THE IMPACT OF PSILOCYBIN ON PAIN IN FIBROMYALGIA PATIENTS:
A MULTICENTER TRIAL

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 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 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 o

This study has been transitioned to CTIS with ID 2024-516890-63-00 check the CTIS register for the current data.

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. Finally, we will test whether the plasma levels of inflammatory
biomarkers (IL-1α, IL-1β, IL-6, IL-8, and TNF-α, C-reactive protein (CRP)) will
decrease in response to psilocybin administration.

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 Neuropsychology and
Psychopharmacology, FPN (Maastricht) and the department of Anaesthesiology,
LUMC (Leiden).

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.

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
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.
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.

Each of the 3 test sessions lasts for 7h. Subjects will arrive at 9 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. Outcome measures will repeatedly be assessed during the
study session.

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). IL-1α,
IL-1β, IL-6, IL-8, and TNF-α plasma concentrations will be determined using
bead-based multiplexing technology using a XMAG- Luminex assay (Bio-Rad,
Hercules, California, USA) (Bio-Plex Pro Human Cytokine Kit Panel). Blood
samples for plasma concentration and analysis of inflammatory biomarkers 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) and
the analysis of microRNA expression levels in brain derived extracellular
vesicles (BDEVs; 3x 5ml EDTA blood per study day). BDNF and microRNAs
expression levels in BDEVs will be measured 4 times per study day (see Table
1). EDTA plasma samples will be centrifuged and stored at -80°C until
biochemical analyses are performed. For the complete study we will collect 225
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.

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. The risk of lasting psychological and physical harm is considered
low. 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.

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).