has also been administered to other clinical populations in modern controlled 
clinical settings with good safety outcomes. Of 9 subjects with OCD who were administered 


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low-to-high doses of oral psilocybin, the only adverse event reported was transient hypertension 
[114]. Of 15 nicotine-dependent smokers receiving moderate-to-high doses of oral psilocybin, 
adverse events included acute anxiety, mild transient increases in hypertension and heart rate, 
and mild headaches [112]. Of 10 subjects with alcohol dependence administered moderate-to- 
high doses of oral psilocybin, the only adverse event reported was mild transient hypertension 
[111]. A recent open-label pilot study of 12 subjects with treatment-resistant depression, each 
receiving a low oral dose (10mg) followed one week later by a high dose (25mg) found transient 
anxiety, thought disorder, nausea and headache, but no severe or unexpected adverse events 
when followed for up to 3 months after the high dose session [156]. Finally, recent 
epidemiological data argue for a positive correlation between lifetime classic psychedelic use 
(including psilocybin) in the US population and reduced rates of past month psychological 
distress, past year suicidal ideation and past year suicidal attempt [157]. 
4.2 
Drug Accountability 
Each UCSF campus investigator using Schedule I substances in research must obtain their own 
Schedule I registration with the DEA and is responsible for the ordering, security, accountability 
and disposition of all product ordered under their registration. Psilocybin will be obtained from a 
DEA-approved Schedule I researcher or distributor (e.g., Dr. Roland Griffiths at Johns Hopkins 
University, or the Usona Institute, or Beckley Labs), and the drug will be shipped to the 
Investigational Drug Service of the Department of Pharmaceutical Services at UCSF Medical 
Center (505 Parnasssus Ave, Room M39C, San Francisco, CA 94143; Phone 415.353.1798). 
The pharmacy has been used for the storage and preparation of Schedule I controlled 
substances for individual campus Schedule I registrants for many years. 
 
Storage: Schedule I substances will be stored in one of two large combination lock safes 
located in the investigational drug storage room of the UCSF Inpatient Pharmacy. The 
investigational drug storage room is a limited access storage room located in the basement of 
Moffitt Hospital on the UCSF Parnassus Campus (505 Parnassus Avenue). The room bears a 
security lock, accessible to the investigational pharmacy staff. The combination of the safe is 
known only to the investigational drug pharmacy staff. 
 
Upon receipt of a medication order from the investigator, the drug supply will be accessed by 
the investigational pharmacy staff. The ordered dose will be obtained, placed in appropriate 
pharmacy dispensing container and labeled for the research subject. The dose contained will 
be sealed with a tamper evident seal. Research staff will escort the patient to the Inpatient 
Pharmacy on the day of dosing. Drug will be dispensed directly to the research subject by the 
pharmacy staff after confirming patient identification and acquiring the patient’s signature on the 
pharmacy’s chain of custody documentation. The subject will then be escorted by study staff 
from the Inpatient Pharmacy through indoor hallways that connect the Moffitt Hospital (where 
the pharmacy is located) to the Langley Porter Psychiatric Institute (where the drug 
administration will take place). 
 
Dispensing: Psilocybin will be shipped in powder form and will need to be allocated into 
gelcaps by the UCSF Investigational Drug Service. Subjects will be dispensed one gelcap with 
their dose based on weight, as measured prior to the drug treatment day by study staff. 
Psilocybin will be ingested by study subjects in the testing area (LP-A312) of the third floor 
annex of Langley Porter Psychiatric Institute. 
 
Records: Record keeping will be in accordance with federal and state regulations for Schedule 
I controlled substances. Inventory will be taken at least every two years at end of the business 
day and maintained in a printed form. 


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4.3 
Drug Ordering 
UCSF will obtain psilocybin directly from a licensed Schedule I distributor (e.g. Usona Institute) or 
from another Schedule I registered investigator (e.g., Dr. Roland Griffiths at Johns Hopkins 
University). 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 


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5 
Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an outpatient basis. 
Table 5.1 Regimen Description 
 
 
 
 
Study 
Drug 
Premedication 
/ precautions 
Dose 
Route 
Schedule 
Psilocybin 
Avoid all other 
psychotropic agents 
within 48hr of each 
dose 
0.3mg/kg 
or    
0.36mg/kg 
(moderate- 
to-high) 
Oral 
After 4 
group 
therapy 
visits 
 
Psilocybin is not physiologically toxic at the doses being used in this study. No human data 
exists that suggest what a toxic dose of psilocybin might be, but experiments in animals 
suggest that the LD50 of psilocybin in humans may be in the range of grams [91], which is 
two orders of magnitude higher than the highest dose to be used in this study. Patients 
could have short-term (<24hr) challenging psychological reactions. Patients who have a 
serious adverse event consisting of a negative psychological reaction that lasts >24hr will 
be followed by a study physician until the resolution of the event and, at the discretion of 
the PI, may be removed from the study. There is reason to believe that participating in the 
integration group therapy sessions after a negative psychological reaction may help in 
recovering from such an event, and so participants will not automatically be removed from 
the study merely for having a prolonged negative psychological reaction to the psilocybin 
session (See Section 7.3 for definitions of Adverse Event.) 
 
5.1.1 Other Modalities 
Patients will participate in group therapy sessions following a modified form of Brief 
Supportive-Expressive Group Therapy (SEGT) [76]. SEGT emphasizes therapeutic goals that 
include enhancing mutual support, openness and emotional expression, improved social and 
family support, and detoxifying death and dying. The weekly sessions will last 90 minutes and 
be conducted by 2 co-facilitators with experience leading psychotherapy groups. 
5.2 
Monitoring and Toxicity Management 
Of the hundreds of subjects administered psilocybin in clinical or research settings over the last 
two decades, none have required emergent psychiatric medications or emergency department 
care [24, 145, 157]. Each subject receiving psilocybin will be evaluable for safety. The safety 
parameters include physical findings and spontaneous reports of adverse events reported to the 
investigator by subjects and primary caregivers. Each subject will be assessed periodically for 
the development of any toxicity as outlined in Section 6 Study Procedures and Observations. 
Toxicity will be assessed according to the NIH Division of AIDS Table of Grading of Severity of 
Adult and Pediatric Adverse Events V2.0 (http://rsc.tech- 
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf) 


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. We will monitor specifically for hypertension, hypotension, tachycardia, nausea, emesis, 
headache, anxiety, dysphoria, mania, suicidality and psychosis during drug sessions using 
the Adverse Event Medication Session Rating Form (see Appendix). Acute physical adverse 
events (e.g., nausea or hypertension) will trigger increased frequency of monitoring. Acute 
psychological adverse events will be managed by supportive reassurance and, if needed, 
medications such as lorazepam or olanzapine. Further management of physical or 
psychiatric adverse events will depend upon the judgment of the on-call study physician and 
may include, if necessary, transportation to the UCSF Parnassus Emergency Department, 
which is located immediately adjacent to the Langley Porter Psychiatric Institute. 
 
 
5.3 Pregnancy 
 
Subjects of childbearing potential must have a negative pregnancy test at enrollment and prior to 
the drug treatment session, and must agree to use adequate birth control through 10 days after the 
drug treatment session. Adequate birth control methods include intrauterine device (IUD), injected 
or implanted hormonal methods, abstinence, oral hormones plus a barrier contraception, or double 
barrier contraception. Two forms of contraception are required with any barrier method or oral 
hormones (i.e. condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal 
contraceptives plus spermicide or condom). Not of childbearing potential is defined as permanent 
sterilization, postmenopausal, or assigned male at birth. 
Any pregnancy occurring after the drug treatment session and before the final group session will 
be followed until an outcome is known. (i.e., spontaneous miscarriage, elective termination, normal 
birth). All live births must be followed for a minimum of 30 days or to the first well-baby visit. 


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See Appendix A for a timeline of all assessments 
 
6 
Study Procedures and Observations 
 
 
 
 
 
6.1 
Study Site 
All in-person pre-treatment and treatment patient contact will occur at the Langley Porter 
Psychiatric Institute (LPPI) at 401 Parnassus Ave, San Francisco. LPPI is a psychiatric hospital 
within the UCSF Medical Center Parnassus Campus and is immediately adjacent to the UCSF 
Parnassus Emergency Department. 
 
6.2 
Selection of Measures 
Antiretroviral Medication Adherence Scale (AMAS)—A single item 11-point Likert scale (0%- 
100%) of ART medication adherence percentage over the past week. This scale was invented 
for this study. 
Alcohol Use Disorders Identification Test (AUDIT) – A 10-item screening tool developed by 
the World Health Organization to assess alcohol consumption, drinking behaviors, and 
alcohol-related problems. 
 
Center for Epidemiologic Studies Depression Scale-Revised (CES-D-R)—A 20-item validated 5- 
point Likert scale self-report scale for the detection of depression [158] that has been shown to 
be sensitive to change in symptoms in palliative care patients. [159]. 
 
Client Satisfaction Scale (CSS)—A 4-item 10-point Likert scale (“very dissatisfied” to “very 
satisfied”) designed for this study assessing satisfaction with the intervention. 
 
Clinical Global Impressions scale (CGI)—A widely-used 3-item clinician-administered 
assessment developed by the NIMH to assess change in patients in psychopharmacology 
trials [160]. 
 
Challenging Experiences Questionnaire (ChEQ)—A validated 26-item 6-point Likert scale of the 
extent to which subjects experienced challenging experiences during a psychedelic drug 
treatment session [161]. The scale has 7 factors: fear, grief, physical distress, insanity, 
isolation, death and paranoia. 
 
Columbia Suicide Severity Rating Scale (C-SSRS)—A validated 17-item scale that assesses 
suicidal ideation and behavior (www.cssrs.columbia.edu) according to the Columbia 
Classification Algorithm for Suicide Assessment (C-CASA), which the FDA Division of 
Psychiatric Products requires be used in clinical trials it oversees. 
 
Community Observer Rating Form (CORF)—A 13-item 10-point Likert scale developed by 
Griffiths et al to triangulate behavioral observations of individuals administered psilocybin [17]. 
 
Concomitant Therapeutics Checklist (CTC)—A checklist designed for this study to assess the 
following categories of mental health therapies used over the last week: Prescription 
medications, non-prescription medications, psychotherapy, mutual aid groups, self-help 


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techniques, integrative medicine modalities, other. 
Credibility/Expectancy Questionnaire (CrEQ)—A 6-item self-report measure of cognitive and 
affective assessments of a mental health therapy with high internal consistency and good test- 
retest reliability [162] that we have adapted for psychological distress. 
 
Demoralization Scale-II (DS-II)—An abbreviated, 16-item and 3-point version of the well- 
validated original 24-item Demoralization Scale [163], which is the most widely used self-report 
measure of demoralization in palliative care patients [29]. The DS-II has two subscales: 
Meaning and Purpose, and Distress and Coping Ability, and shows both good internal and 
external validity in palliative care patients [27, 164]. 
 
Drug Use Disorders Identification Test (DUDIT) – An 11-item screening tool developed as a 
parallel to the AUDIT to assess drug consumption, drug use behaviors, and drug-related 
problems. 
 
Duke UNC Functional Social Support Questionnaire-5 (DUFSS-5)—A 5-item, 3-point Likert, 
self-report measure of perceived functional social support. The abbreviated 5-item scale has 
been validated in patients with severe medical illness (advanced cancer or AIDS) [165]. 
 
Experiences in Close Relationships scale—Modified 16 (ECR-M16)—A 16-item, 7-point Likert 
self-report measure of attachment security. The abbreviated 16-item version is reliable and has 
been validated in patients with severe medical illness (metastatic cancer) [166]. 
 
Group Questionnaire (GQ)—A validated self-report 30-item 7-point Likert questionnaire of 
therapeutic relationships in group therapy [133]. GQ has a three-factor model of group 
cohesion: Positive Bonding, Positive Working, Negative Relationships, all of which manifest in 
both member-member and member-leader relationships [167].  GQ was empirically-derived 
from measures in the AGPA CORE-R Battery [139] that assess therapeutic alliance and 
cohesion—the two factors known to best predict clinical outcomes of group psychotherapy trials 
[132]. 
 
Group Psychotherapy Intervention Rating Scale (GPIRS)—An empirically-derived observer- 
rated 48-item instrument that assesses group therapist behaviors that help create and maintain 
group cohesion [168]. 
 
HIV and Abuse Related Shame Inventory (HARSI)—A validated 22-item 5-point Likert scale (“Not 
at All” to “Very Much”) [169].  
 
Hill Interaction Matrix (HIM)—The gold standard in group therapy process measures [170], the 
HIM is an observer-rated instrument that assesses group therapy sessions using a 4x4 matrix of 
style categories (conventional, assertive, speculative and confrontational) and content 
categories (general, group, personal, relationship). The HIM has been used since the 1960s 
and there exists an extensive database of normative data against which to compare outcomes 
[134]. 
 
International Personality Item Pool-Openness to Experience-20 (IPIP-OE-20)—A 20-item self- 
report measure that uses items in the public domain to evaluate a construct approximately 
equivalent to Openness, which is evaluated by the NEO-PI-R [171]. 
 
Inventory of Complicated Grief (ICG)—A well-validated 19-item 5-point Likert scale (“never” to 
“always”) that is the gold standard self-report instrument for measuring complicated grief [172, 
173]. 
 
Life Event Checklist—5 (LEC5)—A 17-item self-report screening measure of different 
categories of potentially traumatic events that have occurred over the respondent’s 


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lifetime.[174] 
 
McGill Quality of Life Questionnaire-Revised-Short (MQoL-RS)—A well-validated 15-item 11- 
point Likert scale that assess quality of life in palliative care patients by assessing the following 
domains: Overall quality of life, Physical well-being, Psychological well-being, Social support 
and Existential well-being. We will only use 4 items, which are Parts A (Overall quality of life) 
and B (Physical symptoms). 
 
Multidimensional Assessment of Interoceptive Awareness-Revised (MAIA-R)—A well-validated 
32-item 6-point Likert scale of bodily and mental awareness that measures the following 8 
domains: Noticing, Not-distracting, Not-worrying, Attention regulation, Emotional awareness, 
Self-regulation, Body listening and Trusting [175]. If this study, we will use the Emotional 
awareness (5-tiems), Self-regulation (4-items) and Trusting (3-items) subscales. 
 
Mystical Experience Questionnaire-30 (MEQ-30)—A well-validated 30-item 6-point Likert scale 
(“none; not at all” to “extreme [more than any other time in my life]”) self-report measure of 
mystical-type experiences [127], derived from the earlier work of Pahnke et al. [122]. 
 
Nature Relatedness Scale, Short-Form Version (NR-6)—A 6-item version of a well-validated 
5-point Likert scale self-report measure of environmental connectedness [176]. 
 
Palliative Performance Scale version 2 (PPSv2)—A validated clinician-administered tool based 
on the Karnovsky Performance Scale but adapted for a palliative care population [117, 177]. 
 
Persisting Effects Questionnaire—Spirituality (PEQ-S)—An instrument developed by Griffiths et 
al for subjects who have been administered psilocybin to assess enduring changes in attitudes 
about life, attitudes about self, mood changes, relationships, behavioral changes, and spirituality 
[141]. The measure also includes 4 questions about the drug experience itself concerning 
personal meaningfulness, spiritual significance, how psychologically challenging it was, and 
personal psychological insights gained. We will only use the Spirituality subscale (59-item, 6 
point Likert scale [“none; not at all” to “extreme”]), and the four questions about the psilocybin 
experience. 
 
Post-traumatic Growth Inventory-Short Form (PTGI-SF)—A validated 10-item 6-point Likert 
scale meant to assess the following psychological factors in populations that have suffered a 
traumatic event or major crisis: quality of relationships with others, openness to new 
possibilities, personal strengths, spiritual change, and appreciation of life [178]. 
 
PTSD Checklist (PCL-5): A validated 20-item, 5-point Likert scale (from “Not at All” to 
“Extremely”) to measure symptom criteria for PTSD from the DSM-5. [179] 
 
Schedule of Attitudes towards Hastened Death (SAHD)—A 20-item True/False self- report 
measure of the desire for hastened death validated in patients with HIV/AIDS and other 
palliative care conditions [180]. 
 
Social Connectedness Scale-Revised (SCS-R)—A well-validated 8-item 6-point Likert scale 
(negatively-worded items rated from "strongly agree" to "strongly disagree") self-report measure 
which has shown strong construct, convergent and discriminant validity as well as reliability (α > 
.92) for assessing the degree to which subjects feel connected to their social environment [181] 
 
State-Trait Anxiety Inventory (STAI)—A 40-item 4-point Likert scale that is the gold standard in 
self-report measures for state and trait anxiety [182, 183]. 
 
Supportive-Expressive Group Therapy Topic Grid (SEGT-TG)—A measure developed by 
Spiegel and Spira for the original studies of SEGT [75]. Independent raters watch video of 


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therapy sessions and document the number of minutes in which particular target discussion 
topics are handled in the session. 
Structured Clinical Interview for DSM-5 (SCID-5)—The gold standard structured clinical 
interview for DSM-5 criteria for major psychopathology. We will use portions of the SCID to 
screen for lifetime Depressive, Psychotic, Bipolar and Hallucinogen-related disorders. 
 
Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD)—A self-report 
questionnaire based on DSM-5 criteria for personality disorders. We will use this to screen for 
Cluster B personality disorders. 
 
6.3 
Qualitative Analyses 
Qualitative analyses be grounded in Interpretive Phenomenological Analysis (IPA) [184]. Data 
for qualitative analysis will include transcripts from a convenience sample of group therapy 
sessions and psilocybin drug sessions, therapist process notes, patients’ written accounts of 
their psilocybin experiences, verbal feedback elicited from patients throughout the study, 
transcripts from focus groups conducted after the study endpoint, and transcripts from 30-to-
60-minute semi-structured interviews conducted with selected patients after the 3-month follow-
up. IPA is widely used in studies of psychological interventions to better understand a patient’s 
experience of their treatment, and is typically used to elicit convergent and divergent themes in 
studies with small sample sizes [184]. Two investigators with experience in qualitative analysis 
will at first independently code the same transcripts for prominent themes, followed by 
comparison of their codes until a consensus is reached on an appropriate coding scheme. A 
code book will be established which will be used to code further sources. Consensus will be re- 
established on an iterative basis according to the criteria of the coders and the PI. 
 
6.4 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments. Screening assessments will be performed on 
enrollment. Any results falling outside of the reference ranges may be repeated at the 
discretion of the investigator. All on-study visit procedures are allowed a window of ± 7 days 
unless otherwise noted. Treatment or visit delays for public holidays or weather conditions do 
not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records. 
6.4.1 Phone Screening 
Potential subjects will be screened over the phone to assure that they understand the time 
requirements of the study, they are at least 50 years old, they were diagnosed with HIV prior to 
the clinical availability of combination antiretroviral therapy (~1996), they report experiencing 
moderate-to-severe symptoms of demoralization on the DS-II, and that they do not meet any 
major exclusion criteria (e.g., history of psychosis or bipolar disorder; recent active suicidal 
ideation). They will also be screened for complicated grief on the ICG to better characterize their 
clinical appropriateness for the study. A brief orientation to the study protocol, including 
psychoeducation on psilocybin, will be provided to patients who are not excluded. The patient 
will then be scheduled for an in-person screening and enrollment visit. 
 


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6.4.2 In-person Screening and Enrollment 
Screening procedures and assessments to be completed on day of Enrollment (prior laboratory 
results may be considered instead of performing labs at enrollment if the results are less than 1 
month old): 
• 
Informed Consent Form and HIPPA form. Participants will be provided with a 
printed version of the study brochure. 
• 
Demographics questionnaire (Age, ethnicity/race, civil status, years of education, 
income) 
• 
Vital signs; Physical examination; Mental Status Exam; Complete medical and 
psychiatric history, including current medication list; Performance status (PPSv2); 
Cognitive Status (Montreal Cognitive Assessment) 
• 
Complete blood count (WBC, Hgb, Hct, Plt) 
• 
Comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Cr, Gluc, Tbili, Ast, Alt, AlkPhos, 
TProt, Alb) 
• 
TSH, FT4 
• 
CRP 
• 
Urinalysis 
• 
Urine beta-hCG, when applicable (must be completed on day of Enrollment) 
• 
Urine toxicology (must be completed on day of Enrollment) 
• 
HIV viral load, CD4 count, CD8 count 
• 
RPR or Treponemal Antibody 
• 
Electrocardiogram (ECG) 
• 
Selected screening portions of Structured Clinical Interview for DSM-5 Clinical Trials 
Version (SCID-5); sections on current Depressive disorders; lifetime Psychotic disorders, 
Bipolar disorders and Hallucinogen-related disorders), Structured Clinical Interview for 
DSM-5 Personality Disorders (SCID-5-PD) section on Cluster B disorders. 
• 
Columbia Suicide Severity Rating Scale (C-SSRS): Baseline/Screening (last 12 months) 
• 
ART Medication Adherence Scale (AMAS), Centers for Epidemiologic Studies 
Depression Scale—Revised (CESD-R), Demoralization Scale—II (DS-II), Inventory of 
Complicated Grief (ICG), McGill Quality of Life Questionnaire-Revised-Short (MQoL- 
RS), Life Event Checklist—5 (LEC5), PTSD Checklist-5 (PCL-5), Schedule of 
Attitudes towards Hastened Death (SAHD), State-Trait Anxiety Inventory (STAI). 
• 
Clinical interview of about 45 minutes duration to discuss details about the subject’s 
personal life, such as past and current relationships, family dynamics, and concerns 
about their disease. 
• 
Eligible subjects will be placed on the waitlist until 6 subjects are available to start a 
group. 
• 
Subjects who score high on the SCID-5-PD dimensional scale for Borderline 
Personality Disorder and are enrolled in the study will be monitored closely during the 
trial and study clinicians will consider offering them an individual therapy visit around 
the time that the subacute beneficial effects of psilocybin are expected to wear off 
(about 10 days post exposure) if the subjects appear unusually distressed at that 
time. 
 
6.4.3 Baseline Assessments (Week 0) 


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6.4.3.1 Baseline Subject Assessments 
Baseline assessments will be filled out during an individual therapy session wherein the subject 
will meet one or both of the group therapists in the week prior to the first group therapy session. 
Separately, the subject’s caregiver/important other will be invited to meet with study staff for a 
brief interview on their relationship with the subject [see Appendix C for interview guides]. The 
individual session for the study subject is meant to build trust and rapport with the group 
therapists, to learn more about the subject’s life history and struggles with his/her health, to 
elicit the subject’s preferences and intentions for the treatment sessions, and to orient the 
subject further to the intervention protocol. If screening/enrollment measures were completed 
within 1 week of the baseline assessment, those measures will not need to be repeated. 
 
• 
AMAS, AUDIT, CESD-R, CTC, DS-II, DUDIT, DUFSS-5, ECR-M16, ICG, IPIP-OE-20, 
MAIA-R, MQoL- RS, NR-6, PCL-5, PTGI-SF, SAHD, SCS-R, and STAI. A clinical rater 
will perform a CGI and C-SSRS(Interval) for each subject. 
6.4.3.2 Baseline Caregiver/Important Other Assessments 
• 
CORF 
 
6.4.4 Treatment Period 
6.4.4.1 Group Therapy Sessions #1-4 (Weeks 1-2) 
Patients will undergo four 90-minute group therapy preparatory sessions (2 per week) that will 
be audio and video recorded. Video footage of a random sampling of sessions will be analyzed 
with the HIM, SEGT-TG and the GPIRS. Patients will fill out the GQ after the sessions in Week 
2 and 4. Women of child-bearing potential will provide a urine sample for a urine beta-hCG at 
Group Therapy visit #4. A clinical rater will administer the C- SSRS(Interval) to each subject at 
each weekly study visit. 
 
 
6.4.4.2 Individual Drug Sessions (Week 3) 
Patients will undergo individual drug sessions in which they are administered psilocybin 
0.30mg/kg (or 0.36mg/kg) po, with a maximum dose not to exceed that calculated for a BMI of 
35 at their height. The drug will be administered following the safety guidelines outlined by 
Johnson et al [24].  
 
The day prior to the session, patients will be screened over the phone for contraindicated 
medications and reminded about procedures for the medication visit. Specifically, 
participants will be reminded that they cannot drive an automobile for the rest of the 
day after their medication visit, and they will be advised that if they will take the BART, 
they should not drive their car to the BART station.  
 
On the day of the medication visit, patients will arrive at the Langley Porter Psychiatric Institute 
around 08:00 and be oriented to the drug session room, which will contain a couch for the 
patient to lie on and aesthetically pleasing décor. Before the medication session starts, 
participants will complete a urine drug screen and the CrEQ. Patients will also undergo a blood 
draw at the Clinical Research Service for the following tests: CBC, CMP, and CRP. 
Participants will then return to the study room and hand over their shoes, keys, wallet and 
phones to the study therapists for safe keeping; these will all be returned to the patient upon 
completion of the treatment session. 
The entire session will be audio and video recorded for subsequent behavioral analysis and 


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rating of therapist adherence to the therapy protocol. Participants have the option of requesting 
that AV recording be turned off momentarily if they will to discuss material they feel is too 
personal to be recorded.  
During the drug session, vital signs (heart rate and blood pressure) will be recorded at 10 
minutes prior to drug ingestion (“Minute -10”), and then 30, 60, 90, 120, 180, 240, 300, and 
360 minutes after drug ingestion. If at 360 minutes blood pressure is elevated compared to 
Minute -10, blood pressure will continue to be repeatedly assessed until it has returned to its 
Minute -10 measurement. 
If the Minute -10 assessment (the mean of at least two readings separated by at least 2 
minutes) of baseline blood pressure exceeds either 140 systolic or 90 diastolic, periodic blood 
pressure readings will be obtained (e.g. at 5 minute intervals) to determine if the elevation may 
be temporary (e.g. due to anticipatory anxiety). If blood pressure decreases to (or below) 140 
systolic and 90 diastolic within 20 minutes, capsule administration will proceed. If baseline 
blood pressure continues to exceed either 140 systolic or 90 diastolic, periodic blood pressure 
readings will be continued and the study physician will be contacted. The study physician can 
authorize drug administration if the study physician believes that it is safe to proceed and if the 
last two blood pressure readings do not exceed 155 systolic or 95 diastolic. 
The patient will ingest the psilocybin capsules with about 4 ounces of water and then be 
instructed to lie down on the couch wearing eyeshades and listening to a preselected music 
soundtrack via headphones. The subject will be instructed to focus their attention internally and 
to attempt to interact minimally with the two therapists who will be present in the room 
throughout the drug session, but will be as non- directive as possible in their interactions with 
the patient. In the event of a psychologically challenging experience such as significant anxiety 
or confusion, the therapists will provide verbal reassurance. Patients will have been instructed 
in the preparatory therapy session to notify the study therapists if during the treatment they feel 
anxiety or fear. 
In the event of a psychiatric emergency, verbal de-escalation and physical and/or chemical 
restraint will be used to maintain the safety of the subject and the therapists, according to the 
clinical judgment of the on-call study physician. All possible efforts will be made to avoid using 
restraints of any kind. Subjects will not be allowed to leave the premises until the drug effects 
have worn off. 
In the event of a medical emergency, subjects will be evaluated by the on-call study physician 
who will be on-site for all drug administrations. At least one ACLS-certified study clinician will be 
on-site for all drug administrations. While expected to be rare, the most likely serious adverse 
event to occur would be a hypertensive crisis. If a subject’s blood pressure becomes grossly 
elevated (SBP >180mmHg, DBP >110mmHG) or unsafe (BP elevations with associated 
symptoms such as chest pain or shortness of breath), blood pressure will be rechecked 
immediately in both arms and the on-call physician will be notified if s/he is not already in the 
treatment room. If the subject is clinically suspected of being in hypertensive emergency (with 
signs of end-organ damage), then the subject will be transported to the UCSF Emergency 
Department for further evaluation and treatment. The Emergency Department’s door is less than 
a 1 minute walk from the Langley Porter Psychiatric Institute. If the patient if determined to be in 
hypertensive urgency (without clinical signs of end-organ damage), then blood pressure will 
be re-assessed with greater frequency while the study physician continues to her/his evaluation 
for signs of clinical instability, and the study physician may attempt to calm the subject with 
verbal de-escalation or an anxiolytic (e.g. lorazepam) as transient hypertension is most likely to 
be due to a challenging psychological experience. If after 20 minutes the hypertensive urgency 
has not improved, the study physician will evaluate the need for transporting the subject to the 
Emergency Department for further evaluation and treatment. In the case of acute chest pain, 
the on-call study physician will have available sublingual nitroglycerin to administer to the 
subject and an electrocardiogram machine. A crash cart is located in the building, but the goal 
will be to transport a decompensating patient to the Emergency Department prior to the crash 
cart becoming imminently necessary. In the event of a suspected hypoglycemic episode in a 


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subject with diabetes mellitus, a finger stick blood glucose will be checked on an as needed 
basis, and fruit or oral glucose tablets will be available. 
As the drug effects begin to wear off at the 5-6 hour mark, the therapists will engage the patient 
in a therapeutic interview to explore the experience (see Appendix C for interview guide); this 
discussion will also be videotaped. A clinical rater will administer the C-SSRS(Interval). Only 
once patients are deemed to be free of the acute effects of the drug, and after at least 7 hours 
have passed since ingestion of the drug, will the participant be allowed to leave the premise in 
the company of a caregiver who has been instructed on how best to support the patient over 
the coming days.  
The patient and caregiver will be given a study clinician’s pager or work cell phone number in 
case of any clinical event off-site that needs further assessment. Patients must agree not to 
drive themselves home, nor to drive later that same day after they arrive home. Patients will be 
instructed to write a detailed account of their experience during the drug session at some point 
over the next week. 
In the event that a participant did not arrange a friend/family member to accompany 
them home, the participant will be required to stay with the study clinicians longer, will be 
encouraged to eat, and then the participant will be escorted to the curb by study staff and seen 
into a taxi/Lyft/Uber that will be instructed to take them home. The participant will also be 
instructed to call the study MD when they arrive home. All efforts will be made to avoid this 
situation. In the weeks prior to the medication session, participants will be regularly reminded to 
arrange for someone to accompany them home. 
The following day patients will return to the study site to meet with a study therapist and engage 
in a therapeutic discussion of their experience for 90 minutes. Before the session patients will 
present to the Clinical Research Service for a blood draw for these studies: CBC, CMP, CRP. 
Patients will complete the MEQ-30, ChEQ, STAI, SAHD, MQoL, and the C-SSRS(Interval) at 
this visit. Patients may again meet with study staff in person prior to the next group therapy 
session if they request this or if study clinicians deem it clinically warranted. 
 
6.4.4.3 Group Therapy Sessions #5-10 (Weeks 4-6) 
Patients will undergo six group therapy sessions each 90-minutes long. Video footage of a 
random sampling of sessions will be analyzed with the HIM, SEGT-TG, IGMIPS and the 
GPIRS. Prior to each session, patients will be screened for adverse events and evaluated with the 
CSSR-S. Prior to sessions 5, 7 and 9, participants will fill out the CTC. After sessions 6, 8 and 
10, participants will fill out the GQ. At the end of session 5, participants will fill out these 
questionnaires: CESD-R, DS-II, ICG, PCL-5, HARSI. After session 7 participants will fill out the DS-
II and ICG. 
 
6.4.5 Endpoint Assessments 
6.4.5.1 Endpoint (Week 6) Study Measures for Subjects 
Immediately after the last group therapy session (Week 8), patients will complete the AMAS, 
CESD-R, DS-II, DUFSS-5, ECR-M16, ICG, MQoL-RS, NR-6, PCL-5 SAHD, SCS-R, STAI, 
PTGI-SF, IPIP-OE-20, MAIA-R, HARSI, CTC, and CSS. A clinical rater will perform a MoCA 
and CGI for each subject. 
6.4.5.2 Endpoint (Week 6) Study Measures for Caregivers/Important 
Others 
Patients’ primary caregivers/important others will complete the CORF and CSS. 
6.4.6 Post-treatment/Follow Up Assessments 


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6.4.6.1 Focus Group (Week 8) 
Two weeks after the last group therapy session, subjects and their caregivers/important others 
will be invited to participate in a focus group wherein they will be asked to give feedback 
regarding their experiences in the study. Effort will be made to get both responders and non- 
responders to attend the focus groups. A clinical rater will administer the C-SSRS(Interval) to 
each subject. Prior to the focus group each participant will fill out the DS-II and ICG. This will 
be audio-recorded for subsequent qualitative analysis. See Appendix C for focus group guide. 
 
6.4.6.2 3-Month Follow-up for Subjects 
At 3 Months, patients will be emailed a link to the following measures to be completed in 
REDCap: AMAS, AUDIT, CESD-R, DS-II, DUDIT, DUFSS-5, ECR-M16, HARSI, ICG, MQoL-
RS, NR-6, PCL-5, SAHD, SCS-R, STAI, PTGI-SF, IPIP-OE-20, MAIA-R, CTC, and the CSS. 
They will be called and encouraged to complete the measures. If they have difficulty with email 
or filling out the forms electronically, paper-and-pen measures will be sent to them with a self-
addressed envelope for returning the measures. 
 
6.4.6.3 3-Month Patients for Caregivers/Important Others 
At 3 Months, primary caregivers/important others will be emailed a link with the following 
measures to be completed in REDCap: CORF and CSS. They will be called and encouraged 
to complete the packet. 
6.4.6.4 3-Month Qualitative Interviews 
Between the Focus Group and the 3-month follow-up, subjects and caregivers/important others 
will be invited to participate in a semi-structured interview of their experience in the study. These 
interviews will be analyzed to detect potential mechanisms of the intervention as well as 
outcomes not addressed by the study measures. See Appendix C for interview guide. 
6.5 
Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interest. Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s non-compliance or simply significant uncertainty on 
the part of the Investigator that continued participation is prudent. There may also be 
administrative reasons to terminate participation, such as concern about a patient’s 
compliance with the prescribed treatment regimen. 
6.6 
Dietary Restrictions 
No dietary restrictions are included in the protocol. 
6.7 
Prohibited Medications 
Patients are prohibited from using medications from the following classes while enrolled in the 
study: 
 
• 
Serotonin Reuptake Inhibitors (SSRIs and SNRIs) 
• 
Tricyclic Antidepressants (TCAs) 
• 
Monoamine Oxidase Inhibitors (MAOIs) 
• 
Atypical antidepressants (e.g., mirtazapine, nefazodone, buspar) 
• 
Antipsychotics/Neuroleptics (typical and atypical) 
• 
Anti-epileptics or mood stabilizers (e.g., lithium, valproate) 


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• 
Efavirenz (Sustiva, in Atripla) 
• 
OTC supplements intended to affect mood or anxiety (e.g., 5HT-P or St. John’s Wort). 
 
Conditional medication restrictions 
• 
Trazodone 
o Trazodone ≤50mg/24hr for insomnia is allowed, but not within 48hr of psilocybin 
session 
• 
Benzodiazepines 
o PRNs are not allowed 24hr prior to the psilocybin session 
o “z-drugs” (e.g., zolpidem) are not allowed 24hr prior to the psilocybin session 
 
Individuals who at screening would be excluded for taking contraindicated antidepressants, 
anxiolytics, stimulants or herbal supplements can be considered for the study if—under the 
guidance of their usual physician—they successfully taper off these medications and 
demonstrate a period of psychiatric stability lasting at least 2 weeks. One exception to the 
required 2-week period is for individuals taking low dose TCAs (≤50mg imipramine equivalent) 
for reasons other than depression or anxiety (e.g., peripheral neuropathy or insomnia). These 
individuals may, under the guidance of their usual physician, taper off these medications and 
then be enrolled in the study once they are no longer taking the TCA. 
 
6.8 
Study Clinicians 
Study clinicians (group therapists and treatment session guides) will be approved by a panel 
consisting of: Dr. Josh Woolley (PI), Dr. Alicia Danforth (UCLA psilocybin team, and lead clinical 
supervisor for UCSF the team), Dr. Brian Anderson (UCSF psilocybin team), and Robert Jesse 
(Johns Hopkins psilocybin team). Group therapists and treatment session guides will all be 
licensed clinicians (MD, RN, NP, MFT, LCSW, PhD, PsyD, Chaplain, etc) in the state of 
California; an exception will be made if the person is unlicensed but currently enrolled in a clinical 
training program and has had sufficient clinical exposure, according to the judgment of the above-
mentioned panel. The selection of therapists/guides will give preference to those who have: 1) 
prior clinical experience working with the study population; 2) have demographic similarities to the 
study population (age, gender, sexual orientation); 3) prior experience conducting group therapy; 
4) prior experience working with individuals under the influence of psychedelics either in research 
settings or harm-reduction settings (such as the Zendo Project); 5) have completed the CIIS 
certificate program in Psychedelic-assisted Psychotherapy and research. 
 
Group therapist pairs will consist of one lead and one secondary therapist. The lead must 
have had significant experience as a group therapy leader; the secondary must have some 
experience as a group therapy leader. Group therapists will undergo at least 16 hours of 
training in Supportive-Expressive Group Therapy (SEGT) by studying SEGT training videos, 
the SEGT adherence rating scales that will be used in the study, and the 3 following SEGT 
manuals: the original manual for metastatic breast cancer patients [75], the manual for brief 
SEGT in newly diagnosed breast cancer patients [76], and the adaptation by Maldonado et al 
for patients with AIDS [78]. All group therapists will undergo at least one 'dry run' session of 
the SEGT method prior to starting a group. 
 
Each subject will have 2 guides working with them in their drug treatment day (not necessarily 
one male and one female). At least one of the treatment session guides will be one of the 
subject's group therapy co-therapists. Treatment session guides will undergo instruction by Dr. 
Alicia Danforth and/or Dr. Anderson. Overall clinical supervision will be a responsibility shared 
by Dr. Josh Woolley (Co-PI), Dr. Brian Anderson (Pl) and Dr. Danforth (lead psychotherapy 
supervisor). Clinical consultation will be available from others involved in the study, such as Dr. 
Jim Dilley, Co-Investigator of this study and founder and of the UCSF Alliance Health Project, 
as well as Dr. Rob Daroff, a study clinician who is a staff psychiatrist at the SFVA with many 
years experiencing running psychotherapy groups for gay men in San Francisco. 
 


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Clinical supervision specifically related to psilocybin, and SEGT, will happen in the form of 
debriefing sessions after every study visit. Dr. Anderson will be an in-the-room observer of the 
group therapy sessions to take notes and later discuss with the group therapists their 
adherence to the SEGT method and its current adaptation to the psilocybin trial. Dr. Anderson 
and Dr. Danforth will review video of treatment sessions and discuss the technique observed 
with the individual session guides on an as needed basis. Video segments of group therapy 
sessions and psilocybin treatment sessions will be used for discussion in a periodic supervision 
workshop to be held after the completion of each group therapy cohort and which all study 
clinicians will be highly encouraged to attend. The number of supervision sessions a study 
clinician is required to attend to maintain eligibility to work on the study will be up to the 
discretion of the clinical supervisors. 


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7 
Reporting and Documentation of Results 
7.1 
Evaluation of Safety and Feasibility 
The assessment of safety and feasibility will be informed by surveillance of adverse events in all 
patients who enroll in the study. The study will use the NIH Division of AIDS Table of Grading of 
Severity of Adult and Pediatric Adverse Events V2.0 for reporting of adverse events. Analyses 
of feasibility and acceptability will also be informed by rates of patient recruitment and retention, 
therapist protocol adherence, self-report measures (CrEQ and CSS), and spontaneous 
feedback from subjects, caregivers/important others, and study therapists. 
7.2 
Evaluation of Efficacy 
We will evaluate for trends in changes of group mean measures of demoralization, complicated 
grief, depression, anxiety, and other constructs mentioned above. These evaluations will consist 
of self-report measures (e.g., DS-II) and observations from caregivers/important others and 
clinical raters (e.g., CORF and CGI). 
 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality. An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or


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as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.4 
Recording of an Adverse Event 
All adverse events will be entered into UCSF REDCap, whether or not the event is believed to 
be associated with use of the study drug. Data about these events and their severity will be 
recorded using the NIH Division of AIDS Table of Grading of Severity of Adult and Pediatric 
Adverse Events V2.0. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into UCSF REDCap using the 
classification system listed below: 


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Relationship 
Attribution Description 
Unrelated to 
investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to 
the intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Possible 
The AE may be related to the 
intervention 
Related to 
investigational 
drug/intervention 
Probable 
The AE is likely related to the 
intervention 
The AE is clearly related to the 
intervention 
Definite 
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator. 
When specific adverse events are not listed in the above NIH DAIDS Table of Grading of 
Severity, they will be graded by the Investigator as none, mild, moderate or severe according to 
the following grades and definitions: 
 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild: Mild symptoms causing no or minimal interference with usual social & 
functional activities with intervention not indicated 
Grade 2 
Moderate: Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated 
Grade 3 
Severe: Severe symptoms causing inability to perform usual social & functional 
activities with intervention or hospitalization indicated 
Grade 4 
Potentially life-threatening: Potentially life-threatening symptoms causing 
inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death 
Grade 5 
Death related to AE 
 
7.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
7.6 
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into UCSF REDCap, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
Data and Safety Monitor (DSM) and UCSF’s Institutional Review Board, the Committee on 
Human Research (CHR); and, when the study is conducted under an Investigational New Drug 
Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA reporting 
criteria. 
In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into UCSF REDCap will be reviewed and monitored by the Data and Safety Monitor on an 


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ongoing basis, discussed at DSM meetings which take place after each therapy group 
completes the 8-week intervention. 
7.7 
Expedited Reporting 
Reporting to the Data and Safety Monitor 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSM within 1 
business day of knowledge of the event. The contact may be by phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional 
Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
• 
Suspected adverse reaction (as defined in 7.3.2.1) 
• 
Unexpected (as defined in 7.3.2.2) 
• 
Serious (as defined in 7.2.3.3) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug 
Serious adverse reactions will be reported to the Heffter Research Institute and the Usona 
Institute, which are consultants for this study. 


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8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Design 
This open-label single-arm mixed-methods pilot study will use descriptive statistics and 
qualitative methods to evaluate safety and feasibility in terms of rates of adverse events, patient 
recruitment and retention, and feedback on the intervention’s utility, content and duration. Given 
the small sample size of this study, small-to-medium effect sizes will likely be undetectable; and 
so descriptive statistics will be used to report changes in mean measures at baseline compared 
to the endpoint, and again at the 3-month follow-up. Exploratory ANOVAs will also be done to 
model changes in therapeutic process values (e.g., group cohesion) over time. Qualitative 
thematic analysis will also be used to evaluate verbal and written reports of patient and 
caregiver/important other experiences with the study in order to optimize implementation of the 
intervention in larger, future trials. 
 
8.1.1 Randomization 
No randomization procedures will be used. 
8.1.2 Stratification Factors 
No stratification procedures will be used. 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
This pilot study of the safety and feasibility of psilocybin-assisted group therapy aims to enroll at 
least 18 subjects, and will have a maximum total sample size of 36. We estimate needing to 
enroll 18 subjects given attrition rates of up to 45% reported in trials of other group therapies for 
existential distress in palliative care patients [118]. For comparison, four different safety and 
feasibility pilot studies of psilocybin-assisted psychotherapy have been conducted over the last 
two decades, and have included 9, 10, 12 and 15 patients each [18, 111, 112, 114]. Four 
recently published feasibility pilot studies of meaning-focused group psychotherapies for 
palliative care patients have included 5, 11, 11, and 16 patients each [40, 185-187]. 
 
Group therapy studies should include at least 2 groups of at least 4-6 members [138], so we 
plan to have at least 8 subjects complete the intervention. We expect to be able to enroll at least 
6 subjects every 6 months. 
 
Because the proposed study is a pilot focused on investigating safety and feasibility, power 
calculations for efficacy measures are not indicated. Pilot studies are often used to estimate 
values that are then utilized in power calculations for full-scale trials. Indeed, we will estimate 
effect size (ES) and the intraclass correlation coefficient (ICC) [135] for the intervention based 
on our preliminary efficacy results. Group psychotherapy trials generally require large sample 
sizes to demonstrate statistical significance in change in efficacy measures given the likely 
interdependence of clinical outcomes when interventions are delivered in groups [135, 136]. 
Thus, future full-scale trials can utilize our estimates to derive adequate, and likely large, sample 
sizes. 


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8.2.2 Replacement Policy 
Study subjects who have been assigned to a group and drop out prior to the first group session 
can be replaced by a new subject who will be assigned to the same group. Subjects who drop 
out after the first group therapy session will not be replaced. 
8.2.3 Accrual estimates 
The annual number of eligible patients is high given the size of the population of HIV- 
seropositive people in the San Francisco Bay Area. In 2014, San Francisco reported 15,979 
people living with HIV, of whom 9,202 were at least 50 years old [8]. If accrual falls short of 
expectations, advertising and recruitment efforts will be expanded. 
 
8.3 
Interim Analyses and Stopping Rules 
After the occurrence of one Adverse Event judged to be Severe and potentially related to the 
drug/intervention, enrollment will be stopped until a Safety Review has been completed and the 
appropriate protocol amendments implemented. 
 
8.4 
Analyses Plans 
The study’s biostatistician is Matthew Boden, Ph.D. Alongside the PI, Dr. Boden will be co- 
responsible for assuring that clinical data are correctly collected, stored and analyzed. He will 
work directly with the PI to assure that interpretations of these data are coherent and justified. 
Dr. Boden’s professional interests are rooted in the research, evaluation and implementation of 
evidence-based treatments for complex and severe mental disorders. As a Health Science 
Specialist at the Center for Innovation to Implementation (Ci2i), Veterans Affairs (VA) Palo Alto 
Health Care System, Dr. Boden investigates the clinical effects and implementation of evidence- 
based psychosocial treatments for psychotic, anxiety, and substance use disorders. His 
research utilizes a variety of assessment (e.g., structured clinical interviews, biological assays) 
and statistical (e.g., linear mixed models, exploratory structural equation modeling) techniques. 
As a Senior Evaluator at the Program Evaluation and Resource Center (PERC), VA Office of 
Mental Health Operations (OMHO), Dr. Boden supports OMHO’s nationwide program 
evaluation and quality improvement efforts. 
 
 
8.4.1 Analysis Population 
All patients who enroll in the study will be included in analyses of safety and tolerability. 
 
All patients who make any contact at all with the study (including those who are screened out 
over the phone) will be included in analyses of feasibility. 
 
All patients who enroll in the trial will be included in analyses of efficacy. Repeated efficacy 
measures will be gathered and trended, regardless of missing data or protocol non-adherence. 
 
All patients who participate in at least one group therapy session will be included in analyses of 
psychotherapeutic process. 
 
8.5 
Primary Analysis 
Safety analyses will be performed for all patients who enroll in the study. The study will use the 
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classify adverse events. Descriptive statistics (percentages) will be reported for the incidence of 
any Adverse Events reported, including suicidality as measured by the C-SSRS. Median scores 
will also be calculated for total scores of the feasibility measures: CSS, CrEQ, and PEQ-S. The 
differences of mean pre- and post-treatment scores on the CORF will be calculated. Differences 
in individual pre- and post-treatment MoCA scores will be assessed for each individual. 
Therapist protocol adherence will be reported as a rate of discussion topic deviations from the 
protocol. 
8.5.1 Exploratory Analyses 
Change in efficacy measures from pre-treatment to post-treatment to 3-month follow-up will be 
analyzed with descriptive statistics to represent trends in mean levels. Recognizing that the 
calculations will likely be underpowered, we will also perform ANOVAs of the secondary 
outcome measures. To assist in gauging the clinical relevance of these data relative to 
measurement error, and to overcome some of the limitations of the study’s small sample size, 
Reliable Change Indices (RCI) will be calculated [188]. Data from efficacy measures will also be 
used to estimate effect sizes and intraclass correlation coefficients for use in larger, future 
studies. 
Change in process measures (e.g., the HIM, QPIRS and GQ) over time will be analyzed with 
ANOVAs to assess the slopes of individual participants and of the whole sample. 
Qualitative thematic analyses will be conducted according to the methods outlined in Section 
6.3. Iterative inductive analyses will be performed with the aid of NVivo analytical software. 
 
 
8.6 
Study Results 
Study results will be reported following the guidelines of the TREND Statement for reporting of 
results from non-randomized interventions [189]. The study biostatistician will oversee or review 
the interpretation of all the above analyses and descriptive statistics. 


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9 
Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects. 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board). The initial protocol and all 
protocol amendments must be approved by the IRB prior to implementation. 
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. 
The original signed copy of the consent document must be retained in the medical record or 
research file. 
During enrollment, patients will be consented for participation in the study, including having the 
various aspects of their participation video-recorded. They will also sign a Release of 
Information for study staff to speak to the patients’ primary caregivers and primary physicians. 
Primary caregivers/important others will also be consented during enrollment. 
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by the CHR prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval. In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation. The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 


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9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included. The sponsor- 
investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients. Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into UCSF REDCap via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry with a 
secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as 
soon as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
UCSF personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The DSM will routinely review all adverse events and suspected adverse reactions considered 
“serious”. The DSM will audit study-related activities to ensure that the study is conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP). Significant results of the DSM audit will be communicated to the IRB 
and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as applicable. See Appendix for Data and Safety Monitoring Plan for additional 
information. 


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9.8 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 


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ICF_001.pdf: 
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Psilocybin-assisted Group Therapy for Demoralization  
in Long-term AIDS Survivors 
 
NCT02950467 
 
Informed Consent Form 
 
20 February 2019