The Impact of Psilocybin on Pain in Fibromyalgia Patients: a Multicentre Trial.
Phase: NA
Conditions: Fibromyalgia
Sponsor: Maastricht University

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8, date 09.08.2023 
 
1 of 61 
 
  
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL 
THE IMPACT OF PSILOCYBIN ON PAIN IN FIBROMYALGIA 
PATIENTS: A MULTICENTER TRIAL 
 
 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8, date 09.08.2023 
 
2 of 61 
 
PROTOCOL TITLE  : The impact of psilocybin on pain in fibromyalgia patients: a multicentre trial. 
 
Protocol ID 
P137 
Short title 
The impact of Psilocybin on pain 
EudraCT number  
2021-002909-10 
Version 
8 
Date 
09/08/23 
Coordinating 
investigator/project leader 
 
Mauro Cavarra 
Faculty 
of 
Psychology 
and 
Neuroscience, 
Department 
of 
Neuropsychology 
and 
Psychopharmacology, Maastricht University,  
Universiteitssingel 40, 6229 ER 
Maastricht, The Netherlands 
m.cavarra@maastrichtuniversity.nl 
Principal 
investigator(s) 
(in 
Dutch: 
hoofdonderzoeker/ 
uitvoerder) 
 
Prof. Dr. Johannes .G. Ramaekers 
Faculty 
of 
Psychology 
and 
Neuroscience, 
Department 
of 
Neuropsychology 
and 
Psychopharmacology, Maastricht University,  
Universiteitssingel 40, 6229 ER 
Maastricht, The Netherlands 
+31 43 3881951 
j.ramaekers@maastrichtuniversity.nl 
 
Dr. Kim Kuypers 
Faculty 
of 
Psychology 
and 
Neuroscience, 
Department 
of 
Neuropsychology 
and 
Psychopharmacology, Maastricht University,  
Universiteitssingel 40, 6229 ER 
Maastricht, The Netherlands 
+31 43 3881902 
k.kuypers@maastrichtuniversity.nl 
 
Albert Dahan 
Universiteit Leiden 
Faculteit Geneeskunde Divisie 1 Anesthesiologie 
Professor of Anesthesiology 
Albinusdreef 2 
2333 ZA Leiden 
+31 71 526 4554 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8, date 09.08.2023 
 
3 of 61 
 
a.dahan@lumc.nl  
Co-Investigator 
Dr. Nadia Hutten 
Universiteit Maastricht 
Faculteit der Psychologie en Neurowetenschappen 
Capgroep Neuropsychologie & Psychofarmacologie 
Postbus 616 
6200 MD Maastricht 
nadia.hutten@maastrichtuniversity.nl 
 
Dr. Monique Van Velzen 
Leiden University Medical Center 
Anesthesiology 
m.van_velzen@lumc.nl 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
University Maastricht 
 
Independent expert (s) 
Dr. M.P.J. van Boxtel  
Dr. Elise Sarton 
 
Medical supervisor 
Dr. Cees van Leeuwen 
Laboratory sites  
Stefan Toënnes  
Institute of Legal Medicine  
University of Frankfurt,  
Kennedyallee 104 
D-60596 Frankfurt/Main 
 
Rafael De la Torre  
Institute Municipal d`investigació mèdica (IMIM) 
Carrer del Dr. Aiguader, 88,  
08003 Barcelona, Spain 
Pharmacy  
MUMC pharmacy 
P. Debyelaan 25, 6229 HX Maastricht 
Maastricht 
6229 HX, NL 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8, date 09.08.2023 
 
4 of 61 
 
 
Leiden University Medical Center Pharmacy 
Zernikedreef 8, 2333 
CL Leiden, NL 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8, date 09.08.2023 
 
5 of 61 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Dr. A. Blokland 
 
 
Principal Investigator: 
Prof. Dr. J.G. Ramaekers 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
6 of 61 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE 
11 
2. 
OBJECTIVES 
15 
3. 
STUDY DESIGN 
15 
4. 
STUDY POPULATION 
16 
4.1. 
Population (base) 
16 
4.2. 
Eligibility 
16 
4.3. 
Sample size calculation 
17 
5. 
TREATMENT OF SUBJECTS 
18 
5.1. 
Investigational product/treatment 
18 
5.2. 
Use of co-intervention (if applicable) 
18 
5.3. 
Escape medication 
18 
6. 
INVESTIGATIONAL PRODUCT 
18 
6.1. 
Name and description of investigational product(s) 
18 
6.2. 
Summary of findings from non-clinical studies 
18 
6.3. 
Summary of findings from clinical studies 
19 
6.4. 
Summary of known and potential risks and benefits 
20 
6.5. 
Description and justification of route of administration and dosage 
21 
6.6. 
Dosages, dosage modifications and method of administration 
21 
6.7. 
Preparation and labelling of Investigational Medicinal Product 
21 
6.8. 
Drug accountability 
21 
7. 
NON-INVESTIGATIONAL PRODUCT 
22 
7.1. 
Name and description of non-investigational product(s) 
22 
7.2. 
Summary of findings from non-clinical studies 
22 
7.3. 
Summary of findings from clinical studies 
22 
7.4. 
Summary of known and potential risks and benefits 
22 
7.5. 
Description and justification of route of administration and dosage 
22 
7.6. 
Dosages, dosage modifications and method of administration 
22 
7.7. 
Preparation and labelling of Non Investigational Medicinal Product 
22 
7.8. 
Drug accountability 
22 
8. 
METHODS 
23 
8.1. 
Study parameters/endpoints 
23 
8.2. 
Randomisation, blinding and treatment allocation 
24 
8.3. 
Study procedures 
24 
8.4. 
Schedule of experimental session: 
25 
8.5. 
Measurements: 
26 
8.6. 
Withdrawal of individual subjects 
35 
8.7. 
Replacement of individual subjects after withdrawal 
35 
8.8. 
Follow-up of subjects withdrawn from treatment 
35 
8.9. 
Premature termination of the study 
35 
9. 
SAFETY REPORTING 
36 
9.1. 
Temporary halt for reasons of subject safety 
36 
9.2. 
AEs, SAEs and SUSARs 
36 
9.3. 
Annual safety report 
38 
9.4. 
Follow-up of adverse events 
38 
9.5. 
Data Safety Monitoring Board (DSMB) / Safety Committee 
38 
10. STATISTICAL ANALYSIS 
39 
10.1. Primary study parameters 
39 
10.2. Secondary study parameter(s) 
39 
10.3. Other study parameters 
40 
10.4. Interim analysis (if applicable) 
40 
11. ETHICAL CONSIDERATIONS 
41 
11.1. Regulation statement 
41 
11.2. Recruitment and consent 
41 
11.3. Objection by minors or incapacitated subjects 
42 
11.4. Benefits and risks assessment 
42 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
7 of 61 
 
 
11.5. Compensation for injury 
42 
11.6. Incentives 
43 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
44 
12.1. Handling and storage of data and documents 
44 
12.2. Monitoring and Quality Assurance 
44 
12.3. Amendments 
45 
12.4. Annual progress report 
45 
12.5. Temporary halt and (prematurely) end of study report 
45 
12.6. Public disclosure and publication policy 
46 
13. STRUCTURED RISK ANALYSIS 
46 
13.1. Potential issues of concern 
46 
13.2. Synthesis 
48 
- 
48 
14. REFERENCES 
49 
 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
8 of 61 
 
 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
5D-ASC 
5 Dimensions of Altered States of Consciousness 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUT 
Alternate Use Test  
BDNF 
Brain-Derived Neurotrophic Factor 
BFI 
Big Five Inventory 
BPI 
Brief Pain Inventory 
CEQ 
Credibility Expectancy Questionnaire 
COMT 
Catecholamine Methyltransferase 
CPT 
Cold Pressor Task 
DSMB 
Data Safety Monitoring Board 
DSST 
Digit Symbol Substitution Test  
ECG 
Electrocardiogram 
EudraCT 
European Drug Regulatory Affairs Clinical Trials 
FIQ 
Fibromyalgia Impact Questionnaire 
FM 
Fibromyalgia 
IRI 
Interpersonal Reactivity Index 
LSD 
Lysergic Acid Diethylamide 
MET 
Multifaceted Empathy Test  
METC 
Medical Research Ethics Committee (MREC); in Dutch: Medisch Ethische 
Toetsing Commissie (METC) 
MODTAS 
Modified Tellegen Absorption Scale 
NSAIDS 
Non-steroidal anti-inflammatory drugs 
NRS 
Numeric Rating Scale 
POMS 
Profile of Mood States 
PCM 
Paracetamol 
PPT 
Pressure Pain Threshold 
PVT 
Psychomotor Vigilance Task  
QOL 
Quality of Life 
SAE 
Serious Adverse Events 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical company, 
academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as 
the sponsor, but referred to as a subsidising party. 
TEC 
Treatment Expectations in Chronic Pain Scale 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
9 of 61 
 
 
VAS 
Visual Analogue Scale 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
10 of 61 
 
 
SUMMARY 
Rationale: Recent evidence shows that Lysergic Acid Diethylamide (LSD), even when 
administered in low, non-hallucinogenic doses, can produce analgesic effects and improve 
pain tolerance in a sample of healthy volunteers. Such results complement what was 
already observed with other serotonergic psychedelics such as psilocybin: survey studies 
and case series indicate that its use may lead to improvements in chronic pain conditions 
such as migraines, cluster headaches and phantom limb pain even at low, non-psychedelic 
doses. These effects have however not yet been investigated and confirmed in clinical 
populations under controlled experimental conditions. 
Fibromyalgia (FM) is a chronic condition characterised by widespread pain, hyperalgesia, 
anxiety, disturbed sleep patterns, impaired cognitive functioning and comorbid mood 
disorders. It has high direct and indirect costs and it is considered challenging to treat. Most 
suggested therapies, in fact, are only associated with small improvements in pain ratings 
and quality of life. Currently, there is no data concerning the effectiveness of serotonergic 
psychedelics in improving pain ratings in fibromyalgia patients. 
Objective: The present study will explore the effects that the administration of a placebo 
and 2 low psilocybin doses (5 mg or 10 mg) will have on pain perception in a group of 
fibromyalgia patients. 
Study design: The present study uses a double-blind, randomized, placebo-controlled 
design. All participants will receive a placebo and 2 doses of psilocybin (5 mg or 10 mg) 
and will undergo the Cold Pressor Test (CPT) and the Pain Pressure Threshold Task (PPT) 
o test its analgesic effects. 
Study population: 35 fibromyalgia patients aged 18 to 65 years. 
Intervention: Placebo, 5 mg or 10 mg of psilocybin in randomized order. 
Main study parameters/endpoints: Primary outcomes will be subjective and objective 
measures of pain perception. Secondary measures will assess the effects that placebo and 
psilocybin will have on mood, cognition and psychedelic experience. Finally, participants 
will take part to an additional CPT after receiving hypnotic suggestions of analgesia to test 
whether such intervention may moderate pain ratings of individuals who took small doses 
of psilocybin. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Participants will visit the research lab 5 times during 5 weeks. Before 
the first study day, subjects will come for a screening visit during which they will also be 
familiarized with tests and study procedures. This includes a medical screening by a 
licensed physician (medical history review, laboratory screening, electrocardiogram 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
11 of 61 
 
 
recording). The study visits will consist of taking the study treatment (5 mg or 10 mg of 
psilocybin or placebo), taking part to the experimental tasks, taking blood samples, 
completing computer tasks and filling out questionnaires. Finally, participants will take part 
to a final online visit to administer post-study questionnaires. 
 
1. INTRODUCTION AND RATIONALE 
Serotonergic psychedelics are substances whose primary mechanism of action is the 
activation of the serotonin 5-HT2A receptor (1–5). They are considered safe when 
administered in appropriately controlled settings (6,7) and are used for recreational and 
spiritual purposes because of their effects on consciousness (8). Recent clinical studies 
suggest clinical effectiveness in treating a range of conditions such as treatment resistant 
depression (9,10), anxiety and depression in end-of-life settings (11,12), tobacco addiction 
(13,14), alcohol addiction (15). 
The earliest attempt at testing these agents to treat pain dates back to the ‘60s and involved 
patients suffering from neuropathic, ischemic or cancer-related pain (16). In a prospective 
non-randomised trial, authors compared the efficacy of 0.1 mg of LSD with hydromorphone 
HCl, 2 mg., and meperidine HCl, 100 mg. Results showed greater analgesic action of LSD 
compared to the other drugs. Shortly after, another case series involving 128 terminal 
patients treated with the same dose resulted in immediate and sustained (3 weeks) pain 
reduction (17). In a pre-post, no control group clinical study with 60 cancer patients, Grof et 
al. (18) observed that LSD-assisted psychotherapy led to improvements in pain ratings. 
Fanciullacci et al. (19) investigated the effects of a sub-hallucinogenic dose of LSD (25 µg) 
in a case series populated by 7 patients suffering from phantom limb pain, and reported 
improvements in 5 of them. Furthermore, patients experienced rare, transient and mild 
psychic reactions. 
As in other areas of application, these kinds of studies were halted for political reasons as 
a consequence of the Controlled Substances Act of the Comprehensive Drug Abuse 
Prevention and Control Act and it is only in the last decade that we witnessed a resurgence 
of interest in psychedelic research (20).  
A retrospective survey recruiting 53 individuals who met the International Classification of 
Headache Disorders-2 criteria for cluster headache and who reported psilocybin or LSD 
use to self-medicate, provided preliminary evidence on the potential of such agents (21). 
More specifically, participants reported that a single non-hallucinogenic dose of LSD or 
three non-hallucinogenic doses of psilocybin were often sufficient to abort attacks, induce 
the termination of episodes and extend the duration of remission periods. Analogous results 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
12 of 61 
 
 
were obtained via the Clusterbuster.org survey (22), a larger cross-sectional retrospective 
survey aimed at characterizing the effects of conventional and complementary therapies for 
cluster headaches. The survey included data from 496 responders and results indicated 
that psilocybin and LSD were comparably or more efficacious than conventional treatments. 
More specifically, participants - who were recruited through cluster headache websites and 
headache clinics - reported that the serotonergic agents caused cluster periods to shorten, 
aborted attacks and led chronic cluster headaches into remission. Interestingly, even 
infrequent sub-hallucinogenic doses of psilocybin were described as efficacious. Again, 
similar results were found in a smaller sample survey (23). A recent randomised, double-
blind, placebo-controlled, within-subjects study with healthy volunteers showed immediate 
(1.5h after administration) and stable (5h after administration) improvements in pain 
tolerance and ratings of unpleasantness after the administration of 20µg of LSD (24). Effects 
sizes were medium to large and were comparable to those obtained after the administration 
of oxycodone (25) or morphine (26). Earlier research (27) suggests that these analgesic 
effects may outlast the 5h time window that was considered in the study. Patients reported 
small increases in anxiety, somatisation, amnesia, depersonalisation, derealisation and 
dissociation ratings. Taking into account recent studies indicating that 26µg of LSD tartrate 
does not affect or mildly affects cognitive function, mood, perception and state of 
consciousness (28,29), authors suggest that such effects would not interfere with daily 
functioning.  
Recent hypotheses maintain that the effectiveness of psychedelics in various areas of 
clinical relevance is based on an enhancement of neuroplasticity (30) and, consequently, 
of environmental sensitivity (31,32). A possible correlate of this phenomenon is the increase 
in suggestibility that was observed in individuals who took LSD (33). While evidence seem 
to indicate that hypnotic suggestions may lead to a certain degree of relief in patients 
suffering from both procedural and chronic pain (34,35), such techniques were never tested 
as potential tools to improve the effectiveness of psychedelics in both the fields of psychiatry 
and pain management. 
Fibromyalgia (FM) is a syndrome characterised by widespread pain, fatigue, sleep 
disturbances and cognitive impairment that imposes a considerable burden on patients’ 
quality of life (QOL) (36,37) along with high direct and indirect costs (38–40). Comorbid 
depression is common (41,42) as well as high anxiety (43). With a prevalence between 
0.2% and 6.6% (44) in the general population, it is the second most common 
rheumatological disorder (45) and its diagnostic criteria have changed in recent years. 
Current guidelines require the fulfilment of 3 conditions (46): a) Widespread Pain Index ≥ 7 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
13 of 61 
 
 
and Symptom Severity Score ≥ 5 or Widespread Pain Index between 3–6 and Symptom 
Severity Score ≥ 9; b) Symptoms have been present at a similar level for at least 3 months; 
c) The patient does not have a disorder that would otherwise sufficiently explain the pain. 
While multifocal pain is considered the primary manifestation of the condition, its other 
clinical features led to its inclusion in a group of diagnoses called central sensitivity 
syndromes which contain irritable bowel syndrome, chronic fatigue syndrome and 
temporomandibular joint dysfunction among others (47). More specifically, current 
consensus holds that FM results from augmented sensory and pain processing as 
evidenced from lower thresholds for pain, heat, cold, electrical and auditory stimuli (45). Its 
primary causes are considered to reside in dysfunctions of both descending and ascending 
neural pathways resulting in decreased pain inhibitory functions and facilitated pain 
signalling (48,49). Among other factors responsible for the pathogenesis of FM, evidence 
points to mechanisms related to peripheral neuro-inflammation (50) that may be triggered 
by trauma and/or psychological stress, oxidative stress (51), poor sleep quality (52) and 
vitamin deficiency (53–56). Recent evidence emphasises the role of factors such as 
resilience (57), psychological trauma (58), auto-immune reactions (59), gut microbiome 
(60), neuromuscular efficiency (61,62) and neuroendocrine dysregulation (63). 
Twin studies suggest that half of the risk of developing fibromyalgia is due to genetic factors 
(64). More specifically, genes responsible for the serotonin receptor 2A region of 
chromosome 13, the serotonin transporter gene regulatory region, and the HLA region of 
chromosome 6 (65) along with polymorphisms of catecholamine methyltransferase 
(COMT), dopamine-D-3 receptor and adrenergic receptor genes (66). 
Multiple treatments have been proposed for FM including exercise (67), electrotherapy (68), 
pharmacological therapies (69), cognitive-behavioural therapy (70), mindfulness (71,72) 
and mindfulness-based stress reduction (73), attachment-based compassion therapy (74) 
and acupuncture (75). Despite the variety of options, a recent meta-analysis reveals that 
only some of these therapies are associated with small improvements in pain ratings and 
QOL and concludes that evidence is still lacking for most of them (76). 
Given the current need of effective treatments for FM and the analgesic potential that 
low, non-hallucinogenic doses of serotonergic psychedelics have shown in surveys, clinical 
studies and controlled experiments recruiting healthy volunteers, we present a proposal to 
investigate the effects that such agents may have on improving pain perception in FM 
patients. Furthermore, since psychedelics seem to increase blood levels of brain derived 
neurotrophic factor (BDNF) (77,78) and this increase has been hypothesised to play a role 
in determining clinical outcomes (77,78), we will determine its concentration across the 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
14 of 61 
 
 
study days and to test its association with the potential analgesic effects of psilocybin. 
Finally, since recent studies showed that psilocybin has anti-inflammatory properties (167) 
and have proposed its use to reduced peripheral neuroinflammation, we will assess its 
acute and persisting effects on inflammatory markers associated with FM and psychiatric 
conditions 
 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
15 of 61 
 
 
2. OBJECTIVES 
Primary Objective: The primary objective is to assess the effects of low psilocybin doses 
on pain perception in FM patients and their association with BDNF levels. 
  
Secondary Objective(s): The secondary objective is to assess the impact of low psilocybin 
doses on mood, cognition, personality, autobiographical memory functioning and 
psychedelic experience. We will also test whether hypnotic suggestions can moderate the 
potential effects of psilocybin on pain perception and tolerance. 
 
Primary Hypothesis: We hypothesize that psilocybin will induce significant analgesic 
effects at 5 mg and 10 mg compared to placebo as measured by subjective measures and 
the outcomes of the PPT and CPT. We also hypothesize that these potential effects will be 
associated with variations in BDNF levels. 
 
Secondary Hypothesis: We hypothesize that 5 mg and 10 mg of psilocybin will have mild 
to no effects on mood, cognition, and psychedelic experience compared to placebo as 
measured by the outcomes of the Digit Symbol Substitution Test (DSST), Psychomotor 
Vigilance Task (PVT), Multifaceted Empathy Test (MET), Interpersonal Reactivity Index 
(IRI), Alternate Use Test (AUT), Story writing, Profile of Mood States (POMS), 5 Dimensions 
of Altered States of Consciousness (5D-ASC), Clinical Administered Dissociative States 
Scale (CADSS), Brief Symptom Inventory (BSI), Ego Dissolution Inventory (EDI), 
Autobiographical Memory Test (AMT), Autobiographical Recollection Test (ART) and of a 
VAS. Additionally, given the recent interest on the effects that psychedelics have on 
personality, we will administer the Big Five Inventory (BFI) and the Interpersonal Reactivity 
Index (IRI) at the beginning and end of the study. Finally, we expect to find an interaction 
between psilocybin and hypnotic suggestions and hypothesize that participants undergoing 
CPT after receiving hypnotic suggestions will report lower pain intensity and show greater 
pain tolerance. 
 
3. STUDY DESIGN 
The study will use a double-blind, placebo controlled, design. 35 FM patients will receive 
placebo and 2 different doses of psilocybin (5 or 10 mg) in a randomized design. Effects on 
pain perception, mood and cognitive performance will be repeatedly measured throughout 
the study day. Data will be collected in two collaborating centres: 1) the department of 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
16 of 61 
 
 
Neuropsychology and Psychopharmacology, FPN (Maastricht) and the department of 
Anaesthesiology, LUMC (Leiden). 
 
4. STUDY POPULATION 
4.1. Population (base)  
Potential male and female volunteers (18 to 65 years of age) will be recruited from the 
general population.  Volunteers will have to fulfil a number of general inclusion and exclusion 
criteria before being admitted to the study. Initial screening includes a questionnaire on 
medical history and a standard medical screening. Volunteers will then undergo a 
psychiatric history screening (including use of medication, alcohol, nicotine, and other 
drugs) and medical screening including an electrocardiogram, blood biochemistry and 
haematology, urinalysis for drug screening and pregnancy (in women of childbearing 
potential), and a routine medical examination including vital signs. In total, 35 volunteers 
will be selected for participation.  Volunteers will be treated according to the international 
convention governing drug studies in human volunteers; i.e. the declaration of Helsinki and 
its amendments (World-Medical-Association, 2013). 
4.2. Eligibility 
In order to be eligible to participate in this study, volunteers must meet all of the following 
criteria: 
4.2.1. Inclusion Criteria 
● Age between 18 and 65 years 
● Normal weight, body mass index (weight/height2) between 18 and 28 kg/m2 
● Fulfilment of the American College of Rheumatology criteria for FM diagnosis (43) 
● A minimum NRS pain score of 5 out of 10 
● Proficient knowledge of the Dutch  or English language 
● Written Informed Consent 
● Understanding the procedures and the risks associated with the study 
● !"#$%&'()$#'*%#"+#,*-./"0$",1.#2%31.)01"4#*'./#)*#",1)0%*5#)4013%,$%**)40*5#2'*.(%#
$%()6)40*5# )401."47'(*)40*5# *(%%,# )13*5# 8%49"31)9%,14%*:# !"4# ,/)$2)."("&1.)(#
$%&12%4*#;1((#8%#)((";%3#)("4&#<#$%*.'%#0/%$),-#*'./#)*#).%0)214",/%4#=>5???#
2&@3)-5# 18',$"+%4# =<5A??# 2&@3)-5# 4),$"6%4# =BB?# 2&@3)-5# "$# C%0",$"+%4# =DE#

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
17 of 61 
 
 
2&@3)-:# F*%# "+# ,)$).%0)2"(# GHIJK# )43# 4"4L*0%$"13)(# )401L14+()22)0"$-# 3$'&*#
G!MNOPMK#;1((#8%#)((";%3#)43#2"410"$%3: 
● Willingness to refrain from taking psychoactive substances during the study. 
● Willingness to drink only alcohol-free liquids and no coffee, black or green tea, or 
energy drinks after midnight of the evening before the study session, as well as 
during the study days  
● Willingness not to drive a traffic vehicle or to operate machines within 24 h after 
substance administration  
 
4.2.2. Exclusion Criteria 
● Presence of any other painful condition such as inflammatory rheumatic diseases, 
migraines or headaches and of other chronic or acute medical conditions 
● Presence or history of any other psychiatric condition such as primary major 
depressive disorder, anxiety disorders or substance use disorder as determined by 
the medical questionnaire, drug questionnaire and medical examination 
● Previous experience of serious side effects to psychedelic drugs (anxiety or panic 
attacks) 
● Tobacco smoking (>20 per day) 
● Excessive drinking (>20 alcoholic consumptions per week) 
● Psychotic disorder in first-degree relatives 
● Pregnancy or lactation 
● Hypertension (diastolic > 90 mmHg; systolic > 140 mmHg) 
● History of cardiac dysfunctions (arrhythmia, ischemic heart disease…) 
● 
For women: no use of a reliable contraceptive 
 
4.3. Sample size calculation 
The primary outcome is pain perception (pain tolerance time in seconds) in the 3 different 
treatment conditions: placebo, 5 mg or 10 mg of psilocybin. While there are no other studies 
in clinical settings investigating the role of psilocybin on pain perception, a recent work 
focused on the analgesic effects of another serotonergic psychedelic: LSD (79). Results 
show that 20 μg led to significant improvements (η2=0.09). Considering these findings, a 
total sample size of 28 individuals be sufficient to achieve a power of 95% (α = 0.05).  Since 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
18 of 61 
 
 
we expect about 20% of participants to drop out of the study, we plan to recruit 35 
participants in total. 
 
5. TREATMENT OF SUBJECTS 
5.1. Investigational product/treatment 
35 FM patients will receive placebo and oral doses of 5 mg or 10 mg of psilocybin in a 
double-blind, randomized, placebo-controlled design. All participants will receive a brief 
hypnotic induction aimed at producing analgesia before the second administration of CPT. 
5.2. Use of co-intervention (if applicable) 
Participants will be asked to refrain from any drugs, except PCM and NSAIDS 5 days, before 
the first study day and during the whole study period. Subjects will not be allowed to use 
alcohol on the day prior to an experimental session. 
5.3. Escape medication  
NA 
 
6. INVESTIGATIONAL PRODUCT  
6.1. Name and description of investigational product(s) 
Psilocybin will be administered to study its effects on pain perception, mood, cognition and 
psychedelic experience in FM patients. Along with psilocin, it is the primary psychoactive 
compound of psilocybe mushrooms and its effects are mediated by the 5HT2A as well as 
the 5HT1A and 5HT2C serotonin receptors (2,3). Subjective effects are mostly blocked by the 
5-HT2 antagonist ketanserin (80–82) and psychedelic effects occur at doses above 15 mg 
(83). Participants will receive two doses of psilocybin (5 mg or 10 mg) on two different 
occasions while in a third occasion they will receive microcrystalline cellulose (MCC) as a 
placebo. 
6.2. Summary of findings from non-clinical studies 
Psilocybin is the prodrug of the tryptamine psilocin (4-hydroxy-dimethyltryptamine), the 
primary hallucinogenic component of magic mushrooms. Psilocin exerts its effects through 
the serotonergic system, with pharmacodynamic research indicating that its psychedelic 
mechanism of action is through agonism on the serotonin 2A (5-HT2A) receptor (84). 
However, some of psilocin’s psychoactive effects may also be due to downstream effects 
on other neurotransmitter systems, like glutamate and dopamine (85).  
Psilocybin has variable psychological effects depending on the dose and the personal 
conditions such as experience with the drug and mood. Use of psilocybin leads to closed-

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
19 of 61 
 
 
eye hallucinations, in which individuals see multicolored geometric shapes and imaginative 
sequences (85). Further subjective effects consist of intended feelings of relaxation, 
euphoria, giddiness, joy, uncontrollable laughter, disorientation, and in some cases anxiety 
or paranoia (86).  
The physical effects of psilocybin may include increased heart rate, dilation of pupils, 
dizziness, weakness, muscle aching, shivering, and nausea and abdominal pain (87). 
However the latter are thought to be due to the recreational consumption of mushrooms, 
and not attributed to psilocybin itself. These effects are temporary and disappear a few 
hours after use. Additionally, previous research has demonstrated that psilocybin affects 
both subjective and physiological parameters in a dose-dependent manner (85,88–90).  
Early and modern non-clinical research shows that psilocybin, if administered in 
appropriately controlled environments, shows a good safety profile (6,7,91), low toxicity 
(87,92,93) and bears no risk of engendering dependence or addiction (92,94,95). 
Furthermore, its use in recreational settings is associated with a lower rate of required 
emergency medical treatment compared to substances such as alcohol, cannabis or 
methamphetamine (96). Further evidence shows that lifetime use of psychedelics such as 
psilocybin is not associated with the risk of developing mental health conditions or 
decreased cognitive function (93,94,97–99). The analgesic potential of psilocybin and LSD 
(both 5-HT receptor agonists) was investigated in 3 surveys addressed to patients suffering 
from cluster headaches (21–23). More specifically, participants from all three surveys 
reported that both psilocybin and LSD aborted attacks, induced their termination and 
extended the duration of remission periods even when took in low, non-hallucinogenic 
doses. A recent study on healthy volunteers who received microdoses of LSD showed that 
20 µg improved pain tolerance and ratings of unpleasantness with a medium to large effect 
size (24). The magnitude of this improvement is comparable to what was observed in 
studies employing opioids (25,26). Furthermore, this dosage caused only small increases 
in anxiety, somatisation, amnesia, depersonalisation, derealisation and dissociation ratings. 
Earlier studies show that a similar dose (26 µg of LSD) has no or little effect on cognitive 
function, mood, perception and state of consciousness (28,29) and its impact on subjective 
experience and functioning seems smaller than that of other pain management compounds 
such as cannabis or ketamine (100). 
6.3. Summary of findings from clinical studies 
Most clinical evidence on the effectiveness of 5-HT receptor agonists on pain comes from 
early studies employing LSD and involving patients affected by life-threatening conditions. 
More specifically, a prospective non-randomised study showed that a 0.1 mg dose of LSD 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
20 of 61 
 
 
was more effective than hydromorphone HCl, 2 mg., and meperidine HCl, 100 mg in 
reducing pain in a sample of patients suffering from neuropathic, ischemic or cancer-related 
pain (16). A subsequent case series involving terminal patients treated with equal doses 
showed immediate pain reductions that remained stable at the 3-week follow up (101). 
Similarly, a pre-post, no control group clinical study on a sample of 30 cancer patients, 
showed that LSD-assisted psychotherapy was associated with improvements in pain ratings 
(18). Sub-hallucinogenic doses of LSD led to improvements in pain measurements in 5 over 
7 patients suffering from phantom limb pain in a case series study (19).  
Psilocybin has been shown in two double-blind, placebo-controlled, crossover trials to 
produce rapid and enduring anxiolytic and anti-depressant effects in patients with cancer- 
related psychological distress (88,102). 
A study by Ross et al. (102) included 29 patients, each receiving a single-dose of psilocybin 
(0.3 mg/kg). Researchers reported that no pharmacological interventions were needed, no 
participants became addicted to psilocybin, and there were no cases of prolonged 
psychosis. The most common psychiatric adverse effects were transient anxiety (17%) and 
transient psychotic-like symptoms (7%). The most common medical adverse events (AE) 
were non-clinically significant elevations in blood pressure and heart rate (76%), headaches 
(28%), and nausea (14%). 
The study by Griffiths et al. (12) included 51 patients, each receiving a low dose (3 mg/70 
kg) and a high dose (30 mg/70 kg) of psilocybin. The most common psychiatric adverse 
effects were transient anxiety (15% in the low-dose, 26% in the high-dose) and 
psychological discomfort (12% in the low-dose, 32% in the high-dose). The most common 
medical AE were non-clinically significant elevations in systolic (17% in the low dose, 34% 
in the high-dose) and diastolic (2% in the low-dose, 13% in the high-dose) blood pressure. 
Neither aforementioned study reported serious adverse effects. Furthermore, patients in 
both studies reported immediate and sustained improvements in anxiety and depression, 
spiritual wellbeing, attitude toward death, and increased quality of life. At the 6 months follow 
up, psilocybin was further associated with enduring positive effects in 80% of the 
participants. 
6.4. Summary of known and potential risks and benefits 
Psilocybin is considered to be safe when administered in appropriately controlled settings 
(87,91–96) and can incite feelings of relaxation euphoria, giddiness, and joy, and lead 
to altered perception of reality. These sensory distortions may be coupled with negative 
effects like restlessness, anxiety, and a sense of unreality. Thus, the most important acute 
adverse effects are anxiety and panic attacks, and with regard to somatic effects, increased 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
21 of 61 
 
 
heart rate. However a recent survey among 600 subjects showed that the drug effects of 
psilocybin were considered beneficial with a relatively low harm potential (86).  
Carbonaro et al. (103), considering the totality of research related administrations (n. 380) 
of full doses of psilocybin at Johns Hopkins Hospital Center for Psychedelic and 
Consciousness Research, reported that instances of behaviours that could have potentially 
put participants or staff members at risk occurred in 0.9% of cases (uncommon events 
according to the MedDRA international guidelines). Examples of such behaviours are 
vigorous movements and disorientation. Furthermore, in 0.9% of cases, subjects reported 
psychological distress potentially caused by psilocybin that eventually encountered 
spontaneous remission or were found to be related to a yet undiagnosed case of 
hyperthyroidism. Comparable rates of AE were reported in another paper by Studerus et al. 
(104) who pooled data of 110 participants from several studies. 
Under controlled and supportive conditions, the psilocybin experience reportedly had lasting 
positive effects (103) such as decreased depression (105) and anxiety (106); improved 
openness, social relations, altruism (107,108), mood (8,88,109,110), mindfulness (111) and 
QOL (8,112,113). 
6.5. Description and justification of route of administration and dosage 
The study will use low doses of psilocybin (5 mg or 10 mg), all given orally. These low doses 
(114) are justified by the intent to achieve greater pain tolerance in the absence of 
psychedelic effects. These doses are smaller than others used in previous studies (115–
118) and that were shown to be well tolerated. 
6.6. Dosages, dosage modifications and method of administration 
Psilocybin will be administered in the form of 1 or 2 5 mg capsules. In the 5 mg condition 
participants will take 1 psilocybin capsule and 1matching placebo capsule; in the 10 mg 
condition participants will take 2 psilocybin capsules; in the placebo condition participants 
will take 2 matching placebo capsules. 
6.7. Preparation and labelling of Investigational Medicinal Product 
Psilocybin is obtained as 5 mg capsules and will be provided by the Usona Institute 
(www.usonainstitute.org) along with matching placebo. 
6.8. Drug accountability 
LUMC’s pharmacy will import the study medication from Almac Clinical Services, blind the 
treatments and prescribe them to Prof. Albert Dahan. Half of the treatment batch will be 
then sent to MUMC pharmacy that will prescribe the treatments for the Maastricht site to 
Dr. Cees van Leeuwen. In the trial master files, a drug accountability log will be kept where 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
22 of 61 
 
 
information about distribution and return will be registered. An import licence will be 
obtained. 
 
7. NON-INVESTIGATIONAL PRODUCT 
7.1. Name and description of non-investigational product(s) 
Subjects will receive identical MCC capsules serving as placebo. 
7.2. Summary of findings from non-clinical studies 
NA 
7.3. Summary of findings from clinical studies 
NA 
7.4. Summary of known and potential risks and benefits 
None 
7.5. Description and justification of route of administration and dosage 
Capsules identical to the psilocybin ones will be provided to participants. 
7.6. Dosages, dosage modifications and method of administration 
Subjects will receive identical MCC capsules serving as placebo. 
7.7. Preparation and labelling of Non Investigational Medicinal Product 
Identical MCC capsules will be used. 
7.8. Drug accountability 
In the trial master file, there will be drug accountability log where information about 
distribution and return will be registered. 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
23 of 61 
 
 
8. METHODS 
8.1. Study parameters/endpoints 
8.1.1. Main study parameter/endpoint 
• 
Pressure Pain Threshold (PPT) 
• 
Cold pressor task (CPT) 
o Pain tolerance time (in seconds) 
o Subjective pain ratings (Visual Analogue Scale) 
• 
Brief Pain Inventory  - Short Form (BPI) 
8.1.2. Secondary study parameters/endpoints (if applicable) 
• 
Subjective effects  
o 5 Dimensions of altered states of consciousness (5D-ASC)  
o Profile of mood states (POMS) 
o Visual analogue scales (VAS) 
o Ego Dissolution Inventory (EDI) 
o Clinical Administered Dissociative States Scale (CADSS) 
o Brief Symptom Inventory (BSI) 
• 
Cognitive performance  
o Digit Symbol Substitution Test (DSST) 
o Psychomotor Vigilance Task (PVT)  
o Multifaceted Empathy Test (MET)  
o Alternate Use Test (AUT) 
o Story Writing 
• 
Autobiographical memory 
o Autobiographical Memory Test (AMT) 
o Autobiographical Recollection Test (ART) 
8.1.3. Other study parameters (if applicable) 
● Treatment expectancy 
o Credibility/Expectancy Questionnaire (CEQ) 
o Treatment Expectations in Chronic Pain (TEC) 
● FM Pain and impact 
o Fibromyalgia Impact Questionnaire (FIQ) 
● Personality 
o Big Five Inventory (BFI) 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
24 of 61 
 
 
o Modified Tellegen Absorption Scale (MODTAS) 
o Interpersonal Reactivity Index (IRI) 
● Depression 
o Beck Depression Inventory – II (BDI-II) 
 
 
8.2. Randomisation, blinding and treatment allocation 
Each participant will receive 2 different doses of psilocybin and a matching placebo on three 
separate occasions.  
With these 3 treatment conditions there will be a total of 6 possible treatment orders which 
will be allocated to 35 subjects. Blinding will be handled by the LUMC pharmacy and order 
and allocation of the treatment to each participant will be completely randomized. This setup 
ensures that neither the participant nor the experimenter running the test day will be aware 
of the contents of the capsule. 
Following completion of all data collection, the study will be fully unblinded. If necessary, 
e.g. in cases of emergency, the principal investigator will break the blind on a study day. It 
is not possible that the code can be broken by accident or technical issues.  
 
8.3. Study procedures 
Screening: Prior to participation, subjects will have to sign the informed consent form, after 
which they will be requested to fill out a drug and medical questionnaire. Eligible subjects 
are invited for a physical examination (including medical examination, medical history 
anamnesis, ECG). Routine laboratory blood tests (10ml) are performed at the screening 
examination including creatinine, ASAT, ALAT, hemoglobin, hematocrit, white blood cell 
count, red blood cell count, and platelet cell count. Urine tests for urine drug screens as well 
as pregnancy tests in women will be performed. The recruitment process will be supervised 
by Prof. Albert Dahan MD who has ample clinical experience in diagnosing and treating 
patients suffering from FM. When there is no medical objection for participation, subjects 
will be included into the study and invited to a training session during which they will be 
familiarized with the study procedures, questionnaires and trained on the cognitive tasks. 
In case of incidental medically relevant findings, the study physician will contact the subject 
and discuss further steps. All participants will then be advised to contact their general 
practitioner (GP). FM patients’ GPs will be directly informed of the participation by the 
researchers. 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
25 of 61 
 
 
Participants will also be informed about and familiarized with the study procedures, used 
questionnaires will be explained, and they will be trained on the cognitive tasks. 
8.4. Schedule of experimental session: 
Table 1 shows the schedule of events for each experimental session. Each of the 3 test 
sessions lasts for 7h. Subjects will arrive between 9 AM and 10 AM at the test site. Subjects 
are requested to have a light breakfast at home (no caffeine). Pregnancy, drug, and alcohol 
screens will be performed first, using a urine pregnancy and drug test and breathalyzer. In 
case of a positive screen for pregnancy or cannabis, cocaine, alcohol, opiates, 
benzodiazepine, methamphetamine or amphetamine, subjects will be sent home to return 
to the laboratory at a later time. In case tests are negative, an indwelling intravenous 
catheter will be inserted into a subcutaneous vein of the forearm and baseline measures 
will be obtained. Psilocybin or placebo will be administered at 10 AM. All participants will 
always take 2 identical capsules in each condition (2 MCC capsules for the placebo 
condition, 1 psilocybin capsule and 1 MCC capsule for the 5mg condition, 2 psilocybin 
capsules for the 10 mg condition). Outcome measures (see below) will repeatedly be 
assessed during the study session. Subjects will be under continuous medical supervision 
until 6h after drug administration and if necessary, will be additionally supervised until any 
alterations of consciousness have completely subsided (<10% of maximum effects on the 
VAS). There will be a washout phase of at least 5 days between each study day. An 
additional online visit will be performed 1 week after the last study day to administer post 
study measures. 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
26 of 61 
 
 
8.5. Measurements: 
 
 
 
 
 
Pressure Pain Threshold (PPT) 
We will use the FPN 100 N Algometer (FDN 100, Wagner Instruments Inc., Greenwich, CT, 
USA) (119) to deliver pressure pain on a skin area of 1 cm2 between thumb and index 
finger. The FDN 100 has a force capacity (± accuracy) of 100 ± 2 N (10 ± 0.2 kgf) and 
graduation of 1 N (100 gf), respectively. A gradually increasing pressure is manually applied 
and the subjects are asked to indicate when the procedure becomes painful (pressure pain 
threshold, PPT, in kPa). 
 
Cold Pressor Task (CPT) 
The Cold Pressor Task (CPT) (120) will be used to induce a painful sensation. A water tank 
will be filled with water that was cooled to 3°C. Participants will be informed that the 
procedure could be painful and that they will be able to stop the task at any point without 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
27 of 61 
 
 
consequences. The instructions before immersion will be as follows: “The aim of the task is 
to submerge your right hand in this cold water tank for as long as possible until you cannot 
take it anymore. When you cannot take it any longer, you are allowed to remove your hand 
from the water. Try, however, to hold on as long as possible.” The immersion duration will 
be set to 3 min. Participants will not be aware of this time limit. If the 3 min maximum will be 
achieved, the experimenter will signal the participant to remove the hand from the water. 
Dependent measures of the CPT include pain tolerance (seconds), i.e. the number of 
seconds until withdrawal of the hand from the water tank, and subjective ratings of 
painfulness, unpleasantness and stress as assessed on 10cm visual analogue scales. 
Water temperature at onset and completion of the CPT will be assessed as control measure. 
The CPT will be administered repeatedly throughout the day (Table 1) after the PPT with a 
5 minutes interval between the two. At the 2.5 hours mark (between the first and last CPT), 
participants will receive an additional CPT plus hypnotic suggestions. Before the second 
CPT session, participants will listen to a 10-minute-long audio recording of a hypnotic 
induction structured to promote analgesia. The script will be structured in 4 parts: a) 
induction phase to focus attention inward, b) imagery suggestions aimed at reaching a 
comfortable place, c) suggestions evoking strength, confidence, resistance to cold, 
dissociation of the hand and relaxation while doing the CPT, d) alerting. The structure of the 
script will be developed by a trained hypnotherapist and will be based on recent studies 
investigating the analgesic potential of hypnosis in enduring experimental pain-related tasks 
(121,122). 
 
 
Subjective Effects 
Visual analogue scale (VAS) 
A visual analogue scale measuring the subjective drug effects will be repeatedly used to 
assess the drug effect over time. The visual analogue scale will be presented as 100 mm 
horizontal lines marked with “not at all” on the left and “extremely” on the right. VAS scales 
will be administered repeatedly during the study day (Table 1). 
 
Altered states of consciousness questionnaire (5D-ASC) 
The 5 dimensions of altered states of consciousness (5D-ASC) scale is a visual analogue 
scale consisting of 94 items (123,124). The instrument is constructed of five scales and 
allows the assessment mood, anxiety, derealization, depersonalization, changes in 
perception, auditory alterations, and reduced vigilance. The scale is well-validated and has 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
28 of 61 
 
 
been used across different groups with various psychedelic substances (4,85,88,125). The 
5D-ASC scale will be administered once at the end of the session and subjects are 
instructed to retrospectively rate peak alterations during the study session. Each item of the 
scale is scored on a 0-100 mm VAS. The 5D-ASC will be administered once at the end of 
the day (Table1). The 5D-ASC will be administered once at the end of the day (Table 1). 
 
Profile of mood states (POMS) 
The profile of mood states (POMS) questionnaire (126) is a self-assessment mood 
questionnaire that will be used to assess mood before and after drug intake. It consists of 
32 visual analogue scales of 100mm. It will be administered repeatedly to assess the 
different states of mood over time. The questionnaire allows quantification of eight mood 
states (anxiety, depression, anger, vigour, fatigue, confusion, friendliness, and elation), as 
well as two composite scales (arousal and positive mood). The POMS will be administered 
repeatedly throughout the day (Table 1). 
 
Clinician Administered Dissociative States Scale (CADSS) 
The Clinician Administered Dissociative States Scale (CADSS) (127) comprises 19 
subjective items, ranging from 0 ‘not at all’ to 4 ‘extremely. It is divided into 3 components: 
1) depersonalization, 2) derealization and 3) amnesia. Summed together, these subscales 
form a total dissociative score. The CADSS is specifically designed to be a standardized 
measure of present-state dissociative symptomatology. The CADSS will be administered 
repeatedly throughout the day (Table 1). 
 
Ego dissolution inventory (EDI) 
The Ego-Dissolution Inventory (EDI) (128) is a self-report scale that will be used to assess 
ego-dissolution after drug intake. The questionnaire consists of 8-items in which participants 
have to rate retrospectively, including: I experienced a dissolution of my “self” or ego; I felt 
at one with the universe; I felt a sense of union with others; I experienced a decrease in my 
sense of self-importance; I experienced a disintegration of my “self” or ego; I felt far less 
absorbed by my own issues and concerns; I lost all sense of ego; All notion of self and 
identity dissolved away. The EDI will be administered once at the end of the day (Table 1). 
 
Brief Symptom Inventory (BSI) 
The Brief Symptom Inventory (129) is a shortened version of the widely used Symptom 
Check List 90. The BSI18 contains only the three six-item scales somatization (SOMA), 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
29 of 61 
 
 
anxiety (ANX), depression (DEPR), and the global Scale Global Severity Index (GSI). It will 
be administered twice, on arrival and at the end of the day. 
 
Personality  
The Big Five Inventory (BFI) 
Personality traits are known to affect subjective responses to psychoactive substances 
(130,131). The Big Five Inventory (BFI) (132) is a 44-item inventory that measures an 
individual on the big five factors (dimensions) of personality, including extraversion, 
agreeableness, conscientiousness, and openness.  Each of the factors is then further 
divided into personality facets. The BFI will be used to assess personality traits, their 
potential modulatory effects on the responses to low doses of psilocybin and to test its 
stability after the 3 experimental sessions. It will be therefore administered at baseline and 
at the end of the study. 
 
Interpersonal Reactivity Index (IRI) 
The Interpersonal Reactivity Index IRI (133) is a 28-item questionnaire consisting of 4 
discrete seven-item scales i.e. ‘Fantasy’, F (tendency to imaginatively transpose oneself 
into fictional situations), ‘Perspective-Taking’, PT (tendency to spontaneously adopt the 
psychological viewpoint of others), ‘Empathic Concern’, EC (taps the respondents’ feelings 
of warmth, compassion and concern for others), and ‘Personal Distress’, PD (assesses self-
oriented feelings of anxiety and discomfort resulting from tense interpersonal settings). The 
IRI will be used to assess interpersonal reactivity, its potential modulatory effects on the 
responses to low doses of psilocybin and to test its stability after the 3 experimental 
sessions. It will be therefore administered at baseline and at the end of the study. 
 
Modified Tellegen Absorption Scale (MODTAS): 
The Modified Tellegen Absorption Scale (MODTAS) was derived from measures of hypnotic 
susceptibility and assesses the tendency to be deeply involved  (absorbed) by the object of 
the experience and was derived from measures of hypnotic suggestibility (134). The author 
further defined it as a disposition to surrender - in appropriate circumstances - active, 
realistic, voluntary and relatively effortful planning, and decision making and goal directed 
behaviour in favour of an effortless, non-volitional quality of deep involvement with the 
objects of consciousness (135). The MODTAS scale will be administered at baseline and 1 
week after the last experimental session. 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
30 of 61 
 
 
Cognitive effects: 
Multifaceted empathy test (MET) 
The Multifaceted Empathy Test assesses cognitive and affective empathy by inferring the 
mental state of a person in a scene and rating the intensity of how much they were feeling 
for each individual in a scene or how much they were aroused by each scene. The MET is 
a reliable and valid task to assess the cognitive and emotional aspects of empathy (136). 
The MET has been shown to be sensitive to oxytocin (137), MDMA (138,139), LSD (140), 
psilocybin (141). The computer-assisted test consists of 40 photographs that shows people 
in emotionally charged situations. To assess cognitive empathy, the participants are 
required to infer the mental state of the subject in each scene and indicate the correct mental 
state from a list of four responses. Cognitive empathy is defined as the percentage of correct 
responses in the total responses. To measure emotional empathy, the subjects are asked 
to rate how much they are feeling for an individual in each scene (i.e., explicit emotional 
empathy) and how much they are aroused by each scene (i.e., implicit emotional empathy) 
on a 9 point scale. The latter rating provides an inherent additional assessment of emotional 
empathy, which is considered to reduce the likelihood of socially desirable answers. The 
three aspects of empathy are each tested with 20 stimuli with positive valence and 20 stimuli 
with negative valence, resulting in a total of 120 trials. The test requires about 15 minutes. 
The MET will be administered once during the study day (Table 1). 
 
Alternate Use Test (AUT) 
In the AUT (142) participants are asked to list as many possible uses for three everyday 
household items and are given three minutes per item for this task. Responses are scored 
afterward by two independent raters who are blind to the treatment condition. Dependent 
outcome variables are Fluency, Originality, the ratio of Fluency and Originality, Flexibility, 
and Elaboration, and they all convey information about the level of divergent thinking of the 
participant. Fluency is defined as the total number of alternate uses produced by the 
participant. Each response will be rated for uniqueness or ‘originality’ by awarding points 
between 0-2—higher scores signal higher originality. A ‘2’ indicates that the same response 
was given by only 1% of the sample, a ‘1’ will be awarded when the response will be given 
by 5% of the sample, and when the response will be given by more than 5% of the sample, 
a ‘0’ will be awarded. Originality is the sum of the originality points. The ratio of Originality 
and Fluency is calculated as a genuine index of divergent thinking to correct Originality for 
the number of responses that were generated. If a participant would give two responses of 
‘medium’ originality, which is worth one point, and another participant would give only one 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
31 of 61 
 
 
highly original response, which is worth two points, Originality would be awarded two in total 
for both. Even though the scores are the same, the quality is not. The ratio reflects this 
difference in quality with the first participant in the example having Ratio ‘1’ and the second 
participant Ratio ‘2’. The ability to generate a diversity of responses ‘Flexibility’ will be 
assessed by clustering the responses into categories; the sum of categories will be the 
dependent variable. The amount of detail in the responses, ‘Elaboration’ was scored by 
summating the number of details. The interrater reliability will calculated before averaging 
the ratings. Statistics are reported below before findings are presented. Parallel versions 
will be used on separate test days. 
 
Story Writing 
At the beginning of the test day, participants will be given three words and the instruction 
that at noon they will have to write a story with no restrictions on the type ((non-)fiction) or 
emotional tone (happy/sad). In order to assess the level of divergent thinking or creativity 
of the story, two independent raters will assign a creativity score between zero (‘not creative 
at all’) to five (‘extremely creative’) to the stories. The creativity criterion and scoring will be 
similar to the procedure described by Wolfradt and Pretz (143) that was based on the 
‘consensual assessment technique’ (144) in which raters use their own subjective definition 
of novelty and originality to rate creativity. The interrater reliability will be calculated before 
averaging the creativity ratings. This average creativity score will be one of the dependent 
variables in this task. Statistics are reported below before findings are presented. Next to 
that, the written stories will be scored on creative and social content in an automated way 
using a ‘standard dictionary approach’ using a computer program called Linguistic Inquiry 
and Word Count (LIWC) (145,146). LIWC reports word use in percentages indicating the 
number of words used in a particular category, relative to all the words used by a particular 
participant per generated story. Next to that, there are a number of ‘summary’ variables that 
are standardized composites that have been converted to percentiles based on the 
information included in the LIWC database (145,146). We will focus on a selected number 
of categories related to psychological and social processes: Emotional Tone (summary 
variable), Family, Friends, Positive Emotion, Negative Emotion, Anxiety, Anger, Sad, 
Authentic (summary variable), Analytical thinking, and a general measure, Word Count 
(‘Fluency’). Pennebaker et al. (147) provide definitions for the summary variables. A high 
number on Emotional Tone is associated with a more positive, upbeat story style; a lower 
number reveals more significant anxiety, sadness, or hostility; a number around 50 
suggests either a lack of emotionality or different levels of ambivalence. A higher number 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
32 of 61 
 
 
of Authentic is associated with a more honest, personal, disclosing text; lower numbers 
suggest a more guarded, distanced form of discourse. A higher number of Analytical 
thinking reflects formal, logical, and hierarchical thinking, whereas lower numbers reflect 
more informal, personal, here-and-now, narrative thinking. Participants will not be explicitly 
instructed to be creative and will receive fifteen minutes to complete this task. Parallel 
versions of this task will be used on separate test days. 
 
Digit Symbol Substitution test (DSST) 
The DSST (148) is a computerized version of the original paper and pencil test taken from 
the Wechsler Adult Intelligence Scale. The participant is shown an encoding scheme 
consisting of a row of squares at the top of the screen, wherein nine digits are randomly 
associated with particular symbols. The same symbols are presented in a fixed sequence 
at the bottom of the screen as a row of separate response buttons. The randomization 
procedure is chosen such that symbols never appear at the same ordinal position within 
both rows. The encoding scheme and the response buttons remain visible while the 
participant is shown successive presentations of a single digit at the centre of the screen. 
The task is to match each digit with a symbol from the encoding list and click the 
corresponding response button. The number of digits correctly encoded within 3 minutes is 
the performance measure. The DSST will be administered repeatedly throughout the day 
(Table 1). 
 
Psychomotor vigilance task (PVT) 
The psychomotor vigilance task assesses (149) the reaction time in response to a visual 
stimulus. The visual stimulus will be a counter in the center of a computer screen that will run 
in 1 min from 0 to 60 with a fixed inter-stimulus interval of 1 ms. The counter will start at random 
intervals between 2 and 10 s, and the subject will have to react to the onset of the counter as 
quickly as possible by pressing a response button. Duration of the task will be 10 min. This 
task has often been used to assess the impact of sleep loss on performance. The PVT will be 
administered repeatedly throughout the day (Table 1). 
 
Autobiographical memory: 
Autobiographical Memory Test (AMT) 
The Autobiographical Memory Test (AMT) (165) is the most widely used instrument for 
studying the specificity of autobiographical memories. In the written version of the AMT, 
participants report autobiographical memories in response to (emotionally charged) cue 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
33 of 61 
 
 
words, and these memories can then be coded for, e.g., specificity, emotional valence, or 
pain-related content. In this study, the AMT will be used to explore the effects of psilocybin 
on the autobiographical remembering of the participants, especially on the specificity, 
emotional valence, and pain-related content of their memories, and whether any such acute 
or post-acute effects are linked to less experience of pain or pain-related distress, or other 
improvements in mental health and well-being. The AMT will be administered once during 
the test day (Table 1). 
 
Autobiographical Recollection Test (ART) 
 The Autobiographical Recollection Test (ART) (166) assesses individual differences in how 
well people think they remember personal events. The ART comprises seven theoretically 
motivated, empirically supported, interrelated aspects of recollecting autobiographical 
memories: reliving, vividness, visual imagery, scene, narrative coherence, life-story 
relevance, and rehearsal. It consists of 21 likert scale items that range from 1 (strongly 
agree) to 7 (strongly disagree). The ART will be administered at baseline and follow up. 
 
Expectations: 
Credibility/Expectancy Questionnaire (CEQ) 
The Credibility/Expectancy Questionnaire (150) is the most widely self-report measure of 
treatment credibility and expectancy. The scale was developed to be used in clinical 
outcome studies and has good psychometric qualities and is divided into two sets of items. 
The credibility set includes 3 9-point likert scale items and 1 item graded on a scale from 
0% to 100%. The expectancy set includes 2 9-point likert scale item and 1 item graded on 
a scale from 0% to 100%. The CEQ will be administered to FM patients at baseline. 
 
Treatment Expectations in Chronic Pain (TEC) 
The Treatment Expectations in Chronic Pain (151) is a reliable and valid self-report scale 
developed for use in clinical trials to investigate the role of treatment expectations in patients 
suffering from chronic non-cancer pain. It measures both ideal and predicted improvement 
by means of two sets of 9 items each, graded on a 5-point likert scale (1 = I strongly 
disagree; 5 = I strongly agree). The TEC will be administered to FM patients at baseline. 
 
Fibromyalgia Pain and Impact: 
Fibromyalgia Impact Questionnaire (FIQ): 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
34 of 61 
 
 
The Fibromyalgia Impact Questionnaire (FIQ) (152) was developed to measure the 
components that are most affected by the condition such as physical impairment, feeling 
good, missing work, doing work, pain, fatigue, restfulness, stiffness, anxiety, and 
depression. It has good psychometric properties and it shows responsiveness to change 
(153–155). The FIQ will be administered at baseline and 1 week after each experimental 
session. 
 
Brief Pain Inventory – Short Form (BPI): 
The Brief Pain Inventory – Short Form (BPI) (156) is a valid and reliable self-report 
measure (157) that assesses pain severity (BPI-S) and pain interference (BPI-I) on 0-10 
numeric scales. The BPI will be administered at baseline, at the end of each experimental 
session and 1 week after the last experimental session. 
 
Depression 
Beck Depression Inventory-II (BDI-II): 
The Beck Depression Inventory-II (BDI-II) (158) is widely used to screen for depression, 
is composed by 21 questions, each scored 0 to 3, asking about the presence of depressive 
symptoms in the pas 2 weeks. Scores between 0 and 13 indicate minimal depression, 
between 14 and 19 mild depression, between 20 and 28 moderate depression and between 
29 and 63 severe depression. The BDI-II will be administered at baseline. 
 
Blood samples:  
Blood samples for laboratory safety will be collected at screening (2x5 ml). For 
pharmacokinetic analyses, venous blood samples (8x5 ml, Lithium Heparin, per study day) 
will be collected at baseline, and at regular times after treatment to determine psilocin 
plasma concentration (see Table 1). Blood samples for plasma concentration will be 
centrifuged and plasma will be frozen at -20°C until analyses for pharmacokinetic 
assessments. Whole blood samples will be taken to measure brain-derived neurotrophic 
factor (BDNF; 4x 5ml, EDTA blood per study day). BDNF will be measured 4 times per study 
day (see Table 1). For the complete study we will collect 190 mL of blood which is about 
half a blood donation. These samples will be sent to the analytical lab in several batches 
during the study.  
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
35 of 61 
 
 
8.6. Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.7. Replacement of individual subjects after withdrawal 
Any volunteer dropping out of the study will be replaced by a volunteer receiving the 
treatment. About 4 of drop-outs are foreseen i.e. there will be spare medication for the extra 
subjects. Any test day on which a subject has been administered study medication and on 
which tests cannot be conducted, due to unforeseeable technical failures (e.g. computer 
malfunction) that occurred after drug administration, can be repeated on the next visit of the 
subject using spare medication.  
 
8.8. Follow-up of subjects withdrawn from treatment 
In case a subject withdraws or is withdrawn from the study due to an AE or SAE the usual 
procedures will be followed as stated in chapter 9 of this protocol. 
 
8.9. Premature termination of the study 
Premature study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study subjects.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
36 of 61 
 
 
9. SAFETY REPORTING 
9.1. Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study 
if there is sufficient ground that continuation of the study will jeopardise subject health or 
safety.  The sponsor will notify the accredited METC without undue delay of a temporary 
halt including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects 
are kept informed.  
9.2. AEs, SAEs and SUSARs 
9.2.1. Adverse events (AE) 
Adverse events (AE) are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to psilocybin. All AE reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
9.2.2. Serious adverse events (SAEs) 
A serious adverse event (SAE) is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a SAE. 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the 
initial preliminary report. All other SAE will be reported within a period of maximum 15 days 
after the sponsor has first knowledge of the SAE. 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
37 of 61 
 
 
9.2.3. Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC: 
− SUSARs that have arisen in the clinical trial that was assessed by the METC; 
− SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the METC. This line-listing provides an overview of all SUSARs from 
the study medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member 
States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
38 of 61 
 
 
In case of a  SUSAR blinding will be broken to allow for reporting.  
9.3. Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
− a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
− a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4. Follow-up of adverse events 
All AE will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol. 
 
9.5. Data Safety Monitoring Board (DSMB) / Safety Committee 
Not applicable to this study. 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
39 of 61 
 
 
10. STATISTICAL ANALYSIS 
Statistical analyses will be performed by the means of the latest available version of the 
statistical programs SPSS. Descriptive statistics (n, mean, standard deviation, median, 
minimum and maximum values) will be presented for continuous variables. Counts and 
percentages will be presented for categorical variables. 
10.1. Primary study parameters 
Two GLM repeated measures ANOVAs will be conducted with Treatment (0, 5 or 10 mg of 
psilocybin) and Time (1.5 and 5 hours after treatment administration) as within subject 
factors.  
In case of an overall effect, subsequent analyses for comparing Treatment, Time after 
administration carried out using posthoc tests. 
10.2. Secondary study parameter(s)  
Statistical analyses of subjective dependent variables VAS and POMS will be conducted 
using a GLM repeated measures ANOVA, consisting of the within-factors Treatment (0 mg, 
5 mg or 10 mg of psilocybin) and Time after administration (11 timepoints for VAS and 5 
timepoints for POMS). 
Statistical analyses of subjective dependent variables CADSS and BSI will be conducted 
using a GLM repeated measures ANOVA, consisting of the the within-factors Treatment (0 
mg, 5 mg or 10 mg of psilocybin) and Time (before administration, end of session). 
Statistical analyses of the subjective dependent variables 5D-ASC and EDI) will be 
conducted using a GLM repeated measures ANOVA, consisting of the the within-factors 
Treatment (0 mg, 5 mg or 10 mg of psilocybin). 
In case of overall effects, subsequent analyses investigating potential interactions will be 
carried out using posthoc tests. Bonferroni correction will be applied to correct for multiple 
comparisons and all outcomes with effect sizes and measures of precision will be included 
to prevent the risk of selective reporting. 
Data of the VAS and POMS will be checked for normality using Shapiro-Wilks tests. In case 
of normality, Pearson correlations will be used for correlation of mood changes (increase or 
decrease as change from placebo and baseline) with changes in cognitive performance and 
plasma concentrations. Spearman correlations will be used in cases of non-normality. 
Statistical analyses of a selection of the cognitive tests (MET, Story writing task, and AUT) 
will be conducted using a GLM repeated measures ANOVA, consisting of the within-subject 
factor Treatment (0 mg, 5 mg or 10 mg of psilocybin). For DSST and PVT the within-subject 
factor Time after administration (2.5 hours and 4 hours) will be included.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
40 of 61 
 
 
In case of a main effect of Treatment, or a Treatment by Time interaction exploratory 
analyses will be carried out using posthoc tests.  Bonferroni correction will be applied to 
correct for multiple comparisons and all outcomes with effect sizes and measures of 
precision will be included to prevent the risk of selective reporting. Data of the cognitive 
tests will be checked for normality using Shapiro-Wilks tests. In case of normality, Pearson 
correlations will be used for the correlation of performance change (change from placebo 
and baseline) with mood change (change from placebo and baseline) and plasma 
concentrations. Spearman correlations will be used in cases of non-normality. 
10.3. Other study parameters 
Plasma concentrations and subject expectations will be used as potential covariates in the 
above-mentioned analyses to test the influence of these variables on outcome measures. 
10.4. Interim analysis (if applicable) 
Not applicable 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
41 of 61 
 
 
11. ETHICAL CONSIDERATIONS 
11.1. Regulation statement 
This study will be conducted according to the code of ethics on human experimentation 
established by the declaration of Helsinki (1964) and amended in Fortaleza (Brazil, October 
2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO). 
This implies that all subjects will participate voluntarily and will be fully informed of all 
procedures, possible adverse events to drug treatments, legal rights and responsibilities, 
expected benefits of a general scientific nature, and their right for voluntary termination 
without penalty or censure. All subjects shall give their informed consent, in writing, and the 
individual subject’s anonymity shall be maintained in all communications from the project. 
Approval for the studies shall be obtained from the Academic Hospital and University’s 
Medical Ethics committee.  
All data will be treated confidentially using codes and only the researchers involved in the 
study will have access to the data. An independent physician is at the subjects’ disposal for 
additional information. Subjects are offered the possibility to be informed about the results 
of the study. 
11.2. Recruitment and consent 
Participants will be recruited via advertisements which will be put up in university buildings 
and published online or in local newspapers. When potential subjects react to the 
advertisement, they will receive the subject information sheet, which they are requested to 
read carefully.  
The researcher will discuss questions with the potential participant. The individual subjects’ 
pseudonymity shall be maintained in all communications on the project. They will then have 
one week to decide whether they want to participate. If they so wish and after the reflection 
period has expired, they will be invited for a medical screening. During this screening, they 
will be fully informed of all procedures, possible adverse events to drug treatments, legal 
rights and responsibilities, expected benefits of a general scientific nature, and their right 
for voluntary termination without consequences. They will also be given the opportunity to 
ask the investigator any question they may have and the investigator will check whether 
prospective participants have understood what participation entails. Only then, if still willing 
to participate, they will sign the informed consent at the presence of the investigator and will 
be included in the study. Once the consent is signed, participants will fill in the medical 
questionnaire and drug questionnaire before taking part to the medical examination. After 
all (laboratory) results are obtained, one of the researchers and the medical doctor will 
check if all in- and exclusion criteria are met. Subjects are subsequently informed whether 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
42 of 61 
 
 
they fulfil the criteria or not. In case of an incidental medically relevant finding the study 
physician will contact the subject and discuss further steps. The subject will then be advised 
to contact his/her general practitioner. If during screening participants are deemed not 
suitable for participation, they will be regarded as dropouts. 
After consent has been given, data will be collected by experimenters and will be encoded. 
All collected and encoded urine and blood samples will be destroyed after analysis.  
11.3. Objection by minors or incapacitated subjects  
Not applicable 
11.4. Benefits and risks assessment 
Potential benefits to society: The present study will provide data to clarify the potential 
role that psilocybin may have in treating symptoms in FM, a disabling condition that is 
currently considered hard to treat.   
Potential benefits to participants: Should this study consolidate earlier results obtained 
in non-clinical studies, FM participants may experience reductions in pain symptoms. 
Experiencing the altered state of consciousness under psilocybin reportedly has lasting 
positive effects (103) such as decreased depression (105) and anxiety (106); improved 
openness, social relations, altruism (107,108), mood (8,88,109,110), mindfulness (111) and 
quality of life (8,112,113). 
Risk/benefit Ratio: The risk of lasting psychological and physical harm is considered low  
(86,87,91–96,103,104). On the other hand, FM patients may experience reductions in pain 
symptoms, a pleasant alteration of their state of mind and a personally significant 
experience (8,88,103,105–108,110–113). Furthermore, the benefits will include increased 
information that will be of benefit for the society.  
11.5. Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
43 of 61 
 
 
11.6. Incentives 
Subjects will be compensated for their participation by means of a monetary reward. 
Participants will receive € 225 for their participation in the study. This is based on € 10/hour, 
plus € 15 bonus when they participate in all conditions. In case of premature termination of 
the study, compensation will be based on number of participated hours. In addition, their 
tickets for using public transport and parking fees to come to the test site and to return home 
will be reimbursed. 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
44 of 61 
 
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1. Handling and storage of data and documents 
All data is provided with a code that consists of the following information:  
- 
Project number (intern): P137 
- 
Subject number: assigned based on order of inclusion 
- 
Test day: test day 1 is labelled A; test day 2: B; test day 3: C 
- 
In case a test is repeatedly administered on a test day, the repetitions will be labelled: 
1-…. 
All data is collected in electronic and paper format. Data from the questionnaires is collected 
on paper. These (paper) source data are saved in maps which are stored in a locked cabinet 
which. Only researchers and the monitoring involved in the project have access to the 
source data. In case of inspection by national authorities, the inspectors will be granted 
access. Electronic source data is stored on a partition of a server (hosted in the University 
Building) which is only accessible to the principal investigator. The key code is safeguarded 
by the local principal investigator: Prof. Johannes G. Ramaekers for the Maastricht site and 
Prof. Albert Dahan for the Leiden site. Data will be kept for 25 years for further analyses 
regarding this study or future studies on the effects of psychedelics on mental and physical 
health. Body material will be destroyed once analyses are complete. Data will be accessible 
by the research team, interns supervised by the principal investigators, Stefan Toënnes who 
is responsible for laboratory analyses, Rafael de la Torre who is responsible for the BDNF 
analysis. The handling of data will be in accordance with the General Data Protection 
Regulation (GDPR) and the Dutch Act on Implementation of the General Data Protection 
Regulation (UAVG). As part of the contract with the Usona Institute, the supplier of the 
psilocybin, anonymised safety data will be shared with said Institute. The data will be used 
to monitor the substance safety. 
12.2. Monitoring and Quality Assurance  
Monitoring of the study will take place. The monitor, Anita van Oers, will conduct three visits 
in which she will (for details see monitoring plan): 
- 
do the verification of the source documentation 
- 
check the drug accountability plan 
- 
check the trial master file 
- 
discuss the results of the visit and write a report 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
45 of 61 
 
 
12.3. Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to affect 
to a significant degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
12.4. Annual progress report 
The sponsor will submit a summary of the progress of the trial to the accredited METC once 
a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, SAE/ serious 
adverse events, other problems, and amendments.  
 
12.5. Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last patient’s last 
visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature termination. 
The reasons for premature termination prevail over the texts in the protocol. 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
46 of 61 
 
 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority. 
12.6. Public disclosure and publication policy 
All results from this research will be disclosed unreservedly in a scientific paper aimed for 
publication in a peer reviewed scientific journal. Research data collected in the current study 
will be owned by Maastricht University. The publication conditions prevail over the texts in 
the research protocol. 
 
13. STRUCTURED RISK ANALYSIS  
13.1. Potential issues of concern 
a. Level of knowledge about mechanism of action 
Psilocybin is the prodrug of the tryptamine psilocin (4-hydroxy-dimethyltryptamine), the 
primary hallucinogenic component of magic mushrooms. Psilocin exerts its effects through 
the serotonergic system, with pharmacodynamic research indicating that its psychedelic 
mechanism of action is through agonism on the serotonin 2A (5-HT2A) receptor (84). 
However, some of psilocin’s psychoactive effects may also be due to downstream effects 
on other neurotransmitter systems, like glutamate and dopamine (85).  
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
The effects of psilocybin have been investigated previously (4,12,85,102,117,118,159) 
in studies using similar or higher doses to observe its effects on behavioral and biological 
measures similar to our study. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
No, we are specifically interested in changes in human behaviour. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Psychological Effects: Safety concerns regarding psilocybin are primarily psychological. 
Transient anxiety, restlessness and paranoia may occur in some subjects (86). These 
reactions are expected to be rare (given the small administered dose) and to resolve 
spontaneously with supportive care by the investigators (7,103,104). At the doses of 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
47 of 61 
 
 
psilocybin used in the present study, subjects are expected to retain most of their thought 
control and will remain aware of the transient state of the drug-induced experience. Rare 
events of more pronounced anxiety, panic attacks or agitation under psilocybin may be 
treated with benzodiazepine administration if needed. Additionally, the study physician can 
be contacted for assistance.  
Physiological effects: The effects of psilocybin may include increased heart rate, dilation 
of pupils,  dizziness, weakness, muscle aching, shivering, and nausea and abdominal pain 
(7,87). However, the latter are thought to be due to the recreational consumption of 
mushrooms, and not attributed to psilocybin itself. These effects are temporary and 
disappear a few hours after use. 
Additionally, previous research has demonstrated that psilocybin affects both subjective and 
physiological parameters in a dose-dependent manner (85,88–90).  
Abuse liability: psilocybin possesses little if any abuse liability. LSD is not self-
administered by animals and there is no human psilocybin dependence syndrome 
(92,94,95). 
Neurotoxicity: Psilocybin is not neurotoxic (87,92,93).  
 
e. Analysis of potential effect 
The given dose is expected to be well tolerated in participants and will induce effects such 
as relaxation, euphoria, giddiness, and joy, and lead to mild alterations in the perception of 
reality. The most important acute adverse effects of a high dose of psilocybin are anxiety 
and panic attacks, and with regard to somatic effects increased heart rate. 
 
f. Pharmacokinetic considerations 
After oral administration, psilocybin is detectable in significant amounts in the plasma within 
20-40 minutes, its active metabolite, psilocin, is detectable at about 30 minutes, with 
maximum concentrations found around 80 minutes (92). The terminal elimination half-life is 
around 160 minutes (160). 
 
g. Study population 
Participants will be FM patients aged between 18 and 65 years. All subjects will be medically 
screened. In- and exclusion criteria are mentioned under section 4.2 and 4.3. 
 
h. Interaction with other products 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
48 of 61 
 
 
Participants are not allowed to use any psychoactive medication during the study. Use of 
drugs like painkillers (e.g. ibuprofen, aspirin, paracetamol) and oral contraceptives will be 
allowed during the study. Therefore, there will be no risk of drug interactions.  
 
i. Predictability of effect 
At the doses of psilocybin to be used in the present study, subjects are expected to retain 
their thought control and will remain aware of the transient state of the drug-induced 
experience. Given the results of previous research, we expect a reduction in pain tolerance 
and painfulness ratings in the psilocybin conditions. Effects such as relaxation euphoria, 
giddiness, joy, lightly altered perception of reality and anxiety are to be expected.  
 
j. Can effects be managed? 
Noticeable effects will disappear as the drug is eliminated from the body. Any long-term 
effects are regarded as positive. No harmful side effects are expected. If a person 
experiences unwanted effects, the medical supervisor will be contacted immediately and is 
in charge for detecting the cause and the seriousness of the complaints, and to provide a 
solution.  
13.2. Synthesis 
The risk of lasting physical and psychological harm is considered low (87,91–96). With 
regard to subjective distress after psilocybin, experiencing an altered state of 
consciousness may produce transient anxiety and some tolerable adverse effects (86). FM 
participants may experience reductions in pain perception. Experiencing the altered state 
of consciousness under psilocybin reportedly has lasting positive effects (103) such as 
decreased depression (105) and anxiety (106); improved openness, social relations, 
altruism (107,108), mood (8,88,109,110), mindfulness (111) and quality of life (8,112,113). 
Furthermore, based on other studies with psilocybin, subject will mostly experience 
pleasure and positive alterations in their state of mind (103). Subjects may also participate 
because they have an interest in this specific experience which is expected to be of some 
personal value (103). 
 
 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
49 of 61 
 
 
14. REFERENCES 
1.  Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbæk DS, Kristiansen S, et al. 
Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and 
plasma psilocin levels. Neuropsychopharmacology. 2019;44(7).  
2.  Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel 
psychoactive 
tryptamines 
compared 
with 
classic 
hallucinogens. 
European 
Neuropsychopharmacology. 2016;26(8):1327–37.  
3.  Nichols DE. Psychedelics. 2016;(April):264–355.  
4.  Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Stämpfli P, et al. The 
Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 
2A Receptor Activation. Current Biology. 2017;27(3):451–7.  
5.  Liechti ME. Modern Clinical Research on LSD. Vol. 42, Neuropsychopharmacology. 2017.  
6.  Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: Guidelines for 
safety. Journal of Psychopharmacology. 2008;22(6):603–20.  
7.  Tylš F, Páleníček T, Horáček J. Psilocybin - Summary of knowledge and new perspectives. 
European Neuropsychopharmacology. 2014;24(3):342–56.  
8.  Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type 
experiences having substantial and sustained personal meaning and spiritual 
significance. Psychopharmacology. 2006;187(3):268–83.  
9.  Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin 
with psychological support for treatment-resistant depression: six-month follow-up. 
Psychopharmacology. 2018;235(2):399–408.  
10.  
Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al. 
Psilocybin with psychological support for treatment-resistant depression: an open-label 
feasibility study. The Lancet Psychiatry. 2016;3(7):619–27.  
11.  
Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstad AL, et al. Pilot 
study of psilocybin treatment for anxiety in patients with advanced-stage cancer. 
Archives of General Psychiatry. 2011;68(1):71–8.  
12.  
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. 
Psilocybin produces substantial and sustained decreases in depression and anxiety in 
patients with life-threatening cancer: A randomized double-blind trial. Journal of 
Psychopharmacology. 2016;30(12):1181–97.  
13.  
Garcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin-occasioned mystical 
experiences in the treatment of tobacco addiction. Current Drug Abuse Reviews. 
2014;7(3):157–64.  
14.  
Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-
facilitated smoking cessation. American Journal of Drug and Alcohol Abuse. 
2017;43(1):55–60.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
50 of 61 
 
 
15.  
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa P, Strassman RJ. 
Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. 
Journal of Psychopharmacology. 2015;29(3):289–99.  
16.  
KAST EC, COLLINS VJ. STUDY OF LYSERGIC ACID DIETHYLAMIDE AS AN 
ANALGESIC AGENT. Anesthesia and analgesia. 1964;43.  
17.  
Kast E. Attenuation of anticipation: A therapeutic use of lysergic acid diethylamide. The 
Psychiatric Quarterly. 1967;41(4):646–57.  
18.  
Grof S, Goodman LE, Richards WA, Kurland AA. LSD assisted psychotherapy in 
patients with terminal cancer. International Pharmacopsychiatry. 1973;8(3):129–44.  
19.  
Fanciullacci M, Bene E Del, Franchi G, Sicuteri F. Phantom Limb Pain: Sub-
Hallucinogenic Treatment With Lysergic Acid Diethylamide (LSD-25). Headache: The 
Journal of Head and Face Pain. 1977;17(3):118–9.  
20.  
Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, et al. 
Psychedelics and psychedelic-assisted psychotherapy. American Journal of Psychiatry. 
2020;177(5):391–410.  
21.  
Sewell RA, Halpern JH, Pope HG. Response of cluster headache to psilocybin and LSD. 
Neurology. 2006;66(12):1920–2.  
22.  
Schindler EAD, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell RA. 
Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters 
Medication Use Survey. Journal of Psychoactive Drugs. 2015;47(5):372–81.  
23.  
Di Lorenzo C, Coppola G, Di Lorenzo G, Bracaglia M, Rossi P, Pierelli F. The use of 
illicit drugs as self-medication in the treatment of cluster headache: Results from an 
Italian online survey. Cephalalgia. 2016;36(2):194–8.  
24.  
Ramaekers JG, Hutten N, Mason NL, Dolder P, Theunissen EL, Holze F, et al. A low 
dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. 
Journal of Psychopharmacology. 2020;  
25.  
Cooper ZD, Sullivan MA, Vosburg SK, Manubay JM, Haney M, Foltin RW, et al. Effects 
of repeated oxycodone administration on its analgesic and subjective effects in normal, 
healthy volunteers. Behavioural Pharmacology. 2012;23(3).  
26.  
Ravn P, Secher EL, Skram U, Therkildsen T, Christrup LL, Werner MU. Morphine- and 
buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain 
model: A double-blind, randomized, placebo-controlled, five-arm crossover study. 
Journal of Pain Research. 2013;6:23–38.  
27.  
Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The pharmacology of 
lysergic acid diethylamide: A review. Vol. 14, CNS Neuroscience and Therapeutics. 
2008.  
28.  
Bershad AK, Schepers ST, Bremmer MP, Lee R, de Wit H. Acute Subjective and 
Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human 
Volunteers. Biological Psychiatry. 2019;86(10).  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
51 of 61 
 
 
29.  
Yanakieva S, Polychroni N, Family N, Williams LTJ, Luke DP, Terhune DB. Correction 
to: The effects of microdose LSD on time perception: a randomised, double-blind, 
placebo-controlled trial. Psychopharmacology. 2020;237(12).  
30.  
Ly C, Greb AC, Cameron LP, Wong JM, Barragan E V., Wilson PC, et al. Psychedelics 
Promote Structural and Functional Neural Plasticity. Cell Reports. 2018;23(11):3170–
82.  
31.  
Carhart-Harris RL, Nutt DJ. Serotonin and brain function: A tale of two receptors. Journal 
of Psychopharmacology. 2017;31(9):1091–120.  
32.  
Carhart-Harris RL, Friston KJ. REBUS and the anarchic brain: Toward a unified model 
of the brain action of psychedelics. Pharmacological Reviews. 2019;71(3):316–44.  
33.  
Carhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M, Feilding A, Nutt DJ. LSD 
enhances suggestibility in healthy volunteers. Psychopharmacology. 2015;232(4):785–
94.  
34.  
Thompson T, Terhune DB, Oram C, Sharangparni J, Rouf R, Solmi M, et al. The 
effectiveness of hypnosis for pain relief: A systematic review and meta-analysis of 85 
controlled experimental trials. Neuroscience and biobehavioral reviews. 2019 Apr 
1;99:298–310.  
35.  
Jensen MP, Patterson DR. Hypnotic approaches for chronic pain management: clinical 
implications of recent research findings. The American psychologist. 2014;69(2):167–
77.  
36.  
Chinn S, Caldwell W, Gritsenko K. Fibromyalgia Pathogenesis and Treatment Options 
Update. Current Pain and Headache Reports. 2016;20(4):1–10.  
37.  
Wolfe F, Walitt B, Perrot S, Rasker JJ, Häuser W. Fibromyalgia diagnosis and biased 
assessment: Sex, prevalence and bias. PLoS ONE. 2018;13(9):1–14.  
38.  
Sicras-Mainar A, Rejas J, Navarro R, Blanca M, Morcillo A, Larios R, et al. Treating 
patients with fibromyalgia in primary care settings under routine medical practice: a 
claim database cost and burden of illness study. Arthritis research & therapy. 
2009;11(2).  
39.  
Rivera J, Rejas J, Esteve-Vives J, Vallejo MA. Resource utilisation and health care costs 
in patients diagnosed with fibromyalgia in Spain. Clinical and Experimental 
Rheumatology. 2009;27(5 SUPPL. 56).  
40.  
Lacasse A, Bourgault P, Choinière M. Fibromyalgia-related costs and loss of 
productivity: A substantial societal burden. BMC Musculoskeletal Disorders. 2016;17(1).  
41.  
Alciati A, Sgiarovello P, Atzeni F, Sarzi-Puttini P. Psychiatric problems in fibromyalgia: 
Clinical and neurobiological links between mood disorders and fibromyalgia. Vol. 64, 
Reumatismo. 2012.  
42.  
Gelonch O, Garolera M, Valls J, Castella G, Varela O, Rossello L, et al. The effect of 
depressive symptoms on cognition in patients with fibromyalgia. PLoS ONE. 
2018;13(7):1–20.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
52 of 61 
 
 
43.  
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The 
American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and 
measurement of symptom severity. Arthritis Care and Research. 2010;62(5):600–10.  
44.  
Marques AP, Santo A de S do E, Berssaneti AA, Matsutani LA, Yuan SLK. Prevalence 
of fibromyalgia: literature review update. Revista Brasileira de Reumatologia (English 
Edition). 2017;57(4).  
45.  
Fibromyalgia. In: Essentials of Pain Medicine. 2018. p. 345–50.  
46.  
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RS, et al. 
Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A 
modification of the ACR preliminary diagnostic criteria for fibromyalgia. Journal of 
Rheumatology. 2011;38(6):1113–22.  
47.  
Theoharides TC, Tsilioni I, Arbetman L, Panagiotidou S, Stewart JM, Gleason RM, et al. 
Fibromyalgia syndrome in need of effective treatments. Journal of Pharmacology and 
Experimental Therapeutics. 2015;355(2):255–63.  
48.  
Nijs J, Malfliet A, Ickmans K, Baert I, Meeus M. Treatment of central sensitization in 
patients with ‘unexplained’ chronic pain: An update. Vol. 15, Expert Opinion on 
Pharmacotherapy. 2014.  
49.  
Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked 
potentials after painful laser stimulation in patients with fibromyalgia syndrome. 
Electroencephalography 
and 
Clinical 
Neurophysiology 
- 
Evoked 
Potentials. 
1996;100(2).  
50.  
Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain 
syndrome. Vol. 11, Nature Reviews Rheumatology. 2015.  
51.  
Bozkurt M, Caglayan M, Oktayoglu P, Em S, Batmaz I, Sariyildiz MA, et al. Serum 
prolidase enzyme activity and oxidative status in patients with fibromyalgia. Redox 
Report. 2014;19(4).  
52.  
Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskeletal pain syndrome 
by selective sleep stage deprivation. Psychosomatic Medicine. 1976;38(1).  
53.  
Jesus CAS, Feder D, Peres MFP. The Role of Vitamin D in Pathophysiology and 
Treatment of Fibromyalgia. Current Pain and Headache Reports. 2013;17(8).  
54.  
Costantini A, Giorgi R, D’Agostino S, Pala MI. High-dose thiamine improves the 
symptoms of Friedreich’s ataxia. BMJ Case Reports. 2013;  
55.  
Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, et al. 
Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. 
PLoS ONE. 2015;10(4).  
56.  
Sakarya ST, Akyol Y, Bedir A, Canturk F. The relationship between serum antioxidant 
vitamins, magnesium levels, and clinical parameters in patients with primary 
fibromyalgia syndrome. Clinical Rheumatology. 2011;30(8).  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
53 of 61 
 
 
57.  
Casale R, Sarzi-Puttini P, Botto R, Alciati A, Batticciotto A, Marotto D, et al. Fibromyalgia 
and the concept of resilience. Vol. 37, Clinical and experimental rheumatology. 2019.  
58.  
Gündüz N, Erzıncan E, Polat A. The relationship of intimate partner violence with 
psychiatric disorders and severity of pain among female patients with fibromyalgia. 
Archives of Rheumatology. 2019;34(3).  
59.  
Applbaum E, Lichtbroun A. Novel Sjögren’s autoantibodies found in fibromyalgia 
patients with sicca and/or xerostomia. Vol. 18, Autoimmunity Reviews. 2019.  
60.  
Clos-Garcia M, Andrés-Marin N, Fernández-Eulate G, Abecia L, Lavín JL, van Liempd 
S, et al. Gut microbiome and serum metabolome analyses identify molecular biomarkers 
and altered glutamate metabolism in fibromyalgia. EBioMedicine. 2019;46.  
61.  
Casale R, Boccia G, Symeonidou Z, Atzeni F, Batticciotto A, Salaffi F, et al. 
Neuromuscular efficiency in fibromyalgia is improved by hyperbaric oxygen therapy: 
looking inside muscles by means of surface electromyography. Clinical and 
experimental rheumatology. 2019;37(1).  
62.  
De Lima LO, Zicarelli CAM, Matsumura AS, Moroti-Perugini LR, De Castro Teixeira D, 
Fernandes KBP, et al. Lower limb muscle strength and serotonin receptor gene 
polymorphism as factors associated in women with fibromyalgia. Advances in 
Rheumatology. 2019;59(1).  
63.  
Pednekar DD, Amin MR, Azgomi HF, Aschbacher K, Crofford LJ, Faghih RT. A System 
Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic 
Fatigue. In: Proceedings of the Annual International Conference of the IEEE 
Engineering in Medicine and Biology Society, EMBS. 2019.  
64.  
Kato K, Sullivan PF, Evengård B, Pedersen NL. Chronic widespread pain and its 
comorbidities: A population-based study. Archives of Internal Medicine. 2006;166(15).  
65.  
Arnold LM, Fan J, Russell IJ, Yunus MB, Khan MA, Kushner I, et al. The fibromyalgia 
family study: A genome-wide linkage scan study. Arthritis and Rheumatism. 2013;65(4).  
66.  
Vargas-Alarcón G, Fragoso JM, Cruz-Robles D, Vargas A, Martinez A, Lao-Villadóniga 
JI, et al. Association of adrenergic receptor gene polymorphisms with different 
fibromyalgia syndrome domains. Arthritis and Rheumatism. 2009;60(7).  
67.  
Kim SY, Busch AJ, Overend TJ, Schachter CL, van der Spuy I, Boden C, et al. Flexibility 
exercise training for adults with fibromyalgia. Vol. 2019, Cochrane Database of 
Systematic Reviews. 2019.  
68.  
Johnson MI, Claydon LS, Herbison GP, Jones G, Paley CA. Transcutaneous electrical 
nerve stimulation (TENS) for fibromyalgia in adults. Vol. 2017, Cochrane Database of 
Systematic Reviews. 2017.  
69.  
Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W. Serotonin and noradrenaline 
reuptake inhibitors (SNRIs) for fibromyalgia. Vol. 2018, Cochrane Database of 
Systematic Reviews. 2018.  
70.  
Bernardy K, Klose P, Welsch P, Häuser W. Efficacy, acceptability and safety of cognitive 
behavioural therapies in fibromyalgia syndrome – A systematic review and meta-

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
54 of 61 
 
 
analysis of randomized controlled trials. Vol. 22, European Journal of Pain (United 
Kingdom). 2018.  
71.  
Cejudo J, García-Castillo FJ, Luna P, Rodrigo-Ruiz D, Feltrero R, Moreno-Gómez A. 
Using a Mindfulness-Based Intervention to Promote Subjective Well-Being, Trait 
Emotional Intelligence, Mental Health, and Resilience in Women With Fibromyalgia. 
Frontiers in Psychology. 2019;10.  
72.  
Park M, Zhang Y, Price LL, Bannuru RR, Wang C. Mindfulness is associated with sleep 
quality among patients with fibromyalgia. International Journal of Rheumatic Diseases. 
2020;23(3).  
73.  
Pérez-Aranda A, D’Amico F, Feliu-Soler A, McCracken LM, Peñarrubia-María MT, 
Andrés-Rodríguez L, et al. Cost–Utility of Mindfulness-Based Stress Reduction for 
Fibromyalgia versus a Multicomponent Intervention and Usual Care: A 12-Month 
Randomized Controlled Trial (EUDAIMON Study). Journal of Clinical Medicine. 
2019;8(7).  
74.  
Montero-Marin J, Andrés-Rodríguez L, Tops M, Luciano J V., Navarro-Gil M, Feliu-Soler 
A, et al. Effects of attachment-based compassion therapy (ABCT) on brain-derived 
neurotrophic factor and low-grade inflammation among fibromyalgia patients: A 
randomized controlled trial. Scientific Reports. 2019;9(1).  
75.  
Zhang XC, Chen H, Xu WT, Song YY, Gu YH, Ni GX. Acupuncture therapy for 
fibromyalgia: A systematic review and meta-analysis of randomized controlled trials. 
Journal of Pain Research. 2019;12.  
76.  
Mascarenhas RO, Souza MB, Oliveira MX, Lacerda AC, Mendonça VA, Henschke N, et 
al. Association of Therapies with Reduced Pain and Improved Quality of Life in Patients 
with Fibromyalgia: A Systematic Review and Meta-analysis. JAMA Internal Medicine. 
2021;181(1):104–12.  
77.  
Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, et al. Low 
Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS 
Pharmacol Transl Sci. 2021 Apr 9;4(2):461–6.  
78.  
Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for 
the treatment of mood disorders. Nat Rev Neurosci. 2010 Sep;11(9):642–51.  
79.  
Ramaekers JG, Hutten N, Mason NL, Dolder P, Theunissen EL, Holze F, et al. A low 
dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. 
Journal of Psychopharmacology. 2020;  
80.  
Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, Vogel H, Hell D. 
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist 
action. NeuroReport. 1998;9(17):3897–902.  
81.  
Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX. Using 
psilocybin to investigate the relationship between attention, working memory, and the 
serotonin 1A and 2A receptors. Journal of Cognitive Neuroscience. 2005;17(10).  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
55 of 61 
 
 
82.  
Carter OL, Hasler F, Pettigrew JD, Wallis GM, Liu GB, Vollenweider FX. Psilocybin links 
binocular rivalry switch rate to attention and subjective arousal levels in humans. 
Psychopharmacology. 2007;195(3).  
83.  
Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and 
physiological affects of psilocybin in healthy humans: A double-blind, placebo-controlled 
dose-effect study. Psychopharmacology. 2004;172(2).  
84.  
Baumeister D, Barnes G, Giaroli G, Tracy D. Classical hallucinogens as 
antidepressants? A review of pharmacodynamics and putative clinical roles. Vol. 4, 
Therapeutic Advances in Psychopharmacology. 2014.  
85.  
Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and 
physiological affects of psilocybin in healthy humans: A double-blind, placebo-controlled 
dose-effect study. Psychopharmacology. 2004;172(2):145–56.  
86.  
Carhart-Harris RL, Nutt DJ. User perceptions of the benefits and harms of hallucinogenic 
drug use: A web-based questionnaire study. Journal of Substance Use. 2010;15(4).  
87.  
Amsterdam J van, Opperhuizen A, Brink W van den. Harm potential of magic mushroom 
use: A review. Regulatory Toxicology and Pharmacology. 2011;59(3):423–9.  
88.  
Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin 
occasioned mystical-type experiences: Immediate and persisting dose-related effects. 
Psychopharmacology. 2011;218(4).  
89.  
Lyvers M, Meester M. Illicit Use of LSD or Psilocybin, but not MDMA or Nonpsychedelic 
Drugs, is Associated with Mystical Experiences in a Dose-Dependent Manner. Journal 
of Psychoactive Drugs. 2012;44(5).  
90.  
Wackermann J, Wittmann M, Hasler F, Vollenweider FX. Effects of varied doses of 
psilocybin on time interval reproduction in human subjects. Neuroscience Letters. 
2008;435(1).  
91.  
Aday JS, Mitzkovitz CM, Bloesch EK, Davoli CC, Davis AK. Long-term effects of 
psychedelic drugs: A systematic review. Neuroscience and Biobehavioral Reviews. 
2020;113(November 2019):179–89.  
92.  
Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addiction 
Biology. 2002;7(4):357–64.  
93.  
Halpern JH, Pope HG. Do hallucinogens cause residual neuropsychological toxicity? 
Vol. 53, Drug and Alcohol Dependence. 1999.  
94.  
Nichols DE. Hallucinogens. Pharmacology and Therapeutics. 2004;101(2):131–81.  
95.  
Fantegrossi 
WE, 
Woods 
JH, 
Winger 
G. 
Transient 
reinforcing 
effects 
of 
phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys. 
Behavioural Pharmacology. 2004;15(2).  
96.  
Castellanos JP, Woolley C, Bruno KA, Zeidan F, Halberstadt A, Furnish T. Chronic pain 
and psychedelics: A review and proposed mechanism of action. Regional Anesthesia 
and Pain Medicine. 2020;45(7):486–94.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
56 of 61 
 
 
97.  
Nichols DE, Johnson MW, Nichols CD. Psychedelics as Medicines: An Emerging New 
Paradigm. Clinical Pharmacology and Therapeutics. 2017;101(2).  
98.  
Byock I. Taking Psychedelics Seriously. Journal of Palliative Medicine. 2018;21(4).  
99.  
Gable RS. Comparison of acute lethal toxicity of commonly abused psychoactive 
substances. Vol. 99, Addiction. 2004.  
100.  van Heugten-Van der Kloet D, Giesbrecht T, van Wel J, Bosker WM, Kuypers KPC, 
Theunissen EL, et al. MDMA, cannabis, and cocaine produce acute dissociative 
symptoms. Psychiatry Research. 2015;228(3).  
101.  Kast E. Attenuation of anticipation: A therapeutic use of lysergic acid diethylamide. The 
Psychiatric Quarterly. 1967;41(4):646–57.  
102.  Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and sustained 
symptom reduction following psilocybin treatment for anxiety and depression in patients 
with 
life-threatening 
cancer: 
A 
randomized 
controlled 
trial. 
Journal 
of 
Psychopharmacology. 2016;30(12):1165–80.  
103.  Carbonaro TM, Bradstreet MP, Barrett FS, MacLean KA, Jesse R, Johnson MW, et al. 
Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute 
and enduring positive and negative consequences. Journal of Psychopharmacology. 
2016;30(12):1268–78.  
104.  Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term 
subjective effects of psilocybin in healthy humans: A pooled analysis of experimental 
studies. Journal of Psychopharmacology. 2011;25(11):1434–52.  
105.  Barrett FS, Preller KH, Kaelen M. Psychedelics and music: neuroscience and 
therapeutic implications. Vol. 30, International Review of Psychiatry. 2018.  
106.  Aday JS, Bloesch EK, Davoli CC. Beyond LSD: A Broader Psychedelic Zeitgeist during 
the Early to Mid-20th Century. Journal of Psychoactive Drugs. 2019;51(3).  
107.  Bouso JC, Palhano-Fontes F, Rodríguez-Fornells A, Ribeiro S, Sanches R, Crippa JAS, 
et al. Long-term use of psychedelic drugs is associated with differences in brain structure 
and personality in humans. European Neuropsychopharmacology. 2015;25(4).  
108.  MacLean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the 
hallucinogen psilocybin lead to increases in the personality domain of openness. Journal 
of Psychopharmacology. 2011;25(11):1453–61.  
109.  Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type 
experiences occasioned by psilocybin mediate the attribution of personal meaning and 
spiritual significance 14 months later. Journal of Psychopharmacology. 2008;22(6):621–
32.  
110.  Griffiths RR, Johnson MW, Richards WA, Richards BD, Jesse R, MacLean KA, et al. 
Psilocybin-occasioned mystical-type experience in combination with meditation and 
other spiritual practices produces enduring positive changes in psychological functioning 
and 
in 
trait 
measures 
of 
prosocial 
attitudes 
and 
behaviors. 
Journal 
of 
Psychopharmacology. 2018;32(1).  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
57 of 61 
 
 
111.  Madsen MK, Fisher PMD, Stenbæk DS, Kristiansen S, Burmester D, Lehel S, et al. A 
single psilocybin dose is associated with long-term increased mindfulness, preceded by 
a 
proportional 
change 
in 
neocortical 
5-HT2A 
receptor 
binding. 
European 
Neuropsychopharmacology. 2020;33.  
112.  Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, et al. 
Implications for psychedelic-assisted psychotherapy: Functional magnetic resonance 
imaging study with psilocybin. British Journal of Psychiatry. 2012;200(3):238–44.  
113.  Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type 
experiences occasioned by psilocybin mediate the attribution of personal meaning and 
spiritual significance 14 months later. Journal of Psychopharmacology. 2008;22(6):621–
32.  
114.  Kuypers KPC, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, et al. 
Microdosing psychedelics: More questions than answers? An overview and suggestions 
for future research. Journal of Psychopharmacology. 2019;33(9):1039–57.  
115.  Carhart-Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Evans J, et al. 
Functional connectivity measures after psilocybin inform a novel hypothesis of early 
psychosis. Schizophrenia Bulletin. 2013;39(6).  
116.  Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural 
correlates of the psychedelic state as determined by fMRI studies with psilocybin. 
Proceedings of the National Academy of Sciences of the United States of America. 
2012;109(6):2138–43.  
117.  Kraehenmann R, Preller KH, Scheidegger M, Pokorny T, Bosch OG, Seifritz E, et al. 
Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive 
mood in healthy volunteers. Biological Psychiatry. 2015;78(8).  
118.  Roseman L, Leech R, Feilding A, Nutt DJ, Carhart-Harris RL. The effects of psilocybin 
and MDMA on between-network resting state functional connectivity in healthy 
volunteers. Frontiers in Human Neuroscience. 2014;8(MAY).  
119.  Rolke R, Andrews Campbell K, Magerl W, Treede RD. Deep pain thresholds in the distal 
limbs of healthy human subjects. European Journal of Pain. 2005;9(1).  
120.  Smeets T, Cornelisse S, Quaedflieg CWEM, Meyer T, Jelicic M, Merckelbach H. 
Introducing the Maastricht Acute Stress Test (MAST): A quick and non-invasive 
approach 
to 
elicit 
robust 
autonomic 
and 
glucocorticoid 
stress 
responses. 
Psychoneuroendocrinology. 2012;37(12).  
121.  Grover MP, Jensen MP, Ward LC, Ehde DM, Mattingley JB, Thorn BE, et al. An 
Experimental Investigation of the Effects and Mechanisms of Mindfulness Meditation 
Versus Self-Hypnosis Versus an Attention Control on Cold Pressor Outcomes. 
Mindfulness. 2021 Apr 1;12(4):923–35.  
122.  Thompson T, Terhune DB, Oram C, Sharangparni J, Rouf R, Solmi M, et al. The 
effectiveness of hypnosis for pain relief: A systematic review and meta-analysis of 85 
controlled experimental trials. Neuroscience and biobehavioral reviews. 2019 Apr 
1;99:298–310.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
58 of 61 
 
 
123.  Dittrich A. The standardized psychometric assessment of altered states of 
consciousness (ASCs) in humans. Pharmacopsychiatry. 1998;31(SUPPL. 2).  
124.  Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation of the altered states 
of consciousness rating scale (OAV). PLoS ONE. 2010;5(8).  
125.  Liechti ME, Dolder PC, Schmid Y. Alterations of consciousness and mystical-type 
experiences after acute LSD in humans. Psychopharmacology. 2017;234(9–10).  
126.  McNair DM, Lorr M, Droppleman LF. POMS Manual for the Profile of Mood States. San 
Diego, CA: Educational and Industrial Testing Service. Educational and Industrial 
Testing Service. 1992.  
127.  Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. 
Clinician-administered dissociative states scale (CADSS). Journal of Traumatic Stress. 
1998;11(1).  
128.  Nour MM, Evans L, Nutt D, Carhart-Harris RL. Ego-dissolution and psychedelics: 
Validation of the ego-dissolution inventory (EDI). Frontiers in Human Neuroscience. 
2016;10.  
129.  Derogatis LR. The Brief Symptom Inventory. Clinical Psychometric Research. 1975.  
130.  White TL, Lott DC, De Wit H. Personality and the subjective effects of acute 
amphetamine in healthy volunteers. Neuropsychopharmacology. 2006;31(5).  
131.  Studerus E, Gamma A, Kometer M, Vollenweider FX. Prediction of psilocybin response 
in healthy volunteers. PLoS ONE. 2012;7(2).  
132.  John OP, Srivastava S. The Big Five trait taxonomy: History, measurement, and 
theoretical perspectives. Handbook of personality: Theory and research. 1999;2(510).  
133.  Davis MH. A multidimensional approach to individual differences in empathy. In: Catalog 
of selected documents in psychology. 1980.  
134.  Jamieson GA. The modified tellegen absorption scale: A clearer window on the structure 
and meaning of absorption. Australian Journal of Clinical and Experimental Hypnosis. 
2005;33(2).  
135.  Tellegen A. Practicing the two disciplines for relaxation and enlightenment: Comment 
on ‘Role of the feedback signal in electromyograph biofeedback: The relevance of 
attention’ by Qualls and Sheehan. Journal of Experimental Psychology: General. 
1981;110(2).  
136.  Dziobek I, Rogers K, Fleck S, Bahnemann M, Heekeren HR, Wolf OT, et al. Dissociation 
of cognitive and emotional empathy in adults with Asperger syndrome using the 
Multifaceted Empathy Test (MET). Journal of Autism and Developmental Disorders. 
2008;38(3).  
137.  Hurlemann R, Patin A, Onur OA, Cohen MX, Baumgartner T, Metzler S, et al. Oxytocin 
enhances amygdala-dependent, socially reinforced learning and emotional empathy in 
humans. Journal of Neuroscience. 2010;30(14).  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
59 of 61 
 
 
138.  Hysek CM, Schmid Y, Simmler LD, Domes G, Heinrichs M, Eisenegger C, et al. MDMA 
enhances emotional empathy and prosocial behavior. Social Cognitive and Affective 
Neuroscience. 2014;9(11).  
139.  Kuypers KPC, Dolder PC, Ramaekers JG, Liechti ME. Multifaceted empathy of healthy 
volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies. 
Journal of Psychopharmacology. 2017;31(5).  
140.  Dolder PC, Schmid Y, Müller F, Borgwardt S, Liechti ME. LSD acutely impairs fear 
recognition 
and 
enhances 
emotional 
empathy 
and 
sociality. 
Neuropsychopharmacology. 2016;41(11).  
141.  Pokorny T, Preller KH, Kometer M, Dziobek I, Vollenweider FX. Effect of psilocybin on 
empathy 
and 
moral 
decision-making. 
International 
Journal 
of 
Neuropsychopharmacology. 2017;20(9).  
142.  GUILFORD JP. Creativity: Yesterday, Today and Tomorrow. The Journal of Creative 
Behavior. 1967;1(1).  
143.  Wolfradt U, Pretz JE. Individual differences in creativity: Personality, story writing, and 
hobbies. European Journal of Personality. 2001;15(4).  
144.  Amabile TM. Social psychology of creativity: A consensual assessment technique. 
Journal of Personality and Social Psychology. 1982;43(5).  
145.  Booth RJ, Pennebaker JW, Boyd RL, Francis ME. Linguistic inquiry and word count 
(LIWC): LIWC2015. Applied Natural Language Processing: Identification, Investigation 
and Resolution. 2011;(2015).  
146.  Tausczik YR, Pennebaker JW. The psychological meaning of words: LIWC and 
computerized text analysis methods. Vol. 29, Journal of Language and Social 
Psychology. 2010.  
147.  Pennebaker JW, Boyd RL, Jordan K, Blackburn K. The development and psychometric 
properties of LIWC2015. Austin, TX: University of Texas at Austin. 2015;  
148.  McLeod DR, Griffiths RR, Bigelow GE, Yingling J. An automated version of the digit 
symbol substitution test (DSST). Behavior Research Methods & Instrumentation. 
1982;14(5).  
149.  Dinges DF, Powell JW. Microcomputer analyses of performance on a portable, simple 
visual RT task during sustained operations. Behavior Research Methods, Instruments, 
& Computers. 1985;17(6).  
150.  Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy 
questionnaire. 
Journal 
of 
Behavior 
Therapy 
and 
Experimental 
Psychiatry. 
2000;31(2):73–86.  
151.  Pagé MG, Ziemianski D, Martel MO, Shir Y. Development and validation of the 
Treatment Expectations in Chronic Pain Scale. British Journal of Health Psychology. 
2019;24(3):610–28.  

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
60 of 61 
 
 
152.  Burckhardt CS, Clark SR, Bennett RM. The fibromyalgia impact questionnaire: 
development and validation. The Journal of rheumatology. 1991;18(5).  
153.  Bae SC, Lee JH. Cross-cultural adaptation and validation of the Korean fibromyalgia 
impact questionnaire in women patients with fibromyalgia for clinical research. Quality 
of Life Research. 2004;13(4).  
154.  Perrot S, Dumont D, Guillemin F, Pouchot J, Coste J. Quality of life in women with 
fibromyalgia syndrome: Validation of the QIF, the French version of the Fibromyalgia 
Impact Questionnaire. Journal of Rheumatology. 2003;30(5).  
155.  Sarzi-Puttini P, Atzeni F, Fiorini T, Panni B, Randisi G, Turiel M, et al. Validation of an 
Italian version of the fibromyalgia impact questionnaire (FIQ-I). Clinical and 
Experimental Rheumatology. 2003;21(4).  
156.  Cleeland C. Measurement of pain by subjective report. Advances in pain research and 
therapy. 1989;12:391–403.  
157.  Cleeland C. The Brief Pain Inventory User Guide. 2009.  
158.  Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck Depression 
Inventory: Twenty-five years of evaluation. Clinical Psychology Review. 1988;8(1).  
159.  Carhart-Harris RL, Nutt DJ. Experienced Drug Users Assess the Relative Harms and 
Benefits of Drugs: A Web-Based Survey. Journal of Psychoactive Drugs. 
2013;45(4):322–8.  
160.  Hasler F, Bourquin D, Brenneisen R, Bär T, Vollenweider FX. Determination of psilocin 
and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic 
profiles of oral and intravenous psilocybin in man. Pharmaceutica Acta Helvetiae. 
1997;72(3).  
161.  
Bjersing, J. L., Bokarewa, M. I., & Mannerkorpi, K. (2015). Profile of 
circulating microRNAs in fibromyalgia and their relation to symptom severity: An 
exploratory 
study. 
Rheumatology 
International, 
35(4), 
635–642. 
https://doi.org/10.1007/s00296-014-3139-3 
162.  
van den Berg, M. M. J., Krauskopf, J., Ramaekers, J. G., Kleinjans, J. C. S., 
Prickaerts, J., & Briedé, J. J. (2020). Circulating microRNAs as potential biomarkers for 
psychiatric and neurodegenerative disorders. Progress in Neurobiology, 185, 101732. 
https://doi.org/10.1016/j.pneurobio.2019.101732 
163. 
Dutta, S., Hornung, S., Taha, H. B., & Bitan, G. (2023). Biomarkers for 
parkinsonian disorders in CNS-originating EVs: Promise and challenges. Acta 
Neuropathologica, 145(5), 515–540. https://doi.org/10.1007/s00401-023-02557-1 
164. 
Stark, S. M., Kirwan, C. B., & Stark, C. E. L. (2019). Mnemonic Similarity 
Task: A Tool for Assessing Hippocampal Integrity. Trends in Cognitive Sciences, 23(11), 
938–951. https://doi.org/10.1016/j.tics.2019.08.003 
165. Williams, J. M., & Broadbent, K. (1986). Autobiographical memory in suicide 
attempters. 
Journal 
of 
Abnormal 
Psychology, 
95(2), 
144–149. 
https://doi.org/10.1037/0021-843X.95.2.144 

NL78008.068.21 
 
Psilocybin and Fibromyalgia 
Version number: 8  ,date 09.08.23 
 
 
61 of 61 
 
 
166. 
Berntsen, D., Hoyle, R. H., & Rubin, D. C. (2019). The Autobiographical 
Recollection Test (ART): A measure of individual differences in autobiographical 
memory. Journal of Applied Research in Memory and Cognition, 8(3), 305–318. 
https://doi.org/10.1037/h0101839 
167. 
Mason, N. L., Szabo, A., Kuypers, K. P. C., Mallaroni, P. A., de la Torre 
Fornell, R., Reckweg, J. T., Tse, D. H. Y., Hutten, N. R. P. W., Feilding, A., & Ramaekers, 
J. G. (2022). Psilocybin induces acute and persisting alterations in immune status and 
the stress response in healthy volunteers [Preprint]. Pharmacology and Therapeutics. 
https://doi.org/10.1101/2022.10.31.22281688