Methods of Treating Fibromyalgia with Compositions Comprising Psilocybin

Abstract

Provided are methods for treating fibromyalgia or one or more symptoms thereof, comprising administering a hallucinogen, such as psilocybin or its metabolites, and related uses of the hallucinogen. In some embodiments, the present disclosure also relates to methods for identifying subjects for treating fibromyalgia with the administration of a hallucinogen. In some embodiments, the treatment also includes psychotherapy. In some embodiments, subjects receiving treatment are evaluated for various indicators, such as observer-rated and subject-reported outcomes, biological and clinical indicators, and combinations thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 405,786, filed September 12, 2022, entitled "Compositions and Methods for Treating Fibromyalgia," the contents of which are incorporated by reference in their entirety.

[0002] In some embodiments, the present disclosure relates to methods for treating fibromyalgia or one or more symptoms thereof, comprising administering a psychedelic drug, such as psilocybin or a metabolite thereof, and related uses of the psychedelic drug. In some embodiments, the disclosure also relates to methods for identifying subjects for treating fibromyalgia with the administration of a psychedelic drug. In some embodiments, the treatment also includes psychotherapy. In some embodiments, subjects receiving treatment are evaluated for various indicators, such as observer-rated and subject-reported outcomes, biological and clinical indicators, and combinations thereof. [Background technology]

[0003] Fibromyalgia is a chronic syndrome of widespread musculoskeletal pain that can include multiple co-occurring symptom manifestations, including sleep disturbances, fatigue, cognitive impairment, and mood disorders such as anxiety and depression. While treatments and other approaches to managing fibromyalgia are available, existing treatments offer only modest benefits and are associated with a significant side effect burden. Improved therapeutic approaches are needed. Embodiments are provided that meet this need. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Kalberer et al., Biochem Pharmacol. 1962;11:261-9 [Non-patent document 2] Chenら, J Chromatogr B Analyt Technol Biomed Life Sci, 2011;879(25):2669-72 [Non-licensed document 3] Arnoldら、Patient Educ Couns 2008;73(1):114-20

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[0005] Provided herein are methods for treating fibromyalgia (FM) in a subject. In some provided embodiments, the methods include administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state. Related uses, such as therapeutic uses or uses in the manufacture of medicaments, of one or more doses of psilocybin or an active metabolite thereof, or a composition comprising psilocybin or an active metabolite thereof, according to any of the provided embodiments, are also provided.

[0006] Provided herein are methods for treating FM, comprising orally administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state.

[0007] In some all embodiments, the methods also include providing one or more integration sessions to the subject after emerging from the dissociated state.

[0008] In some all embodiments, the methods also include assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin.

[0009] Provided herein are methods for treating FM, the methods comprising: administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state; providing the subject with one or more integration sessions after emergence from the dissociative state; and assessing in the subject one or more indicators related to one or more symptoms of FM, the dissociative state, treatment outcome, safety, and / or related to the subject before and / or after administration of the one or more doses of psilocybin or an active metabolite thereof.

[0010] Provided herein are methods for treating FM, comprising assessing one or more symptoms of FM, the dissociative state, treatment outcome, safety-related, and / or subject-related indicators in a subject suffering from one or more symptoms of FM, before and / or after administration of one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state, and one or more integration sessions following emergence from the dissociative state induced by the one or more doses of psilocybin or an active metabolite thereof.

[0011] Provided herein are methods for treating FM, comprising: administering one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state to a subject suffering from one or more symptoms of FM; providing the subject with one or more integration sessions after emergence from the dissociative state; and assessing one or more indicators in the subject before and / or after administration of the one or more doses of psilocybin or an active metabolite thereof, wherein the one or more indicators include one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical indicator.

[0012] In some all embodiments, the methods also include assessing one or more of the following exclusion parameters in the subject prior to administering one or more doses of psilocybin: (1) use of previous or concomitant medication; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) previous adverse effects from psilocybin.

[0013] In some all embodiments, the methods also include identifying the subject for treatment with psilocybin if the subject does not meet any of the exclusion parameters.

[0014] Provided herein are methods for identifying a subject for treatment of FM with psilocybin or its active metabolite, the methods comprising: (a) assessing one or more of the following exclusion parameters in a subject suffering from one or more symptoms of FM: (1) use of previous or concomitant medication; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) previous adverse effects from psilocybin or its active metabolite; and (b) if the subject does not meet any of the exclusion parameters, identifying the subject for treatment with one or more doses of psilocybin or its active metabolite.

[0015] Provided herein are methods for identifying a subject for treatment of FM with one or more doses of psilocybin or its active metabolite, comprising identifying a subject suffering from one or more symptoms of FM for treatment if the subject does not meet any of the following exclusion parameters assessed in the subject: (1) use of previous or concomitant medication; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) previous adverse effects from psilocybin or its active metabolite.

[0016] In some all embodiments, the methods also include administering to the identified subject one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state; and providing the subject with one or more integration sessions after emergence from the dissociative state.

[0017] In some all embodiments, the methods also include assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin or its active metabolite.

[0018] In some embodiments, the administering step is by oral administration or intravenous administration. In some embodiments, the administering step is by oral administration.

[0019] In some of all embodiments, the psilocybin or its active metabolite is psilocin. In some of all embodiments, the psilocybin or its active metabolite is psilocin.

[0020] In some embodiments, the one or more measures include observer-rated parameters, subject-reported parameters, and / or clinical measures. In some embodiments, the one or more measures are assessed prior to administration as a baseline measure and after administration as an outcome measure, and the change between the baseline measure and the outcome measure is determined. In some embodiments, the one or more measures include one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical measure.

[0021] In some embodiments, the one or more indicators include one or more of: a fibromyalgia survey score, optionally a rating from the 2016 fibromyalgia survey questionnaire (FSQ); a pain intensity numerical rating scale (PI-NRS) rating, optionally the 11-item PI-NRS scale; a PROMIS pain interference rating; a PainDETECT Questionnaire (PD-Q) rating; a chronic pain acceptance rating, optionally measured by a rating from the Chronic Pain Acceptance Questionnaire (CPAQ-8); a pain interference rating, optionally measured by a 4-item PROMIS pain interference scale; and a Complex Medical Symptom Inventory (CMSI). In some embodiments, the one or more indicators include a fibromyalgia survey score. In some of all embodiments, the fibromyalgia survey score includes a rating from the 2016 Fibromyalgia Survey Questionnaire (FSQ).

[0022] In some of all embodiments, the one or more indices include the Pain Intensity Numerical Rating Scale (PI-NRS), an 11-item pain scale.

[0023] In some embodiments, the one or more measures include one or more of a sleep disorder assessment, optionally measured by the PROMIS Sleep-Related Disorder 4a assessment; a PROMIS Sleep Disorder 8b assessment; and the STOP-Bang questionnaire. In some embodiments, the one or more measures include one or more of a PROMIS-29+2 Profile, optionally a v2.1 Multi-Domain Assessment; a Positive and Negative Affect Score (PANAS) assessment; a Patient Global Impression of Change (PGI-C) scale assessment; and a Patient Acceptable Symptom State (PASS) questionnaire. In some embodiments, the one or more measures include a PROMIS-29+2 Profile v2.1 Multi-Domain Assessment.

[0024] In some embodiments, the one or more indicators include one or more of the following: Patient Health Questionnaire depression scale-8 (PHQ-8); Columbia Suicide Severity Rating Scale (C-SSRS); Clinician Global Impression-Improvement (CGI-I) scale; Emotional Breakthrough Inventory (EBI); Acceptance and Action Questionnaire-II (AAQ-II); Patient Global Impression-Improvement (PGI-I); Hospital Anxiety and Depression Scale (HADS); and Life Events Checklist (LEC). In some embodiments, the one or more indicators include the Patient Health Questionnaire depression scale-8 (PHQ-8).

[0025] In some embodiments, the one or more indicators include one or more of: a subject-reported mystical experience rating, optionally measured by the Mystical Experience Questionnaire (MEQ30); a subject-reported challenging experience rating, optionally measured by the Challenging Experience Questionnaire (CEQ27); a subject-reported psychological insight rating, optionally measured by the Psychological Insight Questionnaire (PIQ); and a subject-reported qualitative written assessment. In some embodiments, the one or more indicators include a therapy-reported monitoring rating scale, optionally measured using a form of the Monitoring Rating Scale (MRS).

[0026] In some of all embodiments, the one or more metrics include a Quantitative Sensory Test (QST). In some of all embodiments, the QST is measured using a cuff pressure pain assessment, optionally using a cuff-PPT, a cuff-Pain40, a cuff-Pain50, and / or a cuff-tolerance.

[0027] In some of all embodiments, the one or more metrics include a visual hypersensitivity assessment. In some of all embodiments, the one or more metrics include an electroencephalogram (EEG).

[0028] In some of all embodiments, the one or more indices include QST and EEG, and the QST and EEG are performed simultaneously.

[0029] In some embodiments, the one or more indices include functional magnetic resonance imaging (fMRI). In some embodiments, the fMRI includes one or more of structural MRI, resting-state fMRI, proton magnetic resonance spectroscopy (H-MRS) in the right anterior insula, cuff-pressure-induced persistent experimental pain fMRI, cuff-pressure-induced pain fMRI in a block design, and diffusion tensor imaging (DTI).

[0030] In some of all embodiments, the one or more metrics include one or more of wrist actigraphy, optionally wrist actigraphy used to measure sleep onset latency; sleep onset awakenings; total sleep time; and sleep efficiency (%).

[0031] In some of all embodiments, the one or more indicators include an electrocardiogram (ECG).

[0032] In some of all embodiments, one or more metrics are measured during one or more of the integrated sessions.

[0033] In some of all embodiments, an exclusion parameter is use of prior or concomitant medication, and the subject is not taking any of the following prior or concomitant medications: regular use of psychoactive prescription drugs, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects or monoamine oxidase inhibitors (MAOIs); use of hallucinogens in the past 6 months; concomitant use of sildenafil or tadalafil; concomitant use of alcohol with a blood alcohol content greater than 0.02%; antihypertensive medications; UGT1A9 inhibitors, 1A10 inhibitors, regorafenib, rimampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasiroxor, Subjects are identified for treatment if they are not using any of the following: ginseng; aldehyde dehydrogenase inhibitors, alcohol dehydrogenase inhibitors, or disulfiram; amphetamine, buprenorphine, benzodiazepines, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoids (K2), psychoactive prescription drugs, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs), or use of serotonergic dietary supplements, 5-hydroxy-tryptophan, or St. John's wort.

[0034] In some of all embodiments, the exclusion parameter is hypertension, and the subject is identified for treatment if they do not exhibit a systolic blood pressure greater than or about 139 mmHg, or a diastolic blood pressure greater than or about 89 mmHg, optionally measured as the average of three readings; and / or the exclusion parameter is tachycardia, and the subject is identified for treatment if they do not exhibit a heart rate (bpm) greater than or about 90 beats per minute.

[0035] In some embodiments, an exclusion parameter is the occurrence of epilepsy, and if the subject does not have epilepsy, the subject is identified for treatment. In some embodiments, an exclusion parameter is the occurrence of a psychotic disorder, and if the subject does not have schizophrenia spectrum or other psychotic disorder that meets DSM-5 criteria, major depressive disorder with psychotic features, or bipolar I or bipolar II disorder, the subject is identified for treatment. In some embodiments, an exclusion parameter is moderate or severe alcohol or drug use disorder, and if the subject does not have moderate or severe alcohol or drug use disorder that meets DSM-5 criteria, the subject is identified for treatment.

[0036] In some of all embodiments, if the exclusion parameter is a prior adverse effect from psilocybin or its active metabolites, and the subject has not had a prior adverse effect from psilocybin or its active metabolites, the subject is identified for treatment.

[0037] In some all embodiments, the subject exhibits a remission of one or more measures between the baseline measurement and the outcome measurement.

[0038] In some embodiments, the subject receiving treatment shows improvement in one or more symptoms of FM, or one or more symptoms of FM are alleviated. In some embodiments, the subject receiving treatment shows improvement selected from one or more of the following: Fibromyalgia Survey Score, Pain Interference Assessment, Sleep Assessment, Chronic Pain Acceptance Assessment, or Clinical Index Assessment. In some embodiments, the subject receiving treatment shows improvement selected from one or more of the following: Fibromyalgia Survey Score, optionally assessed by the 2016 Fibromyalgia Survey Questionnaire (FSQ); Pain Intensity Numerical Rating Scale (PI-NRS), optionally assessed by the 11-item PI-NRS scale; PROMIS Pain Interference Assessment; PainDETECT Questionnaire (PD-Q); Chronic Pain Acceptance Assessment, optionally measured by the Chronic Pain Acceptance Questionnaire (CPAQ-8); and Pain Interference Assessment, optionally measured by the 4-item PROMIS Pain Interference Scale.

[0039] In some embodiments, the one or more doses of psilocybin or its active metabolites include a first dose of psilocybin. In some embodiments, the first dose is at or about 10 mg to 50 mg of psilocybin. In some embodiments, the first dose is at or about 15 mg of psilocybin.

[0040] In some of all embodiments, the one or more doses of psilocybin include two or more doses of psilocybin.

[0041] In some embodiments, the one or more doses of psilocybin include a second dose of psilocybin. In some embodiments, the second dose is 20 mg, or about 20 mg to 50 mg, or about 50 mg, of psilocybin. In some embodiments, the second dose is 25 mg, or about 25 mg, of psilocybin. In some embodiments, the second dose is 10 mg, or about 10 mg to 20 mg, or about 20 mg, of psilocybin. In some embodiments, the second dose is 15 mg, or about 15 mg, of psilocybin.

[0042] In some of all embodiments, the second dose is administered 12 days, or about 12 to 16 days, or about 16 days after the first dose. In some of all embodiments, the second dose is administered 14 days, or about 14 days after the first dose.

[0043] In some embodiments, the methods also include providing one or more integration sessions to the subject after the one or more doses of psilocybin. In some embodiments, the one or more integration sessions are provided 3, 4, and / or 5 weeks or about 3, 4, and / or 5 weeks after administration of the first dose of psilocybin. In some embodiments, the one or more integration sessions are provided 1, 2, and / or 3 weeks or about 1, 2, and / or 3 weeks after administration of the second dose of psilocybin. [Brief explanation of the drawings]

[0044] [Figure 1A] Figure 1 shows withdrawal thresholds of the Von Frey assay (VFA) in the rat formalin-induced pain model of the contralateral paw after formalin administration. Baseline, BL; formalin baseline, FBL (post-formalin administration). [Figure 1B]Figure 1 shows withdrawal thresholds of the Von Frey assay (VFA) in the formalin-induced rat pain model of the ipsilateral paw after formalin administration. Baseline, BL; formalin baseline, FBL (post-formalin administration). [Figure 2A] Figure 1 shows the withdrawal thresholds of the von Frey assay (VFA) in the formalin-induced rat pain model after injection of formalin and after intravenous infusion of either psilocybin or saline (day 1). Contralateral paw withdrawal thresholds are shown weekly over the 28-day analysis. Baseline, BL; formalin baseline, FBL (post-formalin administration). [Figure 2B] Figure 1 shows the withdrawal thresholds of the von Frey assay (VFA) in the formalin-induced rat pain model after injection of formalin and after intravenous infusion of either psilocybin or saline (day 1). The withdrawal thresholds of the ipsilateral paw are shown weekly over the 28-day analysis. Baseline, BL; formalin baseline, FBL (post-formalin administration). [Figure 3A] Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 3B] Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 3C]Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 3D] Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 3E] Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 3F] Figures 3A-3C show selected treatment comparison data from the von Frey assay (VFA) described with respect to Figures 1A-B and 2A-B for the contralateral paw (Figures 3A-3C) and ipsilateral paw (Figures 3D-3F) on day 14, including FBL and saline (Figures 3A and 3D), FBL and PSIL (Figures 3B and 3E), and saline and PSIL (Figures 3C and 3F). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 4A]Figures 4A-4D show hot plate assay (HPA) withdrawal latencies from a 52.5°C hot plate in the formalin-induced rat pain model after formalin injection and either psilocybin or saline intravenous infusion (day 1). Escape latencies are shown weekly over the 28-day analysis (Figure 4A). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 4B] Figures 4A-4D show hot plate assay (HPA) withdrawal latencies from a 52.5°C hot plate in a formalin-induced rat pain model after formalin injection and either psilocybin or saline intravenous infusion (day 1). Withdrawal latencies are shown weekly over the 28-day analysis (Figure 4A). Figures 4B-4D show selected treatment comparison data at day 28, including FBL and saline (Figure 4B), FBL and PSIL (Figure 4C), and saline and PSIL (Figure 4D). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 4C] Figures 4A-4D show hot plate assay (HPA) withdrawal latencies from a 52.5°C hot plate in a formalin-induced rat pain model after formalin injection and either psilocybin or saline intravenous infusion (day 1). Withdrawal latencies are shown weekly over the 28-day analysis (Figure 4A). Figures 4B-4D show selected treatment comparison data at day 28, including FBL and saline (Figure 4B), FBL and PSIL (Figure 4C), and saline and PSIL (Figure 4D). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 4D]Figures 4A-4D show hot plate assay (HPA) withdrawal latencies from a 52.5°C hot plate in a formalin-induced rat pain model after formalin injection and either psilocybin or saline intravenous infusion (day 1). Withdrawal latencies are shown weekly over the 28-day analysis (Figure 4A). Figures 4B-4D show selected treatment comparison data at day 28, including FBL and saline (Figure 4B), FBL and PSIL (Figure 4C), and saline and PSIL (Figure 4D). Baseline, BL; formalin baseline, FBL (post-formalin administration); psilocybin, PSIL. [Figure 5] FIG. 5 illustrates an exemplary clinical treatment and evaluation schedule according to provided embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0045] Provided herein are methods for treating or alleviating fibromyalgia (FM) or one or more symptoms of FM, comprising administering a hallucinogen, such as psilocybin or a metabolite thereof, such as psilocin. In some embodiments, provided herein are methods of administering and uses, e.g., therapeutic and prophylactic uses, of hallucinogens such as psilocybin or psilocin to treat or alleviate FM or one or more symptoms of FM. In some embodiments, the provided methods and uses also include psychotherapy, e.g., one or more clinical sessions, e.g., integrative sessions.

[0046] In some embodiments, the provided methods and uses also include measuring one or more indicators before, during, and / or after treatment, for example, before, during, and / or after administration of a hallucinogen, such as psilocybin or psilocin. In some embodiments, the subject undergoing treatment is evaluated for various indicators, such as observer-rated and subject-reported outcomes, biological and clinical indicators, and combinations thereof, before and / or after performing one or more steps of the method or use. In some embodiments, exemplary indicators measured and analyzed include fibromyalgia survey scores, pain interference assessments, sleep assessments, chronic pain acceptance assessments, or evaluations of clinical indicators. In some embodiments, the provided methods and uses result in an improvement, e.g., clinical improvement or alleviation, in one or more symptoms of FM. In some embodiments, the improvement or alleviation can be observed based on one or more of the indicators evaluated in the subject.

[0047] In some embodiments, methods for identifying or selecting subjects for treating or alleviating FM or one or more symptoms thereof with a hallucinogen are also provided, e.g., according to the treatment methods and uses provided.

[0048] Also provided herein is the use of a hallucinogen, such as psilocybin or psilocin, in any of the provided methods and treatments, and in the preparation of medicaments for carrying out such methods. In some embodiments, the methods and uses thereby improve, alleviate, and / or treat FM or one or more symptoms thereof in a subject. In some embodiments, the provided therapeutic methods and uses involve administering a hallucinogen, such as psilocybin or psilocin, to a subject having, exhibiting, or suffering from one or more symptoms of FM, in some cases in combination with psychotherapy. In some aspects, the hallucinogen, such as psilocybin or psilocin, is administered in an amount effective to result in improvement or alleviation of one or more symptoms of FM.

[0049] In some embodiments, treatment also includes psychotherapy. In some embodiments, the provided methods and uses also include psychotherapy, e.g., in one or more clinical sessions. In some embodiments, the provided methods and uses of treatment include administering a hallucinogen to a subject, e.g., in some cases in combination with psychotherapy.

[0050] Fibromyalgia (FM; also known as FM syndrome) is a complex, chronic condition characterized by widespread joint and muscle pain and a variety of symptoms. Currently available treatments and other approaches for managing fibromyalgia or one or more of its symptoms are limited in their benefits, may have a significant burden or risk of side effects, and may have a limited duration of treatment action. Thus, there is a need for an FM treatment that can address one or more of the symptoms associated with FM with a reduced burden or risk of side effects and has an extended duration. Embodiments that meet this need are provided.

[0051] In some aspects, provided embodiments are also based on the observation that administration of hallucinogens, such as psilocybin or psilocin, has beneficial effects on pain perception in animal models of pain associated with pain-related diseases and indications, including fibromyalgia (FM). In some aspects, as demonstrated herein, administration of psilocybin has been shown to reduce tactile pain for up to 28 days in animal models of pain, such as a rat model of pain. In some aspects, as demonstrated herein, administration of psilocybin has been shown to reduce tactile pain for up to 28 days in animal models of pain, such as a rat model of pain. In some aspects, the demonstrated effect of hallucinogen administration on pain perception in the uninjected limb, which persisted for several weeks after administration, supports the utility of provided embodiments in treating pain-related disorders, such as nociceptive pain disorders, e.g., fibromyalgia (FM). In some aspects, this observation supports the benefits of provided embodiments. Because psilocybin catabolism is similar in rats and humans (see, e.g., Kalberer et al., Biochem Pharmacol 1962;11:261-9; Chen et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2011;879(25):2669-72), the results in the rat pain model described herein also provide support for the administration of psilocybin or its active metabolites, such as psilocin, in the treatment of pain-related disorders such as FM in human subjects.

[0052] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. To the extent that a definition set forth herein contradicts or otherwise conflicts with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein shall take precedence over the definition incorporated herein by reference.

[0053] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0054] I. Methods of Treatment of Fibromyalgia (FM) and Use of Hallucinogens Provided herein are methods of treatment, related uses, and methods for identifying or selecting individuals, such as human subjects, for treating fibromyalgia (FM) or one or more symptoms of FM by administering a hallucinogen, such as psilocybin or a metabolite thereof. In some embodiments, the individual also undergoes psychotherapy in combination with or in conjunction with the administration of the hallucinogen, e.g., in one or more clinical sessions.

[0055] A. Fibromyalgia Fibromyalgia (FM; also known as FM syndrome) is a chronic condition or syndrome characterized by widespread joint and muscle pain, which may involve multiple concurrent episodes. FM is reported to affect 0.5-5% of the world's population, primarily middle-aged women (Arnold et al., Patient Educ Couns 2008;73(1):114-20; White and Harth, Curr Pain Headache Rep 2001;5(4):320-9). The cause of chronic pain in FM is difficult to determine, and a defined pathophysiological explanation is often lacking, making diagnosis and treatment challenging. While the etiology and pathophysiology of FM are not fully understood, inflammation in the musculoskeletal system of FM patients suggests the immune system may be involved. Genetic and environmental factors have also been reported to play a role in the etiology and pathophysiology of FM. Symptoms of FM vary widely but include fatigue, muscle and joint stiffness, numbness, tingling, sleep disturbances, insomnia, sleep disturbances, allodynia (an exaggerated painful response to pressure), mood disorders, cognitive impairment, anxiety, depression, general irritability, and the inability to perform routine daily tasks (Qureshi et al., Cureus 2021;13(10):e18692). Overall, individuals with FM suffer a dramatic decrease in quality of life, and these individuals have limited treatment options (Alciati et al., Clin Exp Rheumatol 2021;39 Suppl 130(3):3-12).

[0056] Effective drug interventions for the hallmark symptoms of FM (e.g., hyperalgesia, allodynia, and sleep disturbances) are limited. In some cases, individuals with FM are treated with four major drug classes: serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and antiepileptic drugs (AEDs) (Qureshi et al., Cureus 2021;13(10):e18692). Three drug therapies, pregabalin (Lyrica®), duloxetine (Cymbalta®), and milnacipran (Savella®), are approved by the FDA for the treatment of fibromyalgia. However, reports indicate that currently available drug therapies do not provide substantial clinical benefit (Wolfe et al., Eur J Pain. 2013 Apr;17(4):581-6). People may turn to opioids despite their lack of effectiveness against FM and the potential for side effects and many co-occurring symptoms (Fitzcharles et al., Am J Med 2011;124(10):955-60). Currently, there is a significant unmet need for treatment and therapeutic needs for FM by people seeking relief from its debilitating symptoms.

[0057] Provided embodiments include administration of a hallucinogen, such as psilocybin, for the treatment of one or more symptoms of FM. In some embodiments, one or more symptoms of FM that arise or are exhibited in a subject are measured or assessed before initiating administration of a hallucinogen, such as psilocybin. In some embodiments, one or more indicators are measured, including one or more symptoms of FM (e.g., Fibromyalgia Survey score), dissociative state, treatment outcome, indicators related to safety, and / or one or more indicators related to the subject. In some embodiments, if one or more symptoms of FM are measured or assessed and the subject meets one or more criteria for having one or more symptoms of FM, the subject is identified or selected for treatment according to the methods and uses described herein. In some embodiments, one or more indicators and / or one or more symptoms of FM are measured or assessed during or after administration of a hallucinogen or psychotherapy. In some embodiments, one or more indicators and / or one or more symptoms of FM measured during or after administration of the hallucinogen and / or psychotherapy are assessed to measure outcome during or after treatment, e.g., to determine efficacy, improvement, or alleviation due to treatment. In some embodiments, one or more indicators and / or one or more symptoms of FM are measured using any method for measuring an indicator or parameter related to one or more indicators and / or one or more symptoms of FM, such as those described in Section II.

[0058] In some embodiments, provided herein are methods of treatment comprising administering psilocybin or a metabolite thereof, in some embodiments in combination with psychotherapy, to treat an individual with FM. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, to treat an individual diagnosed with FM. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, to treat an individual exhibiting or experiencing one or more symptoms of FM. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, whereby the severity of one or more symptoms is reduced in the individual receiving treatment.

[0059] In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, whereby the severity of one or more symptoms in an individual receiving treatment is reduced, including, but not limited to, fatigue, muscle and joint stiffness, numbness, tingling, sleep disturbances, insomnia, sleep disorders, allodynia (an exaggerated painful response to pressure), mood disorders, cognitive impairment, anxiety, depression, general irritability, and inability to perform routine daily tasks. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, whereby improvement in one or more symptoms persists for a period of at least three months following treatment. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments in combination with psychotherapy, whereby improvement in one or more symptoms persists for a period of at least six months following treatment. In some embodiments, provided herein are methods of treatment comprising administering psilocybin, in some embodiments administering it in combination with psychotherapy, wherein improvement in one or more symptoms persists for a period of at least 12 months following treatment.

[0060] B. Hallucinogens and Psilocybin In some aspects, the provided therapeutic methods and uses include the administration of a hallucinogen compound, such as psilocybin or a metabolite thereof. In some aspects, the administration of the hallucinogen is in conjunction with one or more clinical sessions, for example, in conjunction with one or more preparatory or integration sessions for psychotherapy. In some embodiments, the methods and uses include orally administering one or more doses of psilocybin or psilocin to a subject suffering from one or more symptoms of FM. In some aspects, if a subject is selected or identified for treatment with psilocybin or psilocin, the subject is orally administered one or more doses of psilocybin or psilocin.

[0061] Hallucinogens ("mind-revealing" drugs) are a class of compounds that have been used to treat certain psychiatric disorders, such as depression and addiction (Nutt et al., Cell 2020;181(1):24-8). Hallucinogens have a remarkable safety profile and are being explored in other clinical applications. However, clinical evidence for hallucinogens in the treatment of chronic pain is lacking.

[0062] Psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]dihydrogenphosphate; 4-phosphoroyloxy-N,N-dimethyltryptamine) is a natural product produced by various species of mushrooms in the genus Palomino; it is manufactured for clinical use to control potency and purity. It is a tryptamine derivative; in humans, the phosphate group is rapidly enzymatically cleaved in the body to produce psilocin, an agonist at various serotonin receptors, most importantly the 5-HT2A receptor (Carhart-Harris et al., 2014, Frontiers in Human Neuroscience, 8; Nichols, 2004, Pharmacol Ther, 101(2), 131-181). Psilocybin is a prodrug, and after administration, the phosphate group is rapidly cleaved in the body by alkaline phosphatase or other nonspecific esterases to produce the active metabolite, psilocin (Dinis-Oliveira R, Drug Metab Rev 2017;49(1):84-91). Psilocin is a prodrug that converts 5-hydroxytryptamine (5-HT) 2APsilocybin is an agonist of multiple serotonin receptors, including the serotonin receptor (Carhart-Harris et al., Front Hum Neurosci 2014;8:20; Nichols D, Pharmacol Ther 2004;101(2):131-81). Psilocybin can induce profound changes in sensory awareness, emotion, thought, and sense of self, characterized by significant alterations in all mental functions, including sensation, mood, will, cognition, and experience of self (Geyer and Vollenweider, Trends Pharmacol Sci. 2008;29(9):445-53; Studerus et al., J Psychopharmacol. 2011;25(11):1434-52). These profound changes are often referred to as mystical-type experiences. Measures of mystical-type experiences that occur during psilocybin treatment have repeatedly been observed to predict subsequent effects on behavior and emotion, such as reduced symptoms of depression and anxiety (Griffiths et al., J Psychopharmacol. 2016;30(12):1181-1197; Maclean et al., J Psychopharmacol. 2011;25(11):1453-1461; Ross et al., J Psychopharmacol. 2016;30(12):1165-1180). Psilocybin has effects similar to those of dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and mescaline. These drugs produce psychoactive effects characterized as producing an intense dream-like state with sensations including colorful visual hallucinations, auditory, tactile, olfactory, gustatory, and kinesthetic changes, altered perception of time and space, changes in body image, and disintegration of the ego, as well as intense mood changes ranging from feelings of wonder and bliss to sadness and grief.

[0063] In some embodiments, psilocybin induces profound changes in sensory awareness, emotions, thoughts, and sense of self, characterized by significant alterations in all mental functions, including sensation, mood, will, cognition, and experience of self (Geyer and Vollenweider, Trends Pharmacol Sci. 2008;29(9):445-53; Studerus et al., J Psychopharmacol. 2011;25(11):1434-52). These profound changes, often referred to as mystical-type experiences, have been repeatedly observed to predict later effects on behavior and emotion, such as reduced symptoms of depression and anxiety (Griffiths et al., J Psychopharmacol. 2016;30(12):1181-1197; Maclean et al., J Psychopharmacol. 2011;25(11):1453-1461; Ross et al., J Psychopharmacol. 2016;30(12):1165-1180). In some embodiments, the effects of psilocybin are primarily associated with activation of 5-HT2A receptors.

[0064] Oral psilocybin has a bioavailability of approximately 50%, and psilocin is detectable in plasma within 20 minutes after administration of the parent compound (Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554; Pharm Acta Helv. 1997;72(3):175-84). The half-life of psilocin in the blood is 2-3 hours. The onset of significant psychoactive effects generally occurs within 1 hour, peaking approximately 2 hours after administration. Loss of significant effects typically occurs approximately 6 hours after administration. Based on this time course, observations in clinical trial settings are limited to 8 hours after administration. Furthermore, exposure after a 25 mg oral dose is associated with both near-maximal occupancy of neocortical serotonin 5-HT2A receptors and subjective intensity ratings of elements of the psychedelic experience, which have repeatedly been associated with longer-term therapeutic benefits (Madsen et al., Neuropsychopharmacology. 2019;44(7):1328-1334).

[0065] Similar to humans, preclinical studies have reported that when psilocybin is orally administered to rats, it is rapidly dephosphorylated to psilocin by alkaline phosphatase and nonspecific esterases in the intestinal mucosa, with approximately 50% of the total volume of psilocin absorbed from the gastrointestinal tract (Kalberer et al., Biochem Pharmacol. 1962;11:261-9). Maximum plasma levels are achieved after approximately 90 minutes (Chen et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2011;879(25):2669-72). When administered systemically (i.e., bypassing the gastrointestinal tract), initial psilocybin metabolism is carried out by tissue phosphatases, with in vitro studies indicating that the kidney is the most active metabolic organ (Horita and Weber, Biochem. Pharmacol. 1961;7(1):47-54). Across species tested, the highest levels of psilocin have been found in the neocortex, hippocampus, and thalamus (Hopf and Eckert, Act Nerv Super(Praha) 1974;16(1):64-6). In certain studies, psilocybin has been shown to reduce symptomatic responses in indications such as obsessive-compulsive disorder (OCD), substance use disorders, depression, and anxiety. Overall, psilocybin has been well tolerated at doses tested in clinical studies.

[0066] Studies in rats have demonstrated that psilocybin catabolism is similar to humans, with approximately 50% of total psilocin absorbed from the gastrointestinal tract (Kalberer et al., Biochem Pharmacol 1962;11:261-9), and maximum plasma levels were achieved approximately 90 minutes after administration (Chen et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2011;879(25):2669-72). In some embodiments, when administered systemically (i.e., bypassing the gastrointestinal tract), initial psilocybin metabolism is carried out by tissue phosphatases, with in vitro studies indicating that the kidney is the most active metabolic organ (Horita and Weber, Biochem Pharmacol 1961;7(1):47-54). Furthermore, maximal levels of psilocin have consistently been found in the neocortex, hippocampus, and thalamus (Hopf and Eckert, Act Nerv Super (Praha) 1974;16(1):64-6).

[0067] In clinical settings, psilocybin administration has been reported to improve certain symptoms of cancer-related psychiatric stress, depression and anxiety, nicotine and alcohol addiction, obsessive-compulsive disorder (OCD) (Nutt et al., Cell 2020;181(1):24-8), and adolescent anorexia, a condition in which intrusive thoughts drive maladaptive and life-threatening behaviors and treatment resistance is common (Foldi et al., 2020, Frontiers in Neuroscience, 14). Psilocybin was well tolerated at doses tested in clinical studies. Furthermore, a single dose of psilocybin was shown to improve patient-reported depression scores after 1 week, and these improvements persisted for up to 6 months (Carhart-Harris et al., Psychopharmacol 2018;235(2):399-408). Psilocybin has since received fast-track approval by the FDA for depression.

[0068] 1. Administration In some aspects, provided herein are methods of treatment including psilocybin or psilocin dosage regimens for treating individuals, such as human subjects, having fibromyalgia (FM) or suffering from or exhibiting one or more symptoms of FM. In some aspects, provided herein are psilocybin or psilocin dosage regimens for treating individuals experiencing one or more symptoms of FM. In some aspects, provided herein are psilocybin or psilocin dosage regimens for treating individuals who have been diagnosed with FM. In some embodiments, a method for treating an individual exhibiting or suffering from one or more symptoms of FM comprises administering one or more therapeutically effective doses of psilocybin or psilocin to the subject.

[0069] In some embodiments, one or more doses of psilocybin are administered to an individual (e.g., a subject having FM, or a subject suffering from or exhibiting one or more symptoms of FM, or a subject identified or selected for treatment). In some embodiments, a first dose and a second dose of psilocybin are administered. In some embodiments, psilocybin is administered orally. In some embodiments, psilocybin is administered intravenously.

[0070] In some embodiments, one or more doses of psilocin are administered to an individual (e.g., a subject having FM, or a subject suffering from or exhibiting one or more symptoms of FM, or a subject identified or selected for treatment). In some embodiments, a first dose and a second dose of psilocin are administered. In some embodiments, psilocin is administered orally. In some embodiments, psilocin is administered intravenously.

[0071] In some cases, the first dose of psilocybin may not produce a sufficient hallucinogen effect. In some embodiments, the first dose can help familiarize the subject with the administration of the hallucinogen and its effects. In some embodiments, the second dose, which in some cases is a therapeutically effective dose or produces a therapeutic effect greater than the first dose, may be used to identify and / or select subjects for treatment according to the provided methods and uses. In some embodiments, the first dose is used to evaluate the subject's suitability for treatment according to the provided embodiments, for example, for receiving a second, higher dose. In some embodiments, the first dose can be used to evaluate adverse effects or side effects that may be associated with the administration of the hallucinogen. In some embodiments, the two-dose treatment regimen also allows for evaluation of subjects who may have higher bioavailability and / or a higher conversion rate to psilocin, reducing the likelihood of unexpected adverse events.

[0072] Oral psilocybin has a bioavailability of approximately 50%, and psilocin is detectable in plasma within 20 minutes after administration of the parent compound (Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554; Pharm Acta Helv. 1997;72(3):175-84). The half-life of psilocin in the blood is 2-3 hours. The onset of significant psychoactive effects occurs within 1 hour, peaking approximately 2 hours after administration. Loss of significant effects typically occurs approximately 6 hours after administration. In one report, peak plasma levels of psilocin after a single oral dose of psilocybin at 0.225 mg / kg occurred after 105 + / - 37 minutes, giving a mean concentration of 8.2 + / - 2.8 ng of psilocin per ml of plasma, and an estimated absolute bioavailability of psilocin after oral administration of psilocybin of 52.7 + / - 20% (Hasler et al., Pharm Acta Helv. 1997 July;72(3):175-84). In one report, exposure after a 25 mg oral dose significantly increased neocortical serotonin 5-HT 2A It is associated with both near-maximal receptor occupancy and subjective intensity ratings of elements of the hallucinogen experience that have repeatedly been associated with longer-term therapeutic usefulness (Madsen et al., Neuropsychopharmacology 2019;44(7):1328-34).

[0073] In some embodiments, one or more doses of a hallucinogen, such as psilocybin or its active metabolite, are administered to a subject. In some embodiments, 1, 2, 3, 4, or 5 doses are administered to a subject. In some embodiments, one dose is administered. In some embodiments, two or more doses are administered to a subject. In some aspects, two doses are administered.

[0074] In some embodiments, the subsequent dose that is not the first may be any dose of a hallucinogen, such as psilocybin or its active metabolite, administered after the first or first dose, in which case at least two doses are administered to the subject. In some embodiments, the subsequent dose that is not the first may be any dose administered after the first or first dose, in which case two or more doses are administered to the subject. In some embodiments, the subsequent dose that is not the first may be a second, third, or fourth dose of psilocybin. In some embodiments, the subject receives the subsequent dose as needed. In some embodiments, the subject receives subsequent intermittent doses as needed.

[0075] In some embodiments, when two or more doses of a hallucinogen, e.g., psilocybin or a metabolite thereof, are administered, the administration interval between the previous and subsequent doses, e.g., the administration interval between the first and second doses, is one week or about one to four weeks. In some embodiments, the second dose is administered one week or about one week, about two weeks, about three weeks, or about four weeks after the first dose. In some aspects, the administration interval, e.g., the time between the first and second doses, is 1 day or about one day, 2 days or about two days, 3 days or about three days, 4 days or about four days, 5 days or about five days, 6 days or about six days, 7 days or about seven days, 8 days or about eight days, 9 days or about nine days, 10 days or about ten days, 11 days or about 11 days, 12 days or about twelve days, 13 days or about thirty days, 14 days or more. or about 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days. In some embodiments, the second dose is administered 1 day or about 1 day, 2 days or about 2 days, 3 days or about 3 days, 4 days or about 4 days, 5 days or about 5 days, 6 days or about 6 days, 7 days or about 7 days, 8 days or about 8 days, 9 days or about 9 days, 10 days or about 10 days, 11 days or about 11 days, 12 days or about 12 days, 13 days or about 13 days, 14 days or about 14 days, or about 15 days, 16 days or about 16 days, 17 days or about 17 days, 18 days or about 18 days, 19 days or about 19 days, 20 days or about 20 days, 21 days or about 21 days, 22 days or about 22 days, 23 days or about 23 days, 24 days or about 24 days, 25 days or about 25 days, 26 days or about 26 days, 27 days or about 27 days, or 28 days or about 28 days later.

[0076] In some embodiments, a dose of a hallucinogen, e.g., psilocybin or a metabolite thereof, is administered to a subject, e.g., a subject with FM. In some embodiments, the dose of psilocybin is a therapeutically effective dose. In some embodiments, the dose of psilocybin is effective and / or sufficient to induce a dissociative state. In some embodiments, the therapeutically effective dose of psilocybin is based on the route of administration. In some embodiments, the dose of psilocin is a therapeutically effective dose. In some embodiments, the dose of psilocin is effective and / or sufficient to induce a dissociative state. In some embodiments, the therapeutically effective dose of psilocin is based on the route of administration.

[0077] In some embodiments, the dose is a flat or fixed dose. In some embodiments, the dose to be administered is 5 mg or about 5 mg to 50 mg or about 50 mg. In some embodiments, the dose to be administered is 5 mg or about 5 mg, 10 mg or about 10 mg, 15 mg or about 15 mg, 20 mg or about 20 mg, 25 mg or about 25 mg, 30 mg or about 30 mg, 35 mg or about 35 mg, 40 mg or about 40 mg, 45 mg or about 45 mg, or 50 mg or about 50 mg. In some aspects, the dose is administered orally. In some embodiments, for oral administration, the dose to be administered is 5 mg or about 5 mg to 50 mg or about 50 mg, for example, 5 mg or about 5 mg, 10 mg or about 10 mg, 15 mg or about 15 mg, 20 mg or about 20 mg, 25 mg or about 25 mg, 30 mg or about 30 mg, 35 mg or about 35 mg, 40 mg or about 40 mg, 45 mg or about 45 mg, or 50 mg or about 50 mg. In some embodiments, for example, by oral administration, the dose to be administered is 25 mg or about 25 mg. In some embodiments, for example, by oral administration, the dose to be administered is 50 mg or about 50 mg.

[0078] In some embodiments, for oral administration, the first dose to be administered is 5 mg or about 5 mg to 50 mg or about 50 mg, for example, 5 mg or about 5 mg, 10 mg or about 10 mg, 15 mg or about 15 mg, 20 mg or about 20 mg, 25 mg or about 25 mg, 30 mg or about 30 mg, 35 mg or about 35 mg, 40 mg or about 40 mg, 45 mg or about 45 mg, or 50 mg or about 50 mg. In some embodiments, the first dose to be administered, for example, by oral administration, is 25 mg or about 25 mg. In some embodiments, the first dose to be administered, for example, by oral administration, is 50 mg or about 50 mg. In some embodiments, when administered orally, the first dose of psilocybin to be administered is 5 mg or about 5 mg to 50 mg or about 50 mg, for example, 5 mg or about 5 mg, 10 mg or about 10 mg, 15 mg or about 15 mg, 20 mg or about 20 mg, 25 mg or about 25 mg, 30 mg or about 30 mg, 35 mg or about 35 mg, 40 mg or about 40 mg, 45 mg or about 45 mg, or 50 mg or about 50 mg. In some embodiments, the first dose of psilocybin to be administered, for example, by oral administration, is 25 mg or about 25 mg. In some embodiments, the first dose of psilocybin to be administered, for example, by oral administration, is 50 mg or about 50 mg.

[0079] In some embodiments, dosage is determined according to body weight. In some embodiments, the first dosage is determined according to body weight. In some aspects, exemplary dosages based on body weight include 0.1 mg / kg, 0.15 mg / kg or about 0.15 mg / kg, 0.25 mg / kg or about 0.25 mg / kg, 0.35 mg / kg or about 0.35 mg / kg, 0.45 mg / kg or about 0.45 mg / kg, 0.55 mg / kg or about 0.55 mg / kg, 0.65 mg / kg or about 0.65 mg / kg, 0.75 mg / kg or about 0.75 mg / kg, 0.85 mg / kg or about 0.85 mg / kg, 0.95 mg / kg or about 0.95 mg / kg, or 1.0 mg / kg or about 1.0 mg / kg. In some embodiments, a dosage of 25 mg or about 25 mg is administered to a subject with a body weight of less than 100 kg (≦100 kg). In some embodiments, a dose of 30 mg or about 30 mg is administered to a subject weighing >100 kg and <117 kg, hi some embodiments, a dose of 35 mg or about 35 mg is administered to a subject weighing >117 kg.

[0080] In some embodiments, doses subsequent to the first dose are determined according to body weight. In some embodiments, subsequent doses are increased by 0.1 mg / kg or about 0.1 mg / kg to 1 mg / kg or about 1 mg / kg compared to the first initial dose, for example, by 0.1 mg / kg or about 0.1 mg / kg, 0.15 mg / kg or about 0.15 mg / kg, 0.25 mg / kg or about 0.25 mg / kg, 0.35 mg / kg or about 0.35 mg / kg, 0.45 mg / kg or about 0.45 mg / kg, 0.55 mg / kg or about 0.55 mg / kg, 0.65 mg / kg or about 0.65 mg / kg, 0.75 mg / kg or about 0.75 mg / kg, 0.85 mg / kg or about 0.85 mg / kg, 0.95 mg / kg or about 0.95 mg / kg, or 1.0 mg / kg or about 1.0 mg / kg. In some embodiments, subsequent doses are increased by 0.15 mg / kg or about 0.15 mg / kg, 0.25 mg / kg or about 0.25 mg / kg, 0.35 mg / kg or about 0.35 mg / kg, 0.45 mg / kg or about 0.45 mg / kg, 0.55 mg / kg or about 0.55 mg / kg, 0.65 mg / kg or about 0.65 mg / kg, 0.75 mg / kg or about 0.75 mg / kg, 0.85 mg / kg or about 0.85 mg / kg, and 0.95 mg / kg or about 0.95 mg / kg compared to the first initial dose.

[0081] In some embodiments, subsequent doses of 30 mg or about 30 mg are administered to subjects weighing less than 80 kg (≦80 kg). In some embodiments, subsequent doses of 35 mg or about 35 mg are administered to subjects weighing more than 80 kg and less than or equal to 90 kg (>80 kg and ≦90 kg). In some embodiments, subsequent doses of 40 mg or about 40 mg are administered to subjects weighing more than 90 kg and less than or equal to 100 kg (>90 kg and ≦100 kg). In some embodiments, subsequent doses of 45 mg or about 45 mg are administered to subjects weighing more than 100 kg and less than or equal to 112 kg (>100 kg and ≦112 kg). In some embodiments, subsequent doses of 50 mg or about 50 mg are administered to subjects weighing more than 112 kg (>112 kg).

[0082] In some embodiments, the first dose is 10 mg or about 10 mg to 20 mg or about 20 mg, e.g., oral psilocybin. In some embodiments, the first dose is 10 mg or about 10 mg, 11 mg or about 11 mg, 12 mg or about 12 mg, 13 mg or about 13 mg, 14 mg or about 14 mg, 15 mg or about 15 mg, 16 mg or about 16 mg, 17 mg or about 17 mg, 18 mg or about 18 mg, 19 mg or about 19 mg, or 20 mg or about 20 mg, e.g., oral psilocybin. In some embodiments, the first dose is 15 mg or about 15 mg, e.g., oral psilocybin.

[0083] In some embodiments, the second dose is greater than the first dose. In some embodiments, the second dose is 20 mg or about 20 mg to 30 mg or about 30 mg, e.g., oral psilocybin. In some embodiments, the second dose is 20 mg or about 20 mg, 21 mg or about 21 mg, 22 mg or about 22 mg, 23 mg or about 23 mg, 24 mg or about 24 mg, 25 mg or about 25 mg, 26 mg or about 26 mg, 27 mg or about 27 mg, 28 mg or about 28 mg, 29 mg or about 29 mg, or 30 mg or about 30 mg, e.g., oral psilocybin. In some embodiments, the second dose is 25 mg or about 25 mg, e.g., oral psilocybin.

[0084] In some embodiments, the second dose is the same as the first dose. In some embodiments, the second dose is 10 mg or about 10 mg to 20 mg or about 20 mg, e.g., oral psilocybin. In some embodiments, the second dose is 10 mg or about 10 mg, 11 mg or about 11 mg, 12 mg or about 12 mg, 13 mg or about 13 mg, 14 mg or about 14 mg, 15 mg or about 15 mg, 16 mg or about 16 mg, 17 mg or about 17 mg, 18 mg or about 18 mg, 19 mg or about 19 mg, or 20 mg or about 20 mg, e.g., oral psilocybin. In some embodiments, the second dose is 15 mg or about 15 mg, e.g., oral psilocybin. In some embodiments, the second dose is the same as the first dose if it is determined that a higher dose is not expected to be advantageous or may not provide additional benefit.

[0085] In some embodiments, the second dose is administered about 1, 2, 3, or 4 weeks after the first dose. In some embodiments, the second dose is administered 12 days, or about 12-16 days, or about 16 days after the first dose. In some embodiments, the second dose is administered 12 days, or about 12 days, 13 days, or about 13 days, 14 days, or about 14 days, 15 days, or about 15 days, or 16 days, or about 16 days after the first dose. In some embodiments, the second dose is administered 14 days, or about 14 days after the first dose.

[0086] In some embodiments, psilocybin is administered orally. In some embodiments, psilocybin is administered in the form of a tablet. In some embodiments, psilocybin is administered in the form of a capsule. In some embodiments, one or more 5 mg psilocybin capsules are administered to meet the desired dosage level in a subject. In some embodiments, one or more 25 mg psilocybin capsules are administered to meet the desired dosage level in a subject. In some embodiments, psilocybin is administered in a capsule comprising one or more of gelatin, hydroxypropyl methylcellulose (HPMC) or hypromellose, and pullulan. In some embodiments, psilocybin is administered in a capsule comprising hydroxypropyl methylcellulose (HPMC) or hypromellose.

[0087] In some embodiments where a hallucinogen, such as psilocybin or a metabolite thereof, is administered to a subject more than once or repeatedly, the amount of the first dose and the amount of another subsequent dose are the same. In some embodiments where a hallucinogen, such as psilocybin or a metabolite thereof, is administered to a subject more than once or repeatedly, the amount of the first dose and the amount of another subsequent dose are different. In some embodiments where a hallucinogen, such as psilocybin or a metabolite thereof, is administered to a subject more than once or repeatedly, the amount of the first dose is less than the amount of another subsequent dose. In some embodiments where a hallucinogen, such as psilocybin or a metabolite thereof, is administered to a subject more than once or repeatedly, the amount of the first dose is greater than the amount of another subsequent dose.

[0088] C. Psychological support In some embodiments, the provided methods and uses include providing psychological support, e.g., psychotherapy or mental health support, in addition to or in conjunction with the administration of a hallucinogen, e.g., psilocybin or psilocin. In some embodiments, the methods or uses include administering a hallucinogen and psychological support or mental health support, e.g., psychotherapy, to an individual, such as a human subject, exhibiting or suffering from one or more symptoms of FM. In some embodiments, the methods or uses include administering a hallucinogen and psychotherapy to an individual exhibiting or suffering from one or more symptoms of FM. In some embodiments, the methods or uses include administering a hallucinogen and talk therapy to an individual exhibiting or suffering from one or more symptoms of FM. In some embodiments, the psychological support or mental health support is provided in person and / or remotely, e.g., by telephone or video conference. In some embodiments, the psychotherapy is provided in person and / or remotely, e.g., by telephone or video conference. In some embodiments, the talk therapy is provided in person and / or remotely, e.g., by telephone or video conference.

[0089] In some embodiments, psychological support includes psychotherapy and / or talk therapy. In some embodiments, psychological support is therapist-led or led by one or more persons other than the individual. In some embodiments, psychological support is self-administered. In some embodiments, psychological support is therapist-led and self-administered. In some embodiments, psychological support precedes administration of the hallucinogen, for example, during a preparation session. In some embodiments, psychological support does not precede administration of the hallucinogen. In some embodiments, psychological support is administered simultaneously with administration of the hallucinogen. In some embodiments, psychological support follows or occurs after administration of the hallucinogen, for example, during an integration session. In some aspects, the initial session of psychological support includes a therapist, and additional sessions do not include a therapist.

[0090] In some aspects, provided embodiments include providing psychological support and / or psychotherapy in one or more sessions, e.g., in one or more preparatory or integration sessions. In some embodiments, the psychological support is facilitated in one or more sessions. In some embodiments, the psychological support and / or psychotherapy is provided prior to administration of the hallucinogen, e.g., during a preparatory session. In some embodiments, the psychological support is concurrent with administration of the hallucinogen. In some embodiments, the psychological support and / or psychotherapy is provided after administration of the hallucinogen, e.g., during an integration session. In some embodiments, the psychological support and / or psychotherapy is provided before, during, or after administration of the hallucinogen, and the hallucinogen is administered at least once, at least twice, at least three times, or at least four times.

[0091] In some embodiments, psychological support and / or psychotherapy are provided in single-subject sessions, where one subject meets with one or more therapists. In some embodiments, psychological support and / or psychotherapy are provided in single-subject sessions, where one subject meets with two or more therapists. In some embodiments, psychological support and / or psychotherapy are provided in group sessions, where more than one subject meets with one or more therapists. In some embodiments, one or more of the subject's family or friends may be present during the pre-administration psychological support session. In some embodiments, the one or more psychological support sessions conducted prior to hallucinogen administration are conducted in person or remotely, for example, by telephone or video conference.

[0092] In some embodiments, psychological support conducted prior to hallucinogen administration includes tracking one or more goals and / or objectives. In some embodiments, one or more goals and / or objectives of the pre-administration session include establishing a therapeutic alliance between the individual and the therapist, answering the individual's questions and addressing any concerns, and demonstrating and implementing spontaneous inquiry and experiential processing. In some embodiments, the pre-administration psychological support session, e.g., one or more preparatory sessions, includes a discussion of the individual's life history, current life circumstances, as well as the individual's understanding, expectations, and intentions for the administration session. In some embodiments, the pre-administration psychological support session includes a discussion of the confirmed and / or potential effects of hallucinogens. In some embodiments, the pre-administration psychological support session includes establishing rapport with the therapist, learning about and building comfort with fibromyalgia, and becoming familiar with the physical space and administration setting and session. In some embodiments, the pre-administration psychological support session includes preparing the individual for hallucinogen administration by implementing relevant therapeutic techniques to reduce avoidance and anxiety, evoking relevant therapeutic goals, building rapport, and / or establishing a therapeutic alliance. In some embodiments, the pre-administration psychological support session includes listening to the individual's narrative about fibromyalgia, including aspects of chronic pain, sleep disturbances, emotional or cognitive dysfunction, and treatment history. In some embodiments, the pre-administration psychological support session includes psychoeducation about hallucinogen experiences and acceptance and commitment therapy (ACT).

[0093] In some embodiments, breathing exercises intended to promote calmness and / or reduce anxiety may be performed and / or practiced. In some embodiments, breathing exercises include instructing the individual to focus on their breathing and / or the sensations associated with breathing throughout the body. In one example, an individual may be instructed to breathe in for a count of four, briefly hold their breath, and then breathe out for a count of approximately eight. In some embodiments, the therapist and individual may discuss the most useful ways to support individuals experiencing emotional distress during a hallucinogen session. In some embodiments, the therapist may assist the individual in setting motivation for the hallucinogen session. In some embodiments, the individual is given access (e.g., online access) to materials regarding the safety and mechanism of action of hallucinogens.

[0094] In some embodiments, the psychological support is provided in one or more sessions. In some embodiments, the method or use includes psychological support prior to administration of the hallucinogen, e.g., during a preparation session. In some embodiments, the psychological support is provided simultaneously with administration of the hallucinogen. In some embodiments, the method or use includes psychological support after administration of the hallucinogen, e.g., during an integration session. In some embodiments, the method or use includes providing psychological support before, during, and after administration of the hallucinogen, wherein the hallucinogen is administered at least once, at least twice, at least three times, or at least four times.

[0095] In some embodiments, the method or use comprises providing one or more sessions of psychological support, for example providing one or more sessions of psychotherapy, for example one or more preparatory sessions, prior to the first or initial dose of the hallucinogen. In some embodiments, the method or use comprises two or more, for example three, four or five, preparatory sessions of psychological support prior to the first or initial dose of the hallucinogen. In some embodiments, the method or use comprises two preparatory sessions of psychological support prior to the first or initial dose of the hallucinogen.

[0096] In some embodiments, the individual receives at least one psychological support session prior to (e.g., pre-administration of) the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session at or about 1 month, 4 weeks at or about 4 weeks, 3 weeks at or about 3 weeks, 2 weeks at or about 2 weeks, or 1 week at or about 1 week before administering the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session about 2 weeks before administering the hallucinogen, e.g., about 2 weeks before the first or initial dose of the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session about 1 week before administering the hallucinogen, e.g., about 1 week before the first or initial dose of the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session 14 days or about 14 days, 13 days or about 13 days, 12 days or about 12 days, 11 days or about 11 days, 10 days or about 10 days, 9 days or about 9 days, 8 days or about 8 days, 7 days or about 7 days, 6 days or about 6 days, 5 days or about 5 days, 4 days or about 4 days, 3 days or about 3 days, 2 days or about 2 days, or 1 day or about 1 day prior to administration of the hallucinogen, e.g., administration of the first or first dose of the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session about 11 days prior to administration of the hallucinogen, e.g., administration of the first or first dose of the hallucinogen. In some embodiments, the method or use comprises conducting a pre-administration psychological support session about 4 days prior to administration of the hallucinogen, e.g., administration of the first or first dose of the hallucinogen. In some embodiments, the method or use comprises administering a pre-administration psychological support session one day prior to administration of the hallucinogen, hi some embodiments, one or more psychological support sessions are conducted prior to the initiation of hallucinogen administration, for example prior to the first or initial dose of the hallucinogen.

[0097] In some embodiments, the method or use comprises two psychological support sessions prior to the first or initial dose of the hallucinogen, e.g., two preparatory sessions. In some embodiments, the preparatory sessions occur within about one or two weeks prior to administration of the hallucinogen. In some embodiments, the first preparatory session occurs about 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day prior to administration of the hallucinogen, e.g., administration of the first or initial dose of the hallucinogen. In some embodiments, the first preparatory session occurs at or about two weeks prior to administration of the hallucinogen, e.g., administration of the first or initial dose of the hallucinogen. In some embodiments, the second preparatory session occurs at or about four, three, two, or 1 day prior to administration of the hallucinogen, e.g., administration of the first or initial dose of the hallucinogen. In some embodiments, the second preparation session occurs about 4 days prior to administration of the hallucinogen, for example, prior to administration of the first or initial dose of the hallucinogen.

[0098] In some embodiments, the method or use comprises providing psychological support during or concurrently with a hallucinogen administration session. In some embodiments, the method or use comprises administering a hallucinogen to an individual in a controlled environment, wherein the individual is provided with psychological support. In some embodiments, the method or use comprises administering one or more doses of a hallucinogen (e.g., an initial dose and one or more subsequent doses, or a first and second dose) to an individual in a controlled environment, wherein the individual is provided with psychological support.

[0099] In some embodiments, the method or use comprises administering a dose of a hallucinogen to an individual in a controlled environment, wherein the individual is provided with psychological support. In some embodiments, the method or use comprises, for example, administering one or more doses of a hallucinogen (e.g., an initial dose and one or more subsequent doses, or a first and second dose) to an individual in a controlled environment, wherein the individual is provided with psychological support. In some embodiments, the hallucinogen is administered in an environment under the guidance of a psychological support provider, such as a therapist. In some aspects, a psychological support provider, such as a therapist, is present during the administration session to provide support for the individual's physical and emotional needs during the administration session. In some aspects, a physician is available nearby at all times during the administration session, for example, for the first 1, 2, 3, or 4 hours and / or until the peak effects of the hallucinogen have subsided. In some aspects, a physician is available nearby at all times to provide consultation throughout the administration session.

[0100] In some embodiments, the hallucinogen is administered in a comfortable setting. In some embodiments, the individual receives the hallucinogen while lying on a comfortable couch or bed, wearing eyeshades, and listening to music via headphones. In some embodiments, the individual is encouraged to direct their attention inward. In some embodiments, during the administration session, a psychological support provider, such as a therapist, measures or evaluates one or more observer-reported parameters and / or indicators, such as any of those described herein, e.g., in Section II. In some embodiments, during the administration session, a psychological support provider, such as a therapist, measures or evaluates behaviors, signs, and reported symptoms, such as calmness, yawning, nausea / vomiting, amount of speech, anxiety, drowsiness, crying, restlessness, visual changes, euphoria, and the presence / intensity of a sense of unreality.

[0101] In some embodiments, the method or use comprises one or more sessions of psychological support after administration of the hallucinogen. In some embodiments, the method or use comprises one or more sessions of psychological support after the first or initial dose of the hallucinogen. In some embodiments, the method or use comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more sessions of psychological support after the first or initial dose of the hallucinogen.

[0102] In some embodiments, the method or use comprises one or more sessions of psychological support after a subsequent dose of the hallucinogen that is not the first. In some embodiments, the method or use comprises one or more sessions of psychological support after a subsequent dose of the hallucinogen that is not the first. In some embodiments, the method or use comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more sessions of psychological support after a subsequent dose of the hallucinogen that is not the first. In some embodiments, the method or use comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more sessions of psychological support after a subsequent dose of the hallucinogen that is not the first. In some embodiments, the method or use comprises at least three sessions of psychological support after a subsequent dose of the hallucinogen that is not the first, for example, after the second dose of the hallucinogen.

[0103] In some embodiments, a subsequent dose that is not the first may be any dose of the hallucinogen administered after the first or initial dose, where at least two doses are administered to an individual exhibiting or suffering from one or more symptoms of FM. In some embodiments, a subsequent dose that is not the first may be any dose of the hallucinogen administered after the first or initial dose, where two or more doses of the hallucinogen are administered to an individual exhibiting or suffering from one or more symptoms of FM. In some embodiments, a subsequent dose that is not the first is a second, third, or fourth dose of the hallucinogen. In some embodiments, a subsequent dose that is not the first is a second dose of the hallucinogen.

[0104] In some embodiments, three psychological support sessions, e.g., three integration sessions, are provided after administration of a subsequent dose, e.g., a second dose, of the hallucinogen. In some embodiments, the three integration sessions occur within about three weeks after administration of the hallucinogen, e.g., after administration of the second dose. In some embodiments, the three integration sessions occur approximately once a week within three weeks after administration of the hallucinogen. In some embodiments, the first of the three integration sessions occurs about one week after the hallucinogen administration session. In some embodiments, the first of the three integration sessions occurs about 5, 6, 7, 8, or 9 days after the hallucinogen administration session. In some embodiments, the second of the three integration sessions occurs about two weeks after the hallucinogen administration session. In some embodiments, the second of the three integration sessions occurs about 11, 12, 13, 14, 15, or 16 days after the hallucinogen administration session. In some embodiments, the third of the three integration sessions occurs about three weeks after the hallucinogen administration session. In some embodiments, the third of the three integration sessions occurs about 18, 19, 20, 21, 22, 23, or 24 days after the hallucinogen administration session.

[0105] In some embodiments, the one or more post-administration or integration sessions include eliciting a full discussion of the individual's experiences during the hallucinogen session(s). In some embodiments, the one or more post-administration or integration sessions include focusing on ACT-based clinical activities related to contact with the present moment, impulse separation, or acceptance based on clinical formation. In some embodiments, the one or more post-administration or integration sessions include reviewing and reflecting on the individual's hallucinogen experience, including any emotional, mental, or lifestyle changes that occur following the administration session(s).

[0106] In some embodiments, the one or more post-administration or integration sessions are conducted under the guidance of a psychological support provider, such as a therapist. In some aspects, the one or more post-administration or integration sessions include a discussion of integration, which helps the subject gain insight and understanding from their experience with the hallucinogen.

[0107] 1. Psychological support before administering hallucinogens In some embodiments, one or more sessions of psychological support and / or psychotherapy are provided prior to the first or initial dose of the hallucinogen (e.g., psilocybin or a metabolite thereof), e.g., prior to one or more preparatory sessions. In some embodiments, two or more sessions of psychological support, e.g., three, four, or five or more sessions of psychological support and / or psychotherapy are provided prior to the first or initial dose of the hallucinogen.

[0108] In some embodiments, the subject participates in at least one psychological support session prior to administration, e.g., prior to administration of the hallucinogen. In some embodiments, the pre-administration psychological support session is provided one month or about one month or less prior to administration of the hallucinogen, for example, four weeks or about four weeks, three weeks or about three weeks, two weeks or about two weeks, or one week or about one week prior. In some embodiments, the subject participates in at least one psychological support session prior to administration, e.g., prior to administration of the hallucinogen. In some embodiments, the pre-administration psychological support session is provided one week or about one week or less prior to administration of the hallucinogen, for example, seven days or about seven days, six days or about six days, five days or about five days, four days or about four days, three days or about three days, two days or about two days, or one day or about one day prior.

[0109] In some embodiments, one or more psychological support sessions are conducted prior to administration of the hallucinogen. In some aspects, two psychological support sessions are provided prior to administration of the hallucinogen. In some embodiments, two psychological support sessions are provided prior to the first hallucinogen administration session, e.g., prior to two preparatory sessions. In some aspects, two psychological support sessions are provided prior to administration of the hallucinogen, with the first session being provided at or about one week prior to administration of the hallucinogen, and at or about one to three days prior to administration of the hallucinogen, e.g., at or about two days prior to administration of the hallucinogen.

[0110] In some embodiments, the one or more psychological support sessions conducted prior to administration of the hallucinogen are conducted in person or remotely, for example by telephone or video conference.

[0111] In some embodiments, breathing exercises intended to promote calmness and / or reduce anxiety may be provided, performed, and / or practiced. In some embodiments, the breathing exercises include instructing the subject to focus on their breathing and / or the sensations associated with breathing throughout the body. In one example, a subject may be instructed to breathe in for a count of four, briefly hold their breath, and then breathe out for a count of eight. In some embodiments, the therapist and subject may discuss the most useful ways to support in cases where emotional distress arises during a hallucinogen session. In some embodiments, the therapist may assist the subject in setting motivation for the hallucinogen session. In some embodiments, the subject is given access (e.g., online access) to materials regarding the safety and mechanism of action of hallucinogens. In some embodiments, during one or more psychological support sessions, the subject may listen to, or the therapist may provide, programmed music.

[0112] In some embodiments, psychological support and / or psychotherapy conducted prior to hallucinogen administration includes tracking one or more goals and / or objectives. In some embodiments, one or more goals and / or objectives of the pre-administration session include establishing a therapeutic alliance between the subject and the therapist, answering the subject's questions and addressing any concerns, and demonstrating and implementing spontaneous inquiry and experiential processing. In some embodiments, the pre-administration psychological support session includes a discussion of the confirmed and / or potential effects of the hallucinogen.

[0113] In some embodiments, the pre-administration psychological support session includes preparing the subject for hallucinogen administration by implementing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting relevant therapeutic goals, building rapport, and / or establishing a therapeutic alliance. In some embodiments, the pre-administration psychological support session includes preparing the subject for hallucinogen administration by implementing relevant therapeutic techniques to build rapport and trust between the individual and the therapist, e.g., so that the therapist can guide the individual through the experience. In some embodiments, the pre-administration psychological support session includes listening to the subject's discourse about pain and other issues to understand, for example, patterns of most prominent psychological rigidity. In some embodiments, the pre-administration psychological support session includes psychoeducation regarding the hallucinogen experience and acceptance and commitment therapy (ACT). In some embodiments, one or more, two or more, or three or more psychological support sessions are conducted prior to hallucinogen administration.

[0114] 2. Psychological support given alongside hallucinogens In some embodiments, psychological support is provided during the administration session. In some aspects, provided embodiments include administering a hallucinogen, such as psilocybin, to a subject in a controlled environment, where psychological support is provided to the subject. In some aspects, provided embodiments include administering one or more doses of psilocybin to a subject in a controlled environment, such as an initial dose and one or more subsequent doses, or a first and second dose, where psychological support is provided to the subject. In some embodiments, the subject receives an initial psychological support session led by a therapist by meeting in person at the administration location, with additional or subsequent support sessions being provided remotely or self-administered.

[0115] In some embodiments, a therapeutically effective dose of a hallucinogen is administered to a subject in a controlled environment, and psychological support is provided to the subject. In some embodiments, one or more doses of a hallucinogen, such as a first dose and one or more subsequent doses, or a first and second dose of a hallucinogen, are administered to a subject in a controlled environment, and psychological support is provided to the subject. In some embodiments, the psychological support provider does not provide meaningful Acceptance and Commitment Therapy (ACT) intervention or feedback. In some embodiments, the ACT-based clinical formation continues with the psychological support provider listening to the emerging discourse and recording instances of psychological flexibility and rigidity, particularly instances of present-moment awareness, avoidance, and valuing. In some embodiments, the psychological support provider listens to the individual during administration.

[0116] 3. Psychological support following hallucinogen administration In some embodiments, one or more sessions of psychological support and / or psychotherapy are provided after administration of one or more doses of a hallucinogen (e.g., psilocybin or a metabolite thereof), e.g., a first dose of a hallucinogen. In some embodiments, one or more sessions of psychological support and / or psychotherapy are provided as one or more integration sessions. In some aspects, one or more integration sessions are provided to a subject after they emerge from the dissociative state from the one or more doses of a hallucinogen.

[0117] In some embodiments, one or more integrative sessions are provided after each dose, for example, two, three, or four or more integrative sessions. In some embodiments, two integrative sessions are provided after each dose. In some embodiments, two integrative sessions are provided after the first dose. In some embodiments, two integrative sessions are provided after a subsequent dose, for example, the second dose. In some embodiments, the integrative sessions include psychological support, psychotherapy, and / or talk therapy. In some embodiments, the psychological support is therapist-led or led by one or more people other than the subject. In some embodiments, the psychological support is self-administered. In some embodiments, the psychological support aspects are therapist-led and self-administered.

[0118] In some embodiments, two psychological support sessions, e.g., two integration sessions, are provided following administration of the first dose and / or subsequent doses. In some embodiments, the two integration sessions are provided within two weeks of administration. In some embodiments, the two integration sessions are provided within one week of administration. In some embodiments, the first of the two integration sessions is provided about one day or about one day after the psilocybin administration session. In some embodiments, the second of the two integration sessions is provided about one week after administration. In some embodiments, the second of the two integration sessions is provided 7 days, or about 7-14 days, or about 14 days after administration. In some embodiments, the second of the two integration sessions is provided about 7 days after administration. In some embodiments, the second of the two integration sessions is provided 14 days after administration. In some embodiments, the second of the two integration sessions is provided about two weeks after administration.

[0119] In some embodiments, the one or more post-administration sessions or one or more integration sessions include eliciting a full discussion of the subject's experiences during the administration session(s). In some embodiments, the post-administration or integration sessions include focusing on Acceptance and Commitment Therapy (ACT)-based clinical activities related to contact with the present moment, impulse detachment, or acceptance, based on clinical formation. In some embodiments, the post-administration or integration sessions include reviewing and reflecting on the subject's hallucinogen experience, including any emotional, mental, or lifestyle changes that occur following the administration session(s).

[0120] 4. Settings and configuration In some embodiments, the safety of subjects receiving a dose of psilocybin is enhanced by testing psilocybin during a "setting and setting" protocol, given the psychoactive properties of psilocybin (Lyons and Carhart-Harris, J Psychopharmacology 2018;32(7):811-819), and in some cases due to the psychoactive properties of psilocybin. In some embodiments, the "setting" refers to one or more of the subject's emotional, cognitive, and behavioral context, mindset, and expectations prior to, e.g., immediately prior to, administration of a hallucinogen such as psilocybin. In some embodiments, the "setting" is addressed by a therapist in a pre-administration psychotherapy session. In some embodiments, the "setting" refers to the physical environment in which the administration of psilocybin occurs. In some embodiments, addressing the setting and setting of the experience can reduce the risk that a subject will report a distressing event or harm themselves. In some embodiments, this approach includes three components: 1) psychological support prior to administration of a hallucinogen, e.g., psilocybin, e.g., a preparation; 2) administration; and 3) psychological support after administration, e.g., integration, to integrate a typical hallucinogen experience.

[0121] In some embodiments, prior to administration, subjects undergo a pre-exposure preparation session, including rapport building with the therapist who will be present during administration. In some embodiments, prior to administration, subjects undergo a pre-exposure preparation session, including identifying personal themes and issues that are particularly likely to affect the session experience. In some embodiments, the administration itself is performed by a single therapist. In some embodiments, the administration itself is performed by two therapists, e.g., a male and a female therapist, who will be present throughout the session. In some embodiments, the session is typically performed in a room designed to be quiet, comfortable, and aesthetically pleasing. In some embodiments, subjects are encouraged to wear eye shades and listen to a music program via headphones during administration to help direct their attention inward.

[0122] In some embodiments, the subject is managed until the observer determines that the effects of the hallucinogen, e.g., psilocybin, have completely subsided. In some embodiments, the subject can be discharged if they meet the discharge criteria. In some embodiments, one criterion must be met for a subject to be discharged. In some embodiments, more than one criterion must be met for a subject to be discharged. In some embodiments, all criteria must be met for a subject to be discharged. In some embodiments, the discharge criteria include one or more of: whether a responsible friend or family member is available to accompany the subject to their home; whether the subject's blood pressure and heart rate have returned to pre-drug or normal levels; whether the subject is deemed by management personnel to be free of any acute drug effects; whether the subject believes they have returned to their psychological baseline; whether the observer determines it is safe to discharge the subject; and whether the subject is ready to go home.

[0123] D. Identification and Exclusion of Subjects for Treatment Also provided herein are methods for identifying or selecting individuals or subjects, e.g., human subjects, for treatment with a hallucinogen, e.g., psilocybin or a metabolite thereof. In some aspects, a hallucinogen, e.g., psilocybin or a metabolite thereof, is administered to an identified or selected subject according to provided embodiments. In some aspects, a subject for treatment has or suffers from one or more symptoms of nociceptive pain, such as fibromyalgia. In some embodiments, a subject is identified or selected as a candidate or suitable for treatment with a hallucinogen if the subject meets one or more criteria for one or more evaluated parameters described herein. In some embodiments, a subject is identified or selected as a candidate or suitable for treatment with a hallucinogen if the subject does not have any of the exclusion parameters described herein. In some embodiments, a subject is excluded from treatment or not treated if the subject has or meets criteria for one or more of the exclusion parameters described herein.

[0124] In some embodiments, one or more parameters, e.g., exclusion parameters, are assessed prior to administering one or more doses of a hallucinogen and / or psychotherapy. In some embodiments, one or more parameters, e.g., exclusion parameters, are assessed in a screening session, e.g., assessed prior to administering a hallucinogen and / or psychotherapy. In some embodiments, if a subject meets one or more criteria for one or more assessed parameters, e.g., exclusion parameters, the subject is identified or selected for treatment, e.g., with a hallucinogen and / or psychotherapy, in accordance with provided embodiments; in some embodiments, if a subject does not have any of the exclusion parameters, e.g., the exclusion parameters described herein, the subject is identified or selected for treatment, e.g., with a hallucinogen and / or psychotherapy, in accordance with provided embodiments.

[0125] In some embodiments, exemplary exclusion parameters that may be evaluated, for example, to identify a subject for treatment, include one or more of: previous or concomitant medication use, hypertension and / or tachycardia, incident epilepsy, incident schizophrenia spectrum or other psychotic disorder, moderate or severe alcohol or drug use disorder, and previous adverse effects from hallucinogens. In some embodiments, if a subject meets the criteria for all of the exclusion parameters of previous or concomitant medication use, hypertension and / or tachycardia, incident epilepsy, incident schizophrenia spectrum or other psychotic disorder, moderate or severe alcohol or drug use disorder, and previous adverse effects from hallucinogens, the subject is identified for treatment with a hallucinogen.

[0126] In some embodiments, exemplary assessed parameters include one or more of the following: demographics and baseline characteristics; medical history; fibromyalgia survey scores (e.g., 2016 FM Survey Criteria); prior / concomitant medications; Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders, 5th Edition (SCID-5) and SCID-5 for Personality Disorders (SCID-5-PD); 12-lead electrocardiogram (ECG); pregnancy test for women of childbearing potential (WOCBP); urine drug and breath alcohol test (Breatherizer); blood chemistry and hematology tests; hypertension and / or tachycardia; Patient Health Questionnaire Depression Scale-8 (PHQ-8); and Columbia-Suicide Severity Rating Scale (C-SSRS). In some embodiments, exemplary assessed parameters include any of the indicators described herein, e.g., indicators for monitoring treatment, monitoring adverse effects, and / or measuring effects, such as those described in Sections II and III herein. In some embodiments, one or more of the following parameters are assessed: Fibromyalgia Survey score; blood chemistry and hematology tests; hypertension and / or tachycardia; and use of previous or concomitant medications.

[0127] In some embodiments, a subject is identified or selected for treatment if the subject has FM, has been diagnosed with FM, has or has had one or more symptoms of FM, has or has had one or more symptoms of FM for an extended period of time, e.g., at least one year or longer, and / or meets fibromyalgia survey score criteria, e.g., the 2016 Fibromyalgia (FM) Survey Criteria (see, e.g., Wolfe et al., Semin Arthritis Rheum 2016;46(3):319-29). In some embodiments, a subject is identified or selected for treatment if they have been diagnosed with FM for three months or longer or have had one or more symptoms of FM for at least one year. In some embodiments, a subject is identified or selected for treatment if they meet the 2016 FM Survey Criteria. In some embodiments, a subject meets the criteria if they exhibit a fibromyalgia survey score of 13 or greater, e.g., according to the 2016 FM Survey Criteria.

[0128] In some embodiments, if a subject is deemed medically stable, for example, as determined by screening for medical problems via a personal interview, a medical questionnaire, and / or an electrocardiogram (ECG), for example, within about one month of the start of one or more steps of the treatment regimen, the subject is identified or selected for treatment. In some embodiments, exemplary methods for assessing medical stability and / or ECG are described. In some embodiments, the method or use comprises an electrocardiogram (ECG). In some embodiments, ECG is completed at various time points during the treatment regimen, for example, at screening.

[0129] In some embodiments, a subject is identified or selected for treatment if the subject abstains from the use of alcoholic beverages and any psychoactive drugs, including nicotine, within about 24 hours before and after each administration of one or more doses of a hallucinogen.

[0130] In some embodiments, a subject is identified or selected for treatment if they are not receiving concurrent psychotherapy. In some embodiments, a subject is identified or selected for treatment if they are receiving concurrent psychotherapy, but the type and frequency of that therapy has been stable for at least about two months prior to administration or assessment and is expected to remain stable during the treatment regimen.

[0131] In some embodiments, a subject is identified or selected for treatment if the subject is a non-smoker (tobacco). In some embodiments, a subject is identified or selected for treatment if the subject has no previous adverse effects from hallucinogens.

[0132] In some embodiments, a subject is identified or selected for treatment if the subject has not taken sildenafil (Viagra®), tadalafil, or a similar medication within about 72 hours before and after each administration of one or more doses of a hallucinogen.

[0133] In some embodiments, if the subject has a particular comorbid psychiatric disorder, e.g., psychotic disorder, bipolar I or II disorder, e.g., schizophrenia spectrum or other psychotic disorder (excluding those substance / medication induced or due to another medical condition), or bipolar I or II disorder as measured via SCID-5 and SCID-5-PD, or Diagnostic and Statistical Manual of Mental Disorders for Substance Use Disorders, the subject may be at risk for a comorbid psychiatric disorder. A subject will be excluded from treatment, not identified for treatment, or not administered one or more doses of hallucinogens if they have a current or past history of meeting Disorders, Fifth Edition (DSM-5) criteria, e.g., a current or past (e.g., within one year of assessment) history of moderate or severe alcohol, tobacco, or other drug use disorder (but excluding caffeine) as measured via relevant questions from the SCID-5, or a medically significant history of suicide attempts, or a psychiatric condition deemed incompatible with establishing a trusting relationship or safe exposure to hallucinogens. In some embodiments, suicide risk can be defined by suicidal ideation guaranteed by items 4 or 5 of the C-SSRS within one year prior to assessment, suicidal behavior within one year prior to assessment, or a clinical assessment of significant suicide risk during the subject's interview. In some embodiments, a subject will be excluded from treatment, or not identified or selected for treatment, if they have severe depression as measured by the PHQ-8. In some embodiments, exemplary methods of assessing such psychiatric disorders or conditions are described.

[0134] In some embodiments, the parameters assessed include the Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (SCID-5) and / or the SCID-5 for Personality Disorders (SCID-5-PD). In some embodiments, the SCID-5 and / or SCID-5-PD are completed at various time points prior to and / or during a treatment regimen, e.g., at screening.

[0135] In some embodiments, the parameters assessed include assessment of the Patient Health Questionnaire Depression Scale-8 (PHQ-8), which is completed prior to and / or at various time points during the treatment regimen, e.g., at screening.

[0136] In some embodiments, the parameters evaluated include assessment of the Columbia-Suicide Severity Rating Scale (C-SSRS). In some embodiments, clinical C-SSRS assessments are completed at various time points during an exemplary treatment regimen, for example, at one or more of all or nearly all visits and / or sessions.

[0137] In some embodiments, a subject will be excluded from treatment or will not be identified or selected for treatment if they have a first- or second-degree relative confirmed to have schizophrenia spectrum or other psychotic disorder (other than substance / medication induced or due to another medical condition), or bipolar I or II disorder.

[0138] In some embodiments, the parameter is moderate or severe alcohol or drug use disorder, and if the subject has a moderate or severe alcohol or drug use disorder that meets DSM-5 criteria, the subject is excluded from treatment.

[0139] In some aspects, if a subject has had a cardiovascular condition, such as coronary artery disease, stroke, angina, uncontrolled hypertension, clinically significant ECG abnormalities (e.g., atrial fibrillation), prolonged corrected QT interval (i.e., QTc>450 msec), prosthetic heart valve, or transient ischemic attack, for example, within one year prior to evaluation, the subject will be excluded from treatment, or will not be identified for treatment, or will not receive one or more doses of a hallucinogen. In some embodiments, exemplary methods of assessing such cardiovascular conditions or abnormalities are described.

[0140] In some embodiments, if a subject has epilepsy, for example, epilepsy with a history of seizures, the subject is excluded from treatment, or is not identified for treatment, or is not administered one or more doses of a hallucinogen. In some embodiments, if a subject has epilepsy, the subject is excluded from treatment, or is not identified for treatment, or is not administered one or more doses of a hallucinogen. In some embodiments, if a subject does not have epilepsy, the subject is identified for treatment.

[0141] In some embodiments, if a subject has insulin-dependent diabetes, the subject is excluded from treatment, or not identified for treatment, or not administered one or more doses of a hallucinogen. In some embodiments, if a subject is taking oral hypoglycemic agents and has a history of hypoglycemia, the subject is excluded from treatment, or not identified for treatment, or not administered one or more doses of a hallucinogen. In some embodiments, if a subject has an active autoimmune disease, such as lupus or rheumatoid arthritis, the subject is excluded from treatment, or not identified for treatment, or not administered one or more doses of a hallucinogen.

[0142] In some embodiments, if a subject has uncontrolled high blood pressure, e.g., a systolic blood pressure greater than or equal to 139 mmHg or a diastolic blood pressure greater than or equal to 89 mmHg, e.g., as measured as an average of three readings, the subject is excluded for treatment, not identified for treatment, or not administered one or more doses of hallucinogen. In some embodiments, if a subject exhibits a systolic blood pressure greater than or equal to 200 mmHg or a diastolic blood pressure greater than or equal to 110 mmHg, e.g., as measured as an average of three readings, for more than 15 minutes and / or in an average of four consecutive readings, the treatment regimen is immediately discontinued.

[0143] In some embodiments, if a subject has tachycardia, e.g., a heart rate greater than or about 90 beats per minute (bpm), e.g., on repeated measurements, the subject is excluded from treatment, or is not identified for treatment, or is not administered one or more doses of a hallucinogen.

[0144] In some embodiments, if a subject has one or more clinically significant abnormalities in clinical laboratory tests, such as a complete blood count and a metabolic panel, the subject is excluded from treatment, or is not identified for treatment, or is not administered one or more doses of a hallucinogen. In some embodiments, the abnormalities in the metabolic panel include elevated liver enzymes. In some embodiments, the metabolic panel includes elevated Na + , K. + , Cl - , HCO3 - , Ca ++ , Mg ++ In some embodiments, the hematology laboratory tests may include one or more of: complete blood count (CBC), CBC with differential and platelet count, white blood cell count (WBC), red blood cell count (RBC), platelet count, and hematocrit / corpuscular volume (HCT).

[0145] In some embodiments, if a subject is taking or using a particular medication or therapy in combination with, or has taken or used, a particular medication or therapy (e.g., one on a list of prohibited medications) or therapy, the subject will be excluded from treatment, or will not be identified for treatment, or will not receive one or more doses of a hallucinogen. In some embodiments, the subject is taking serotonergic dietary supplements (e.g., 5-hydroxy-tryptophan or St. John's wort), medication with an antihypertensive agent, a UDP-glucuronosyltransferase (UGT) 1A9 or 1A10 inhibitor (e.g., regorafenib, rimampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasirox, ginseng), an aldehyde or alcohol dehydrogenase inhibitor (e.g., disulfiram), a drug of abuse, a regular (i.e., more than twice a week) psychoactive prescription medication (e.g., opioids, tramadol, benzodiazepines), or if concurrently taking an antidepressant, any antidepressant medication for at least about the past two weeks (or in the case of fluoxetine, at least the past four weeks). Subjects will be excluded from treatment, or will not be identified for treatment, or will not receive one or more doses of a hallucinogen if they have ever taken (for a period of time), are concurrently taking medications with primary centrally acting serotonergic effects such as monoamine oxidase inhibitors (MAOIs) on a regular (e.g., daily) basis, are using psychotropic medications, including prescription and recreational drugs except as part of a treatment regimen, have used any hallucinogen in the past six months or have used hallucinogens 10 or more times in their lifetime, have a blood alcohol content greater than 0.02% on a breath alcohol test, and / or test positive for cocaine, methamphetamine, or opioids on a urine drug test.In some aspects, prior or concomitant use of compounds such as primary centrally acting serotonergic agents, MAOIs, aldehyde dehydrogenase inhibitors, UGT1A9 and UGT1A10 inhibitors, alcohol, or tobacco may affect the metabolism and / or activity of hallucinogens, and therefore may affect the effects of hallucinogens, such as psilocybin.

[0146] In some embodiments, the subject is taking any of the following prior or concomitant medications: regular use of psychoactive prescription drugs, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects or monoamine oxidase inhibitors (MAOIs); use of hallucinogens in the past 6 months; concomitant use of sildenafil or tadalafil; concomitant use of alcohol with a blood alcohol content greater than 0.02%; medication with antihypertensives; UGT1A9 inhibitors, 1A10 inhibitors, regorafenib, rimampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasirox, ginseng; aldehyde dehydrogenase inhibitors, alcohol If the subject does not use any of the following drugs, the subject will be identified or selected for treatment: dehydrogenase inhibitors, or disulfiram; amphetamine, buprenorphine, benzodiazepines, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoids (K2), psychoactive prescription drugs, opioids, tramadol, or benzodiazepines; concurrent use of antidepressants; concurrent use of medications with primary centrally acting serotonergic effects, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs), or use of serotonergic dietary supplements, 5-hydroxytryptophan, or St. John's wort.Therefore, in some embodiments, subjects who have previously or concurrently used these compounds may be excluded from treatment.

[0147] In some embodiments, if a subject does not abstain from antidepressant medication, the subject will be excluded from treatment, not identified for treatment, or not administered one or more doses of hallucinogens. In some cases, if the subject begins tapering off medication with the consent and support of a physician, the subject may receive hallucinogens and / or psychotherapy. In some embodiments, if the subject is intermittently taking a drug with a primary centrally acting serotonergic effect or an MAOI, the subject may receive hallucinogens and / or psychotherapy after at least five half-lives of the drug have elapsed since the last dose of the drug. In some embodiments, if the subject is taking a non-prescription medication, nutritional supplement, or herbal supplement, unless approved by a physician, the administration of hallucinogens and / or psychotherapy may be discontinued.

[0148] In some embodiments, the subject is an adult, for example, an adult between the ages of 25 and 64. In some embodiments, the subject is consenting to a treatment regimen.

[0149] E. Exemplary Treatment Regimens An exemplary treatment regimen is described according to the provided embodiments. In the exemplary treatment regimen, the clinical benefits of a hallucinogen, such as oral psilocybin, combined with psychotherapy to treat chronic pain symptoms in patients with FM are explored. In some embodiments, the treatment regimen includes baseline deep phenotyping, preparation, hallucinogen administration, consolidation, and EOT deep phenotyping. Individuals, such as human subjects, who are candidates for the treatment regimen undergo an initial pain phenotyping assessment and complete daily electronic pain diaries until the end of active intervention. Hallucinogen psychotherapy intervention, the structure of which has been used in previous hallucinogen clinical trials, is initiated. Between the two hallucinogen administration sessions, individuals receive the hallucinogen in a comfortable environment under the guidance of two therapists. Individuals undergo a clinical visit the day after each hallucinogen administration visit to confirm their safety and comfort. Psychotherapy, using the same two therapists, occurs between and after hallucinogen sessions, focusing on integration, which helps individuals gain insight and understanding from their experiences. After the final dose session, individuals undergo three weekly integration sessions and then complete a post-treatment deep phenotyping session. Individuals complete subject-reported outcome questionnaires at or about 84 days and at or about 168 days after the final hallucinogen dose to examine persistence of change.

[0150] Individuals with FM and no comorbid psychiatric disorders to exclude are treated. An exemplary treatment regimen includes an approximately 28-day screening period (approximately day -28 to day -1), an approximately 3-week baseline and run-in period (approximately day 1 to day 18), a two-dose administration period (approximately day 22 to day 37), consolidation (approximately day 43 to day 57), an end-of-therapy (EOT) visit (approximately day 64; the last aggregated worst pain score over the 7 days immediately preceding the EOT visit was assessed for change from baseline), and 1-, 3-, and / or 6-month follow-up visits (approximately days 120 and 204). In an exemplary treatment regimen, the total duration, including screening, run-in, administration, consolidation, EOT, and follow-up, may be approximately 8 months. An exemplary treatment and evaluation schedule according to provided embodiments is depicted in FIG. 5.

[0151] II. Treatment Monitoring: Subject-Reported Outcomes, Observer-Rated Outcomes, and Clinical Indicators In some embodiments, one or more indicators are measured, evaluated, or assessed to monitor the effectiveness of the treatment. In some aspects, the one or more indicators are related to one or more symptoms of fibromyalgia, related to the subject, and / or related to the treatment. In some aspects, the one or more indicators include subject-reported outcomes, observer-rated outcomes, and / or indicators associated with or related to clinical indicators. In some embodiments, evaluation of an individual receiving treatment includes subject-reported outcomes, quantitative clinical indicators, and combinations thereof.

[0152] In some aspects, one or more indicators are measured, evaluated, or assessed before, during, or after administration of one or more doses of a hallucinogen, e.g., psilocybin or its metabolite, e.g., psilocin, and / or psychotherapy. In some aspects, an individual undergoing treatment according to provided embodiments is subjected to one or more assessments before, during, and after treatment. In some aspects, a method or use comprises assessing one or more indicators in a subject before and / or after administration of one or more doses of a hallucinogen. In some aspects, one or more indicators are assessed before administration as a baseline measurement and after administration as an outcome measurement. In some aspects, a change between the baseline measurement and the outcome measurement of one or more measured or assessed indicators is determined. In some aspects, such a change, e.g., a change from baseline, is associated with or indicates a therapeutic outcome of treatment, e.g., improvement or alleviation of one or more symptoms, effective therapy, or effective treatment, of a disease or condition, such as FM or one or more symptoms thereof.

[0153] In some aspects, individuals undergoing treatment according to provided embodiments are subjected to one or more assessments before, during, and after treatment. In some embodiments, the one or more assessments of the individual undergoing treatment include one or more subject-reported assessments, one or more observer-rated assessments, one or more quantified clinical indicators, and combinations thereof. In some embodiments, the one or more assessments of the individual undergoing treatment include assessment of primary and / or secondary endpoints.

[0154] A. Subject-reported and observer-rated indicators In some embodiments, the evaluation of the individual receiving treatment includes one or more subject-reported or observer-rated assessments. In some embodiments, the one or more indicators include those related to one or more symptoms of fibromyalgia or those related to a diagnosis of fibromyalgia. In some embodiments, the evaluation of the individual receiving treatment includes a qualitative documented assessment of treatment experience, opinions, and insights.

[0155] In some embodiments, exemplary indicators include pain and pain-related symptom assessments, sleep assessments, response to treatment assessments, psychological assessments, hallucinogen experience assessments, and / or clinical activity assessments. In some embodiments, one or more indicators measured, assessed, or evaluated according to any of the provided embodiments, e.g., before, during, and / or after administration of one or more doses of a hallucinogen, e.g., psilocybin, and / or psychotherapy, include a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an evaluation of a clinical indicator. In some embodiments, one or more indicators include observer-rated and subject-reported parameters, e.g., one or more symptoms or behaviors associated with FM, treatment outcomes, and / or experiences related to administration of a hallucinogen, e.g., parameters described above related to the subject's hallucinogen experience. In some embodiments, one or more of the observer-rated and subject-reported parameters are indicative of a treatment effect of provided embodiments, e.g., resulting in an improvement in one or more symptoms associated with FM, using the provided methods and uses.

[0156] In some embodiments, the assessment comprises one or more assessments selected from a comprehensive pain intensity numeric rating scale (PI-NRS) assessment, a PROMIS pain interference assessment, a Chronic Pain Acceptance Questionnaire (CPAQ-8) assessment, a 2016 Fibromyalgia Survey Questionnaire (FSQ) assessment, a coping strategies questionnaire (CSQ) assessment, a PainDETECT assessment, a PROMIS sleep disturbance 8b assessment, a PROMIS sleep-related disorder 4a assessment, a Patient Global Impression-C (PGI-C) scale assessment, a Positive and Negative Affect Score (PANAS) assessment, a PROMIS-29+2 Profile v2.1 Multi-Domain Assessment, a Patient Acceptable Symptom State (PASS) questionnaire, a Mystical Experiences Questionnaire (MEQ30), a challenging experiences questionnaire (CEQ), a psychological insight questionnaire (PIQ), and / or a monitor rating scale (MRS), among others.

[0157] In some embodiments, one or more indicators are assessed or measured at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, first dose, second dose, end of treatment deep profiling, 1 month follow-up, 3 month follow-up, and 6 month follow-up.

[0158] 1. Pain Assessment and Characterization In some embodiments, the one or more indicators include one or more symptoms of fibromyalgia (FM), such as pain, or a diagnosis of FM. Exemplary indicators of one or more symptoms of FM or pain include fibromyalgia survey scores, such as ratings on the 2016 Fibromyalgia Survey Questionnaire (FSQ). In some embodiments, exemplary indicators of one or more symptoms of FM, such as pain, include one or more of the following: a Fibromyalgia Survey score, e.g., a 2016 Fibromyalgia Survey Questionnaire (FSQ) assessment; a Pain Intensity Numerical Rating Scale (PI-NRS) assessment, e.g., the 11-item PI-NRS scale; a PROMIS Pain Interference Assessment; a PainDETECT Questionnaire (PD-Q) assessment; a Chronic Pain Acceptance Assessment, e.g., as measured by the Chronic Pain Acceptance Questionnaire (CPAQ-8) assessment; a Pain Interference Assessment, e.g., as measured by the 4-item PROMIS Pain Interference Scale; a Composite Medical Symptom Inventory (CMSI), and a Brief Pain Inventory, e.g., as measured by the Interference subscale of the Brief Pain Inventory (BPI-IS).

[0159] a.FM survey score In some embodiments, the one or more indices include an FM survey score. An exemplary FM survey score includes a rating on the 2016 FM Survey Questionnaire (FSQ). The 2016 FM Survey criteria, also referred to as the FSQ, is a revised diagnostic tool that combines other established aspects of pain assessment to provide a definitive FM diagnosis. The FSQ includes a 19-site Widespread Pain Index (WPI) scale derived from the Michigan Body Map (Brummett et al., Pain 2016;157(6):1205-12), where each painful site is scored as 1 point and the pain sites are summed. The FSQ also includes symptom severity scale (SSS) assessments (e.g., fatigue, cognitive problems, headache, bad mood) (Neville et al., Clin J Pain 2018 34(10):909-17; Brummett et al., Arthritis Rheumatol 2015;67(5):1386-94; Janda et al., Anesthesiology 2015;122(5):1103-11; Brummett et al., Anesthesiology 2013;119(6):1434-43), where three items are scored 0-3 and three more items are scored 0 or 1 and summed (0-12). Taken together, the WPI and SSS scores are used to form a continuous surrogate index (ranging from 0 to 31) of the characteristics of nociceptive pain (Wolfe et al., Semin Arthritis Rheum 2016;46(3):319-29; Wolfe et al., J Rheumatol 2011;38(6):1113-22; Wolfe F, Arthritis Rheum 2009;61(6):715-16). Based on the individual WPI and SSS scores, as well as the total score, an accurate diagnosis of FM is possible.

[0160] In some embodiments, the FSQ is repeated one or more times, e.g., before, during, and / or after administration of a hallucinogen, such as psilocybin, and / or hallucinogen support, such as an integration session. In some aspects, embodiments provided herein include assessment of change from baseline in the FSQ. In some aspects, assessment of the FSQ is completed at one or more time points after administration of one or more doses of a hallucinogen, e.g., 2 weeks, or about 2 weeks to 20 weeks, or about 2 weeks after administration of one or more doses of a hallucinogen, e.g., at or about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after administration. In some embodiments, the FSQ score of an individual undergoing treatment decreases during treatment and / or after treatment is completed, where the FSQ score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, 6 points or more, 7 points or more, 8 points or more, 9 points or more, 10 points or more, 11 points or more, or 12 points or more.

[0161] b. Pain Intensity Numeric Rating Scale (PI-NRS) score In some embodiments, the one or more indices include a pain intensity rating, such as a pain intensity numeric rating scale (PI-NRS), e.g., a total PI-NRS. In some embodiments, the PI-NRS (also called the Numeric Pain Rating Scale or NPRS) is a self-reported 11-point rating scale used to assess the severity of pain experienced by an individual (Farrar et al., Pain 2001;94(2):149-58). Individuals rate their pain symptoms using a 0-10 numerical scale, where, for example, 0 represents "no pain" and 10 represents "the worst pain imaginable" or "the worst pain imaginable." Individuals are often instructed to complete this rating daily to aid in monitoring changes in pain intensity over time, e.g., during treatment. In some embodiments, baseline scores (days 1-7) are summed and compared to the sum of the last 7 days (days 57-63) immediately prior to the end of treatment (day 64) to determine the change in PI-NRS score. A reduction of approximately 2 points on the PI-NRS, or approximately a 30% reduction, corresponds to a clinically important difference (Farrar et al., Pain 2001;94(2):149-58).

[0162] In some embodiments, the method or use comprises assessing the maximum change from baseline in worst pain summation after completion of treatment, where worst pain summation is measured by a Pain Intensity Numerical Rating Scale (PI-NRS) rating. In some embodiments, the assessment comprises one or more worst pain summation assessments before, during, and / or after completion of treatment. In some embodiments, the assessment is concluded just prior to the end of treatment, where the final summation pain is compared to the baseline summation pain to determine the maximum change from baseline in worst pain summation after completion of treatment.

[0163] In some embodiments, the PI-NRS is used to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, the PI-NRS is repeated one or more times. In some embodiments, an individual receiving treatment completes four or more PI-NRS assessments per week, five or more PI-NRS assessments per week, six or more PI-NRS assessments per week, or seven or more PI-NRS assessments per week, with this routine continuing until therapy is completed. In some embodiments, two or more PI-NRS assessment scores from adjacent days or days are summed together. In some embodiments, the change from baseline in the total PI-NRS score is used to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, the PI-NRS score of an individual receiving treatment decreases during treatment and / or after completion of treatment, where the PI-NRS score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 6 points or more. In some embodiments, the total PI-NRS score of an individual receiving treatment decreases during treatment and / or after completion of treatment, where the PI-NRS score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 6 points or more compared to baseline.

[0164] c. Pain Interference - PROMIS In some embodiments, the one or more indicators include a pain interference assessment, such as a PROMIS pain interference assessment, e.g., a PROMIS-29+2 profile. In some embodiments, pain interference is the degree to which pain affects important aspects of an individual's daily life, such as social interactions, cognitive tasks, and physical activity (Adams et al., J Pain 2018;19(9):1074-81). Pain interference is assessed using the patient-reported outcomes measurement information system (PROMIS) pain interference (PI) scale from the PROMIS-29+2 profile v2.1 (PROPr) (see, e.g., HealthMeasures.net). In some embodiments, the PI assessment may contain four items, and individuals respond to each item using a 5-point Likert scale before converting raw scores to standardized T-scores using a conversion table (see, e.g., nihpromis.org), where higher scores correspond to more significant pain interference.

[0165] In some embodiments, the PROMIS-29+2PI is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, PROMIS-29+2PI assessments are repeated for treated individuals at various time points during an exemplary treatment regimen, e.g., at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the PROMIS-29+2PI score of treated individuals decreases during treatment and / or after completion of treatment. In some cases, the PROMIS-29+2PI score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0166] d.Chronic Pain Acceptance Questionnaire (CPAQ-8) In some embodiments, the one or more indicators include a pain avoidance or pain acceptance assessment, such as an assessment of the Chronic Pain Acceptance Questionnaire-8 (CPAQ-8). In some aspects, individuals enduring severe chronic pain often exhibit pain avoidance, in which individuals attempt to control or avoid their pain, even though these behaviors are maladaptive and / or counterproductive (Volders et al., BehavRes Ther 2015;64:31-7). In some aspects, the CPAQ-8 is a validated assessment for assessing this behavior by focusing on activity engagement and pain acceptance (Fish et al., Pain 2010;149(3):435-43). In some cases, items 1, 3, 5, and 6 correspond to activity engagement, and items 2, 4, 7, and 8 correspond to pain acceptance. Individuals rate eight items on a 7-point scale from 0 to 6, where 0 is "never," 1 is "very rarely," 2 is "rarely," 3 is "sometimes," 4 is "often," 5 is "almost always," and 6 is "always." All responses are summed (ranging from 0 to 48) and rated, where higher total scores correspond to higher levels of chronic pain acceptance.

[0167] In some embodiments, CPAQ-8 is utilized to evaluate the effect of hallucinogens to improve one or more symptoms of FM. In some embodiments, CPAQ-8 assessments are repeated for treated individuals at various time points during an exemplary treatment regimen, such as at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the treated individual's total CPAQ-8 score increases during treatment and / or after completion of treatment. In some aspects, the CPAQ-8 score increases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more. In some embodiments, the treated individual's CPAQ-8 activity engagement score increases during treatment and / or after completion of treatment. In some embodiments, the CPAQ-8 score increases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more. In some embodiments, the CPAQ-8 score of the pain acceptance of the individual undergoing treatment decreases during treatment and / or after treatment is completed. In some embodiments, the CPAQ-8 score increases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0168] e. Pain Catastrophizing Coping Strategies Questionnaire (CSQ) In some embodiments, the one or more indicators include an assessment of pain catastrophizing, such as the Coping Strategies Questionnaire (CSQ). In some embodiments, pain catastrophizing is characterized by a constant and uncontrollable fixation on painful events before, during, or after the painful event, frequent exaggeration of the threat of pain, and a general feeling of embarrassment or helplessness in painful situations (Quartana et al., 2009; 9(5):745-58). The Coping Strategies Questionnaire (CSQ) is a self-reported six-item assessment that assesses pain catastrophizing, which deals with pain-related helplessness and pessimism (Rosenstiel and Keefe Pain 1983; 17(1):33-44), which is strongly associated with the transition from acute pain to chronic pain and poorer outcomes (Kratz et al., J Pain 2015; 16(6):527-36). Individuals respond to each item using a 7-point scale from 0 to 6, where 0 is "never," 3 is "sometimes," and 6 is "always." Responses are summed and rated, with higher total scores corresponding to higher levels of coping behaviors and pain catastrophizing.

[0169] In some embodiments, the CSQ is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some aspects, the index assessed includes a modified CSQ, referred to as the Pain Catastrophizing Scale (PCS) (see, e.g., Sullivan et al., Psychological assessment 7.4(1995):524). In some embodiments, assessment of the CSQ is repeated for the treated individual at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the treated individual's total CSQ score decreases during treatment and / or after completion of treatment. In some embodiments, the CSQ score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0170] f. Neuropathic Pain-PainDETECT Questionnaire (PD-Q) In some embodiments, the one or more indicators include an assessment of neuropathic pain, such as the PainDETECT Questionnaire (PD-Q). Neuropathic pain is associated with lesions or diseases of the somatosensory system (Bouhassira D, Rev Neurol (Paris) 2019; 175 (1-2): 16-25), and together with nociceptive pain (i.e., caused by tissue injury or physical damage), contributes to the overall pain experience. In some embodiments, the PainDETECT Questionnaire (PD-Q) is a self-reported 9-item assessment used to determine the prevalence of neuropathic pain (Freynhagen et al., Curr Med Res Opin 2006; 22 (10): 1911-20). Of these nine items, there are seven sensory symptom items related to pain, one temporal item for pain course pattern, and one spatial item for pain radiation; each item category has a separate scoring system (Cappelleri et al., Clinicoecon Outcome Res 2014;6:497-504). Individuals respond to the sensory symptom items using a 6-point scale from 0 to 5, where 0 is not at all and 5 is severe. Individuals respond to the temporal items using a 3-point scale from -1 to 1, and to the spatial items using a 4-point scale from 0 to 2, where 0 is no radiation and 2 is radiating pain. Responses are summed and scored; higher total scores correspond to higher levels of neuropathic pain.

[0171] In some embodiments, PD-Q assessments are utilized to evaluate the effect of hallucinogens on improving one or more symptoms of FM. In some embodiments, PD-Q assessments are repeated for treated individuals at various time points during an exemplary treatment regimen, such as at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, one or more PD-Q scores for treated individuals decrease during treatment and / or after treatment is completed. In some aspects, one or more PD-Q scores decrease by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0172] g. Composite Medical Symptom Inventory (CMSI) In some embodiments, the one or more indices include the Composite Medical Symptom Inventory (CMSI). The CMSI is a 52-item questionnaire that measures the presence or absence of persistent physical symptoms (lasting at least 3 months) over the past year and throughout life (see, e.g., Geisser et al., J. Pain 9(4, S2):75; Williams et al., Rheum Dis Clin North Am. 2016 May;42(2):317-332). In some aspects, the CMSI is used to screen for chronic pain conditions, as well as other pain conditions that commonly coexist in FM. In some embodiments, the method or use comprises CMSI assessment. In some embodiments, the CMSI is completed at various time points during a treatment regimen, e.g., with deep phenotyping.

[0173] In some embodiments, the CMSI is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, CMSI assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, such as at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the CMSI score of the treated individual decreases during treatment and / or after completion of treatment. In some aspects, the CMSI score decreases by 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, or at least 25% compared to baseline.

[0174] h. Brief Pain Inventory, Interference subscale (BPI-IS) In some embodiments, the one or more indices include the Brief Pain Inventory (BPI) (also known as the Wisconsin Brief Pain Questionnaire). The BPI is a validated, self-reported measure of pain that can be assessed by two subscales: (1) pain intensity (i.e., worse, least, average, current) as measured by the "Pain Severity Score"; and (2) functional interference from pain (i.e., activities, mood, ability to walk, usual tasks, relationships with others, sleep, and enjoying life) as measured by the "Pain Interference Scale." See, e.g., Williams and Arnold, Arthritis Care Res, 2011, 63:S86-S97. For both the "Severity" and "Interference" scales, scores range from 0 to 10, with higher scores indicating greater pain. In some embodiments, the one or more indices are based on the Interference subscale. In some embodiments, the method or use includes a BPI assessment, e.g., a BPI assessment using the Interference subscale.

[0175] In some embodiments, BPI assessment is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, BPI assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, such as at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the treated individual's one or more BPI scores decrease during treatment and / or after completion of treatment. In some aspects, the one or more BPI scores decrease by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0176] 2. Sleep Assessment and Characterization In some embodiments, the one or more indicators include one or more symptoms of FM, such as an assessment of sleep disturbances or sleep patterns. Exemplary indicators of one or more symptoms of FM, such as sleep disturbances, include a sleep disturbance assessment, optionally measured by the PROMIS Sleep-Related Disorder 4a assessment; a PROMIS Sleep Disorder 8b assessment; and a STOP-Bang assessment. In some embodiments, the one or more indicators include a PROMIS-29+2 profile, optionally including a v2.1 multi-domain assessment.

[0177] In some embodiments, individuals with FM and pain-related disorders often experience sleep disorders, sleep problems, physical decline, and depression. In this context, sleep disorders and problems affecting sleep quality can manifest in many forms, including, but not limited to, difficulty falling asleep, insomnia, frequent awakenings due to nightmares, hypervigilance, sleep apnea, restless leg syndrome, and increased shallow sleep, which can lead to increased daytime sleep and increased nocturnal activity and interruptions (Bigatti et al., Arthritis Rheum 2008;59(7):961-7). Sleep disorders, sleep problems, and sleep deprivation are likely to worsen pain sensitivity, tolerance, intensity, and interference, but also affect the individual's mood, behavior, activity level, and physical condition (Choy E, Nat Rev Rheumatol 2015;11(9):513-20). In some embodiments, sleep-related problems can be closely monitored and evaluated during the treatment of individuals with FM or pain-related disorders, for example, according to the methods and uses provided herein. In some embodiments, sleep assessments are utilized to evaluate the effect of hallucinogens on improving one or more symptoms of FM. In some embodiments, one or more sleep assessments are utilized to evaluate the effect of hallucinogens on improving one or more symptoms of FM and related pain disorders. In some embodiments, exemplary sleep metrics include the PROMIS Sleep-Related Disorder 8b assessment, the PROMIS Sleep-Related Disorder 4a assessment, or the STOP-Bang assessment. In some embodiments, one or more assessments are completed at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up.

[0178] a.PROMIS Sleep Disorder 8b In some embodiments, one or more indicators include a PROMIS sleep disorder assessment. In some embodiments, sleep disorder assessments include sleep quality assessments, perceived ability to fall asleep and stay asleep, sleep satisfaction, and sleep depth (Cella et al., J Clin Epidemiol 2011;63(11):1179-94). In some embodiments, sleep disorder is measured using the PROMIS Sleep Disorder Short Form 8b (see, e.g., HealthMeasures.net). In some embodiments, this assessment may contain four items, and individuals respond to each item using a 5-point Likert scale before using a conversion table to convert the raw scores into standardized T-scores (see, e.g., nihpromis.org), where higher scores correspond to more severe sleep disorder.

[0179] In some embodiments, the PROMIS Sleep Disorder 8b is utilized to evaluate the effect of hallucinogens to improve one or more symptoms of FM. In some embodiments, the PROMIS Sleep Disorder 8b assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, such as at one or more of a baseline deep profiling, an end-of-treatment deep profiling, a one-month follow-up, a three-month follow-up, and / or a six-month follow-up. In some embodiments, the treated individual's total PROMIS Sleep Disorder 8b score decreases during treatment and / or after treatment is completed. In some aspects, the PROMIS Sleep Disorder 8b score decreases by 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, or at least 25% compared to baseline.

[0180] b. PROMIS Sleep-Related Disorder 4a In some embodiments, one or more indicators include the PROMIS sleep disorder assessment.Similar to sleep disorder, sleep disturbance relates to functional impairment during wakefulness related to one or more sleep problems (Hanish et al., Nurs Res 2017;66(3):246-51).The PROMIS sleep-related disorder 4a assessment focuses on the sensation of alertness, sleepiness, fatigue, and functional impairment during normal waking hours.In some embodiments, this assessment may contain four items, and individuals respond to each item using a 5-point Likert scale before using a conversion table to convert raw scores into standardized T-scores (see, for example, nihpromis.org), where higher scores correspond to more severe sleep disturbances.

[0181] In some embodiments, the PROMIS Sleep-Related Disorders 4a is used to evaluate the effect of hallucinogens to improve one or more symptoms of FM. In some embodiments, the PROMIS Sleep-Related Disorders 4a assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, such as one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the treated individual's total PROMIS Sleep-Related Disorders 4a score decreases during treatment and / or after treatment is completed. In some aspects, the PROMIS Sleep-Related Disorders 4a score decreases by 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, or at least 25% compared to baseline.

[0182] c.STOP-Bang In some embodiments, the one or more indicators include a STOP-Bang assessment. In some embodiments, the STOP-Bang (Chung et al., Chest 2016;149(3):631-38; Nagappa et al., PLoS One 2015;10(12):e0143697) is used to screen for sleep apnea, which may interfere with sleep. In some embodiments, the STOP-Bang questionnaire consists of eight items that assess the risk of sleep apnea, including snoring, fatigue, whether breathing pauses during sleep are observed, high blood pressure, body mass index, age, neck circumference >16 inches, and gender. In some embodiments, the method or use includes a STOP-Bang assessment. In some embodiments, the STOP-Bang is completed at various time points during the treatment regimen, e.g., with deep phenotyping.

[0183] In some embodiments, STOP-Bang is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, STOP-Bang assessments are repeated for treated individuals at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the treated individual's total STOP-Bang assessment decreases during treatment and / or after completion of treatment. In some aspects, the STOP-Bang assessment is improved compared to baseline.

[0184] 3. Response to treatment evaluation and psychological evaluation In some embodiments, the one or more indicators include one or more subject-reported parameters related to treatment and psychological status. In some aspects, to evaluate an individual receiving treatment according to provided embodiments, the individual is subjected to one or more assessments to determine response to treatment (e.g., change from baseline) and psychological status (Davis et al., J Psychopharmacol 2021;35(4):437-46). In some aspects, different approaches to quantifying treatment outcomes for administration of hallucinogens have been adopted (Davis et al., J Psychopharmacol 2021;35(4):437-46; Haijen et al., Front Pharmacol 2018;9:897). Exemplary approaches include observer-rated and subject-reported outcomes, often administered in the form of time-sensitive surveys.

[0185] In some embodiments, exemplary measures for assessment to determine response to treatment and psychological status include one or more of the PROMIS-29+2 profile, optionally the v2.1 Multi-Domain Assessment; Positive and Negative Affect Score (PANAS) assessment; Patient Global Impression-Change (PGI-C) scale assessment; and Patient Acceptable Symptom Status (PASS) questionnaire.

[0186] In some embodiments, exemplary measures for evaluation to determine response to treatment and psychological status include one or more of the Patient Health Questionnaire Depression Scale-8 (PHQ-8); Columbia-Suicide Severity Rating Scale (C-SSRS); Clinical Global Impression-Improvement (CGI-I) scale; Emotional Breakthrough Inventory (EBI); Acceptance and Action Questionnaire-II (AAQ-II); Patient Global Impression-Improvement (PGI-I); Hospital Anxiety and Depression Scale (HADS); Life Events Checklist (LEC); Multidimensional Experiential Avoidance Questionnaire (MEAQ); and Brief Experiential Avoidance Questionnaire (BEAQ).

[0187] In some embodiments, one or more assessments are completed for each individual receiving treatment at various time points during the exemplary treatment regimen, for example, at one or more of baseline deep profiling and from the first dose to a six-month follow-up. In some embodiments, the assessment is completed one month after the dose. In some embodiments, the assessment is completed two months after the dose. In some embodiments, the assessment is completed three months after the dose. In some embodiments, the assessment is completed four months after the dose. In some embodiments, the assessment is completed five months after the dose.

[0188] a. Patient Global Impression (PGI-C) In some embodiments, the one or more indices include the Patient Global Impression-Change (PGI-C). In some aspects, the PGI-C is a patient-reported measure that reflects the patient's belief about the effectiveness of treatment (Guy W., Assessment Manual for Psychopharmacology (revised) 1976:217-21). The individual receiving treatment then rates their current condition on a scale of 1 to 7, where 1 is very much improved from baseline (at the start of treatment), 4 is no change from baseline, and 7 is very much worse from baseline.

[0189] In some embodiments, the PGI-C scale is utilized to evaluate the effect of a hallucinogen to improve one or more symptoms of FM. In some embodiments, PGI-C assessments are completed for each individual receiving treatment at various time points during an exemplary treatment regimen, for example, one or more times over a 6-month follow-up period from the first dose. In some embodiments, the PGI-C score of the individual receiving treatment decreases during treatment and / or after treatment is completed. In some aspects, the PGI-C score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, or 5 points or more.

[0190] b. Positive and Negative Affect Score (PANAS) In some embodiments, the one or more indices include the Positive and Negative Affect Schedule (PANAS). Positive and negative affect (e.g., emotions and facial expressions) are two opposing situations that describe contrasting perspectives for considering life and related problems. PANAS is a 20-item assessment that measures positive and negative affect (Watson et al., J Pers Soc Psychol 1988;54(6):1063-70), including measures of emotional balance, such as greater negativity than positivity (McAllister et al., Stress Health 2015;31(4):299-305; Toussaint et al., Scand J Pain 2014;5(3):161-66; Hassett et al., Arthritis Rheum 2008;59(6):833-40). Items 1, 3, 5, 9, 10, 12, 14, 16, 17, and 19 address positive emotions, while items 2, 4, 6-8, 11, 13, 15, 18, and 20 address negative emotions. Furthermore, the PANAS can be used to assess traits or situations depending on the time scale used. In some embodiments, a situational scale is used. Individuals respond to each item using a 5-point Likert scale from 1 to 5, where 1 is very little or none, 3 is moderate, and 5 is extreme. Responses are summed separately for each subscale, with higher scores corresponding to higher levels of positive / negative emotions (and vice versa).

[0191] In some embodiments, the PANAS assessment is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, the PANAS assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the PANAS positive affect score of the treated individual increases during treatment and / or after completion of treatment. In some aspects, the PANAS positive affect score increases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline. In some embodiments, the PANAS negative affect score of the treated individual decreases during treatment and / or after completion of treatment. In some embodiments, the PANAS negative affect score is reduced by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0192] c. Multi-Domain Analysis - PROMIS-29+2 Profile v2.1 In some embodiments, the one or more indicators include the PROMIS-29+2 Profile v2.1 (PROPr) (see, e.g., HealthMeasures.net). In some aspects, the PROPr is described and is used to assess multiple domains, such as physical function, anxiety, depression, fatigue, sleep disturbances, ability to participate in social roles, pain interference, cognitive function, and pain intensity. The addition of two cognitive function items distinguishes this instrument from its parent, the PROMIS Profile 29 (Hays et al., Qual Life Res 2018;27(7):1885-1891). PROMIS-29+2 is used to calculate preference scores (PROMIS Preferences, PROPr) (Dewitt et al., Value Health 2020;23(3):370-78; Dewitt et al., Med Decis Making 2018;38(6):683-98; Hammer et al., PLoS One 2018;13(7):e0201093), which provide an overall summary of health-related quality of life based on common metrics. For each domain, a preference-based score is calculated ranging from 0 (as bad as death) to 1 (perfect or ideal health). In some cases, responses are summed separately for each subscale, with higher scores corresponding to higher levels of domain characteristics.

[0193] In some embodiments, PROPr assessment is utilized to evaluate the effect of hallucinogens to improve one or more symptoms of FM. In some embodiments, PROPr assessment is repeated for treated individuals at various time points during an exemplary treatment regimen, such as at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, one or more PROPr domain scores for treated individuals increase during treatment and / or after treatment completion. In some aspects, one or more PROPr domain scores increase by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0194] d. Patient Acceptable Symptom Status (PASS) Questionnaire In some embodiments, the one or more indicators include the Patient Acceptable Symptom Status (PASS) questionnaire. In some embodiments, one or more items from the PASS questionnaire can be used in addition to PROPr. The addition of this element to each domain allows for the assessment and collection of patient beliefs regarding the adequacy of domain management (Salaffi et al., Biomed Res Int 2015:930756). Individuals receiving treatment respond to the following question: "Considering all the different ways your disease affects you, if you remained in this situation for the next few months, would you consider your current situation to be sufficient?" Individuals respond using yes or no, and this response is examined in terms of overall individual status and improvement.

[0195] In some embodiments, assessment of PASS is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, assessment of PASS is completed at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, the PASS response of individuals receiving treatment improves compared to baseline.

[0196] e. Clinical Global Impression-Improvement Scale (CGI-I) Clinical Global Impression-Improvement (CGI-I) assessment is a physician-rated change in the medical condition of an individual receiving treatment, where the individual is compared to their baseline condition at intervals over the past seven days (Guy W., Assessment Manual for Psychopharmacology (revised) 1976:217-21). The individual receiving treatment is rated on a scale of 1 to 7 relative to their baseline condition, where 1 is the patient not at all ill and 7 is the patient with the most severe illness. The individual receiving treatment is then rated on a scale of 1 to 7 relative to their current condition, where 1 is "much improved" from baseline (at the start of treatment), 4 is unchanged from baseline, and 7 is "much worse" compared to baseline. In some embodiments, the change from baseline on the CGI-I scale is used to evaluate treatment of FM.

[0197] In some embodiments, the methods provided herein include change from baseline in assessment of Clinical Global Impression-Improvement (CGI-I). In some aspects, CGI-I assessments are completed at one or more time points after administration of one or more doses of a hallucinogen, such as at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, one-month follow-up, three-month follow-up, and / or six-month follow-up.

[0198] In some embodiments, the CGI-I score of an individual receiving treatment improves during and / or after treatment. In some aspects, the CGI-I score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, or 5-7 points. In some aspects, the CGI-I-related improvement includes a decrease in the baseline condition score and a decrease in the current condition score.

[0199] f. Hospital Anxiety and Depression Scale (HADS) The Hospital Anxiety and Depression Scale (HADS) assessment uses a 14-item questionnaire to measure psychological distress, anxiety, and depression symptoms, with seven items assigned to the depression subscale (HADS Depression) and seven items assigned to the anxiety subscale (HADS Anxiety) (Zigmond and Snaith, Acta Psychiatr Scand 1983;67(6):361-70). The depression domain specifically focuses on sexual anhedonia, or the ability to experience pleasure, while the anxiety domain addresses global symptoms common to many anxiety disorders. As a means of assessment, each HADS item is scored on a four-choice response scale ranging from 0 to 3. Responses are then summed to obtain a total score for each of the two subscales, and individuals can be rated as normal (0-7), borderline abnormal (8-10), or abnormal (11-21). Interpretation using cutoff scores of 8 or higher for both the HADS anxiety and HADS depression subscales is generally considered best practice.

[0200] In some aspects, embodiments provided herein include assessment of change from baseline in Hospital Anxiety and Depression Scale (HADS) assessments. In some aspects, HADS assessments are completed at one or more time points after administration of one or more doses of a hallucinogen, such as at one or more of baseline deep profiling, first dose, second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up.

[0201] In some embodiments, the HADS is used to evaluate treatment of FM. In some embodiments, the HADS score of an individual receiving treatment decreases during and / or after treatment. In some aspects, the HADS score decreases by at least or about 1 point, 2 points or about 2 points, 3 points or about 3 points, 4 points or about 4 points, 5 points or about 5 points, 6 points or about 6 points, 7 points or about 7 points, or 8 points or about 8 points, or more.

[0202] g. Acceptance and Action Questionnaire (AAQ-II) The Acceptance and Action Questionnaire (AAQ-II) assessment is a measure of psychosocial flexibility, which is generally defined as the ability to fully connect with the present moment and the thoughts and feelings it harbors without unnecessary defenses (Hayes et al., The Psychological Record 2004;54:553-78; Bond et al., Behav Ther 2011;42(4):676-88). The AAQ-II assessment includes seven items, with each response ranging from 1 to 7, where 1 is never, 4 is sometimes, and 7 is always. Responses for each item are summed, and the total score can be interpreted to determine an individual's psychological flexibility, with a range of 24 to 28 generally associated with depression, anxiety, and / or related symptoms. In some embodiments, the AAQ-II is utilized to assess the treatment of one or more symptoms or signs associated with FM, such as depression, anxiety, and / or related symptoms associated with FM, such as pain or sleep disorders.

[0203] In some aspects, embodiments provided herein include an assessment of change from baseline in the Assessment of Acceptance and Behavior Questionnaire (AAQ-II). In some aspects, an AAQ-II assessment is completed at one or more time points after administration of one or more doses of a hallucinogen, such as at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, one-month follow-up, three-month follow-up, and / or six-month follow-up.

[0204] In some embodiments, the AAQ-II score of an individual undergoing treatment decreases during and / or after treatment. In some aspects, the AAQ-II score decreases by at least 1 point or about 1 point, 2 points or about 2 points, 3 points or about 3 points, 4 points or about 4 points, 5 points or about 5 points, 6 points or about 6 points, 7 points or about 7 points, 8 points or about 8 points, 9 points or about 9 points, 10 points or about 10 points, 15 points or about 15 points, 20 points or about 20 points, 25 points or about 25 points, 30 points or about 30 points, 35 points or about 35 points, 40 points or about 40 points, or 45 points.

[0205] h. Life Events Checklist (LEC) In some embodiments, the one or more indicators include a Life Events Checklist (LEC). In some embodiments, the Life Events Checklist for DSM-5 (LEC-5) (Weathers et al., 2013; National Center for PTSD, https: / / www ptsd.va.gov) is used to assess an individual's history and exposure to trauma. Individuals indicate how many of 17 potentially traumatic events (e.g., natural disasters, physical assaults) they have personally experienced or witnessed, as well as additional items assessing any other highly stressful events or experiences. In some embodiments, the method or use includes an LEC assessment. In some embodiments, the LEC is completed at various time points during the treatment regimen, e.g., with deep phenotyping.

[0206] In some embodiments, assessment of LEC is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, assessment of LEC is repeated for the treated individual at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep profiling, the first dose, the second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up. In some embodiments, one or more LEC scores of the treated individual increase during treatment and / or after completion of treatment. In some embodiments, the LEC of the treated individual improves compared to baseline.

[0207] i. Avoidance Questionnaire In some embodiments, the index relates to the assessment of experiential avoidance (EA). EA is the unwillingness to remain in contact with painful emotions, thoughts, memories, and physical sensations, and may be associated with the development and maintenance of emotional problems. In some cases, EA may actually exacerbate the problem (S. Edwards (2020) Value Living with Fibromyalgia. Doctoral thesis, Florida Institute of Technology). In one study, young subjects with fibromyalgia who were able to rationalize their pain experienced lower levels of pain and distress (Libby and Glenwick, 2010, Rehabilitation Psychology, 55(2):151; see also S. Edwards (2020) Value Living with Fibromyalgia. Doctoral thesis, Florida Institute of Technology). Thus, a reduction in EA in a subject with FM, e.g., a reduction from baseline, is associated with or indicates a therapeutic outcome of a treatment, e.g., an improvement or alleviation of one or more symptoms of a disease or condition, such as FM or one or more symptoms thereof, an effective therapy thereof, or an effective treatment thereof. In some embodiments, EA can be measured by any of a variety of known methods (see, e.g., Kirk et al., 2021 Behavior Therapy, 52:208-220). In some embodiments, EA is measured by the Multidimensional Experiential Avoidance Questionnaire (MEAQ), a 62-item questionnaire. In some embodiments, EA is measured by the Brief Experiential Avoidance Questionnaire (BEAQ), which is a simplified version of the MEAQ and is a 15-item short form of the MEAQ.

[0208] 4. Experience with hallucinogens and clinical activity evaluation In some embodiments, hallucinogen experience and associated clinical impact are assessed before, during, and / or after administration of one or more doses of the hallucinogen and / or psychotherapy. In some embodiments, to assess the hallucinogen experience and associated clinical impact of an individual receiving treatment according to provided embodiments, the individual is subjected to one or more assessments to evaluate hallucinogen experience and clinical activity in response to treatment (Davis et al., J Psychopharmacol 2021;35(4):437-46). In some embodiments, assessments to assess hallucinogen experience and clinical activity in response to treatment include one or more of the Mystical Experiences Questionnaire (MEQ30) assessment, the Challenging Experiences Questionnaire (CEQ) assessment, the Psychological Insight Questionnaire (PIQ) assessment, a qualitative written assessment, and / or the Monitoring Rating Scale (MRS) questionnaire. In some embodiments, hallucinogen experience and clinical activity are utilized to assess the hallucinogen experience of an individual receiving a hallucinogen. In some embodiments, one or more assessments are completed at various time points during an exemplary treatment regimen, for example, at one or more of the first dose, second dose, 1-month follow-up, 3-month follow-up, and / or 6-month follow-up.

[0209] a. Mystical Experience Questionnaire (MEQ30) In some embodiments, the one or more indices include the Mystical Experiences Questionnaire (MEQ). In some embodiments, the MEQ can include the MEQ30 (derived and abbreviated from the MEQ43), which is a patient-completed assessment that includes four components: mysticism (e.g., inner cohesion, outer cohesion, intellectual qualities, and sacredness scales), positive mood, time and space transcendence, and ineffability (Barrett et al., J Psychopharmacol 2015;29(11):1182-90). The MEQ30 predicts the sustained therapeutic benefits (e.g., changes in feelings, behavior, and well-being) resulting from hallucinogen experiences and serves as a primary measure of an individual's mystical experiences. There are 30 items included in the MEQ30 assessment, which are divided into four components, and each item is rated on a 0-5 point scale, where 0 is "none; not at all," 1 is "very slight, undetermined," 2 is "slight," 3 is "moderate," 4 is "strong (similar to either a previous strong experience or expectation of this description)," and 5 is "extremely strong (stronger than ever before in one's life, stronger than 4)." Across these 30 items, four components, or subcategories, contain different items: mysticism consists of items 4-6, 9, 14-16, 18, 20, 21, 23-26, and 28; positive mood consists of items 2, 8, 12, 17, 27, and 30; space / time consists of items 1, 7, 11, 13, 19, and 22; and indescribability consists of items 3, 10, and 29. Scores for each item within a subcategory or across the complete MEQ30 set are summed together and converted to a percentage by dividing by the corresponding total points. A "complete experience" is defined by a MEQ30 score equal to or exceeding 60% (of the total) across all four subcategories, where a complete experience correlates with more pronounced and / or prolonged therapeutic benefit.

[0210] In some embodiments, the MEQ30 is utilized to assess the hallucinogen experience of an individual receiving a hallucinogen. In some embodiments, MEQ30 assessments are completed at various time points during an exemplary treatment regimen, e.g., at one or more of the first and second doses. In some embodiments, the MEQ30 score of the individual receiving treatment improves during treatment and / or after completion of treatment. In some aspects, one or more MEQ30 scores improve by at least 1 point, at least 5 points, at least 10 points, at least 15 points, at least 20 points, or at least 30 points compared to baseline.

[0211] b. Challenging Experiences Questionnaire (CEQ) In some embodiments, the one or more indicators include the Challenging Experiences Questionnaire (CEQ). Due to the powerful experiences induced by classical hallucinogens (e.g., psilocybin), patients undergoing treatment may experience one or more acute adverse psychological reactions (i.e., frightening or challenging experiences). In some embodiments, evidence supports the possibility of symptoms including emotional (panic, depressed mood), cognitive (confusion, feeling of losing one's mind), and physical (nausea, heart palpitations) (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). Understanding the range and severity of symptoms is useful in coordinating patient care and anticipating the patient's needs during future treatment sessions. The CEQ addresses seven salient components (grief, fear, death, madness, isolation, physical pain, and paranoia) and provides a phenomenological profile of problematic aspects patients have experienced or may experience during treatment (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). There are 26 items included in the CEQ assessment, each with a numerical response ranging from 0 to 5, where 0 is "none; not at all" and 5 is "extremely strong (stronger than ever before in one's life)." Across these 26 items, seven components, or subcategories, contain different items, where grief consists of items 2, 6, 9, 11, 23, and 25; fear consists of items 4, 7, 14, 21, and 26; death consists of items 16 and 20; insanity consists of items 8, 13, and 19; isolation consists of items 1, 10, and 24; physical pain consists of items 3, 5, 15, 17, and 18; and paranoia consists of items 12 and 22. Responses are summed within each subcategory and converted into a percentage of the total possible points. Additionally, responses across all items are summed and converted into a percentage of the total possible points.

[0212] In some embodiments, the CEQ is utilized to assess the hallucinogen experience of an individual receiving a hallucinogen. In some embodiments, CEQ assessments are completed at various time points during an exemplary treatment regimen, e.g., at one or more of the first and second doses. In some embodiments, the CEQ score of the individual receiving treatment decreases during treatment and / or after completion of treatment. In some aspects, one or more CEQ scores decrease by at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, or more than 0.5% compared to baseline.

[0213] c. Psychological Insight Questionnaire (PIQ) In some embodiments, the one or more indices include the Psychological Insight Questionnaire (PIQ). The PIQ is a tool for assessing the strength of broad, short-term insight (Davis et al., J Psychopharm 2021;35(4):437-46). The PIQ is a 23-item assessment that includes two subscales: one assessing insight into avoidance and maladaptive patterns (AMP) and the other assessing goal and adaptive patterns (GAP) (Davis et al., J Psychopharm 2021;35(4):437-46). Items 1, 3, 5, 7, 9, 10, 12, 14, 15, 17-19, 21, and 23 relate to the AMP subscale, while items 2, 4, 6, 8, 11, 13, 16, 20, and 21 relate to the GAP subscale. Individuals respond to each item using a 6-point scale from 0 to 5, where 0 is "none, not at all," 3 is "moderate," and 5 is "strong (stronger than ever before in their life)." Responses are summed and averaged across each subscale, with higher scores corresponding to higher levels of short-term insight experiences. PIQ, AMP, and GAP scores correlate well with increased psychological flexibility, well-being, and long-term positive outcomes.

[0214] In some embodiments, PIQ assessment is utilized to evaluate the hallucinogen experience of an individual receiving the hallucinogen. In some embodiments, PIQ assessment is repeated for the treated individual at various time points during an exemplary treatment regimen, for example, at one or more of the following: the first dose, the second dose, deep profiling at the end of treatment, a one-month follow-up, a three-month follow-up, and / or a six-month follow-up. In some embodiments, the treated individual's total PIQ score decreases during treatment and / or after completion of treatment. In some aspects, the PIQ score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline. In some embodiments, the treated individual's one or more PIQ subscale scores decrease during treatment and / or after completion of treatment. In some embodiments, one or more PIQ subscale scores decrease by 1 point or more, 2 points or more, 3 points or more, 4 points or more, 5 points or more, or 10 points or more compared to baseline.

[0215] d. Monitoring Rating Scale (MRS) In some embodiments, the one or more indicators include a Monitoring Rating Scale (MRS) questionnaire. In some embodiments, the MRS is completed by a physician and includes rating and scoring dimensions of the subject's behavior and / or mood during treatment sessions (Griffiths et al., Psychopharmacology Berl 2006;187(3):268-83). There are 20 items (or dimensions) included in the MRS assessment, and some dimensions are assigned numerical values ​​ranging from 0 to 4, where 0 is "none; no effect" and 4 is "peak effect; occurs often." For other dimensions, scoring is assigned as the total duration (in minutes, over a defined time frame) observed for the patient's behavior (e.g., conversation with the physician or total speech). Dimension scores are summed within each subcategory or across all dimensions.

[0216] In some embodiments, MRS is used to evaluate the clinical activity of hallucinogens. In some embodiments, MRS assessments are completed at various time points during an exemplary treatment regimen, for example, at one or more of the first and second doses. In some embodiments, the MRS score of an individual receiving treatment improves during treatment and / or after treatment is completed. In some aspects, one or more MRS scores improve by at least 1 point, at least 5 points, at least 10 points, at least 15 points, at least 20 points, or at least 30 points compared to baseline.

[0217] e. Qualitative (documented) evaluation Subjective narrative accounts of hallucinogen experiences can provide insight into the unique aspects, needs, and concerns of a particular individual during treatment and / or after treatment completion. Narrative accounts are documented after each treatment dose session (e.g., the first or second dose). After the final administration session, individuals participate in a therapy integration session (e.g., weekly, one hour), in which discussion of one or more narrative accounts helps individuals gain insight and understanding from their experience. Narrative accounts are also used to explore common themes related to the therapy. Finally, individuals are asked open-ended questions during a three-month follow-up to determine sustained changes in behavior, thought patterns, and emotions in response to receiving treatment.

[0218] In some embodiments, qualitative documented assessments are utilized to evaluate the hallucinogen experience and clinical activity of individuals receiving the hallucinogen. In some embodiments, qualitative documented assessments are completed at various time points during an exemplary treatment regimen, for example, one or more of after the first dose and after the second dose. In some embodiments, the qualitative documented assessments are discussed after the assessment. In some embodiments, the qualitative documented assessments of individuals receiving treatment improve during and / or after completion of treatment. In some aspects, one or more characteristic aspects of the documented assessments improve, including overall mood, tone, mood, and / or attitude, or reflections thereon.

[0219] B. Clinical indicators In some aspects, individuals undergoing treatment according to provided embodiments are subjected to one or more assessments of one or more clinical indicators, e.g., indicators measurable at a clinic and / or using specific devices, before, during, and after treatment. In some aspects, the clinical indicators relate to one or more symptoms of FM, such as sensory measurements, pain, or sleep disturbances. In some embodiments, the evaluation of the individual undergoing treatment includes a quantitative measure of the clinical indicator. In some embodiments, the one or more indicators, e.g., clinical indicators, evaluated include sensory sensitivity, neuroimaging measurements, and sleep criteria. In some embodiments, the change from baseline in one or more clinical indicators is assessed. In some embodiments, the evaluation of the individual undergoing treatment includes the evaluation of an endpoint analysis.

[0220] In some embodiments, the clinical endpoint relates to one or more symptoms of FM, such as sensory sensitivity and pain assessment. In some embodiments, the clinical endpoint relates to one or more symptoms of FM related to sleep. In some embodiments, the clinical endpoint relates to changes in the brain associated with hallucinogen experience.

[0221] In some embodiments, evaluation of the individual undergoing treatment includes quantitative measurement of clinical indicators, where the clinical indicators are measured using quantitative sensory testing, electroencephalogram (EEG) analysis, functional magnetic resonance imaging (fMRI) analysis, proton magnetic resonance spectroscopy ( 1 This may be measured by one or more methods, such as 1H-MRS, diffusion tensor imaging (DTI), voxel-based morphometry (VBM), and / or wrist actigraphy.

[0222] In some embodiments, changes from baseline assessment in sensory sensitivity, neuroimaging measures, and sleep criteria are measured using QST, EEG, fMRI, 1Sensory sensitivity is measured using one or more methods and / or devices, such as H-MRS, DTI, VBM, and / or wrist actigraphy. In some embodiments, sensory sensitivity assessments include cuff pressure pain assessments and visual hypersensitivity assessments. In some embodiments, neuroimaging assessments include burst synchronization assessments, power spectral analysis, default mode network analysis, functional connectivity and activity analysis, glutamine and glutamate measurements, GABA measurements, and gray matter volume assessments. In some embodiments, sleep metrics include sleep onset latency assessments, wake-after-sleep assessments, total sleep assessments, and sleep efficiency assessments. In some embodiments, sensory sensitivity and neuroimaging assessments are completed at various time points during an exemplary treatment regimen, for example, during one or more of baseline deep profiling and end-of-treatment deep profiling. In some embodiments, baseline sleep index assessments are completed at various time points during an exemplary treatment regimen, for example, from one or more of baseline deep profiling to preparatory therapy, and consolidation to end-of-treatment deep profiling.

[0223] In some aspects, individuals undergoing treatment in accordance with provided embodiments are subjected to assessment of one or more clinical indicators, where assessment may include quantitative sensory testing (QST), electroencephalogram (EEG) analysis, functional magnetic resonance imaging (fMRI) analysis, proton magnetic resonance spectroscopy ( 1In some embodiments, the evaluation of the individual receiving treatment includes quantitative measures of clinical indicators, where the clinical indicators are measured by quantitative sensory testing (QST), electroencephalography (EEG), functional magnetic resonance imaging (VBM), wrist actigraphy, and combinations thereof. In some embodiments, the evaluation of the individual receiving treatment includes quantitative measures of clinical indicators. In some embodiments, the quantified clinical indicators relate to the individual receiving treatment's sensory sensitivity, examples of which include, but are not limited to, cuff pressure pain assessment and visual hypersensitivity assessment. In some embodiments, the quantified clinical indicators relate to the individual receiving treatment's neurobiology, examples of which include, but are not limited to, brain activity, functional connectivity, functional activity, and brain morphology. In some embodiments, the quantified clinical indicators relate to the individual receiving treatment's sleep aspects, examples of which include, but are not limited to, sleep onset latency, wakefulness after sleep onset, total sleep time, and sleep efficiency. In some embodiments, the evaluation of the individual receiving treatment includes quantitative measures of clinical indicators, where the clinical indicators are measured by quantitative sensory testing (QST), electroencephalography (EEG) analysis, functional magnetic resonance imaging (fMRI) analysis, proton magnetic resonance spectroscopy ( 1 It may be measured by one or more methods such as 1H-MRS, diffusion tensor imaging (DTI), voxel-based morphometry (VBM), wrist actigraphy, and combinations thereof.

[0224] 1. Sensory sensitivity In some embodiments, the quantified clinical endpoint relates to the sensory sensitivity of the individual undergoing treatment. Exemplary clinical endpoints include, for example, a cuff pressure pain assessment and a visual hypersensitivity assessment.

[0225] In some embodiments, exemplary indices include a measure of sensory sensitivity. Examining the sensory sensitivity of individuals experiencing chronic pain (e.g., individuals with FM) can be beneficial for quantifying and better understanding the individual's symptoms and sensitivity (Uddin and MacDermid, Pain Med 2016;17(9):1694-703). Quantitative sensory testing (QST) is a psychophysical testing approach defined as "the determination of thresholds or stimulus response curves for sensory processing under normal and pathological conditions" (Arendt-Nielsen and Yarnitsky, J Pain 2009;10(6):556-72), in which stimuli are quantified and used to measure sensation (Yarnitsky and Granot, Handb Clin Neurol 2006;81:397-409). QST is a semi-subjective technique (e.g., assessing subjective responses), but responses are elicited using known stimulus inputs, providing an objective framework for assessing individuals (e.g., before, during, or after therapeutic intervention). Examples of stimulus modalities include electrical, thermal, immersion thermal, mechanical, chemical, and light touch, where pain measurements can include pain threshold / tolerance, temporal summation, conditioned pain modulation, pain ratings, pain region mapping, brain responses (e.g., EEG, fMRI, PET), or muscle reflexes (Uddin and MacDermid, Pain Med 2016;17(9):1694-703). All QST procedures have been evaluated for safety and are well tolerated by chronic pain patients (Petersen et al., Pain 2015;156(1):55-61; Goodin et al., J Pain 2009;10(2):180-90; Weissman-Fogel et al., J Pain 2009;10(6):628-36; Price et al., Pain 2002;99(1-2):49-59).In some embodiments, the evaluation of the individual receiving treatment includes a quantitative measure of a clinical indicator. In some embodiments, the quantified clinical indicator relates to the sensory sensitivity of the individual receiving treatment, examples of which include, but are not limited to, cuff pressure pain assessment and visual hypersensitivity assessment. In some embodiments, the evaluation is measured by one or more methods, such as, but not limited to, quantitative sensory testing, electroencephalogram (EEG) analysis, functional magnetic resonance imaging (fMRI) analysis, and combinations thereof. In some embodiments, QST assessments are performed at various time points during the exemplary treatment regimen, for example, at one or more of baseline deep phenotyping and end-of-treatment deep phenotyping.

[0226] a. Pain caused by cuff pressure In some cases, pressure sensitivity of large volumes of deep muscles (Graven-Nielsen et al., Pain 2015;156(11):2193-2202; Izumi et al., 2014 Pain 155(4):792-800) is assessed using an MRI-compatible rapid cuff inflator (Hokanson, Bellevue, WA) (Loggia et al., Pain 2012;153(10):2140-51; Polianskis et al., Eur J Pain 2002;6(6):475-84; Polianskis et al., Eur J Pain 2001;5(3):267-77). In some embodiments, such assessments include cuff pressure pain assessment. Individuals undergoing treatment are subjected to a series of increasing cuff pressures (10 seconds of pressure, 20 seconds of intervals) starting at 20 mmHg and 40 mmHg, then increasing by 20 mmHg to a tolerance or maximum value of 400 mmHg. Each pressure is rated on a 0-100 numerical rating scale after venting. Individual-reported pain ratings are used to determine a series of eight tolerable cuff pressures, which are delivered in pseudorandomized order and individually rated for pain intensity and unpleasantness using the same 0-100 scale. Stimulus-response curves are constructed for each individual and used in analysis along with a number of derived variables (e.g., cuff pain threshold (cPTT), cuff-pain score, and cuff-tolerance). In addition, persistent pain induced by successive cuff pressures is expected to be assessed (persistent-cuff). The use of a pain 40-60 pressure (i.e., pressure that elicits a pain rating of 40-60 / 100) calibrated for each individual will be applied to one gastrocnemius muscle for 6-8 minutes. Pain intensity and unpleasantness ratings will be obtained every 60 seconds. This continuous cuff procedure will also be performed during fMRI and EEG analysis.

[0227] In some embodiments, cuff pressure pain is assessed to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, the change from baseline in cuff pressure pain is utilized to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, cuff pressure pain assessment is performed before and after completion of treatment. In some embodiments, cuff pressure pain assessment is performed at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the cuff pressure pain of an individual receiving treatment is reduced during treatment and / or after completion of treatment. In some aspects, cuff pressure pain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0228] b. Visual sensitivity In addition to painful hypersensitivity, many people with chronic pain report hypersensitivity to non-painful sensory stimuli, such as auditory, olfactory, and visual stimuli (Lopez-Sola et al., Arthritis Rheumatol 2014;66(11):3200-9; Wilbarger and Cook, Arch Phys Med Rehabil 2011;92(4):653-56; Geisser et al., J Pain 2008;9(5):417-22), which indicates a general state of multisensory amplification in a single-point pain. To measure non-physical sensitivity, individuals are presented with a series of non-painful but aversive visual stimuli (Harte et al., Pain 2016;157(9):1933-45). This task lasts 10 minutes and consists of different visual stimuli presented in an alternating block design. The control stimulus is a fixed crosshair centered on a solid-color background or black screen, whereas the experimental stimulus is a circular checkerboard with flashing lights. Subjects view the stimuli on a calibrated HD-dissipative LCD monitor. The stimuli are delivered in ascending and random order, adjusted to varying degrees of frequency (i.e., checkerboard flashing only), color, shape, movement, and / or whiteness level, and rated on a 0-100 numerical rating scale for sensation intensity and unpleasantness. To avoid potential adverse events in vulnerable patients, subjects with a history of light-induced migraines or seizures will not be administered the visual stimulation task. These subjects will be allowed to complete all other procedures. In some embodiments, visual hypersensitivity is assessed to evaluate the effect of hallucinogens on ameliorating one or more symptoms of FM.

[0229] In some embodiments, the change from baseline in visual sensitivity is utilized to evaluate the effect of the hallucinogen to improve one or more symptoms of FM. In some embodiments, the visual sensitivity assessment is performed before and after completion of treatment. In some embodiments, the visual sensitivity assessment is performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the visual sensitivity of the individual receiving treatment is reduced during treatment and / or after completion of treatment. In some aspects, the visual sensitivity is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0230] 2. Sleep Standards In some embodiments, the quantified clinical indicators relate to aspects of the sleep of the individual undergoing treatment, such as sleep onset latency, wakefulness after sleep, total sleep time, and sleep efficiency. In some aspects, sleep metrics can be measured using methods such as wrist actigraphy.

[0231] a. Wrist actigraphy Wrist actigraphy is a method of tracking sleep and sleep-related movements in ambulatory or at-home environments, where an actigraph device is worn on the wrist and the recorded information is used to computerize sleep parameters (Martin and Hakim, Chest 2011;139(6):1514-27). Individuals undergoing treatment are provided with a device for wrist actigraphy. In some embodiments, the device is selected from one or more of the following: Actiwatch Spectrum (Philips Respironics), PROdiary (CamNtech), and GT9X-BT Actiwatch (Actigraph). Wrist actigraphy devices are used to collect objective measurements of individuals, such as, but not limited to, total sleep time (i.e., sleep duration), wakefulness (i.e., sleep continuity), and sleep timing (e.g., time to fall asleep and time to wake). Individuals also complete two sleep logs (0-10 numerical rating scales for daily sleep quality, time to bed, number of awakenings, final awakening time, and estimated sleep onset) via actigraphy devices in a morning diary (Burgess H, J Biol Rhythms 2010;25(6):460-8; Burgess et al., J Clin Endocrinol Metab;2010 95(7):3325-31). Data extraction, cleaning, and analysis are performed using proprietary algorithms provided by the manufacturer.

[0232] In some embodiments, wrist actigraphy is assessed to evaluate the effect of the hallucinogen on improving one or more symptoms of FM and sleep-related symptoms. In some embodiments, the change from baseline in wrist actigraphy is assessed. In some embodiments, wrist actigraphy assessments are performed before and after completion of treatment. In some embodiments, wrist actigraphy assessments are performed at various time points during an exemplary treatment regimen, such as one or more of baseline deep phenotyping, preparatory therapy, integration sessions, and end-of-treatment deep phenotyping. In some embodiments, one or more aspects of the wrist actigraphy assessment of an individual receiving treatment improve during treatment and / or after completion of treatment. In some embodiments, one or more aspects improve by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0233] (i) Sleep onset latency Sleep onset latency (SOL) is an important parameter in sleep analysis; it is defined as the duration from "lights out" when an individual attempts to fall asleep to the time when the individual actually falls asleep, and is determined by changes in EEG signals and behavioral parameters consistent with sleep (Shrivastava et al., J Community Hosp Intern Med Perspect 2014;4(5):24983).

[0234] In some embodiments, SOL assessment is performed before and after completion of treatment. In some embodiments, SOL assessment is performed at various time points during an exemplary treatment regimen, such as one or more of baseline deep phenotyping, preparatory therapy, integration session, and end-of-treatment deep phenotyping. In some embodiments, SOL measurements of individuals receiving treatment improve during treatment and / or after completion of treatment. In some aspects, SOL assessment improves by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0235] (ii) Waking up in the middle of the night Wake-up-after-sleep-onset (WASO) refers to periods of sleeplessness that occur after defined sleep onset. WASO measures the duration of sleeplessness that occurs after sleep onset and reliably reflects sleep fragmentation (Shrivastava et al., J Community Hosp Intern Med Perspect 2014;4(5):24983).

[0236] In some embodiments, WASO assessments are performed before and after completion of treatment. In some embodiments, WASO assessments are performed at various time points during an exemplary treatment regimen, such as one or more of baseline deep phenotyping, preparatory therapy, integration sessions, and end-of-treatment deep phenotyping. In some embodiments, the WASO measure of an individual receiving treatment improves during treatment and / or after completion of treatment. In some aspects, the WASO measure decreases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0237] (iii) total sleep Total sleep time refers to the total sleep time from sleep onset to sleep end. In some embodiments, total sleep time is the sum of non-rapid eye movement stage 1, 2, and 3 sleep plus rapid eye movement (REM) sleep (Shrivastava et al., J Community Hosp Intern Med Perspect 2014;4(5):24983). Total sleep time is collected in combination with other parameters to assess sleep quality and sleep-related disorders. Low total sleep time may indicate a medical disorder or sleep disorder, while high total sleep time may indicate the effects of previous sleep deprivation, a medical condition, or current medication. In some embodiments, total sleep assessment is performed before and after completion of treatment. In some embodiments, total sleep assessment is performed at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep phenotyping, preparatory therapy, integration session, and end-of-treatment deep phenotyping.

[0238] In some embodiments, the total sleep measure of the individual receiving treatment improves during treatment and / or after treatment is completed, hi some aspects, the total sleep measure improves by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0239] (iv) Sleep efficiency Sleep efficiency refers to the percentage of total bedtime spent actually sleeping, which is calculated by dividing total sleep by total bedtime multiplied by 100. Sleep efficiency provides an overall assessment of sleep quality but does not account for high levels of sleep fragmentation (Shrivastava et al., J Community Hosp Intern Med Perspect 2014;4(5):24983).

[0240] In some embodiments, sleep efficiency assessment is performed before and after completion of treatment. In some embodiments, sleep efficiency assessment is performed at various time points during an exemplary treatment regimen, such as one or more of baseline deep phenotyping, preparatory therapy, integration session, and end-of-treatment deep phenotyping. In some embodiments, the sleep efficiency measurement of the treated individual increases during treatment and / or after completion of treatment. In some aspects, the sleep efficiency measurement increases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0241] 3. Neuroimaging Measurements In some embodiments, quantified clinical endpoints include those related to the neurobiology of the individual undergoing treatment, such as brain activity, functional connectivity, functional activity, and brain morphology.

[0242] Research aimed at defining and utilizing neurophysiological and clinical indices, including but not limited to brain activity, functional connectivity, functional activity, and brain morphology, is being intensified by the emergence of new methods, technological advances, and the rapidly evolving field of neuroinformatics key elements in the subsequent analysis of large datasets from population-sized cohorts (Roalf and Gur, Neuropsychology 2017;31(8):954-71; Woo et al., Nat Neurosci 2017;20(3):365-77; Horien et al., Nat Hum Behav 2021;5(2):185-93). These advances have provided new neurological tools to more quantitatively measure brain-specific changes in response to acute stimuli, including small molecule compounds and / or biomolecules, during development, aging, learning, and disease (Borsook et al., Nat Rev Drug Discov 2006;5(5):411-24; Matthews and Hampshire, Neuron 2016;91(3):511-28; Carmichael et al., Drug Discov Today 2018;23(2):333-48). While the benefits of psychedelic drug interventions have been qualitatively observed for centuries, the recent struggle for clinical acceptance is spurring the development and implementation of more thorough and quantitative approaches.

[0243] Brain activity Brain activity can be routinely monitored using non-invasive methods such as EEG and fMRI (Abreu et al., Front Hum Neurosci 2018;12:29). EEG records electrical activity through the scalp on a millisecond timescale. In some embodiments, the recorded signal represents macroscopic brain activity. fMRI detects changes in blood flow within the brain. In some embodiments, these changes correspond to local and region-specific changes in activity (Carhart-Harris et al., Sci Rep 2017;7(1):13187). 1H-MRS is another non-invasive neuroimaging technique that allows for the detection, identification, and quantification of metabolites and biochemical compounds in brain tissue (Castillo et al., AJNR Am J Neuroradiol 1996;17(1):1-15; Sidek et al., Eur Radiol 2016;26(12):4404-12). Finally, diffusion tensor imaging (DTI) is a newer method for anatomical mapping and characterization of microstructures in the brain (Alexander et al., Neurotherapeutics 2007;4(3):316-29), making it useful for bridging the gap between EEG and fMRI data and collectively enhancing the value of neurological datasets. In some aspects, individuals undergoing treatment in accordance with provided embodiments are subjected to one or more assessments before, during, and after treatment. In some embodiments, the assessment of the individual undergoing treatment includes quantification of clinical indicators. In some embodiments, the method or use includes changes from baseline assessment in neuroimaging measures.

[0244] In some embodiments, the change from baseline assessment in neuroimaging measures includes QST, EEG, fMRI, 1Neuroimaging measures may be measured using one or more methods and / or devices, such as H-MRS, DTI, VBM, and combinations thereof. In some embodiments, baseline neuroimaging measures include burst synchronization assessment, power spectral analysis, default mode network analysis, functional connectivity and activity analysis, glutamine and glutamate measurements, GABA measurements, and gray matter volume assessment. In some embodiments, baseline neuroimaging measures may be completed at various time points during an exemplary treatment regimen, such as one or more of baseline deep profiling and end-of-treatment deep profiling.

[0245] (i) Explosive synchronization and QST In some embodiments, reports indicate that chronic pain results from the disruption or dysfunction of complex neural networks, specifically an imbalance in excitatory and inhibitory brain activity that sensitizes unstable neural networks to external pain stimuli (Crofford L, Trans Am Clin Climatol Assoc 2015;126:167-83). Explosive synchronization (ES) is a phenomenon in which a small increase in stimulus intensity applied to a network can trigger a sudden state transition through global network synchronization (Arenas et al., Phys Rep 2008;469:93; Wang et al., Sci Rep 2017;7(1):561). Electroencephalogram (EEG) analysis can be used to collect various aspects of brain activity to examine ES events (Kim et al., Front Comput Neurosci 2016;10:1).

[0246] In some embodiments, EEG analysis provides high-resolution temporal recording of brain activity (Michel and Brunet, Front Neurol 2019;10:325), measuring electrical signals directly through the scalp and providing information on the millisecond time scale compared to the seconds or minutes required for other preferred methods. EEG data can be collected from multiple different situations (e.g., during rest, during continuous cuff pressure, during visual stimulation) to capture objective response signals and changes in brain activity.

[0247] In some embodiments, EEG is assessed to evaluate the effect of the hallucinogen on improving one or more symptoms of FM. In some embodiments, EEG assessments additionally including one or more sensory stimuli are utilized. In some embodiments, changes from baseline in ES measurements are utilized. In some embodiments, changes from baseline in resting EEG measurements are utilized. In some embodiments, changes from baseline in resting EEG measurements during and / or after sensory stimulation are utilized. In some embodiments, EEG assessments are performed before and after completion of treatment. In some embodiments, EEG assessments additionally including one or more sensory stimuli are performed before and after completion of treatment. In some aspects, the sensory stimuli include pain via cuff pressure and visual paradigms. In some embodiments, EEG assessments are performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping.

[0248] In some embodiments, EEG assessments additionally including one or more sensory stimuli are performed at various time points during an exemplary treatment regimen, e.g., one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the ES measurements of the individual receiving treatment improve during treatment and / or after completion of treatment. In some aspects, the ES measurements improve by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. In some embodiments, the resting EEG measurements of the individual receiving treatment improve during treatment and / or after completion of treatment. In some aspects, the resting EEG measurements improve by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. In some embodiments, the EEG measurements of the individual receiving treatment additionally including one or more sensory stimuli improve during treatment and / or after completion of treatment. In some embodiments, EEG measurements that additionally include one or more sensory stimuli improve by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0249] (ii) Default mode network, functional connectivity, and sensory testing In some embodiments, functional connectivity MRI (fMRI) focuses on the default mode network (DMN) and salience network (SLN). The DMN is a configuration of brain regions involved in self-referential cognition, which is "deactivated" during externally focused tasks (Buckner and Vincent, Neuroimage 2007;37(4):1091-99; Fox and Raichle Nat Rev Neurosci 2007;8(9):700-11). Patients with more focal pain show increased connectivity between the DMN and the insula (SLN region), and this connectivity decreases with successful treatment (Napadow et al., Arthritis Rheum 2012;64(7):2398-2403). At the beginning of the scanning session, while the subject is comfortably resting in the scanner with their eyes closed for approximately 8 minutes, whole-brain BOLD functional images are acquired to obtain a baseline measure of functional brain connectivity. Immediately afterward, subjects undergo fMRI scanning in conjunction with sensory stimulation (e.g., pain induced by sustained cuff pressure) to assess functional brain connectivity responses to deep pain. Pressure intensity is set to each subject's pain level of 30-50, as determined during the behavioral visit, and is applied for approximately 8 minutes. Pressure levels are verified before the start of the scan and recalibrated if they induce more or less pain than expected. Pain intensity and unpleasantness ratings are obtained up to three times during the study and at specific intervals after the presentation of the stimulus.

[0250] In some embodiments, fMRI is assessed to evaluate the effect of a hallucinogen to improve one or more symptoms of FM. In some embodiments, fMRI assessment is utilized that additionally includes one or more sensory stimuli. In some embodiments, fMRI assessment is utilized that additionally includes one or more sensory stimuli. In some aspects, the sensory stimuli are applied at one or more intensities. In some embodiments, changes from baseline in the default mode network are utilized. In some embodiments, changes from baseline in default mode network connectivity are utilized. In some embodiments, changes from baseline in default mode connectivity are utilized.

[0251] In some embodiments, the functional brain connectivity assessment is completed in a resting state to obtain a baseline measurement. In some embodiments, the functional brain connectivity assessment is completed during one or more sensory stimuli. In some embodiments, the functional brain connectivity assessment is completed during one or more sensory stimuli. In some aspects, the sensory stimuli are applied at one or more intensities. In some embodiments, the sensory stimuli include pain via cuff pressure and visual stimuli. In some embodiments, the functional brain connectivity assessment is completed during pain via sustained cuff pressure, where the response to pain is recorded. In some embodiments, the functional brain connectivity assessment is completed during visual stimuli, where the response to visual cues is recorded.

[0252] In some embodiments, the assessment of functional brain connectivity in the resting state is performed before and after completion of treatment. In some embodiments, the assessment of functional brain connectivity in the stress state is performed before and after completion of treatment. In some embodiments, the assessment of functional brain connectivity in the resting state is performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the assessment of functional brain connectivity in the stress state is performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the resting state functional brain connectivity of an individual receiving treatment improves during treatment and / or after completion of treatment. In some aspects, the resting state functional brain connectivity improves by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. In some embodiments, the resting state functional brain connectivity of an individual receiving treatment improves during treatment and / or after completion of treatment. In some embodiments, functional brain connectivity during the stress state improves by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0253] (iii) glutamine, glutamate (Glx), and gamma-aminobutyric acid (GABA) levels In some cases, proton magnetic resonance spectroscopy ( 1Using H-MRS, changes in glutamine and glutamate (Glx) and gamma-aminobutyric acid (GABA) levels within specific brain regions (e.g., the posterior and anterior insula) have reportedly been shown to strongly correlate with pain improvement, with reductions in clinical pain associated with decreased Glx and increased GABA levels (Mawla et al., Arthritis Rheumatol 2021;73(7):1318-28; Harris et al., Arthritis Rheum 2009;60(10):3146-52; Harris et al., Arthritis Rheum 2008;58(3):903-7). 1 H-MRS provides a metric suitable for longitudinal studies, in which high-resolution anatomical scans isolate identical brain structures within individuals over time, minimizing errors that would otherwise be expected due to small differences in voxel location from assessment to assessment. 1 H-MRS will be directed at the right posterior insular cortex both before and after the induction of pain stimuli with cuff pressure. Because both the right and left sides of the brain have been shown to be involved in chronic FM pain (Harris et al., Arthritis Rheum 2009;60(10):3146-52; Harris et al., Arthritis Rheum 2008;58(3):903-7), it is anticipated that both sides will be explored using this approach. Individuals undergoing treatment will: 1 During the H-MRS session, the patient is in a resting state and one or more 1 H-MRS assessment is integrated into the fMRI neuroimaging workflow.

[0254] In some embodiments, Glx is assessed to evaluate the effect of a hallucinogen on improving one or more symptoms of FM, where Glx is glutamine and glutamate. In some embodiments, GABA is assessed. 1 H-MRS is assessed. 1 H-MRS is assessed. 1H-MRS assessment is completed before one or more sensory stimuli are induced. 1 H-MRS is assessed. 1 H-MRS assessment is completed after one or more sensory stimuli are induced. In some embodiments, the change from baseline in the level of Glx is utilized.

[0255] In some embodiments, the change from baseline in GABA levels is used to assess the effect of a hallucinogen to ameliorate one or more symptoms of FM. 1 H-MRS assessment is performed on one or more brain regions, including the right posterior insular cortex. In some embodiments, Glx assessment is performed at various time points during the exemplary treatment regimen, for example, at one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, GABA assessment is performed at various time points during the exemplary treatment regimen, for example, at one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, 1 H-MRS assessments are performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the level of Glx in an individual undergoing treatment decreases during treatment and / or after completion of treatment. In some aspects, the level of Glx decreases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. In some embodiments, the level of GABA in an individual undergoing treatment decreases during treatment and / or after completion of treatment. In some aspects, the level of GABA decreases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. In some embodiments, the level of GABA in an individual undergoing treatment decreases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline. 1The H-MRS signal improves during treatment and / or after treatment is completed. 1 The H-MRS signal improves by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0256] (iv) Diffusion Tensor Imaging Diffusion tensor imaging (DTI) is another neuroimaging technique that utilizes the fMRI platform and is used to characterize small changes in brain structure during neuropathological processes and treatments (Alexander et al., Neurotherapeutics 2007;4(3):316-29; Soares et al., Fron Neurosci 2013;7:31). Here, DTI data is collected during the fMRI neuroimaging procedure to assist in the spatial mapping of EEG data. A unique structural brain network is created for each individual undergoing treatment, better informing prior and subsequent EEG analysis.

[0257] In some embodiments, DTI is assessed to evaluate the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, DTI is assessed to complement or augment other neuroimaging data for evaluating the effect of a hallucinogen. In some embodiments, DTI is assessed to complement or augment EEG data for evaluating the effect of a hallucinogen. In some embodiments, DTI assessments are performed at various time points during an exemplary treatment regimen, for example, at one or more of baseline deep phenotyping and end-of-treatment deep phenotyping.

[0258] B. Brain morphology (i) Gray matter volume Gray matter is the region of the brain that contains most of its neuronal cell bodies (Lee et al., Sci Total Environ 2020;707:135603; Chiao et al., Methods Mol Biol 2020;2092:65-75), and gray matter volume is associated with cognitive performance, with reduced gray matter volume correlating with cognitive impairment (Spulber et al., Curr Alzheimer Res 2012;9(4):516-24; Valdes et al., Neuroimage Clin 2020;25:102158; Dicks et al., Neuroimage Clin 2019;22:101786). In some embodiments, voxel-based morphometry (VBM) is a neuroimaging technique that quantifies regional differences in brain anatomy; images of core elements in the brain (e.g., gray matter, white matter, and cerebrospinal fluid) are anatomically normalized and processed according to various computer algorithms and statistics (Wright et al., Schizophr Res 1999;35(1):1-14; Ashburner and Friston Neuroimage 2000;11(6 Pt 1):805-21). VBM thus allows for global and regional volumetric comparisons between different groups (Andujar et al., Brain Sci 2021;11(8):999).

[0259] In some embodiments, gray matter volume is utilized to assess the effect of a hallucinogen on improving one or more symptoms of FM. In some embodiments, VBM is assessed. In some embodiments, changes from baseline in gray matter volume are utilized. In some embodiments, assessment of VBM is performed at various time points during an exemplary treatment regimen, for example, one or more of baseline deep phenotyping and end-of-treatment deep phenotyping. In some embodiments, the gray matter volume of an individual receiving treatment increases during treatment and / or after completion of treatment. In some aspects, gray matter volume increases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to baseline.

[0260] C. Exemplary Monitoring and Evaluation In some aspects, individuals undergoing treatment in accordance with provided embodiments are subjected to one or more assessments before, during, and after treatment, e.g., before, during, and after administration of one or more doses of a hallucinogen, e.g., psilocybin or a metabolite thereof. In some embodiments, the one or more assessments of the individual undergoing treatment include one or more subject-reported assessments, one or more observer-rated assessments, one or more quantified clinical indicators, and combinations thereof. In some embodiments, the one or more assessments of the individual undergoing treatment include assessment of primary and / or secondary endpoints. In some embodiments, the assessment of the individual undergoing treatment includes assessment of secondary efficacy endpoints.

[0261] In some embodiments, the method or use comprises assessing change from baseline in the 2016 FM Survey Questionnaire (FSQ), the Coping Strategies Questionnaire (CSQ), the PainDETECT assessment, the Positive and Negative Affect Score (PANAS), the PROMIS-29+2 Profile v2.1 Multi-Domain Assessment, the Patient-Acceptable Symptom State (PASS) questionnaire, the Mystical Experiences Questionnaire (MEQ30), the Challenging Experiences Questionnaire (CEQ), the Psychological Insight Questionnaire (PIQ), and / or the Monitoring Rating Scale (MRS). In some embodiments, the assessment of the individual receiving treatment includes a qualitative, documented assessment of treatment experience, opinions, and insights. In some embodiments, the FSQ assessment is completed at various time points during an exemplary treatment regimen, for example, at one or more of screening, baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and 6-month follow-up.

[0262] In some embodiments, CSQ assessments, PainDETECT assessments, and Positive and Negative Affect Score (PANAS) assessments are completed at various time points during the exemplary treatment regimen, e.g., at one or more of baseline deep profiling, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and 6-month follow-up. In some embodiments, PROMIS-29+2 Profile v2.1 multi-domain assessments are completed at various time points during the exemplary treatment regimen, e.g., at one or more of baseline deep profiling, first dose, second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and 6-month follow-up. In some embodiments, the PROMIS-29+2 Profile v2.1 Multi-Domain Assessment and PASS questionnaire are completed at various time points during the exemplary treatment regimen, e.g., at one or more of baseline deep profiling, first dose, second dose, end-of-treatment deep profiling, 1-month follow-up, 3-month follow-up, and 6-month follow-up. In some embodiments, assessments of the MEQ30, CEQ, PIQ, and MRS are completed at various time points during the exemplary treatment regimen, e.g., at one or more of the first and second doses. In some embodiments, qualitative written assessments are completed at various time points during the exemplary treatment regimen, e.g., at one or more of the first dose, second dose, 1-month follow-up, 3-month follow-up, and 6-month follow-up.

[0263] Exemplary schemes for monitoring and evaluation according to provided embodiments are listed in Table 1. In some aspects, monitoring and evaluation include subject-reported and observer-rated outcomes, quantification of clinical indicators, and combinations thereof.

[0264] [Table 1A]

[0265] [Table 1B]

[0266] [Table 1C]

[0267] D. Treatment Monitoring: Adverse Events In some embodiments, the method or use comprises monitoring an adverse event (AE). In some embodiments, one or more parameters or indicators related to an adverse event (AE) or a potential adverse event are monitored or assessed before, during, or after administration of the hallucinogen and / or psychotherapy.

[0268] In some embodiments, psychological support providers, observers, or session monitors are trained to reassure subjects when they experience psychological distress, such as one or more of acute anxiety, agitation, paranoia, and panic. In some embodiments, in the unlikely event that the psychological distress does not respond to reassurance, or if the subject experiences an adverse event, one of the session monitors contacts a physician. In some embodiments, the physician uses their clinical judgment to determine the most appropriate medical intervention.

[0269] In some embodiments, AEs are monitored throughout the treatment regimen, for example, at each visit. In some embodiments, observers are available throughout the treatment regimen for emergent AEs. In some embodiments, throughout the administration period, a psychological support provider, for example, a therapist, assesses the presence and intensity of the subject's behaviors, symptoms, and non-verbal cues, including questions about behaviors, signs, and reported symptoms, such as calmness, yawning, nausea / vomiting, speech volume, anxiety, drowsiness, crying, restlessness, visual changes, euphoria, and the presence / intensity of a sense of unreality. Individuals complete mood and safety assessments at the end of each administration session. In some embodiments, any of the parameters or indicators described herein can be used to monitor or assess possible AEs, and treatment can be adjusted, suspended, or discontinued accordingly.

[0270] In some embodiments, if an individual exhibits an increased risk of harming themselves or others, or any other indication that continuing the treatment regimen would present a disproportionate risk, the second dose will not be administered.In some cases, if an individual has a serious adverse event, such as psychosis or hypertension, the individual will not receive the second dose.In some embodiments, if a female subject becomes pregnant during the treatment regimen, the treatment regimen will be discontinued.

[0271] In some cases, clinical studies involving the administration of hallucinogens have reported similar safety profiles, with both psychological and physical adverse events reported. Oral psilocybin is well tolerated in healthy individuals. No drug-related serious adverse events (SAEs) have been reported. Overall, the most common adverse events associated with psilocybin administration are psychological in nature, including the induction of anxiety, negative emotional states, and paranoid / delusional thinking during psilocybin sessions. In addition, the frequency of reports of hallucinogen persistent perception disorder (HPPD) is relatively low (Johnson et al., J Psychopharmacol 2008;22(6):603-20; Tyls et al., European Neuropsychopharmacology 2014;24(3), 342-56). The prevalence of any type of long-term psychiatric symptom after psilocybin exposure in healthy study subjects is estimated to be 0.08-0.09%.

[0272] In some embodiments, oral benzodiazepines (e.g., lorazepam) are administered to treat panic or anxiety. In some embodiments, oral antipsychotics (e.g., risperidone) are available for the on-the-spot treatment of psychosis or severe agitation. Common physical effects of psilocybin administration include increased blood pressure (BP) and heart rate (HR), gastrointestinal effects (nausea, vomiting, and diarrhea), and mild headache.

[0273] III. Definition Unless otherwise specified, all technical terms, notation, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, for clarity and / or ready reference, terms having commonly understood meanings are defined herein, and the incorporation of such definitions herein shall not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0274] In some aspects, it will be understood that the term "comprise" or variations such as "comprises" or "comprising" necessarily includes the inclusion of a stated element, integer or step, or group of elements, integers or steps, but does not exclude any other element, integer or step, or group of elements, integers or steps.

[0275] Any discussion of documents, acts, materials, devices, articles or the like in this specification is solely for the purpose of providing a context for the technology of the present invention and is not to be construed as an admission that any or all of such matter formed part of the prior art or was common general knowledge in the art relevant to the technology of the present invention as it existed prior to the priority date of each claim set forth herein.

[0276] In some aspects, integers, steps, or elements of the technology recited herein as singular integers, steps, or elements explicitly encompass both the singular and plural forms of the recited integer, step, or element.

[0277] In some contexts, the terms "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, a reference to "an element" means one element or more than one element.

[0278] In some contexts, the term "about" means that reference to a number or value is not to be construed as an absolute number or value, but includes a range of variation above or below that number or value consistent with what one of ordinary skill in the art would be expected to understand in accordance with the art, such as within a typical error range or instrument limit. In some cases, the word "about" is understood to refer to a range or approximation that one of ordinary skill in the art would be expected to consider equivalent to the recited value under circumstances that achieve the same function or result.

[0279] In some contexts, the terms "treat," "treatment," and "therapy" refer to curative therapy, prophylactic therapy, palliative therapy, and preventative therapy. Thus, in the context of the present disclosure, the term "treat" encompasses curing, alleviating, or mitigating the severity of one or more of a mental condition or its associated symptoms. Desired effects of treatment include, but are not limited to, preventing the appearance or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of a disease, reducing the rate of disease progression, ameliorating or palliative relief of the condition, and remission or improved prognosis. These terms do not imply a complete cure of a disease or complete elimination of all symptoms or effects of all symptoms or outcomes.

[0280] In some contexts, the terms "therapeutically effective amount" or "pharmacologically effective amount" or "effective amount" refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in a treated subject. These terms are synonymous and are intended to specify the amount of each agent that would be expected to achieve the goal of improvement in disease severity and / or incidence over treatment with each agent alone, preferably while avoiding or minimizing adverse side effects, including those typically associated with other therapies.

[0281] In some contexts, "pharmaceutical carriers," "diluents," or "excipients" include, but are not limited to, suitable water-soluble organic carriers, conventional solvents, dispersion media, fillers, carriers, coatings, antibacterial and antifungal agents, any physiologically buffered medium (i.e., a pH of about 7.0 to 7.4), including isotonic and absorption delaying agents.

[0282] In some contexts, the term "administer" and variations of this term, such as "administering" and "administration," include contacting, applying, delivering, or providing a compound or composition of the invention to a subject by any suitable means.

[0283] IV. Illustrative Embodiments The embodiments provided are as follows: 1. A method of treating fibromyalgia (FM), comprising administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state. 2. A method of treating fibromyalgia (FM), comprising orally administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state. 3. The method of embodiment 1 or 2, further comprising providing one or more integration sessions to the subject after emerging from the dissociated state. 4. The method of any one of embodiments 1-3, further comprising assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin. 5. A method of treating fibromyalgia (FM), comprising: administering one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state to a subject suffering from one or more symptoms of FM; providing one or more integration sessions to the subject after emergence from the dissociative state; and assessing one or more indicators related to one or more symptoms of FM, the dissociative state, treatment outcome, safety, and / or subject-related indices in the subject before and / or after administration of one or more doses of psilocybin or an active metabolite thereof. A method comprising: 6. A method for treating fibromyalgia (FM), comprising assessing one or more indicators related to one or more symptoms of FM, the dissociative state, treatment outcome, safety, and / or related to the subject, in a subject suffering from one or more symptoms of FM, before and / or after administration of one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state, and one or more integration sessions after emergence from the dissociative state induced by the one or more doses of psilocybin or an active metabolite thereof. 7. A method of treating fibromyalgia (FM), comprising: administering one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state to a subject suffering from one or more symptoms of FM; providing one or more integration sessions to the subject after emergence from the dissociative state; and assessing one or more indicators in the subject before and / or after administration of one or more doses of psilocybin or an active metabolite thereof, wherein the one or more indicators comprise one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical indicator. A method comprising: 8. Prior to administration of one or more doses of psilocybin, the following exclusion parameters are present in the subject: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) previous adverse effects from psilocybin 8. The method of any one of embodiments 1 to 7, further comprising assessing one or more of: 9. The method of embodiment 8, further comprising identifying the subject for treatment with psilocybin if the subject does not meet any of the exclusion parameters. 10. A method of identifying a subject for treatment of fibromyalgia (FM) with psilocybin or an active metabolite thereof, comprising: (a) In subjects suffering from one or more symptoms of FM, the following exclusion parameters: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) Previous adverse effects from psilocybin or its active metabolites evaluating one or more of (b) if the subject does not meet any of the exclusion parameters, identifying the subject for treatment with one or more doses of psilocybin or an active metabolite thereof. A method comprising: 11. A method of identifying a subject for treatment of fibromyalgia (FM) with one or more doses of psilocybin or its active metabolites, wherein the subject has one or more of the following exclusion parameters assessed in the subject: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) Previous adverse effects from psilocybin or its active metabolites If none of the above conditions is met, identifying the subject suffering from one or more symptoms of FM for treatment. 12. Administering to the identified subject one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state; and providing the subject with one or more integration sessions after emerging from the dissociative state. 12. The method of embodiment 10 or 11, further comprising: 13. The method of any one of embodiments 10-12, further comprising assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin or an active metabolite thereof. 14. The method of any one of embodiments 1-13, wherein the administering is by oral administration or intravenous administration. 15. The method of any one of embodiments 1-14, wherein the administering is by oral administration. 16. The method of any one of embodiments 1-14, wherein the psilocybin or an active metabolite thereof is psilocybin. 17. The method of any one of embodiments 4-9 and 13-16, wherein the one or more indicators include observer-rated parameters, subject-reported parameters and / or clinical indicators. 18. The method of any one of embodiments 4-9 and 13-17, wherein one or more indicators are assessed prior to administration as a baseline measure and after administration as an outcome measure, and the change between the baseline measure and the outcome measure is determined. 19. The method of any one of embodiments 4-9 and 13-18, wherein the one or more indicators include one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical indicator. 20. The method of any one of embodiments 4-9 and 13-19, wherein the one or more indicators comprise one or more of: a Fibromyalgia Survey Score, optionally a 2016 Fibromyalgia Survey Questionnaire (FSQ) assessment; a Pain Intensity Numerical Rating Scale (PI-NRS) assessment, optionally the 11-item PI-NRS scale; a PROMIS Pain Interference Assessment; a PainDETECT Questionnaire (PD-Q) assessment; a Chronic Pain Acceptance Assessment, optionally measured by a Chronic Pain Acceptance Questionnaire (CPAQ-8) assessment; a Pain Interference Assessment, optionally measured by a 4-item PROMIS Pain Interference Scale; and a Composite Medical Symptom Inventory (CMSI). 21. The method of any one of embodiments 4-9 and 13-20, wherein the one or more indicators include a Fibromyalgia Survey Score. 22. The method of any one of embodiments 7 and 19-21, wherein the Fibromyalgia Survey Score comprises an assessment of the 2016 Fibromyalgia Survey Questionnaire (FSQ). 23. The method of any one of embodiments 4-9 and 13-22, wherein the one or more indices include the Pain Intensity Numerical Rating Scale (PI-NRS), an 11-item pain scale. 24. The method of any one of embodiments 4-9 and 13-23, wherein the one or more indicators include one or more of a sleep disturbance assessment, optionally measured by the PROMIS Sleep-Related Disorders 4a assessment; the PROMIS Sleep Disorders 8b assessment; and the STOP-Bang questionnaire. 25. The method of any one of embodiments 4-9 and 13-24, wherein the one or more indicators include one or more of the following: a PROMIS-29+2 profile, optionally a v2.1 Multi-Domain Assessment; a Positive and Negative Affect Score (PANAS) assessment; a Patient Global Impression-Change (PGI-C) scale assessment; and a Patient Acceptable Symptom Status (PASS) questionnaire. 26. The method of any one of embodiments 4-9 and 13-25, wherein the one or more indicators include a PROMIS-29+2 Profile v2.1 Multi-Domain Assessment. 27. The method of any one of embodiments 4-9 and 13-26, wherein the one or more indicators include one or more of the following: Patient Health Questionnaire Depression Scale-8 (PHQ-8); Columbia-Suicide Severity Rating Scale (C-SSRS); Clinical Global Impression-Improvement (CGI-I) scale; Emotional Breakthrough Inventory (EBI); Acceptance and Behavior Questionnaire-II (AAQ-II); Patient Global Impression-Improvement (PGI-I); Hospital Anxiety and Depression Scale (HADS); and Life Events Checklist (LEC). 28. The method of any one of embodiments 4-9 and 13-27, wherein the one or more indicators include the Patient Health Questionnaire Depression Scale-8 (PHQ-8). 29. The method of any one of embodiments 4-9 and 13-28, wherein the one or more indicators include one or more of: a subject-reported mystical experience rating, optionally measured by the Mystical Experiences Questionnaire (MEQ30); a subject-reported challenging experience rating, optionally measured by the Challenging Experiences Questionnaire (CEQ27); a subject-reported psychological insight rating, optionally measured by the Psychological Insight Questionnaire (PIQ); and a subject-reported qualitative documented assessment. 30. The method of any one of embodiments 4-9 and 13-29, wherein the one or more indicators include a therapist-reported monitoring rating scale, optionally measured using a form of the monitoring rating scale (MRS). 31. The method of any one of embodiments 4-9 and 13-30, wherein the one or more indicators include a quantitative sensory test (QST). 32. The method of embodiment 31, wherein QST is measured using a cuff tenderness assessment, and optionally using cuff-PPT, cuff-pain40, cuff-pain50, and / or cuff-tolerance. 33. The method of any one of embodiments 4-9 and 13-31, wherein the one or more indicators include a visual hypersensitivity assessment. 34. The method of any one of embodiments 4-9 and 13-33, wherein the one or more indicators include an electroencephalogram (EEG). 35. The method of any one of embodiments 4 to 9 and 13 to 33, wherein the one or more indicators include QST and EEG, and the QST and EEG are performed simultaneously. 36. The method of any one of embodiments 4 to 9 and 13 to 35, wherein the one or more indicators include functional magnetic resonance imaging (fMRI). 37. The method of embodiment 36, wherein the fMRI comprises one or more of: structural MRI; resting-state fMRI; proton magnetic resonance spectroscopy (1H-MRS) in the right anterior insula; fMRI using experimental pain induced by tonic cuff pressure; fMRI using pain with cuff pressure in a block design; and diffusion tensor imaging (DTI). 38. The method of any one of embodiments 4-9 and 13-37, wherein the one or more metrics include one or more of wrist actigraphy, optionally wrist actigraphy used to measure sleep onset latency; sleep onset awakening; total sleep time; and sleep efficiency (%). 39. The method of any one of embodiments 4-9 and 13-38, wherein the one or more indicators include an electrocardiogram (ECG). 40. The method of any one of embodiments 4-9 and 13-38, wherein one or more indicators are measured during one or more integration sessions. 41. The exclusion parameter is use of prior or concomitant medications and the subject is on the following prior or concomitant medications: Regular use of psychoactive prescription medications, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects or monoamine oxidase inhibitors (MAOIs); use of hallucinogens in the past 6 months; concomitant use of sildenafil or tadalafil; concomitant use of alcohol with a blood alcohol content greater than 0.02%; medication with antihypertensives; UGT1A9 inhibitors, 1A10 inhibitors, regorafenib, rimampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasirox, ginseng; aldehyde dehydrogenase inhibitors, alfalfa, benzodiazepines, benzocaine ... Alcohol dehydrogenase inhibitors, or disulfiram; amphetamine, buprenorphine, benzodiazepines, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoids (K2); regular use of psychoactive prescription drugs, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs), or use of serotonergic dietary supplements, 5-hydroxytryptophan, or St. John's wort The method of any one of embodiments 8 to 40, wherein the subject is identified for treatment if the subject is not currently using any of the following: 42. The method of any one of embodiments 8-41, wherein the exclusion parameter is hypertension, and the subject is identified for treatment if the subject does not exhibit a systolic blood pressure greater than or about 139 mmHg, or a diastolic blood pressure greater than or about 89 mmHg, optionally measured as the average of three readings; and / or the exclusion parameter is tachycardia, and the subject is identified for treatment if the subject does not exhibit a heart rate (bpm) greater than or about 90 beats per minute. 43. The method of any one of embodiments 6 to 42, wherein the exclusion parameter is the occurrence of epilepsy and if the subject does not have epilepsy, the subject is identified for treatment. 44. The method of any one of embodiments 6-43, wherein the exclusion parameter is the occurrence of a psychotic disorder and the subject is identified for treatment if the subject does not have schizophrenia spectrum or other psychotic disorder meeting DSM-5 criteria, major depressive disorder with psychotic features, or bipolar I or bipolar II disorder. 45. The method of any one of embodiments 6-44, wherein the exclusion parameter is moderate or severe alcohol or drug use disorder, and the subject is identified for treatment if the subject does not have a moderate or severe alcohol or drug use disorder that meets DSM-5 criteria. 46. ​​The method of any one of embodiments 6-45, wherein the exclusion parameter is a previous adverse effect from psilocybin or its active metabolite, and the subject is identified for treatment if the subject has never had a previous adverse effect from psilocybin or its active metabolite. 47. The method of any one of embodiments 4-9 and 13-46, wherein the subject exhibits improvement in one or more indicators between the baseline measurement and the outcome measurement. 48. The method of any one of embodiments 1-47, wherein the subject undergoing treatment shows improvement in one or more symptoms of FM, or one or more symptoms of FM are alleviated. 49. The method of any one of embodiments 1-48, wherein the subject undergoing treatment exhibits an improvement selected from among one or more of the following: Fibromyalgia Survey score, pain interference assessment, sleep assessment, chronic pain acceptance assessment, or clinical index assessment. 50. The method of any one of embodiments 1-49, wherein the subject undergoing treatment exhibits improvement selected from one or more of: Fibromyalgia Survey score, optionally as assessed by the 2016 Fibromyalgia Survey Questionnaire (FSQ); Pain Intensity Numerical Rating Scale (PI-NRS), optionally as assessed by the 11-item PI-NRS scale; PROMIS Pain Interference Assessment; PainDETECT Questionnaire (PD-Q); Chronic Pain Acceptance Assessment, optionally as measured by the Chronic Pain Acceptance Questionnaire (CPAQ-8); and Pain Interference Assessment, optionally as measured by the 4-item PROMIS Pain Interference Scale. 51. The method of any one of embodiments 1-50, wherein the one or more doses of psilocybin or an active metabolite thereof comprises a first dose of psilocybin. 52. The method of embodiment 51, wherein the first dose is at or about 10 mg to 50 mg or about 50 mg of psilocybin. 53. The method of embodiment 51 or 52, wherein the first dose is 15 mg or about 15 mg of psilocybin. 54. The method of any one of embodiments 1-53, wherein the one or more doses of psilocybin comprise two or more doses of psilocybin. 55. The method of any one of embodiments 1-54, wherein the one or more doses of psilocybin comprise a second dose of psilocybin. 56. The method of embodiment 55, wherein the second dose is at or about 20 mg to 50 mg or about 50 mg of psilocybin. 57. The method of embodiment 55 or 56, wherein the second dose is 25 mg or about 25 mg of psilocybin. 58. The method of embodiment 55, wherein the second dose is at or about 10 mg to 20 mg or about 20 mg of psilocybin. 59. The method of embodiment 58 or 59, wherein the second dose is 15 mg or about 15 mg of psilocybin. 60. The method of any one of embodiments 55-59, wherein the second dose is administered 12 days or about 12 to 16 days or about 16 days after the first dose. 61. The method of any one of embodiments 55-60, wherein the second dose is administered 14 days or about 14 days after the first dose. 62. The method of any one of embodiments 1-61, further comprising providing one or more integration sessions to the subject after the one or more doses of psilocybin. 63. The method of embodiment 62, wherein the one or more integrated sessions are provided at or about 3, 4, and / or 5 weeks after administering the first dose of psilocybin. 64. The method of embodiment 62 or 63, wherein the one or more integrated sessions are provided at or about 1, 2, and / or 3 weeks after administration of the second dose of psilocybin. [Example]

[0284] V. Working Examples The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0285] Example 1 Effects of intravenous hallucinogens on pain-related disorders This example describes the effects of intravenous administration of hallucinogens on pain perception and pain-related disorders in animal models of pain, such as nociceptive pain. A rat model of chronic pain induced by formalin (FML) was used to examine the effects of psilocybin administration on mechanical allodynia and thermal hyperalgesia.

[0286] Chronic pain in rats was induced by injection of formalin into the hind paw. The rats were then intravenously administered psilocybin and evaluated for changes in pain perception over time. The formalin pain model is a translational animal model for chronic nociceptive pain, including fibromyalgia (FM) (Vanini G., Sleep 2016;39(1):133-42). In the formalin pain model, in addition to experiencing extra pain in the formalin-injected paw, animals also experience increased pain perception (i.e., hyperalgesia) in the limb not injected with formalin (e.g., the contralateral hind paw) compared to the limb injected with formalin (e.g., the ipsilateral hind paw). Pain perception in the contralateral and ipsilateral paws was measured to assess the potential benefit of hallucinogens (e.g., psilocybin) in nociceptive pain disorders. Reduction in pain perception and duration of pain reduction were examined after an intravenous bolus of 10 mg / kg psilocybin or saline, respectively, administered over 3 minutes.

[0287] Adult male Sprague Dawley rats (300-350 g) were implanted with a catheter in the jugular vein for delivery of 10 mg / kg psilocybin or 0.9% saline. Mechanical allodynia was assessed using the von Frey assay (VFA) and expressed as threshold in grams (g). Thermal hyperalgesia was measured as paw withdrawal latency in seconds (s) using the hot plate assay (HPA) (52.5°C). After post-surgical recovery (7-10 days), baseline responses to mechanical and thermal stimuli were measured. 24 h after baseline measurements, rats received a subcutaneous formalin injection (5%; 50 μL) into one hind paw (day 0). Two hours after formalin injection, paw withdrawal thresholds in response to mechanical and thermal stimuli were measured. Twenty-four hours after FML injection (Day 1), rats received an intravenous infusion of 10 mg / kg psilocybin (N=6) or 0.9% saline (N=6), and paw withdrawal thresholds in the VFA and HPA were measured 3-4 hours after injection. Rats were tested every other day for the first week, then once a week for a total of 4 weeks. Data are reported as mean ± standard deviation.

[0288] Two types of pain perception were measured. First, the von Frey assay (VFA) was used to measure pain resulting from pressure applied to the paw (i.e., mechanical allodynia). Specifically, the VFA employed seven filaments: 1, 2, 4, 6, 8, 10, and 15 g. Each filament was applied in ascending order to the plantar surface of the rat's hind paw (contralateral and ipsilateral) until it bent. Once bent, the filament was held in place for 5 seconds or until the rat withdrew its paw. No stimuli were applied if the rat was walking, grooming, or sniffing. Stimuli were applied to the injected ipsilateral and contralateral hind paws for five trials each, with at least a 30-second break between stimuli. The minimum amount of force required to elicit a paw withdrawal response in each trial was determined to be the minimum withdrawal threshold for that trial in that animal. After five trials for each paw, the minimum amount of force required to elicit a paw withdrawal response was averaged across all trials to calculate the mean minimum withdrawal threshold for each paw, respectively.

[0289] The second pain measurement was based on the hot plate assay (HPA), which measures withdrawal latency to temperatures indicative of a painful response (i.e., thermal hyperalgesia). The HPA began 15–20 min after the completion of the VFA. The hot plate was preheated to 52.5°C. Once heated, each animal was placed in a cylindrical tube on the hot plate, and the latency to lick its hind paw or any overt withdrawal behavior (e.g., attempting to jump out of the tube) was recorded (Ingram et al., Neuropsychopharmacology 2007;32(3):600-6; Gunn et al., J Pain 2011;12(2):222-7; Hestehave et al., Lab Anim 2016;51(3):264-72). For safety reasons, the maximum time the rats spent on the hot plate was limited to 30 s. After a 15-min break, the exercise was repeated.

[0290] Full testing of pain perception continued for 28 days for each animal, as described in Table E1 below.

[0291] [Table 2]

[0292] Figures 1A and 1B show the results of a VFA comparing the effect of formalin injection (day 0) on withdrawal thresholds (i.e., mechanical allodynia) in the contralateral (Figure 1A) and ipsilateral (Figure 1B) paws. Withdrawal thresholds in both groups were initially high at baseline (BL) and significantly reduced after formalin injection (FBL). Following psilocybin or saline injection on day 1, a significant acute difference in withdrawal thresholds was observed in both the contralateral (Figure 2A) and ipsilateral (Figure 2B) paws of psilocybin-injected rats, demonstrating the analgesic properties of psilocybin administration. In the case of other analgesics (e.g., NSAIDs, opioids), this response rapidly disappears after drug clearance from the circulation. In contrast, rats administered intravenous psilocybin showed reduced pain sensitivity in both the contralateral (Figures 3A-3C) and ipsilateral paws (Figures 3D-3F) for at least 2 weeks after a single psilocybin administration, demonstrating sustained analgesia. A statistically significant increase in withdrawal threshold in the contralateral paw was observed over a 3-week period after a single psilocybin administration (Figure 2A).

[0293] Similar results were observed for heat sensitivity, as indicated by the HPA results, as shown in Figure 4A. Following the acute recovery response in escape latency after psilocybin administration, the enhanced pain sensitivity response persisted for at least 4 weeks compared to saline controls (Figures 4B-4D), demonstrating sustained analgesic effects.

[0294] The results demonstrated the acute and sustained effects of intravenous administration of hallucinogens such as psilocybin on mechanical and thermal pain sensitivity. The results showed long-lasting improvements in pain sensitivity for at least up to four weeks in an animal model of nociceptive pain after a single dose of hallucinogens such as psilocybin. This effect was observed in the uninjected contralateral paw, which is closely associated with nociceptive pain. The results support the utility of administering hallucinogens to treat and ameliorate diseases and disorders related to pain perception, such as nociceptive pain disorders, e.g., fibromyalgia (FM).

[0295] Example 2 Administration of psilocybin and psychotherapy in subjects with fibromyalgia Current fibromyalgia (FM) management strategies and pharmacotherapy offer only modest benefits and impose a substantial side effect burden, indicating a need for therapies with improved efficacy and safety. The therapeutic efficacy and safety of two separate oral doses of psilocybin in combination with psychotherapy will be evaluated in a clinical study in human subjects with FM.

[0296] A. Inclusion Criteria Inclusion criteria for FM disease characteristics include, but are not limited to, a diagnosis of FM for at least 3 months or longer, experiencing FM symptoms for at least 1 year, or a score of ≥ 13 on the 2016 FM Survey Scale for at least 1 year or longer. Subjects are eligible for inclusion in the study only if they meet all inclusion criteria.

[0297] B. Exclusion criteria Prospective subjects will be excluded from the study based on certain criteria, including, but not limited to, physiological and psychological medical conditions, certain previous and / or concomitant therapies, and diagnostic assessments made during subject screening. If any of the exclusion criteria apply, the prospective subject will be excluded.

[0298] C. Research design Subjects who have FM or have had symptoms of FM for at least one year and meet the 2016 FM Study criteria for FM will be enrolled in the clinical study.

[0299] The total duration of individual study participation is approximately 8 months (Figure 5). The study includes a screening period of up to 28 days prior to study initiation (Visit 1; Days -28 to -1), a baseline assessment (Visit 2; Days 1 to 7), a one-week preparatory period with two therapy sessions (Visits 3 and 4; Days 11 and 18), and a follow-up administration period (Visits 5 to 9; Days 22 to 37). Two psilocybin doses are administered to subjects, two weeks apart. After the final psilocybin dose is administered, a two-week consolidation period begins (Visits 10 to 12; Days 43 to 57). End-of-treatment (EOT) assessments (Visit 13; Day 64) are conducted one week after the final consolidation session. Follow-up assessments are conducted 3 and 6 months after the second, final psilocybin dose. Scheduling flexibility of at least ±3 days is allowed for each visit, beginning with Visit 3, the start of preparatory therapy.

[0300] Patient-reported outcomes will be assessed from day 0 through the final 6-month follow-up visit. The end of the study will be defined as the date of the last study subject's final visit. Subjects will be considered to have completed the study if all phases of the study, including the 6-month follow-up visit, are completed. Flexibility in scheduling study visits and sessions will be allowed to account for unexpected absences, as there is no reason to believe that minor differences in the timing of study visits and measurements will have an adverse effect on subjects or the efficacy of the study.

[0301] 1. Screening (Visit 1; Day -28 to Day -1) Candidates who express interest in participating in the study are pre-screened either electronically or by telephone. Potential subjects are interviewed to determine if they meet the inclusion / exclusion criteria. Potential subjects are invited to an in-person screening visit. An informed consent process may occur either electronically prior to the scheduled screening visit or during the screening visit before any assessments are performed.

[0302] Once candidates have been pre-screened for interest and meet all eligibility pre-screening measures, subjects complete a screening visit (Visit 1). Inclusion and exclusion criteria are confirmed. The Structured Clinical Interview for DSM-5 (SCID-5) and SCID-5-PD (for personality disorders) are administered to determine whether subjects meet criteria for specific psychiatric disorders, such as schizophrenia, other psychotic disorders, bipolar I or II disorder, or severe alcohol, tobacco, or other substance use disorders, that would lead to exclusion from the study. Demographic information and medical history are also assessed.

[0303] At this visit and each subsequent visit, previous and concomitant medications will be assessed. At this initial visit, physical and physiological characteristics will be assessed, including, for example, a 12-lead electrocardiogram (ECG), a pregnancy test for women of childbearing potential or a follicle stimulating test (FSH) in postmenopausal women, urine drug and breath alcohol tests, and vital signs throughout the study. Subject-reported outcomes will be collected, including responses to the 2016 Fibromyalgia (FM) Survey, the Patient Health Questionnaire Depression Scale (PHQ-8), and the Columbia-Suicide Severity Rating Scale (C-SSRS). Because new onset of suicidal ideation is considered an adverse event (AE), response to the C-SSRS will be assessed at each visit up to the 6-month follow-up.

[0304] 2. Baseline pain phenotyping (Visit 2; Days 1-7) During the second study visit, subjects undergo a rigorous pain phenotyping assessment, referred to herein as deep phenotyping, which serves as a baseline assessment for comparison with subsequent assessments. AEs are assessed and reported via applicable pathways at each visit until the end of active treatment (End of Treatment; Visit 13), when the final deep phenotyping assessment is completed. Deep phenotyping includes a set of validated subject-reported outcomes related to pain and quality of life. Self-report surveys include, for example, the Numeric Rating Scale (NRS), Daily Pain Diary (0-10), Sleep-Related Disorder 8b, Sleep-Related Disorder 4a, painDETECT, the Catastrophizing Scale from the Pain Coping Strategies Questionnaire, Chronic Pain Acceptance Questionnaire-8 (CPAQ-8), C-SSRS, snoring, fatigue, observed apnea, blood pressure, body mass index, age, neck circumference, and gender (STOP-Bang), the 2016 FM Survey Scale, Positive and Negative Affect Score (PANAS) Short Form (State), Life Events Checklist, Complex Multi-symptom Inventory (CMSI), and Patient Reported Outcomes Measurement Information System 29-item profile measure (PROMIS-29+2).

[0305] From this initial deep phenotyping session until the end-of-treatment (EOT) visit, subjects complete a daily electronic pain diary recording their pain level on a 0-10 scale on the Pain Intensity Numerical Rating Scale (PI-NRS). Each evening, subjects receive a text or email containing the pain diary questions. If subjects do not respond within two hours, a reminder text or email is sent. Response options close at midnight. Subjects who miss a day are contacted the next day to be reminded to complete their daily diary. The self-reported NRS in the daily pain diary is assessed at each visit until the EOT visit, during which the final deep phenotyping assessment is completed.

[0306] Neurological and other physiological assessments are also performed during deep phenotyping. Neurological assessments include, for example, functional MRI (fMRI) and electroencephalography (EEG). Quantitative sensory testing (QST) is performed, including tasks related to pain pressure threshold and pain catastrophizing, the tendency to exaggerate the threat value of painful stimuli, and to feel helpless in the experience. Subjects are provided with a means for wrist actigraphy, a non-invasive method for monitoring rest-activity cycles, and actigraphy measurements are assessed at each visit until EOT. Vital signs and past and concomitant medication surveys are determined at baseline and throughout the study.

[0307] 3. Preparation Session (Visits 3 and 4; Days 11 to 18 (± 3 days)) Subjects begin their psilocybin-psychotherapy intervention by preparing for psilocybin administration. Subjects undergo eight hours of preparatory therapy in weeks 1 and 2 (four hours per preparatory session). During these preparatory visits, subjects build rapport with two designated therapist facilitators, gain understanding of what will occur during the administration session, and build comfort and understanding around the physical space in which the psilocybin sessions will occur.

[0308] 4. Psilocybin administration sessions (visits 5-9; days 22-37 (± 3 days)) Subjects receive two doses of psilocybin (15 mg and 25 mg) separated by a two-week interval. Psilocybin sessions last approximately eight hours and are supervised by two therapist facilitators. During the psilocybin administration sessions, subjects orally ingest psilocybin capsules at a fixed dose of 15 mg during the first session or a fixed dose of 25 mg during the second session. The 25 mg fixed dose of psilocybin approaches the circulating psilocin levels produced when psilocybin is administered at a dose of 0.3 mg / kg (Brown et al., Clin Pharmacokinet. 2017;56(12):1543-1554 and Dahmane et al., Clin Pharmacol Drug Dev. 2021;10(1):78-85). If the subject or investigator determines that a higher dose may not provide further benefit, the 15 mg dose may be repeated during the second session.

[0309] Sessions are conducted in a room designed to be quiet, comfortable, and aesthetically pleasing. Subjects are encouraged to wear eyeshades and listen to a music program via headphones during drug exposure to help direct their attention inward. Audio and video recordings of each session are made. After the effects of psilocybin subside, subjects complete the Mystical Experiences Q-30, Challenging Experiences Q, and Psychological Insights Q questionnaires. The PROMIS-29+2 is administered at each dosing session. Patients complete the Patient Global Impression of Change (PGI-C) questionnaire after the first dose of psilocybin and at each subsequent visit up to the six-month follow-up.

[0310] To ensure subject safety and comfort, two follow-up visits will occur after the first administration session (one day and one week after administration). An additional follow-up session will occur one day after the second psilocybin administration. Participants will be asked to process their experiences at home by writing a reflection about their experience during the administration session. This reflection will be discussed during the follow-up meeting.

[0311] 5. Consolidation period (visits 10-12; days 43-57 (± 3 days) One week after the second and final administration session, subjects complete three one-hour integration sessions over a three-week period. To facilitate integration, psychotherapy is performed, focusing on helping subjects gain insight and understanding from their experiences. Sleep is assessed during the integration period by wrist actigraphy and responses to the 2016 FM survey criteria and PGI-C.

[0312] 6. End of treatment (visit 13; day 64 (± 3 days) Subjects will complete their final deep phenotyping session during the EOT visit, which will occur approximately 4 weeks after the final psilocybin dose. Assessments will include those made during the initial deep phenotyping session, which are important for evaluation of the primary, secondary, and exploratory endpoints. Subject-documented NRS will be collected from electronic diaries, vital signs will be taken, and concomitant medications will be reported. All AEs will be documented and reported via appropriate applicable channels.

[0313] 7. Follow-up period (visits 14 and 15; days 120 and 204 (± 7 days) Subjects will complete electronic subject-reported outcome questionnaires 3 and 6 months after the final psilocybin dose to examine the durability of changes in primary, secondary, and exploratory endpoints. Assessments will include the C-SSRS, 2016 FM Survey Criteria, PANAS Short Form, PGI-C, Sleep-Related Disorders 8b, Sleep-Related Disorders (4a), CPAQ-8, painDETECT, PANAS Short Form (State), Catastrophizing, Psychological Insight Q, and PROMIS-29+2. Neurological assessments, including fMRI, EEG, and QST, will also be performed during these visits. A qualitative written assessment will be completed at the 3-month follow-up visit to determine subjective experience.

[0314] D. Study Endpoints The study's endpoint is to evaluate the safety of oral psilocybin in combination with psychotherapy to treat chronic pain symptoms in subjects with FM. Safety assessments are always performed before efficacy assessments at each visit. Safety is assessed during psilocybin administration sessions and across trials.

[0315] Safety is assessed during the administration session by measuring the subject's vital signs, such as blood pressure (BP), pulse, and heart rate (HR), as well as dissociation. Vital signs, such as BP and HR, are measured before psilocybin administration and 30, 60, 90, 120, 180, 240, 300, and 360 minutes after administration. Prior to BP and pulse measurements, the subject is allowed to rest for at least 5 minutes in a quiet, noise-free environment. BP and pulse measurements are assessed using fully automated devices. Manual techniques are used only if automated devices are unavailable. At the same time points as BP and HR measurements, the session monitor completes a monitoring rating form that includes rating or scoring several dimensions of the subject's behavior and mood, including behaviors, signs, and reported symptoms, such as calmness, yawning, nausea / vomiting, speech volume, anxiety, drowsiness, crying, restlessness, visual changes, euphoria, and the presence / intensity of feelings of unreality.

[0316] Safety throughout the trial will be assessed by monitoring AEs, ECG measurements, and suicidality. All AEs will be collected and reported from the time of signing the informed consent form until EOT (day 64). Free-response and non-leading verbal questioning of subjects is the preferred method for inquiring about the occurrence of AEs. A baseline ECG and pregnancy test will be performed to determine eligibility. Physical and laboratory examinations, including urine drug and breath alcohol tests, will be performed throughout the study. A pregnancy test (for all menstruating women or adolescents) will be performed throughout the study to determine continued eligibility.

[0317] The C-SSRS is used to assess the severity of suicidal ideation at each clinical visit. The C-SSRS is used to assess the severity and intensity of suicidal ideation, the type of suicidal behavior, and the lethality of suicide attempts at set time points and over a period of time typical of a randomized controlled trial. It was developed by researchers at Columbia University and is widely used in clinical and research settings.

[0318] Other endpoints include assessing the clinical usefulness or efficacy of oral psilocybin in combination with psychotherapy. Efficacy endpoints include changes in total worst pain score, pain interference, sleep, chronic pain acceptance (CPAQ response), and Patient Global Impression Scale change (PGI-C response). Pain score, pain interference, sleep disturbance, chronic pain acceptance, and Patient Global Impression change were selected as secondary measures given their association with symptom management of FM (Clauw, JAMA. 2014;311(15):1547-1555; Williams, Arthritis Care Res. 2011;63 Suppl 11:S86-S97. doi:10.1002 / acr.20531; Kratz et al., Ann Behav Med. 2007;33(3):291-301; Farrar et al., Pain. 20001;94(2):149-158).

[0319] Change in Worst Pain Score Total: Self-reported pain assessments are recorded in daily electronic pain diaries throughout the study as described herein. The baseline worst pain score total is compared to the worst pain score total determined during the week prior to the EOT visit (Days 57-63). Therapeutic benefit is based on a comparison of the baseline score with the final score (NRS 0-10). A 30% or 2-point reduction in the worst pain score total at either exercise or rest is considered a clinically significant response (Farrar et al., Pain. 2001;94(2):149-158).

[0320] Pain Interference: In addition to potential therapeutic benefit for chronic pain, the effects of psilocybin and psychotherapy on pain interference and chronic pain acceptance will also be assessed. Pain interference is the degree to which pain affects important aspects of an individual's life, such as social, cognitive, and physical activities. Pain interference will be assessed using the 4-item PROMIS Pain Interference Scale from the PROMIS-29+2 Profile v2.1 (PROPr), available at HealthMeasures.net.

[0321] Sleep: Improvement or deterioration of sleep and clinical status was also assessed. Sleep disturbances were measured using the PROMIS Sleep Disorders 8b Short Form. This measure includes assessment of sleep quality, perceived ability to fall asleep and stay asleep, sleep satisfaction, and sleep depth. This measure partially overlaps with PROMIS 29+2 PROPr, and items were combined where appropriate.

[0322] Chronic Pain Acceptance: The 8-item Chronic Pain Acceptance Questionnaire (CPAQ-8) is a validated measure that assesses activity engagement and acceptance of pain (e.g., recognizing that trying to avoid or control pain can be maladaptive to chronic pain) (Fish et al., Pain. 2010;149(3):435-443). Subjects rate items on a 0-10 scale, with 0 being "never" and 10 being "always true."

[0323] Patient Global Impression of Change: The Patient Global Impression of Change (PGIC) is a questionnaire that measures patient response to medical interventions using a 7-point Likert scale ranging from "much worse" to "much better" and has been used as a secondary outcome in many pain clinical trials (Dworkin et al., Pain 2005;113(1-2):9-19 and Dworkin et al., Pain 2008;9(2):105-21).

[0324] Additional study endpoints include subject-reported outcomes and observer-reported outcomes. Subject-reported outcomes will be determined from responses to various questionnaires, surveys, and other forms. Various aspects of pain, FM symptoms, fatigue, anxiety, depression, catastrophizing, affect, and cognitive function will be assessed. A number of treatment-specific patient-reported outcomes will be assessed, including mystical experiences, psychological insights, and challenging experiences.

[0325] The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the described compositions and methods will become apparent from the description and teachings set forth herein. Such variations can be made without departing from the true scope and spirit of the present disclosure, and are intended to be included within the scope of the present disclosure.

Claims

1. A method of treating fibromyalgia (FM), comprising administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state.

2. A method of treating fibromyalgia (FM), comprising orally administering to a subject suffering from one or more symptoms of FM one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state.

3. 3. The method of claim 1 or 2, further comprising providing one or more integration sessions to the subject after emerging from the dissociated state.

4. 4. The method of any one of claims 1 to 3, further comprising assessing in the subject one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators before and / or after administration of one or more doses of psilocybin.

5. 1. A method of treating fibromyalgia (FM), comprising: administering one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state to a subject suffering from one or more symptoms of FM; providing one or more integration sessions to the subject after emerging from the dissociative state; and assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related, and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin or its active metabolite. A method comprising:

6. A method for treating fibromyalgia (FM), comprising assessing one or more indicators related to one or more symptoms of FM, the dissociative state, treatment outcome, safety, and / or related to the subject, in a subject suffering from one or more symptoms of FM, before and / or after administration of one or more doses of psilocybin or its active metabolite effective to induce a dissociative state, and one or more integration sessions after emergence from the dissociative state induced by the one or more doses of psilocybin or its active metabolite.

7. 1. A method of treating fibromyalgia (FM), comprising: administering one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state to a subject suffering from one or more symptoms of FM; providing one or more integration sessions to the subject after emerging from the dissociative state; and assessing one or more indicators in the subject before and / or after administration of one or more doses of psilocybin or an active metabolite thereof. wherein the one or more indicators include one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical indicator.

8. Prior to administering one or more doses of psilocybin, subjects are screened for the following exclusion parameters: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) previous adverse effects from psilocybin 8. The method of claim 1, further comprising assessing one or more of:

9. 10. The method of claim 8, further comprising identifying the subject for treatment with psilocybin if the subject does not meet any of the exclusion parameters.

10. 1. A method of identifying a subject for treating fibromyalgia (FM) with psilocybin or an active metabolite thereof, comprising: (a) In subjects suffering from one or more symptoms of FM, the following exclusion parameters: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) Previous adverse effects from psilocybin or its active metabolites evaluating one or more of: (b) if the subject does not meet any of the exclusion parameters, identifying the subject for treatment with one or more doses of psilocybin or an active metabolite thereof. A method comprising:

11. 1. A method of identifying a subject for treatment of fibromyalgia (FM) with one or more doses of psilocybin or an active metabolite thereof, comprising: Subjects are evaluated for the following exclusion parameters: (1) previous or concomitant medication use; (2) hypertension and / or tachycardia; (3) occurrence of epilepsy; (4) occurrence of schizophrenia spectrum or other psychotic disorder; (5) moderate or severe alcohol or drug use disorder; and (6) Previous adverse effects from psilocybin or its active metabolites If none of the above conditions is met, identifying the subject suffering from one or more symptoms of FM for treatment.

12. administering to the identified subject one or more doses of psilocybin or an active metabolite thereof effective to induce a dissociative state; and providing the subject with one or more integration sessions after emerging from the dissociative state.

12. The method of claim 10 or 11, further comprising:

13. 13. The method of any one of claims 10 to 12, further comprising assessing one or more symptoms of FM, dissociative state, treatment outcome, safety-related and / or subject-related indicators in the subject before and / or after administration of one or more doses of psilocybin or its active metabolite.

14. 14. The method of any one of claims 1 to 13, wherein the administering step is by oral administration or intravenous administration.

15. 15. The method of any one of claims 1 to 14, wherein the administering step is by oral administration.

16. 15. The method of any one of claims 1 to 14, wherein the psilocybin or an active metabolite thereof is psilocybin.

17. 17. The method of any one of claims 4 to 9 and 13 to 16, wherein the one or more indices comprise observer-rated parameters, subject-reported parameters and / or clinical indices.

18. 18. The method of any one of claims 4 to 9 and 13 to 17, wherein one or more indicators are assessed prior to administration as a baseline measure and after administration as an outcome measure, and the change between the baseline measure and the outcome measure is determined.

19. 19. The method of any one of claims 4 to 9 and 13 to 18, wherein the one or more indicators include one or more of a fibromyalgia survey score, a pain interference assessment, a sleep assessment, a chronic pain acceptance assessment, or an assessment of a clinical indicator.

20. 20. The method of any one of claims 4 to 9 and 13 to 19, wherein the one or more indicators comprise one or more of: a Fibromyalgia Survey Score, optionally assessed by the 2016 Fibromyalgia Survey Questionnaire (FSQ); a Pain Intensity Numerical Rating Scale (PI-NRS), optionally assessed by the 11-item PI-NRS scale; a PROMIS Pain Interference Assessment; a PainDETECT Questionnaire (PD-Q) assessment; a Chronic Pain Acceptance Assessment, optionally measured by the Chronic Pain Acceptance Questionnaire (CPAQ-8) assessment; a Pain Interference Assessment, optionally measured by the 4-item PROMIS Pain Interference Scale; a Composite Medical Symptom Inventory (CMSI); and a Brief Pain Inventory (BPI), optionally measured by the Interference subscale (BPI-IS).

21. 21. The method of any one of claims 4 to 9 and 13 to 20, wherein the one or more indicators include a fibromyalgia survey score.

22. 22. The method of any one of claims 7 and 19 to 21, wherein the fibromyalgia survey score comprises a rating of the 2016 Fibromyalgia Survey Questionnaire (FSQ).

23. 23. The method of any one of claims 4 to 9 and 13 to 22, wherein the one or more indices comprises the Pain Intensity Numerical Rating Scale (PI-NRS) 11-item pain scale.

24. 24. The method of any one of claims 4 to 9 and 13 to 23, wherein the one or more indicators include one or more of a sleep disturbance assessment, optionally measured by the PROMIS Sleep-Related Disorders 4a assessment; the PROMIS Sleep Disorders 8b assessment; and the STOP-Bang questionnaire.

25. 25. The method of any one of claims 4 to 9 and 13 to 24, wherein the one or more indicators include one or more of the following: a PROMIS-29+2 profile, optionally a v2.1 Multi-Domain Assessment; a Positive and Negative Affect Score (PANAS) assessment; a Patient Global Impression-Change (PGI-C) scale assessment; and a Patient Acceptable Symptom Status (PASS) questionnaire.

26. 26. The method of any one of claims 4 to 9 and 13 to 25, wherein the one or more indicators include the PROMIS-29+2 Profile v2.1 Multi-Domain Assessment.

27. 27. The method of any one of claims 4 to 9 and 13 to 26, wherein the one or more indicators include one or more of the following: Patient Health Questionnaire Depression Scale-8 (PHQ-8); Columbia-Suicide Severity Rating Scale (C-SSRS); Clinical Global Impression-Improvement (CGI-I) scale; Emotional Breakthrough Inventory (EBI); Acceptance and Action Questionnaire-II (AAQ-II); Patient Global Impression-Improvement (PGI-I); Hospital Anxiety and Depression Scale (HADS); Life Events Checklist (LEC), Multidimensional Experiential Avoidance Questionnaire (MEAQ), and Brief Experiential Avoidance Questionnaire (BEAQ).

28. 28. The method of any one of claims 4 to 9 and 13 to 27, wherein the one or more indicators include the Patient Health Questionnaire Depression Scale-8 (PHQ-8).

29. 29. The method of any one of claims 4 to 9 and 13 to 28, wherein the one or more indicators include one or more of: a subject-reported mystical experience rating, optionally measured by the Mystical Experiences Questionnaire (MEQ30); a subject-reported challenging experience rating, optionally measured by the Challenging Experiences Questionnaire (CEQ27); a subject-reported psychological insight rating, optionally measured by the Psychological Insight Questionnaire (PIQ); and a subject-reported qualitative documented assessment.

30. 30. The method of any one of claims 4 to 9 and 13 to 29, wherein the one or more indicators include a therapist-reported monitoring rating scale, optionally measured using a form of the monitoring rating scale (MRS).

31. 31. The method of any one of claims 4 to 9 and 13 to 30, wherein the one or more indicators include a quantitative sensory test (QST).

32. 32. The method of claim 31 , wherein QST is measured using a cuff pressure pain assessment, optionally using cuff-PPT, cuff-pain40, cuff-pain50, and / or cuff-tolerance.

33. 32. The method of any one of claims 4 to 9 and 13 to 31, wherein the one or more indicators include a visual hypersensitivity assessment.

34. 34. The method of any one of claims 4 to 9 and 13 to 33, wherein the one or more indicators include an electroencephalogram (EEG).

35. 34. The method of any one of claims 4 to 9 and 13 to 33, wherein the one or more indicators include QST and EEG, and the QST and EEG are performed simultaneously.

36. 36. The method of any one of claims 4 to 9 and 13 to 35, wherein the one or more indicators include functional magnetic resonance imaging (fMRI).

37. 37. The method of claim 36, wherein the fMRI comprises one or more of structural MRI; resting-state fMRI; proton magnetic resonance spectroscopy (1H-MRS) in the right anterior insula; fMRI using experimental pain induced by tonic cuff pressure; fMRI using cuff pressure pain in a block design; and diffusion tensor imaging (DTI).

38. 38. The method of any one of claims 4 to 9 and 13 to 37, wherein the one or more metrics include one or more of: wrist actigraphy, optionally wrist actigraphy used to measure sleep onset latency; sleep onset awakening; total sleep time; and sleep efficiency (%).

39. 39. The method of any one of claims 4 to 9 and 13 to 38, wherein the one or more indicators include an electrocardiogram (ECG).

40. 39. The method of any one of claims 4 to 9 and 13 to 38, wherein one or more indicators are measured during one or more integration sessions.

41. The exclusion parameter is use of prior or concomitant medications, and subjects are on the following prior or concomitant medications: Regular use of psychoactive prescription medications, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; regular use of medications with primary centrally acting serotonergic effects or monoamine oxidase inhibitors (MAOIs); use of hallucinogen in the past 6 months; concomitant use of sildenafil or tadalafil; concomitant use of alcohol with a blood alcohol content greater than 0.02%; medication with antihypertensives; UGT1A9 inhibitors, 1A10 inhibitors, regorafenib, rimampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasirox, ginseng; aldehyde dehydrogenase inhibitors, alcohol dehydrogenase inhibitors chronic use of prescription psychoactive drugs, opioids, tramadol, or benzodiazepines; concomitant use of antidepressants; chronic use of medications with primary centrally acting serotonergic effects, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs), or use of serotonergic dietary supplements, 5-hydroxytryptophan, or St. John's wort.

41. The method of any one of claims 8 to 40, wherein the subject is identified for treatment if the subject is not using any of the methods described above.

42. 42. The method of any one of claims 8 to 41, wherein the exclusion parameter is hypertension, and the subject is identified for treatment if they do not exhibit a systolic blood pressure greater than or about 139 mmHg, or a diastolic blood pressure greater than or about 89 mmHg, optionally measured as the average of three readings; and / or the exclusion parameter is tachycardia, and the subject is identified for treatment if they do not exhibit a heart rate (bpm) greater than or about 90 beats per minute.

43. 43. The method of any one of claims 6 to 42, wherein the exclusion parameter is the occurrence of epilepsy and if the subject does not have epilepsy, the subject is identified for treatment.

44. 44. The method of any one of claims 6 to 43, wherein the exclusion parameter is occurrence of a psychotic disorder and the subject is identified for treatment if the subject does not have schizophrenia spectrum or other psychotic disorder meeting DSM-5 criteria, major depressive disorder with psychotic features, or bipolar I or bipolar II disorder.

45. 45. The method of any one of claims 6 to 44, wherein the exclusion parameter is moderate or severe alcohol or drug use disorder, and the subject is identified for treatment if they do not have a moderate or severe alcohol or drug use disorder that meets DSM-5 criteria.

46. 46. ​​The method of any one of claims 6-45, wherein the exclusion parameter is a previous adverse effect from psilocybin or its active metabolite, and the subject is identified for treatment if the subject has not had a previous adverse effect from psilocybin or its active metabolite.

47. 47. The method of any one of claims 18 to 46, wherein the subject exhibits an improvement in one or more indicators between the baseline measure and the outcome measure.

48. 48. The method of any one of claims 1 to 47, wherein the subject undergoing treatment shows improvement in one or more symptoms of FM or one or more symptoms of FM are alleviated.

49. 49. The method of any one of claims 1 to 48, wherein the subject undergoing treatment shows an improvement selected from among one or more of the following: Fibromyalgia Survey score, pain interference assessment, sleep assessment, chronic pain acceptance assessment, or clinical index assessment.

50. 50. The method of any one of claims 1 to 49, wherein the subject undergoing treatment shows improvement selected from one or more of: Fibromyalgia Survey score, optionally as assessed by the 2016 Fibromyalgia Survey Questionnaire (FSQ); Pain Intensity Numerical Rating Scale (PI-NRS), optionally as assessed by the 11-item PI-NRS scale; PROMIS Pain Interference Assessment; PainDETECT Questionnaire (PD-Q); Chronic Pain Acceptance Assessment, optionally as measured by the Chronic Pain Acceptance Questionnaire (CPAQ-8); and Pain Interference Assessment, optionally as measured by the 4-item PROMIS Pain Interference scale.

51. 51. The method of any one of claims 1-50, wherein the one or more doses of psilocybin or an active metabolite thereof comprises a first dose of psilocybin.

52. 52. The method of claim 51, wherein the first dose is at or about 10 mg to at or about 50 mg of psilocybin.

53. 53. The method of claim 51 or 52, wherein the first dose is at or about 15 mg of psilocybin.

54. 54. The method of any one of claims 1-53, wherein the one or more doses of psilocybin comprise two or more doses of psilocybin.

55. 55. The method of any one of claims 1-54, wherein the one or more doses of psilocybin include a second dose of psilocybin.

56. 56. The method of claim 55, wherein the second dose is at or about 20 mg to 50 mg or about 50 mg of psilocybin.

57. 57. The method of claim 55 or 56, wherein the second dose is at or about 25 mg of psilocybin.

58. 56. The method of claim 55, wherein the second dose is at or about 10 mg to 20 mg or about 20 mg of psilocybin.

59. 59. The method of claim 55 or 58, wherein the second dose is at or about 15 mg of psilocybin.

60. 60. The method of any one of claims 55 to 59, wherein the second dose is administered 12 days, or about 12 days, to 16 days, or about 16 days, after the first dose.

61. 61. The method of any one of claims 55 to 60, wherein the second dose is administered 14 days or about 14 days after the first dose.

62. 62. The method of any one of claims 1-61, further comprising providing one or more integration sessions to the subject after the one or more doses of psilocybin.

63. 63. The method of claim 62, wherein the one or more integration sessions are provided at or about 3, 4, and / or 5 weeks after administration of the first dose of psilocybin.

64. 64. The method of claim 62 or 63, wherein the one or more integration sessions are provided at or about 1, 2, and / or 3 weeks after administration of the second dose of psilocybin.

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