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Preliminary safety and effectiveness of psilocybin-assisted therapy in adults with
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fibromyalgia: An open-label, pilot clinical trial
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Jacob S. Aday1,2, Jenna McAfee1, Deirdre A. Conroy3, Avinash Hosanagar3,4, Vijay Tarnal1,2,
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Cody Weston4, Katharine Scott1, Dana Horowitz5, Steven E. Harte1,2,3, Niloufar Pouyan1,2,3,
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Nicolas G. Glynos1,2, Anne K. Baker1,2, Jeffrey Guss6, Alan K. Davis7,8,9, Helen J. Burgess3,
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George A. Mashour1,2,3, Daniel J. Clauw1, Kevin F. Boehnke*1,2
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1. Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI,
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USA
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2. Michigan Psychedelic Center, University of Michigan, Ann Arbor, MI, USA
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3. Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
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4. Psychiatry Department, University of Michigan Medical School, Ann Arbor, MI, USA
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5. Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
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6. Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA
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7. Center for Psychedelic Drug Research and Education, College of Social Work, The Ohio
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State University, Columbus, OH, USA
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8. Comprehensive Cancer Center, Department of Internal Medicine, Division of Medical
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Oncology, The Ohio State University, Columbus, OH USA
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9. Center for Psychedelic and Consciousness Research, Department of Psychiatry and
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Behavioral Sciences, Johns Hopkins University, Baltimore, MD USA
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*Corresponding author: Kevin Boehnke, 24 Frank Lloyd Wright Drive, Ann Arbor, MI, 48106.
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Email: kboehnke@med.umich.edu Phone: 734-998-6939
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Abstract
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Fibromyalgia (FM) is the prototypical nociplastic pain condition, characterized by widespread
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pain and issues with cognition, mood, and sleep. Currently, there are limited treatment options
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available that effectively treat FM symptoms. Psilocybin-assisted therapy (PAT) is an emerging
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combined drug-therapy intervention, but no studies to-date have investigated PAT for FM. Here,
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we report findings from an open-label, pilot trial of PAT for FM (N=5; NCT05128162). In
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conjunction with psychotherapy (two preparatory, four integration sessions), participants
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received two doses of oral psilocybin (15mg and 25mg) delivered two weeks apart. Regarding
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safety (primary outcome), there were transient elevations of blood pressure or heart rate during
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dosing which normalized by the end of treatment, with no serious adverse events. Four of five
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participants reported transient headaches following dosing. Compared to baseline, participants
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reported clinically meaningful improvements in the following secondary outcomes one month
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following their second psilocybin dose (reported as Cohen’s d): pain severity (d=-2.1, 95% CI[-
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3.7 to -0.49]), pain interference (d=-1.8, 95% CI [-3.27 to -0.24]), and sleep disturbance (d=-2.5,
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95% CI [-4.21 to -0.75]). Using the Patient Global Impression of Change, one participant
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reported their symptoms “very much improved,” two reported “much improved,” and two
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reported “minimally improved.” Compared to baseline, there were improvements in the
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following exploratory outcomes after the intervention: FM symptoms, anxiety, and fatigue. This
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small open-label trial preliminarily supports that PAT is well-tolerated by people with FM,
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establishing a basis for larger randomized controlled trials.
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1. Introduction
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Fibromyalgia (FM) is a common chronic pain condition that affects 2–4% of the general
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population[1]. FM is currently understood as the prototypical nociplastic pain condition, i.e., a
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disorder of pain regulation via altered centralized pain processing[2]. Common FM symptoms
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include widespread pain, poor sleep quality, fatigue, and cognitive difficulties[3], and many
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individuals with FM have a history of trauma and/or comorbid psychiatric conditions[4]. The
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heterogeneous nature of FM manifests clinically as varied phenotypic expressions, which makes
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many treatment options, such as pharmacotherapy and physical interventions, only minimally
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effective[5]. This leads to considerable divergence in patient outcomes and results in significant
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economic and personal burden[6]. Given the mixed success of existing treatments, there is a
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pressing need to develop tailored and more effective therapeutic approaches[7].
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One potential treatment for FM is psilocybin-assisted therapy (PAT)[8], a treatment paradigm
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that combines psychotherapy with administration of psilocybin[9]. Psilocybin is a serotonergic
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compound found in numerous mushroom species that causes substantial alterations in cognition,
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mood, affect, and sensory experience[10]. Human studies with psilocybin indicate altered
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functional connectivity of neuronal networks associated with clinical benefits[11]. Speculatively,
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the subsequent changes in functional connectivity by psilocybin might also facilitate changes
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associated with clinical benefits in conditions characterized by nociplastic pain, but this remains
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untested. Additionally, psychedelic use and PAT have been linked with increased psychological
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flexibility[12, 13], and it hypothesized that insights gained during PAT therapy sessions may be
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more likely to “stick” and facilitate lasting psychological and behavioral change, particularly in
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disorders characterized by psychological rigidity[14-16]. Indeed, recent studies of PAT have
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demonstrated promising findings for treatment of major and treatment-resistant depression[17-
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20], anxiety[19-22], end-of-life distress[23, 24], obsessive compulsive disorder[25], and
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substance use disorders[26, 27].
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Preliminary clinical trials and case studies suggest that psilocybin may produce analgesic effects
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in intractable phantom limb pain[28], cluster headache[29], and migraine[30]. This has been
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complemented by recent preclinical research demonstrating that single-dose psilocybin reduced
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mechanical hypersensitivity in rats for at least 28 days[31]. Similarly, surveys show that many
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individuals using psilocybin and other psychedelics for chronic pain report substantial pain
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relief[32-34]. In a North American survey study of participants with fibromyalgia[35],
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perceptions of benefit from psychedelic use were generally neutral (59.4%) or positive (36.8%),
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with less than 3% reporting negative impacts on overall health or pain symptoms. Notably, of the
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12 participants in that study who reported using psychedelics with the specific intention of
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treating chronic pain, 11 reported improved symptoms.
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In summary, converging lines of research support the mechanistic potential of PAT in the
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treatment of FM. However, clinical studies assessing the safety and tolerability of psilocybin and
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associated therapy in people with FM are limited. Thus, in the current pilot study, we evaluated
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the preliminary safety and effectiveness of PAT in the treatment of FM using an open-label
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design among five individuals.
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2. Methods
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This open-label clinical trial was conducted at the University of Michigan Chronic Pain and
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Fatigue Center in Ann Arbor, Michigan. All study procedures were approved by the University
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of Michigan Medical School Institutional Review Board under protocol HUM00208367. The
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study was prospectively registered on clinicaltrials.gov under identifier NCT05128162. The study
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protocol is available in supplement 1. In addition to the study procedures outlined below,
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participants also completed phenotyping visits consisting of sensory testing and magnetic
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resonance imaging, the results of which will be reported separately.
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2.1 Study Design and Participants
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Participants in this trial were adults aged 25-64 who did not smoke tobacco and had a diagnosis
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of FM or who had reported FM symptoms for the past year. At screening, all participants also
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met the 2016 FM survey criteria for fibromyalgia[36]. Exclusion criteria included being pregnant
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or nursing, cardiovascular condition in the past year (e.g., coronary artery disease, stroke, angina,
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uncontrolled hypertension, transient ischemic attack), epilepsy, insulin-dependent diabetes,
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active autoimmune disease, clinically significant laboratory abnormalities per a complete blood
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count and metabolic panel, past year or current substance use disorder (other than caffeine), past
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or current history of having a psychotic disorder or bipolar I or II disorder. All screened subjects’
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(n=17) medical records were reviewed by study physicians and those found to be eligible after
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medical record review met with study physicians to ensure they did not meet any exclusionary
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medical criteria. Participants with scores representing severe depression on the Patient Health
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Questionnaire 8 were also excluded[37]. Exclusionary medications included monoamine oxidase
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inhibitors, psychoactive prescription medications (e.g., benzodiazepines, opioids) more than
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twice per week, prohibited drugs of abuse including illicit opioids, cocaine, methamphetamines,
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3,4-Methylenedioxymethamphetamine, and any use of hallucinogens in the past 6 months or
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more than 10 lifetime hallucinogen uses. Other prohibited medications included antihypertensive
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medications, UGT1A9 or 1A10 inhibitors (e.g., regorafenib, rifampicin, deferasiroxor, ginseng)
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and aldehyde or alcohol dehydrogenase inhibitor (e.g,, disulfiram). Initially, participants taking
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antidepressant medications of any variety were excluded, but following recent studies showing
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the safety of concomitant antidepressant use during PAT[38], we amended our protocol to
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include individuals taking selective serotonin reuptake inhibitors (SSRIs) and selective
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norepinephrine reuptake inhibitors (SNRIs) as well as less than 300 mg/day of bupropion. A full
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description of eligibility criteria are included in the study protocol. Participants were recruited
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through flyers posted in University of Michigan clinics, UMhealthresearch.org, and electronic
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health record searches with IRB permission between September 2023 and April 2024.
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Figure 1. Overall study design.
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2.2 Description of therapy
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Therapy visits occurred at the Sleep and Circadian Research Laboratory and via Zoom (certain
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therapy visits only). The study therapy manual was generally consistent with the Yale Manual
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for Psilocybin-Assisted Therapy of Depression[39]. However, the manual was modified for
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fibromyalgia with input from Fluence, a continuing education organization in the emerging field
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of PAT, as well as consultation with experts in delivering PAT (co-authors AKD and JG). Each
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participant was paired with a consistent therapist dyad throughout the study, consisting of a lead
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therapist and co-therapist. The lead therapists were doctoral level psychotherapists (JM and
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DAC) and the co-therapist had a Masters of Social Work (DH).
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As is standard in PAT research, the therapy component included preparatory, dosing, and
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integration sessions with the therapist dyad[40]. During the preparatory sessions, the therapists a)
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developed a trusting therapeutic rapport with participants, b) gathered information about lived
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experience with FM, c) provided education regarding psychedelic experiences, d) described the
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therapeutic approach to be used, and e) explored participants’ expectations for treatment.
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Therapists explained the logistics of the dosing sessions (e.g., dosing day procedures, session
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duration, music, use of eyeshades), delineated behavioral boundaries of interaction between the
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participant and the therapists, and discussed safety measures. In dosing sessions, therapists
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maintained an attentive but non-intrusive presence, encouraging participants to focus inward on
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their thoughts, emotions, and body sensations, including engaging with difficult content that
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arose. They also assisted the participant by meeting any immediate needs for comfort or safety.
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Toward the end of the dosing sessions, participants were invited to talk about their experiences in
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the session and the emotions that were evoked. Therapists focused on eliciting descriptions of
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phenomenology, rather than interpreting or guiding this report. The integration phase began the
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day after the dosing sessions and involved thoroughly reviewing the participant’s experience
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during the dosing session and, in some cases, reinforcing aspects of the experience to foster
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changes in thought and behavior. Therapists accomplished this by asking open-ended questions
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about the session, intended to elicit introspective, interpersonal, spiritual, or noetic insights that
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occurred during the session that the participant may otherwise forget or have difficulty
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verbalizing. Therapists supported the participants’ narrative expression of their experience and
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emphasized this over interpretive interventions.
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2.3 Study drug
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Study drug was provided as psilocybin in 15 mg and 25 mg gel capsules synthesized by the
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analytical chemistry lab at the Usona Institute. Participants received two doses of psilocybin
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(15mg followed by 25mg) approximately two weeks apart. Sequential dosing was chosen in
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alignment with previous studies[18, 41], as well as to allow participants to acclimate to the
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pharmacodynamic effects of psilocybin in the first dose and thus to prepare for the more intense
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effects in the second dosing session. Participants could decide to not increase their dose to 25mg
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at the second dosing session, and one participant (001) chose not to do so. 25mg was selected as
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the high dose based on research that demonstrates tight dose-response curves across studies of
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various indications, which are supplemented by findings that body mass index[42] and
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weight[43] are not significantly related to drug effects.
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2.4 Dosing days
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For 7 days prior to dosing sessions, participants agreed to abstain from taking nonprescription
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medications, nutritional supplements, or herbal supplements except when approved by the study
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team. Similarly, they agreed to abstain from alcoholic beverages and psychoactive drugs 24
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hours before and after each dosing session, and sildenafil within 72 hours before or after dosing
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days. On the day of drug administration, participants were asked to eat a low-fat breakfast before
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reporting to the laboratory. Upon arrival, participants provided urine samples to test for
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exclusionary drugs and pregnancy and completed breath alcohol and COVID-19 tests. Study
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therapists also underwent COVID-19 testing on dosing days. If all tests were negative,
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participants met with the study team for a brief interview to discuss if the session was
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contraindicated. After review of their vital signs and clearance from the study physician,
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participants then proceeded to a comfortable dosing suite with the same therapists that were
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present during preparatory sessions. The dosing suite included a living room-like space with a
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couch for the participant and two armchairs for the therapists as well as an adjacent bedroom
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where the participants could lie down if they preferred and a bathroom. During these sessions,
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participants were instructed to lie on the couch or bed, wear eyeshades, and listen to music
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through headphones or a headband, all of which are meant to enhance and encourage internal
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attention and reflection. The same playlist, created by researchers at The Ohio State University,
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was used for every dosing session. Vitals (i.e., heart rate and blood pressure) were intermittently
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monitored throughout the 8-hour dosing sessions (30, 60, 90, 120, 180, 240, 300, and 360
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minutes after administration). During the same period as the vital signs measurements, therapists
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also completed a monitor rating form, which included questions about the presence/intensity of
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behaviors, signs, and reported symptoms, such as peacefulness, yawning, nausea/vomiting,
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quantity of speech, anxiety, sleepiness, crying, restlessness, visual changes, euphoria, and
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feelings of unreality. Study physicians examined the participant if any concerns were raised by
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study therapists or if there was a concern for elevated vitals. Dosing sessions were video and
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audio recorded. After the study drug effects subsided, participants completed questionnaires that
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assessed the subjective experiences of the dosing session (e.g., Mystical Experience
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Questionnaire, Challenging Experiences Questionnaire, Psychological Insight Questionnaire),
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and the therapists completed questionnaires assessing participant mood and safety. Participants
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were medically cleared by the study team (including a study physician) and were discharged
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home with a responsible adult. Participants were asked to process the experience at home by
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writing a reflection about their experiences during the dosing session and this reflection was
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discussed during follow-up integration sessions.
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2.5 Measures
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Primary outcome
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The primary outcome for this study was safety. This was assessed acutely during dosing sessions
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via heart rate per minute and blood pressure, as well as globally via adverse event capture from
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Days 1 (baseline) through 64 (end of treatment). Blood pressure greater than 200 systolic or
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greater than 110 diastolic for more than 15 minutes was considered to be an adverse event. For
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heart rate, our goal was to maintain a target heart rate within 20% of baseline. An elevated heart
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rate was considered clinically significant if it was accompanied by cardiovascular symptoms and
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an increase in blood pressure (exceeding 20% of baseline) that persisted for over 15 minutes.
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Secondary outcomes
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Aggregate Worst Pain Score Change
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We assessed participants’ worst pain intensity daily using a 0-10 (0 = no pain, 10 = worst pain
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imaginable) numeric rating scale via a daily Qualtrics survey. We compared the average of pain
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scores from Days 1 to 7 (prior to preparation therapy) to the average of pain scores from the 7-
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day window (Days 57 to 63) immediately prior to the end of treatment visit (Day 64).
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Pain Interference
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Pain interference is the degree to which pain affects important aspects of an individual’s life,
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such as social, cognitive, and physical activities. We assessed pain interference using the 4‑item
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PROMIS pain interference scale from the PROMIS‐29+2 Profile v2.1 (PROPr)[44, 45]. This
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uses a 5-point Likert scale to generate raw scores. We then used the HealthMeasures Scoring
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Service to generate standardized T-scores, which range from 0-100 (median = 50, which
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represents the general population mean, standard deviation = 10). Higher scores indicate worse
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pain interference.
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Sleep disturbance
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Sleep disturbance includes assessment of sleep quality, perceived ability to fall and stay asleep,
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satisfaction of sleep, and depth of sleep. We assessed sleep disturbance using the PROMIS Sleep
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Disturbance Short Form 8b. Scoring was performed the same way as for pain interference, with
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standardized t-scores ranging from 0-100 (median = 50, which represents the general population
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mean, standard deviation = 10). Higher scores indicate worse sleep disturbance.
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Chronic Pain Acceptance
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The Chronic Pain Acceptance Questionnaire (8 item version) is a validated measure that assesses
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activity engagement and pain willingness, e.g., recognizing that trying to avoid or control pain
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may be maladaptive for chronic pain[46]. Participants rate items on a 0 to 6 scale, with 0 being
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“never true” and 6 being “always true”. Higher scores indicate higher acceptance of chronic pain.
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Patient Global Impression of Change (PGIC)
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We assessed participant impressions of how PAT affected their global functioning using the
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PGIC, a one-item questionnaire that uses a 7-point Likert scale ranging from 1 (“very much
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improved”) to 7 (“very much worse”)[47-49].
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Exploratory Outcomes
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Challenging Experiences Questionnaire
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The Challenging Experiences Questionnaire is a 26-item self-report survey that was used to
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assess the extent to which participants endorsed having psychologically challenging experiences
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during their dosing sessions[50]. The survey includes seven factors: grief, fear, death, insanity,
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isolation, physical distress, and paranoia.
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Other psychosocial functioning
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We assessed anxiety, depression, fatigue, participation in social activities, and cognitive abilities,
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using the scales from the PROMIS‐29+2. Scoring was conducted in the same way as for pain
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interference and sleep disturbance, with standardized t-scores for each subscale ranging from 0-
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100 (median = 50, standard deviation = 10). Higher scores indicate worse symptoms for pain
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severity, pain interference, sleep disturbance, anxiety, depression, fatigue, and cognitive abilities.
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Lower scores indicate worse symptoms for physical function and participation in social
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activities. Due to a coding error, the data on participation in social activities was not usable so
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will not be reported in this manuscript.
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Narrative of dosing experiences
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At the end of each dosing session (Visits 5 and 8), study therapists asked participants to write a
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narrative describing their experience of the sessions prior to their next in-person meeting. This
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narrative description was discussed in Visits 6 and 9, respectively, and used as content to draw
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from in the integration sessions. We present summaries of how each participant experienced
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psilocybin dosing sessions, drawing directly from the content of their narratives.
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2.6. Statistical analysis
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We present descriptive statistics for primary and secondary outcomes. We present measures of
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effect sizes (baseline vs. end of treatment) as Cohen’s d with 95% confidence intervals for
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secondary outcomes (sleep disturbance, chronic pain acceptance, pain severity, pain interference)
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and exploratory outcomes (physical function, anxiety, depression, fatigue, cognitive abilities).
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For the Patient Global Impression of Change, we present the participant ratings at the end of
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treatment. Results are presented for each individual participant as well for participants in
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aggregate. Two researchers (JSA & KFB) individually reviewed participants’ written narratives
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of the dosing sessions and each generated a list of prominent themes and quotes. They then
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compared thematic categories and generated a combined set of themes for each dosing session.
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These themes and quotes were distilled into brief narratives for each participant included below.
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3. Results
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Overall, 368 individuals expressed interest in the study, 265 were pre-screened, 54 were eligible
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for screening, 17 were brought in for screening, and 7 were eligible for participation (Figure 2).
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Two participants were withdrawn by the study team after consenting given concerns about
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ability to follow through with study procedures (n=1) and concern about their ability to build
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rapport with study therapists (n=1). Our original recruitment target was n=10 individuals, but we
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stopped recruitment early due to challenges with recruitment, concerns about the generalizability
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of our results given the stringent exclusion criteria, and that standards for psychedelic research
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changed during the conduct of our trial following the US Food and Drug Administration’s
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publication of guidance for psychedelic clinical trials[51].
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Figure 2. CONSORT diagram.
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Of the n=5 participants who completed the protocol, all were female, four identified as
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White/Caucasian, and one identified as Black/African American (Table 1).
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3.1 Safety
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Overall, the dosing scheme in this protocol was well-tolerated, with no serious adverse events
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(Table 2). Participant 001 opted to have their second dose be 15mg rather than 25mg, with their
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rationale being that they thought the 15mg dose was sufficient and they wanted to experience it
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again. AEs related to the study treatment occurred on or the day after dosing and were deemed
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Table 1. Participant demographics and baseline clinical characteristics
Participant 001
Participant 002
Participant 003
Participant
004
Participant 005
Age (years)
63
41
46
62
37
Sex at Birth
Female
Female
Female
Female
Female
Race
Black African Amer
White
White
White
White
Highest education achieved
Bachelor’s
Bachelor’s
Advanced/Professional
Bachelor’s
Advanced/Professional
Employment status
Retired
Full time
employed
Full time employed
Retired
Marked Unemployed –
wrote self-employed
Previous psychedelic use
No
No
Yes
No
Yes
Current cannabis use
(confirmed by urinalysis)
Yes
No
Yes
Yes
No
Clinical symptoms
Pain severity
5.9
4.0
5.4
5.4
3.7
Chronic pain acceptance
31.0
31.0
25.0
32.0
23.0
Sleep disturbance
58.3
55.3
62.6
58.3
56.3
Pain Interference
66.6
57.1
63.8
63.8
61.2
Physical Function
36.7
48.3
40.5
40.5
41.9
Anxiety
51.2
55.8
55.8
48.0
55.8
Depression
41.0
41.0
51.8
41.0
53.9
Fatigue
58.8
53.1
64.6
64.6
62.7
Cognitive abilities
44.3
50.5
44.3
44.3
44.3
FM survey score
17.0
11.0
19.0
14.0
12.0
Table 1. Pain Severity: 0-10 numeric rating scale. Sleep disturbance, pain interference, physical function, anxiety, depression, fatigue,
cognitive abilities, and participation in social activities are reported as T-scores, with 50 being the general population mean. Most
participants had substantially worse sleep, pain interference, physical function, fatigue, cognitive abilities, and participation in social
activities than the population mean.
16
minor or moderate, with the most common being headache (n=4), diarrhea (n=2), stomach ache
302
(n=1), and migraine (n=1). The headaches were of minor or moderate severity, and three
303
participants took over the counter pain medications (acetaminophen, celecoxib) to help relieve
304
headaches. Headaches resolved within two days. Blood pressure and heart rate stayed within the
305
pre-specified ranges during dosing and were not associated with any other cardiovascular
306
symptoms (Figures 3 and 4). Results from the Challenging Experiences Questionnaire are
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presented in Table 3. Physical distress and grief were the most commonly reported domains of
308
challenging experiences.
309
Table 2. Adverse events prior, during, and after dosing
310
V 2-4 (preparation)
V5-V9
(administration)
V10-V13
(integration)
Adverse Event (AE) a
5
11
8
Related AEb
0 (5)
4 (5)
0 (5)
Serious AE
0 (5)
0 (5)
0 (5)
AE Severity for Related
Mild
0 (5)
4(5)
0 (5)
Moderate
0 (5)
1(5)
0 (5)
Severe
0 (5)
0 (5)
0 (5)
AE Type
Headache
1 (5)
4 (5)
0 (5)
Diarrhea
0 (5)
2 (5)
1 (5)
17
Stomach Ache
0 (5)
1 (5)
0 (5)
Migraine
0 (5)
1 (5)
0 (5)
Leg throbbing
0 (5)
0 (5)
1 (5)
Back Ache
1 (5)
1 (5)
0 (5)
Jaw pain
1 (5)
1 (5)
0 (5)
Fatigue
1 (5)
0 (5)
0 (5)
Sore Throat
0 (5)
0 (5)
1 (5)
Sinus Pressure
0 (5)
0 (5)
1 (5)
Vomiting
0 (5)
0 (5)
1 (5)
Fever
0 (5)
0 (5)
1 (5)
Chills
0 (5)
0 (5)
1 (5)
Body Aches
0 (5)
0 (5)
1 (5)
Tight L side of neck
1 (5)
1 (5)
0 (5)
Medication taken for
Related AE
0 (5)
3 (5)
0(5)
311
Table 2. Adverse Event (AE) a: Participants are counted once for each category regardless of the number of events. Related AEb:
312
An AE was classified as “related” if there was a reasonable possibility that the study drug or procedure caused the event. Severity
313
and relationship to study drug or procedure were determined by the Principal Investigator. Note: Participant 001 repeated the
314
15mg dose at 2nd dosing session. All other participants had the 15mg followed by the 25mg dose.
315
316
Table 3. Challenging Experiences Questionnaire (%)
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Participant
Fear
(Dose 1,
Dose 2)
Grief
(Dose 1,
Dose 2)
Physical
Distress
(Dose 1,
Dose 2)
Insanity
(Dose 1,
Dose 2)
Isolation
(Dose 1,
Dose 2)
Death
(Dose 1,
Dose 2)
Paranoia
(Dose 1,
Dose 2)
CEQ Total
(Dose 1,
Dose 2)
001
0%, 0%
50%, 27%
0%, 0%
0%, 0%
0%, 0%
0%, 0%
0%, 0%
12%, 6%
18
002
20%, 20%
17%, 13%
88%, 76%
0%, 0%
0%, 0%
0%, 0%
0%, 0%
25%, 22%
003
0%, 16%
60%, 37%
20%, 48%
0%, 20%
47%, 20%
0%, 80%
30%, 0%
25%, 32%
004
0%, 12%
0%, 47%
64%, 60%
0%, 0%
0%, 40%
0%, 0%
0%, 0%
12%, 29%
005
12%, 0%
0%, 0%
28%, 16%
0%, 0%
0%, 0%
0%, 0%
0%, 0%
8%, 18%
Table 3. Note: Participant 001 received 15mg at both dosing sessions.
318
319
Figure 3. Heart rate in beats per minute after dosing. D1: Dose 1 (15mg). D2: Dose 2 (25mg).
320
001 D2 was 15mg rather than 25mg per request of the participant.
321
322
323
Figure 4. Systolic and diastolic blood pressure after doses 1 and 2. D1: Dose 1 (15mg). D2:
324
Dose 2 (25mg). If a participant had blood pressure >200 systolic or >110 diastolic for >15
325
minutes, they would be transferred to the emergency department.
326
3.2 Preliminary effectiveness
327
40
60
80
100
120
30 60 90 120 180 240 300 360
Beats per minute
Time after dosing (min)
001 D1 002 D1 003 D1 004 D1 005 D1
001 D2 002 D2 003 D2 004 D2 005 D2
19
Some participants reported clinically significant improvements across numerous symptom
328
domains. Figure 5 shows changes by individual as well as on average for each symptom domain.
329
For secondary outcomes, three of five participants reported >2 point decrease in pain severity,
330
four reported >4 point decreases in pain interference, and 4 reported >6 point decreases in sleep
331
disturbance. Three participants reported enhanced chronic pain acceptance while two reported
332
slight decreases in chronic pain acceptance. On average, there was a 2.3±1.3 point decrease in
333
pain severity (d=-2.1, 95% CI [-3.7 to -0.49]), 7±4.2 point decrease in sleep disturbance (d=-2.5,
334
95% CI [-4.21 to -0.75]), 9.4±4.2 point decrease in pain interference (d=-1.8, 95% CI [-3.27 to -
335
0.24]), and 2±2.8 point increase in chronic pain acceptance (d=0.54, 95% CI [-74 to 1.79]). Via
336
the PGIC, one participant (001) reported that their symptoms were “very much improved,” two
337
reported “much improved” (002, 004), and two reported “minimally improved” (003, 005). On
338
average, FM survey scores improved by 4.2±6.1 points (d=-0.78, 95% CI [-2.06 to 0.53]).
339
340
Figure 5. CPAQ: Chronic Pain Acceptance Questionnaire. Pain Severity reported as change in
341
aggregate pain score from the 7 days prior to the intervention to the end of the intervention.
342
Sleep disturbance, pain interference, physical function, anxiety, depression, fatigue, participation
343
in social activities, and cognitive abilities are all reported as T-scores per PROMIS scoring.
344
Negative change scores indicate improvement for pain severity, pain interference, sleep
345
disturbance, FM score, anxiety, depression, and fatigue. Positive change scores indicate
346
improvement for CPAQ, physical function, participation in social activities, and cognitive
347
abilities.
348
349
20
For exploratory outcomes (Figure 5), four of five participants reported decreases in anxiety,
350
physical function, and fatigue, and three reported improvements in cognitive abilities. On
351
average, there was a 5.4±8.8 point increase in physical function (d=2.1, 95% CI [-0.29 to 2.40]),
352
4.6±4.5 point increase in cognitive abilities (d=1.39, 95% CI [-0.05 to 2.77]), a 5.9±3.7 point
353
decrease in fatigue (d=-1.1, 95% CI [-2.46 to 0.25]), and a 5.6±4.1 point decrease in anxiety
354
(d=-1.4, 95% CI [-2.75 to 0.06]). There were no substantial changes in depression scores
355
(d=0.03, 95% CI [-1.27 to 1.21]).
356
357
3.3 Qualitative narratives
358
Participant 001 reported strong feelings of connectedness with her family as well as dreamlike
359
experiences during the first dosing session (15mg) that included “time travel to ancient Egypt.”
360
She also practiced yoga during this dosing session. During the second dosing session (also
361
15mg), this sense of connectedness extended to messaging with a forest and stars, with the forest
362
saying, “We’re in trouble. Humans are destroying us. We are all connected.” and the stars
363
pointing to the “origin of original injury,” which was a car accident when the participant was 13
364
years old. Following this, the participant noted that these interactions gave her insight on how to
365
“repair” her body so she “started moving & doing yoga.”
366
367
In contrast to 001, Participant 002 did not have a pleasant experience for either dose, and was
368
“disappointed it was not a more enjoyable time”. She “felt almost as if I was not a good
369
participant simply for having to use the bathroom” or removing headphones and the eyemask,
370
tying into a realization that she had high expectations of herself and others that were not often
371
met. Participant 002 also reported moderate pain during both sessions, including back pain
372
21
during the first dosing sessions and that she “felt muscle spasms and parts of my body throb”
373
during the second. Despite these negative experiences, she noted that the “medicine had numbed
374
me” so the pain felt more manageable than it otherwise did. Although she experienced “no grand
375
visions or revelations” and a headache like the “worst hangover” after the session, she believed
376
“the medicine does help so its [sic] worth a day of being uncomfortable”.
377
378
The first dosing session for Participant 003 began with “slight visual distortions” and reflections
379
on “lost loved ones, lost family members, things, places, people I don’t think of often.” Early in
380
the session, the participant was “surprised I’ve no pain to report” but experienced sweating
381
throughout much of the day. At the end of session, she reported to be “awake, present, tired,
382
limited pain, but altogether in a good place.” Themes of connection and a focus on loved ones
383
continued in the second dosing session. The participant noted “I met my grandparents and great
384
aunt again and gained such a sense of pride and love, I felt my grandmother’s touch, as clear as
385
can be.” This second dosing session had stronger visual components, including visiting a “shark
386
habitat,” traveling “back to the caves, tunnels, and trees,” and a brief encounter with an “Asian
387
red dragon” while “in the sky.” Another prominent theme seemed to be a generalized sense of
388
gratitude: “Gratitude keeps surfacing – grateful for the journey, the time and space to rest, even
389
gratitude for this often challenging body, since it means I’m still alive.”
390
391
Participant 004 noted powerful imagery in the first experience that involved moving spatially
392
between different locations, such as moving from a lake into a forest, being “lifted to the sky to
393
dance”, and then being in a cave where she could see the Northern Lights through a crevice. She
394
was “physically comfortable” and was able to “push the music down my body to relieve the
395
22
pain”. By the end of the experience, she was “warm, cozy and almost pain free”. The second
396
experience also involved spatial movement between locations, such as moving from a hammock
397
on a porch, to sitting at a kitchen table with family, then moving to a temple. Her reflections
398
touched on constructing a narrative around her challenges in a way that suited her, noting
399
“trauma has a negative connotation but for me it’s been useful and even beautiful”. She also
400
“acquired… the skill of ‘toughness’”, reflecting that “I hold it, I have used it well” despite not
401
wanting to have acquired it in the first place.
402
403
Participant 005 began by noting that “I had little expectations of what would come from this as
404
far as long-term progress reduction of pain [sic]”. Their first dosing session was characterized by
405
increased mental imagery, mindfulness (i.e., present moment awareness), and a sense of
406
creativity. The participant was particularly engaged with the visual effects of the drug, often
407
finding symbolism and beauty in their visions. They reported a lack of focus the day after dosing,
408
feeling sadness and rejection “around certain issues”, and also sadness because she did not feel
409
like doing the write-up and was worried it would not be good enough. The participant’s second
410
dosing session included a strong focus on introspection and connection to family, ancestors, and
411
nature. They reported insights on familial relationships and on how to let her pain go and cope.
412
They came to the conclusion that much of their pain stemmed from ancestral trauma and that it
413
“felt really good knowing the pain is not mine. It’s my ancestors but they’re [sic] there’s
414
something that I can do about it for me and them.”
415
416
4. Discussion
417
23
This open-label investigation of PAT for fibromyalgia demonstrated that PAT was well-
418
tolerated, with no serious adverse events associated with the study treatment. Mild and moderate
419
AEs, such as headaches or diarrhea on the day of or after dosing, resolved shortly thereafter.
420
There were no persistent psychological AEs by the end of treatment. Most participants also
421
reported improvements in pain severity, pain interference, and sleep disturbance, with small
422
improvements in chronic pain acceptance in three participants and a decrease in chronic pain
423
acceptance in two. The improvements in secondary outcomes of pain severity, pain interference,
424
sleep disturbance, and PGIC all align with what are considered clinically meaningful changes for
425
these domains[49, 52-54].
426
427
Although there have been limited clinical trials of PAT for chronic pain conditions, our findings
428
align with other preliminary work supporting analgesic effects of psilocybin. For instance, a
429
small exploratory study in n=16 participants with cluster headaches found that cluster attack
430
frequency was significantly reduced in the three weeks following administration of psilocybin
431
compared with placebo (d = 0.69)[29]. Similarly, a proof-of-concept, double blinded,
432
randomized, placebo controlled trial of migraine (n=10) reported that the reduction in weekly
433
migraine days from baseline was significantly greater after psilocybin than placebo[30]. Our
434
findings also align with results from naturalistic studies of people using psilocybin for chronic
435
pain[55]. Survey studies have reported that a number of people using psilocybin and other
436
psychedelics for a range of chronic pain conditions often report decreased pain symptoms
437
following psychedelic use, and that in some cases psychedelics are more effective than their
438
other pain medications[32, 56].
439
440
24
In addition to improvements in pain symptoms, participants also reported positive changes in
441
mood, social cognition, sleep, and global functioning. These findings complement findings from
442
the past decade indicating transdiagnostic potential of PAT for a variety of clinical
443
conditions[57] as well as broad improvements in wellbeing observed when psychedelics are
444
studied in healthy adults[58]. For example, numerous studies have noted robust decreases in
445
depression[17, 41] and anxiety following PAT[59]. Although most participants in the current
446
study reported decreases in anxiety, only one had a decrease in depression. This could possibly
447
be driven by floor effects, given that the sample had below average depression scores at baseline
448
because we excluded participants with severe depression. Similar to the current study,
449
improvements in sleep have been observed in studies with psilocybin[60] and other
450
psychedelics[61]. Lastly, all participants reported at least some improvements in global
451
functioning (e.g., one reported “very much improved”, two reported “much improved”, and two
452
reported “minimally improved”). In summary, our preliminary findings motivate future research
453
into the effects of PAT on the multimodal underpinnings of FM, including pain, mood, and
454
sleep.
455
456
There were also numerous themes that emerged from participants’ reports of the dosing sessions
457
that are consistent with those reported in previous research. First, most participants reported
458
experiencing dreamlike states and vivid mental imagery that at times were considered to be
459
highly symbolic and meaningful. This aligns with the well-established perceptual effects of the
460
drugs[62] as well as recent findings that the visual effects of psilocybin and other psychedelics
461
may play a role in long-term outcomes[63-65]. A second theme that was common among
462
participants was a sense of connection to loved ones and ancestors, with several participants
463
25
additionally remarking on connections to nature and the universe more broadly. Although rarely
464
reported in clinical trials, experiences of connecting with ancestors have been anecdotally noted
465
in the psychedelic community[66] and are common in indigenous psychedelic ceremonies. In a
466
trial of PAT for alcohol dependence, one participant had struggled with alcohol use since her
467
mother’s death approximately two decades prior[67]. During the dosing session, she “reported to
468
her guides that she saw her deceased mother present in the room with her standing to her left.”
469
Such experiences could potentially be opportunities to process previous traumas and estranged
470
relationships, but further research is needed to delineate the nuances and ethics of such work.
471
Many participants also remarked on a generalized sense of increased gratitude during their
472
dosing sessions, which is consistent with previous research noting enduring increases in the
473
subjective emotion of gratitude following psychedelic experiences[60, 68, 69]. Finally, many of
474
these themes align with a qualitative study of people who had self-medicated with psychedelics,
475
which found that reported pain scores improved acutely and after taking psychedelics, with
476
positive reframing and somatic presence playing important roles in improvement[33].
477
478
Limitations
479
Although promising, these findings are limited by a number of important factors which must be
480
addressed with future research. First, our study design did not use a model of PAT that was
481
clinically translational given the large time commitment associated with therapy (e.g., two
482
therapists present during dosing), so our safety results may not translate to larger studies with
483
less psychotherapeutic support or clinical settings. Second, our results are limited by a small
484
sample size that likely does not generalize to typical clinical populations of fibromyalgia given
485
the rigorous screening process that excluded a very high proportion of individuals who were
486
26
seeking this therapy. The small sample size also means that the findings should be considered as
487
highly preliminary. Third, we had no control group and did not blind study participants or study
488
staff to the treatments administered, which may have affected outcomes given the strong societal
489
narratives around positive treatment outcomes associated with PAT[70]. Lastly, further research
490
is needed to validate and explore the role of psychotherapy in the safety and potential efficacy of
491
this treatment[71]. The preliminary findings from our small, unblinded study will soon be added
492
to by three other ongoing clinical trials of PAT for FM being conducted elsewhere (Table 4).
493
Table 4. Other clinical trials of psilocybin-assisted therapy for fibromyalgia
Study title
Sponsor
Study design
N
Primary outcome
Psilocybin in Patients
with Fibromyalgia:
EEG-measured Brain
Biomarkers of Action
NCT05548075
Imperial
College
London
Mechanistic, within-
subjects design. 2 doses of
up to 25mg psilocybin
with psychotherapeutic
support
20
1. Lempel-Ziv
complexity
2. The Brief
Experiential
Avoidance
Questionnaire
Psilocybin-facilitated
treatment for chronic
pain
NCT05068791
University of
Alabama at
Birmingham
Parallel group design,
double-blind, placebo
controlled.
0.36mg psilocybin/kg
body weight (active)
2.5mg
dextromethorphan/kg
body weight (placebo)
30
1. Change in daily
self-reported pain
severity (0-100
visual analog scale)
The impact of
Psilocybin on Pain in
Fibromyalgia Patients
(PsiloFM)
NCT06368492
Maastricht
University
Double-blind,
randomized, placebo-
controlled. All
participants receive doses
of placebo, 5mg
psilocybin, 10mg
psilocybin
35
1. Ischemic Pain
perception
2. Pressure-evoked
pain perception
3. Self-reported
pain (0-10 visual
analog scale)
Table 4. Currently, there are three additional ongoing trials evaluating the safety and efficacy of PAT in the
494
treatment of FM.
495
27
Conclusions
496
In this small, open-label clinical trial, we show that PAT was safe and well-tolerated among
497
people with FM, and that individuals generally reported positive impacts on global symptoms
498
and across many FM-related symptom domains. Some participants reported clinically
499
meaningful improvements in pain severity, pain interference, anxiety, and sleep disturbance,
500
with small improvements in chronic pain acceptance. Nonetheless, given the study limitations,
501
larger, controlled studies with a more clinically translational design are necessary to understand
502
whether this therapy is safe and effective in the treatment of FM.
503
Preregistration Statement: The study was not posted to a preregistration website.
504
Data Availability Statement: Given the personalized and sensitive nature of the collected data,
505
the dataset is not publicly available.
506
Acknowledgements
507
This project was supported by funds from Tryp Therapeutics, the Michigan Psychedelic Center,
508
and Department of Anesthesiology of the University of Michigan Medical School.
509
Disclosures
510
JSA’s effort on this publication was partially supported by the National Institute of Arthritis and
511
Musculoskeletal and Skin Diseases of the National Institutes of Health under T32AR007080-
512
44S1. JSA has received speaking fees for lectures at The Women's Center of Southeastern
513
Michigan, Massachusetts General Hospital, and Bicycle Day SF. KFB has received grant
514
funding from the National Institute on Drug Abuse and the National Institutes of Arthritis,
515
Musculoskeletal, and Skin Diseases of the National Institutes of Health, as well as from the State
516
of Michigan Veteran Marijuana Research Program. KFB has received speaking fees for lectures
517
from the Medical Cannabis Research Advocacy Alliance, Provide Holy Cross Medical Center,
518
the Southern Pain Society, and the Michigan Center of Clinical Systems Improvement. KFB
519
received an honorarium for developing a podcast on fibromyalgia with Viatris Inc. JRG is a
520
consultant and teacher with Fluence, International and receives no grant funding. Dr. Davis is
521
supported by the Johns Hopkins Center for Psychedelic and Consciousness Research, funded by
522
private philanthropic funding from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, Blake
523
Mycoskie, and the Steven and Alexandra Cohen Foundation. Dr. Davis is also supported by the
524
Center for Psychedelic Drug Research and Education, funded by anonymous private donors, and
525
the Comprehensive Cancer Center at Ohio State University. Dr. Davis is also a board member at
526
Source Research Foundation. AH is a sub investigator in a COMPASS pathways Psilocybin
527
research study ongoing at the University of Michigan. VT serves as the site Principal
528
Investigator at the University of Michigan for a project supported by funding from Takeda
529
Development Center Americas, Inc. SEH is supported by grants from NIH and Arbor Medical
530
28
Innovations, is a member of Arbor Medical Innovations , and consults for Memorial Sloan
531
Kettering Cancer Center, Dana Farber Cancer Institute, Indiana University, and Wayne State
532
University. The content is solely the responsibility of the authors and does not necessarily
533
represent the official views of the National Institutes of Health. Dr. Clauw has received
534
consulting fees from AbbVie Inc, Heron Therapeutics Inc, Aptinyx Inc, Neumentum Inc,
535
Regeneron Pharmaceuticals Inc, Swing Therapeutics Inc, Virios Inc, Allergan Sales LLC, Eli
536
Lily and Company, H. Lundbeck A/S, Pfizer Inc, Samumed LLC, and Tonix Pharmaceuticals
537
Inc. Dr. Clauw has received payment for expert testimony from Fasken Martinueau DuMoulin
538
LLP, Marks & Clerk Law LLP, Pfizer Inc, Nix Patterson LLP, Zuber Lawler & Del Duca LLP as
539
well as Kellogg, Hansen, Todd, Figel & Frederick PLLC.
540
541
542
543
29
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