Treatment of binge eating disorder using psychostimulants

Abstract

A method for treating binge eating disorder (BED) or one or more symptoms thereof is provided, including the administration of a psychoactive drug such as silibinin and related uses of said psychoactive drug. In some aspects, the present disclosure also relates to a method for identifying a subject for the treatment of BED by administration of a psychoactive drug. In some aspects, said treatment also includes psychotherapy. In some aspects, the subjects undergoing said treatment are evaluated on various metrics, such as the results of observer assessment and subject self-report, biological and clinical indicators, and combinations thereof.

Description

Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 350,393, filed on June 8, 2022, entitled "Treatment of Binge Eating Disorder with Psychedelics", and U.S. Provisional Application No. 63 / 437,347, filed on January 5, 2023, entitled "Treatment of Binge Eating Disorder with Psychedelics", the contents of which are hereby incorporated by reference in their entirety. Field

[0002] In some aspects, the present disclosure relates to methods of treating binge eating disorder (BED) or one or more symptoms thereof, including administration of a psychedelic such as psilocybin and related uses of said psychedelic. In some aspects, the present disclosure also relates to methods of identifying subjects for treatment of BED by administration of a psychedelic. In some aspects, the treatment includes psychotherapy. In some aspects, subjects undergoing the treatment are evaluated on various metrics such as results of observer assessment and subject self - reporting, biological and clinical indicators, and combinations thereof. Background

[0003] Binge eating disorder (BED) is the most common eating disorder and is associated with obesity and mental or behavioral comorbidities (including depression, anxiety, compulsive and impulsive behaviors). Although drug therapy and other approaches are available for the treatment of BED, existing drug therapies have only marginal effectiveness and may be associated with side effects. There is a need for improved treatment approaches. Embodiments are provided that meet such needs. Summary

[0004] Provided herein is a method of treating binge eating disorder (BED), which includes administration of a psychedelic such as psilocybin or its active metabolite and use of a psychedelic such as psilocybin in such treatment. In some aspects, the provided embodiments also include psychotherapy or its active metabolite.

[0005] Provided herein is a method for treating binge eating disorder (BED), which comprises orally administering once or multiple times to a subject suffering from one or more symptoms of BED, psilocybin or its active metabolite effective in inducing a dissociative state; providing to the subject one or more integration sessions after recovery from the dissociative state; and evaluating the subject for one or more metrics before and / or after administering psilocybin or its active metabolite once or multiple times. In any of the provided embodiments, the one or more metrics are related to one or more symptoms of BED, dissociative state, treatment outcome, and safety, and / or related to the subject.

[0006] Provided herein is a method for treating binge eating disorder (BED), which comprises evaluating the subject for one or more metrics before, during, and / or after administering psilocybin or its active metabolite once or multiple times in a subject suffering from one or more symptoms of BED, in which one or more integration sessions are provided after recovery from a dissociative state induced by once or multiple times of oral administration of psilocybin or its active metabolite effective in inducing a dissociative state. In any of the provided embodiments, one or more symptoms of BED, dissociative state, treatment outcome, and / or safety related to the subject are evaluated before and / or after administering psilocybin or its active metabolite once or multiple times.

[0007] In any of the provided embodiments, the one or more metrics are selected from the frequency of binge eating episodes, Binge Eating Scale (BES), binge eating episodes per day, anxiety about food, depressive state related to eating behavior, depressive state related to weight management, Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, waist circumference, Body Mass Index (BMI), general anxiety, anxiety about food, self - awareness, confidence, genuine well - being, binge eating cravings, weight, eating behavior, Hospital Anxiety and Depression Scale (HADS) for anxiety or depressive state related to hospitalization, Patient Global Impression - Improvement (PGI - I), and Acceptance and Action Questionnaire - II (AAQ - II).

[0008] Provided herein is a method for treating binge eating disorder (BED), which comprises orally administering to a subject suffering from one or more symptoms of BED, psilocybin or an active metabolite thereof, one or more times, in an amount effective to induce a dissociative state; providing to the subject one or more integration sessions after recovery from the dissociative state; and evaluating the subject for one or more metrics before and / or after administering psilocybin or an active metabolite thereof one or more times. In any of the provided embodiments, the one or more metrics are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), binge eating episodes per day, anxiety about food, depression related to eating behavior, depression related to weight management, Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, waist circumference, body mass index (BMI), general anxiety, anxiety about food, self - awareness, confidence, genuine well - being, appetite for overeating, weight, eating behavior, Hospital Anxiety and Depression Scale (HADS), Patient Global Impression - Improvement (PGI - I), and the Acceptance and Action Questionnaire - II (AAQ - II).

[0009] Provided herein is a method for treating binge eating disorder (BED), which comprises evaluating the subject for one or more metrics before, after, or both before and after one or more administrations of silibinin or its active metabolite, to a subject suffering from one or more symptoms of BED, after recovery from a dissociative state induced by one or more oral administrations of silibinin or its active metabolite effective to induce a dissociative state, and providing one or more integration sessions. In any of the provided embodiments, the one or more metrics are selected from the frequency of binge episodes, Binge Eating Scale (BES), binge episodes per day, food-related anxiety, depressive state related to eating behavior, depressive state related to weight management, Clinical Global Impression - Improvement (CGI-I), interest in the intake of trigger foods, waist circumference, Body Mass Index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, genuine well-being, binge appetite, weight, eating behavior, Hospital Anxiety and Depression Scale (HADS), Patient Global Impression - Improvement (PGI-I), and Acceptance and Action Questionnaire - II (AAQ-II).

[0010] Provided herein is a method for treating binge eating disorder (BED), which comprises orally administering to a subject suffering from one or more symptoms of BED, one or more times, silibinin or its active metabolite effective to induce a dissociative state; and, after recovery from the dissociative state, providing the subject with one or more integration sessions.

[0011] Provided herein is a method for treating binge eating disorder (BED), which comprises providing one or more integration sessions after recovery from a dissociative state induced by one or more oral administrations of silibinin or its active metabolite effective to induce a dissociative state, to a subject suffering from one or more symptoms of BED.

[0012] In some optional embodiments, the method also includes evaluating the subject for one or more indicators before and / or after administering silibinin or its active metabolite one or more times.

[0013] In some optional embodiments, the one or more indicators are related to one or more BED symptoms, dissociation states, treatment outcomes, and safety, and / or are related to the subject.

[0014] In some optional embodiments, the method also includes evaluating the subject for one or more of the following parameters before administering silibinin or its active metabolite one or more times: (1) risk of suicide, (2) vital signs, (3) incidence of cardiovascular disease, (4) incidence of gastrointestinal disease, (5) incidence of epilepsy, (6) incidence of the schizophrenia spectrum or other psychotic disorders, (7) family history of mental illness, (8) moderate or severe alcohol or drug use disorder, (9) side effects from previous silibinin or its active metabolite, and (10) use of concomitant medications.

[0015] In some optional embodiments, when the subject meets the criteria for the one or more parameters, the method also includes identifying the subject for treatment with silibinin or its active metabolite.

[0016] Provided herein is a method for identifying a subject for treating binge eating disorder (BED) with psilocybin or an active metabolite thereof, which comprises evaluating a subject suffering from one or more symptoms of BED for one or more of the following parameters: (1) risk of suicide, (2) vital signs, (3) incidence of cardiovascular disease, (4) incidence of gastrointestinal disease, (5) incidence of epilepsy, (6) incidence of schizophrenia spectrum or other psychotic disorders, (7) family history of mental illness, (8) moderate or severe alcohol or drug use disorder, (9) side effects due to past psilocybin or an active metabolite thereof, and (10) use of prior medications or concomitant medications; and identifying a subject for treatment with one or more administrations of psilocybin or an active metabolite thereof if the subject meets the criteria for one or more of the parameters.

[0017] Provided herein is a method for identifying a subject for treating binge eating disorder (BED) with one or more administrations of psilocybin or an active metabolite thereof, which comprises identifying a subject suffering from one or more symptoms of BED for treatment with psilocybin or an active metabolite thereof if the subject meets the criteria for one or more of the following parameters evaluated in the subject: (1) risk of suicide, (2) vital signs, (3) incidence of cardiovascular disease, (4) incidence of gastrointestinal disease, (5) incidence of epilepsy, (6) incidence of schizophrenia spectrum or other psychotic disorders, (7) family history of mental illness, (8) moderate or severe alcohol or drug use disorder, (9) side effects due to past psilocybin or an active metabolite thereof, and (10) use of prior medications or concomitant medications; and identifying a subject for treatment with one or more administrations of psilocybin or an active metabolite thereof if the subject meets the criteria for one or more of the parameters.

[0018] In some optional embodiments, the method further includes orally administering to a subject one or more doses of silibinin or its active metabolite effective to induce a dissociative state, and providing one or more integration sessions to the subject after recovery from the dissociative state.

[0019] In some optional embodiments, the method further includes evaluating the subject for one or more metrics before and / or after administering the one or more doses of silibinin or its active metabolite.

[0020] In some optional embodiments, the one or more metrics are related to one or more symptoms of BED, dissociative state, treatment outcome, and safety, and / or pertain to the subject.

[0021] In some optional embodiments, the one or more metrics include parameters of observer evaluation, parameters of subject reporting, and / or clinical metrics.

[0022] In some optional embodiments, the one or more metrics are evaluated as baseline measurements before administration and as outcome measurements after administration. In some optional embodiments, the change between the baseline and outcome measurements is measured.

[0023] In some optional embodiments, the subject shows improvement in the one or more metrics between the baseline and outcome measurements.

[0024] In some optional embodiments, the one or more indicators are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, food-related anxiety, depression related to eating behavior, depression related to weight management, the Clinical Global Impression - Improvement (CGI-I), interest in the intake of trigger foods, waist circumference, body mass index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, genuine well-being, binge eating cravings, weight, eating behavior, the Hospital Anxiety and Depression Scale (HADS), the Patient Global Impression - Improvement (PGI-I), and the Acceptance and Action Questionnaire-II (AAQ-II). In some optional embodiments, the one or more indicators are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, food-related anxiety, depression related to eating behavior, depression related to weight management, the Clinical Global Impression - Improvement (CGI-I), interest in the intake of trigger foods, waist circumference, body mass index (BMI).

[0025] In some optional embodiments, the one or more indicators include the frequency of overeating episodes. In some optional embodiments, the frequency of overeating episodes is measured using a questionnaire regarding eating. In some optional embodiments, the frequency of overeating episodes is measured daily. In some optional embodiments, the one or more indicators include the number of overeating episodes per day. In some optional embodiments, the frequency of overeating episodes is measured over a 28-day period prior to the measurement date. In some optional embodiments, the one or more indicators include the frequency of overeating episodes over a 28-day period prior to the measurement date. In some optional embodiments, the one or more indicators include the frequency of hyperphagia cravings indicated by a sense of loss of eating control. In some optional embodiments, the sense of loss of eating control is measured using a questionnaire regarding eating. In some optional embodiments, the sense of loss of eating control is measured daily. In some optional embodiments, the one or more indicators include the frequency of the sense of loss of eating control per day. In some optional embodiments, the one or more indicators include interest in the intake of trigger foods. In some optional embodiments, the one or more indicators are measured using a questionnaire regarding eating.

[0026] In some optional embodiments, the one or more indicators are selected from the Emotional Breakthrough Inventory (EBI), the Acceptance and Action Questionnaire - II (AAQ-II), the Patient Global Impression of Improvement (PGI-I), and the Hospital Anxiety and Depression Scale (HADS). In some optional embodiments, the one or more indicators are the Hospital Anxiety and Depression Scale (HADS) - anxiety. In some optional embodiments, the one or more indicators are the Hospital Anxiety and Depression Scale (HADS) - depression.

[0027] In some optional embodiments, the one or more indicators are one or more neurophysiological biomarkers selected from resting-state functional connectivity (during feeding and fasting) by functional magnetic resonance imaging (fMRI), task-related functional activation and connectivity (during feeding and fasting) during food cue reactivity tasks by fMRI, voxel-based morphometry (gray and white matter volume / structure) by fMRI, and resting electroencephalogram (EEG).

[0028] In some optional embodiments, the one or more indicators are one or more metabolic biomarkers selected from ghrelin, leptin, adiponectin, insulin, glucose, and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance).

[0029] In some optional embodiments, the one or more indicators are selected from the Monitor Rating Scale (MRS), Mystical Experience Questionnaire (MEQ30), and Challenging Experience Questionnaire (CEQ).

[0030] In some optional embodiments, the one or more indicators are measured during one or more integrated sessions.

[0031] In some optional embodiments, the one or more indicators are selected from vital signs, blood chemistry and hematology tests, urine tests, electrocardiogram (ECG), and Columbia Suicide Severity Rating Scale (C-SSRS). In some optional embodiments, the blood chemistry and hematology tests include Na + , K + , Cl - , HCO3 - , Ca ++ , Mg ++、P, BUN, creatinine, glucose, total bilirubin, albumin, ALT, AST, GGT, CK, LDH, alkaline phosphatase, complete blood count, white blood cell differential count, and platelet count, including measuring one or more levels thereof. In some optional embodiments, the urine test includes one or more measurements of pH, specific gravity, protein, occult blood, glucose, and ketones, as well as microscopic examination of sediment of RBC, WBC, epithelial cells, casts, crystals, and bacteria.

[0032] In some optional embodiments, the parameter is the presence of a gastrointestinal disease. If the subject does not have a gastrointestinal disease that may prevent the absorption of silibinin or its active metabolite orally administered to the subject, the subject meets the criteria of the parameter. In some optional embodiments, the parameter is the incidence of epilepsy. If the subject does not have epilepsy, the subject meets the criteria of the parameter. In some optional embodiments, the parameter is the incidence of schizophrenia spectrum or other psychotic disorders. If the subject does not have a schizophrenia spectrum or other psychotic disorder, major depressive disorder with psychotic features, or bipolar type I or bipolar type II disorder that meets the DSM-5 criteria, the subject meets the criteria of the parameter. In some optional embodiments, the parameter is a family history of psychosis. If the subject does not have a family history of psychosis, the subject meets the criteria of the parameter. In some optional embodiments, the parameter is moderate or severe alcohol use disorder or drug use disorder. If the subject does not have a moderate or severe alcohol use disorder or drug use disorder that meets the DSM-5 criteria, the subject meets the criteria of the parameter. In some optional embodiments, the parameter is a past adverse effect caused by silibinin or its active metabolite. If the subject does not have a past adverse effect caused by silibinin or its active metabolite, the subject meets the criteria of the parameter.In some optional embodiments, the parameter is the use of a prior medication or concomitant medication, and if the subject is not using any of the following prior medications or concomitant medications, the subject meets the criteria of the parameter: UGT1A9 inhibitor, 1A10 inhibitor, regorafenib, rifampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, itraconazole, deferasirox, Korean ginseng, aldehyde or alcohol dehydrogenase inhibitor, disulfiram, amphetamine, buprenorphine, benzodiazepine, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoid (K2), psychoactive prescription drug, opioid, tramadol, or regular use of benzodiazepine; concomitant use of antidepressants, drugs with central serotonergic effects, monoamine oxidase inhibitors (MAOIs), or regular use of selective serotonin reuptake inhibitors (SSRIs), or use of serotonergic dietary supplements, 5-hydroxytryptophan, St. John's wort.

[0033] In some optional embodiments, if the subject meets all the criteria of the parameters (1)-(10), the subject is identified for treatment with psilocybin or its active metabolite.

[0034] In some optional embodiments, the one or more indicators are measured at about 4 weeks and about 12 weeks after one or more administrations of psilocybin or its active metabolite. In some optional embodiments, the one or more indicators are measured at about 4 weeks, about 8 weeks, and about 12 weeks after one or more administrations of psilocybin or its active metabolite. In some optional embodiments, the one or more indicators are measured at about 4 weeks after one or more administrations of psilocybin or its active metabolite.

[0035] In some optional embodiments, in the subjects undergoing treatment, one or more symptoms of BED are improved, or one or more symptoms of BED are alleviated.

[0036] In some optional embodiments, in the subject being treated, one or more improvements are shown, selected from a decrease in the frequency of binge eating episodes, a decrease in the binge eating scale (BES), a decrease in the number of binge eating episodes per day, a decrease in the frequency of the sense of loss of control over eating per day, a reduction in food-related anxiety, a reduction in food-related depression, a reduction in depression related to eating behavior, a reduction in depression related to weight management, an improvement in the overall clinical impression improvement degree (CGI-I), a reduction in interest in the intake of trigger foods, a decrease in waist circumference, a reduction in body mass index (BMI), a reduction in overall anxiety, a reduction in food-related anxiety, an improvement in self-awareness, an improvement in confidence, an improvement in depression and a sense of well-being, a lack of overeating craving, weight loss, an improvement in eating behavior, a reduction in the anxiety and depression scale (HADS) related to hospitalization, a reduction in HADS-anxiety, a reduction in HADS-depression, an improvement in the overall impression improvement degree (PGI-I) of the patient, and an improvement in the questionnaire response related to acceptance and behavior (AAQ-II). In some optional embodiments, in the subject being treated, one or more improvements are shown, selected from a decrease in the frequency of binge eating episodes, a decrease in the binge eating scale (BES), a decrease in the number of binge eating episodes per day, a reduction in food-related anxiety, a reduction in depression related to eating behavior, a reduction in depression related to weight management, an improvement in the overall clinical impression improvement degree (CGI-I), a reduction in interest in the intake of trigger foods, a decrease in waist circumference, a reduction in body mass index (BMI), a reduction in overall anxiety, a reduction in food-related anxiety, an improvement in self-awareness, an improvement in confidence, an improvement in depression and a sense of well-being, a lack of overeating craving, weight loss, an improvement in eating behavior, a reduction in the anxiety and depression scale (HADS) related to hospitalization, an improvement in the overall impression improvement degree (PGI-I) of the patient, and an improvement in the questionnaire response related to acceptance and behavior (AAQ-II).In some optional embodiments, in the subject being treated, one or more improvements are shown, selected from a decrease in the frequency of binge eating episodes, a decrease in the Binge Eating Scale (BES), a decrease in the number of binge eating episodes per day, a reduction in food-related anxiety, a reduction in depressive states related to eating behavior, a reduction in depressive states related to weight management, an improvement in the Clinical Global Impression - Improvement (CGI-I), a reduction in interest in the intake of trigger foods, a decrease in waist circumference, a reduction in body mass index (BMI), a reduction in anxiety about hospitalization and the Hospital Anxiety and Depression Scale (HADS), an improvement in the Patient Global Impression - Improvement (PGI-I), and an improvement in the Acceptance and Action Questionnaire - II (AAQ-II).

[0037] In some optional embodiments, in the subject being treated, one or more improvements are shown, selected from a reduction in general anxiety, a reduction in food-related anxiety, an improvement in self-awareness, an increase in confidence, an improvement in depressive states and a sense of well-being from the heart, a lack of overeating desire, weight loss, and an improvement in eating behavior.

[0038] In some optional embodiments, the administration of the one or more times of silibinin or its active metabolite includes the administration of silibinin or its active metabolite once, twice, three times, four times, or five times. In some optional embodiments, the administration of the one or more times of silibinin or its active metabolite includes the administration of silibinin or its active metabolite once. In some optional embodiments, the administration of the one or more times of silibinin or its active metabolite includes the administration of silibinin or its active metabolite twice.

[0039] In some optional embodiments, the dose is 10 mg or about 10 mg to 50 mg or about 50 mg of silibinin or its active metabolite. In some optional embodiments, the dose is 25 mg and about 25 mg of silibinin or its active metabolite.

[0040] In some optional embodiments, the one or more integrated sessions include one, two, three, four, or five integrated sessions. In some optional embodiments, the one or more integrated sessions include one integrated session. In some optional embodiments, the one or more integrated sessions include two integrated sessions.

[0041] In some optional embodiments, the integrated session is provided 1 day or about 1 day after administration of silibinin or its active metabolite. In some optional embodiments, the method further includes providing one or more additional integrated sessions. In some optional embodiments, the one or more additional integrated sessions are provided between about 6 days to 9 days or about 9 days after administration of silibinin or its active metabolite. In some optional embodiments, the one or more additional integrated sessions are provided on or about 7 days after administration of silibinin or its active metabolite.

[0042] In some optional embodiments, the administration of the one or more times of silibinin or its active metabolite includes the first administration of silibinin or its active metabolite. In some optional embodiments, the first dose is 10 mg or about 10 mg to 50 mg or about 50 mg of silibinin or its active metabolite. In some optional embodiments, the first dose is 25 mg or about 25 mg of silibinin or its active metabolite.

[0043] In some optional embodiments, the one or more integrated sessions include a first integrated session and a second integrated session. In some optional embodiments, the first integrated session is provided one day or about one day after the first administration of sirolimus or its active metabolite. In some optional embodiments, the second integrated session is provided between about 6 days to 9 days or about 9 days after the first administration of sirolimus or its active metabolite. In some optional embodiments, the second integrated session is provided 7 days or about 7 days after the first administration of sirolimus or its active metabolite.

[0044] In some optional embodiments, the administration of the one or more sirolimus or its active metabolites includes a second administration of sirolimus or its active metabolite. In some optional embodiments, the method also includes providing one or more additional integrated sessions after the second administration.

Brief Description of the Drawings

[0045] FIG. 1 shows an exemplary treatment and evaluation schedule according to the provided embodiments.

[0046] FIGS. 2A (Q1) and 2B (Q2) provide the scores over time for questionnaires Q1 and Q2 regarding daily eating in subjects administered sirolimus for the treatment of binge eating disorder (BED).

[0047] FIGS. 3A (Q1), 3B (Q2), and 3C (Q3) provide the score changes for questionnaires Q1 - Q3 regarding daily eating before and after administration in 5 subjects administered sirolimus for the treatment of BED.

[0048] FIGS. 4A (Hospital Anxiety and Depression Scale (HADS) - Anxiety) and 4B (HADS - Depression) show the changes over time in the average HADS scores for 5 subjects administered sirolimus for the treatment of BED, up to 4 weeks before administration and 14 weeks after administration.

[0049] Figure 5A shows a histogram of the eye opening and closing states and test sessions (before treatment vs. after treatment) for the average spectral power within the delta spectral band (1 - 3 Hz).

[0050] Figure 5B shows nodules of the substantia nigra (SN). Figure 5C shows (a) the left middle frontal gyrus, (b) the left supramarginal gyrus, and (c) the left angular gyrus. DETAILED DESCRIPTION OF THE INVENTION

[0051] Provided herein is a method for treating binge - eating disorder (BED) or one or more symptoms of BED, including the administration of a psychoactive drug such as psilocybin, in combination with psychotherapy, and related use of a psychoactive drug. In some embodiments, the method and use include the concurrent use of psilocybin or its active metabolite and psychotherapy. In some embodiments, the provided method and use include psychotherapy, for example, in one or more clinical sessions. In some embodiments, the method includes evaluating the therapeutic effect based on the measurement of one or more metrics, including, for example, measurements of treatment outcome values, observer - based evaluations and subject - reported results, quantification of clinical metrics, and combinations thereof. In some embodiments, the method and use result in one or more clinical improvements in individuals suffering from BED.

[0052] In some embodiments, the provided method includes evaluating one or more metrics in a subject before and / or after administering psilocybin or its active metabolite one or more times, wherein the one or more metrics are related to one or more BED symptoms, dissociation states, treatment outcomes, and safety, and / or are related to the subject.

[0053] For example, in some embodiments, one or more indicators associated with the symptoms of one or more BEDs include, but are not limited to, the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, food-related anxiety, depressive states related to eating behavior, depressive states related to weight management, the Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, hyperphagia craving, eating behavior, the Hospital Anxiety and Depression Scale (HADS) for anxiety and depressive states related to hospitalization, the Patient Global Impression - Improvement (PGI - I) scale, and the Acceptance and Action Questionnaire - II (AAQ - II).

[0054] In some embodiments, one or more indicators associated with dissociative states include, but are not limited to, the Monitor - Rated Scale (MRS), the Mystical Experience Questionnaire (MEQ30), and the Challenging Experience Questionnaire (CEQ). In some embodiments, one or more indicators associated with treatment outcomes include, but are not limited to, resting state functional connectivity (during eating and fasting) by functional magnetic resonance imaging (fMRI), task - related functional activation and connectivity (during eating and fasting) during food - cue reactivity tasks by fMRI, voxel - based morphometry (gray and white matter volume / structure) by fMRI, resting - state electroencephalogram (EEG), metabolic biomarkers selected from ghrelin, leptin, adiponectin, insulin, glucose, and HOMA - IR (Homeostatic Model Assessment of Insulin Resistance).

[0055] In some embodiments, the indicators related to the subject include any physical, emotional, or clinical parameters that represent the characteristics of the patient. These may be self-reported or determined by caregivers such as healthcare providers or psychologists. In some embodiments, the indicators related to the subject include, but are not limited to, observer-based evaluation and subject-reported parameters, clinical indicators, and indicators related to body and weight. In some embodiments, the indicators related to the subject include, but are not limited to, waist circumference, body mass index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, genuine well-being, weight, vital signs, blood chemistry and hematology tests, urine tests, electrocardiogram (ECG), and Columbia Suicide Severity Rating Scale (C-SSRS).

[0056] Provided are methods and uses for treating individuals suffering from BED, which include orally administering psilocybin or its active metabolite to the individual one or more times, and providing one or more integration sessions to the patient after recovery from dissociation.

[0057] In some embodiments, psilocybin or its active metabolite, and compositions containing psilocybin or its active metabolite are useful in various therapeutic and prophylactic indicators. For example, the composition is useful for treating diseases, conditions, or disorders such as BED in a subject. Such methods and uses include, for example, therapeutic methods and uses involving administering a psychedelic to a subject suffering from a disease, condition, or disorder such as BED. In some embodiments, psilocybin or its active metabolite is administered in an amount effective for treating a disease or disorder such as BED, for example. The uses include the use of the composition in such methods and treatments and the preparation of a medicament for carrying out such treatment methods. In some embodiments, the method is carried out by administering psilocybin or its active metabolite to a subject suffering from or suspected of suffering from BED. Thus, in some embodiments, the method treats a disease, condition, or disorder such as BED in the subject.

[0058] Also provided herein are the use of psilocybin or its active metabolite in such methods and treatments, and the preparation of medicaments for carrying out such methods. In some embodiments, the methods and uses result in the improvement, alleviation, and / or treatment of BED or one or more of its symptoms in the subject. In some embodiments, the treatment methods and uses provided include administering to a subject having, indicating, or suffering from one or more symptoms of BED, for example, an amount sufficient to rapidly induce a dissociative or hallucinatory state in the subject and / or an effective amount to improve or alleviate one or more symptoms of BED, an administration such as intravenous administration of psilocybin or its active metabolite.

[0059] BED is a common eating disorder associated with the co-occurrence of obesity and mental disorders (psychological distress related to food and eating, depressive states, anxiety, etc.). BED is also characterized in some cases by repetitive excessive food intake accompanied by a sense of loss of control and psychological distress. Existing treatment options for BED are limited. Pharmacotherapy and other approaches are available for the management of BED, but existing pharmacotherapies have only modest effects and are accompanied by side effects. There is a need for improved treatment approaches for BED. Provided are methods and uses that meet such needs, including administering psilocybin or its active metabolite for treating BED.

[0060] In some embodiments, the methods and uses provided result in the improvement of one or more symptoms, signs, or clinical features of BED. In some embodiments, the methods result in the improvement of one or more symptoms of BED, and the one or more symptoms include frequent dieting and weight loss, food hoarding, late-night eating, hiding evidence of eating behaviors and those behaviors, blaming success or failure on weight, avoiding social situations where food may be present, feelings of depression or anxiety, rapid and unhealthy weight gain and / or loss, and chronically irregular eating behaviors. In some embodiments, when patients with BED are treated according to the embodiments described herein, the one or more symptoms of BED are alleviated or improved.

[0061] In some aspects, the methods and uses provided are based on observations in clinical trials where subjects with BED were treated according to the exemplary methods described herein. This included the administration of psilocybin or its active metabolite in combination with psychotherapy, and positive behavioral changes were shown immediately following an integrated session that continued for at least 4 weeks or 14 weeks after administration. As a result, no adverse events were observed, and overall depression and anxiety, reduction of depression and anxiety related to food, reduction of the urge to eat, improvement of self-awareness and confidence, improvement of satisfaction with oneself, and weight loss at 4 weeks were observed. According to the provided embodiments, it was observed that a single administration of psilocybin or its active metabolite in combination with psychotherapy achieved improvements similar to those achievable by 12 months of intensive psychotherapy in both BED symptoms and quality of life. As described herein, the magnitude of change in most subjects in overeating, anxiety, and depression is dramatic and is usually only observable after treatment based on evidence over a much longer period. Also, a sustained and lasting treatment effect was observed even after a single administration of a psychotropic drug, and it was shown that improvement of BED symptoms may continue for more than 80 days after a single administration of psilocybin. Thus, the results described herein demonstrate the substantial effectiveness of the methods and uses according to the provided embodiments.

[0062] All publications, including patent documents, scientific papers, and databases, referred to in this application are hereby incorporated by reference in their entirety for all purposes as if each individual publication were individually incorporated. If the definitions set forth herein are contrary to or inconsistent with the definitions set forth in patents, applications, published applications, and other publications incorporated by reference herein, the definitions set forth herein shall control over the definitions incorporated by reference herein.

[0063] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0064] I. Methods of Treating Binge Eating Disorder (BED) and Use of Silybin In some embodiments, the methods and uses include administration of silybin or an active metabolite thereof and psychotherapy for treating a subject suffering from BED.

[0065] In some embodiments, psilocybin or its active metabolites can alter neural connectivity, and as such, they are considered useful for the treatment of anxiety, food-related depression and anxiety, compulsive and impulsive behaviors, self-harm behaviors, and particularly repetitive and intrusive thoughts related to food in BED patients. In some embodiments, the methods and uses include the administration of psilocybin or its active metabolites and psychotherapy for treating a subject diagnosed with BED. In some embodiments, the methods and uses include the administration of psilocybin or its active metabolites and psychotherapy for treating a subject who has exhibited or experienced one or more symptoms of BED. In some embodiments, a treatment method including the administration of psilocybin or its active metabolites and psychotherapy ameliorates or treats BED. In some embodiments, after implementing a treatment method including the administration of psilocybin or its active metabolites and psychotherapy, the severity of one or more symptoms of BED is reduced. In some embodiments, after implementing a treatment method including the administration of psilocybin or its active metabolites and psychotherapy, one or more indicators, signs, symptoms, or behaviors of BED, including but not limited to the frequency of binge eating episodes, are reduced, delayed, and / or prevented.

[0066] In some embodiments, the embodiments provided herein include treating an individual by administering to the individual one or more therapeutically effective doses of psilocybin or an active metabolite thereof. In some embodiments, the methods and uses involve administering psilocybin or an active metabolite thereof to the subject and providing psychological or mental health support. In some embodiments, the methods and uses involve administering psilocybin or an active metabolite thereof to the subject and providing psychotherapy. In some embodiments, the embodiments provided include providing one or more psychological support sessions, such as one or more preparatory sessions, prior to the first or initial administration of psilocybin or an active metabolite thereof. In some embodiments, the embodiments provided include providing psychological support during the administration session of psilocybin or an active metabolite thereof. In some embodiments, the embodiments provided include administering psilocybin or an active metabolite thereof to a subject in a controlled environment, and providing psychological support to the subject. In some embodiments, the embodiments provided include one or more psychological support sessions following the administration of psilocybin or an active metabolite thereof.

[0067] In some embodiments, an individual undergoing treatment according to the provided embodiments receives one or more evaluations before, during, and after treatment. In some embodiments, the evaluation of the individual undergoing treatment includes physical measurements of effectiveness, results of observer evaluations and subject reports, quantification of clinical metrics, and combinations thereof. In some embodiments, the evaluation includes a measurement of effectiveness, which is a measure of physique and / or weight, including but not limited to body mass index (BMI), waist circumference, and changes from a weight baseline. In some embodiments, the evaluation of the individual undergoing treatment includes an analysis of observer evaluations and subject reports that include an evaluation of eating behavior, an evaluation of response to treatment, a psychological evaluation, an evaluation of the experience of psychostimulants, and / or an evaluation of clinical activities, the evaluation of the clinical activities including, but not limited to, an evaluation of binge eating, an evaluation of the binge eating scale (BES), an evaluation of the improvement of the overall clinical impression (CGI-I), an evaluation of the improvement of the patient's overall impression (PGI-I), an evaluation of the anxiety or depression scale (HADS) for admission, an evaluation of the emotional breakthrough inventory (EBI), a questionnaire on acceptance and action (AAQ-II), a questionnaire on mystical experience (MEQ30), a questionnaire on difficult experience (CEQ), and / or an evaluation of the monitor-based evaluation scale (MRS). In some embodiments, the evaluation of the individual undergoing treatment includes quantitative measurements of neurological clinical metrics and metabolic biomarkers, including but not limited to brain morphology, brain activity, functional activation and / or functional connectivity, leptin concentration, adiponectin concentration, ghrelin concentration, glucose concentration, insulin concentration, and homeostasis model assessment of insulin resistance.

[0068] A.BED The provided embodiments relate to the treatment of binge eating disorder (BED) using psychostimulants and / or psychotherapy. In some aspects, the provided embodiments can reduce, delay, or prevent one or more BED indicators, signs, or symptoms, including any of those described herein. In some aspects, any one or more of these indicators, signs, or symptoms can be alleviated based on the methods and uses provided herein.

[0069] BED is one of the most common eating disorders and is associated with obesity and co-occurring mental illnesses, including depression (Guerdjikova et al., 2021, Contemporary Clinical Trials, 110, 106587). BED is characterized by recurrent episodes of excessive food intake with a sense of loss of control and psychological distress, without the inappropriate compensatory weight loss behaviors of bulimia nervosa (Guerdjikova et al., 2021, Contemporary Clinical Trials, 110, 106587; McElroy et al., 2015, JAMA Psychiatry, 72, 236). In some cases, BED is associated with abnormal neural responses, particularly to highly palatable foods (Citrome, 2019, CNS Spectr, 24(S1), 4-13; Donnelly et al., 2018, J. Eating Disorders, 6:3; Boswell et al., 2021, Clinical Therapeutics, 43). People with BED suffer from severe anxiety and may engage in compulsive and impulsive behaviors, particularly related to food (Guerdjikova et al., 2019, Med Clin North Am, 103(4), 669-680; Samodien & Chellan, 2021, Front Neuroendocrinol, 60, 100871). Self-harming behaviors such as skin picking are observed in BED and are thought to be possibly related to abnormal neural connectivity (Houazene et al., 2021, Behav Res Ther, 138, 103804). Therapeutic agents that affect the reward and executive function systems are thought to be effective in the treatment of BED (Boswell et al., 2021, Clinical Therapeutics, 43).

[0070] BED is characterized by repeated binge eating episodes. During a binge eating episode, most people consume more food than they would consume in a similar situation, repeating episodes where they feel unable to stop eating large amounts of food. In some cases, symptoms of BED are seen in about 30% of people seeking weight loss treatment, with up to 3.5% of women and up to 2.0% of men developing BED at some point in their lives. In the United States, about 4 million women and about 2 million men develop BED. Existing treatments have not been effective.

[0071] Subjects suffering from BED experience a lack of control over their eating during binge episodes, significant psychological distress related to binge eating (e.g., shame, guilt), and may exhibit behaviors such as vomiting, fasting, excessive exercise, etc. to compensate for binge eating. Common symptoms of BED include frequent dieting and weight loss, food hoarding, late-night eating and concealment of evidence of such behavior, blaming success or failure on weight, avoiding social situations where food may be present, feelings of depression and anxiety, etc. Binge eating can cause rapid and unhealthy weight changes, such as weight gain or loss, chronic / irregular eating behaviors, etc. Symptoms associated with BED and binge eating disorders can lead to obesity. However, BED is not necessarily associated with obesity. Subjects with non-obese or normal-weight BED may exhibit binge eating behaviors similar to those of obese BED subjects, but it has been found that normal-weight individuals engage significantly more in weight management behaviors such as reducing the number of daily meals and snacks, exercising, skipping meals, avoiding certain foods, etc. (Goldschmidt et al., Obesity (Silver Spring). 2011;19(7):1515-1518). Table 1 below shows the DSM-IV and DSM-5 diagnostic criteria for BED (Berkman et al., Comparative Effectiveness Reviews, No. 160., Rockville (MD): Agency for Healthcare Research and Quality (US), 2015;ES-1). Exemplary indicators, signs, symptoms, or behaviors associated with BED include a sense of lack of control, rapid eating pace, eating beyond feelings of fullness or satisfaction, binge eating, secretive eating behaviors, self-loathing, depression, anxiety, frequency and intensity of excessive self-awareness or critical thinking such as feelings of guilt and shame, and inappropriate compensatory behaviors, such as vomiting, fasting, and / or excessive exercise. In some aspects, the provided embodiments can reduce, delay, or prevent any one or more of the indicators, signs, or symptoms of BED, including any of those described herein.

[0072] In some embodiments, the methods and uses provided improve one or more symptoms, signs, or clinical features of BED, such as binge eating episodes per day, food-related anxiety, a sense of loss of control over eating, depression related to eating behavior, depression related to weight control, resulting weight gain, hyperleptinemia, hyperinsulinemia, rapid weight gain, obesity, decreased resting energy expenditure, decreased physical activity, uncontrollable appetite, leptin resistance, metabolic disorders, fatigue, and uncontrollable weight gain. In some embodiments, the methods improve one or more symptoms of BED, such as frequent dieting and weight loss, a sense of loss of control over eating, hoarding of food, concealment of evidence of late-night eating and its behavior, blaming success or failure on weight, avoidance of social situations that may involve meals, feelings of depression and anxiety, rapid and unhealthy weight gain and / or weight loss, chronic / irregular eating behavior, etc. In some embodiments, the methods improve one or more symptoms of BED, such as neurological abnormalities, cognitive abnormalities, endocrine abnormalities, behavioral abnormalities, or obsessive behaviors, etc. In some aspects, the methods and uses provided reduce general anxiety, reduce food-related anxiety, reduce depression, reduce food-related depression, improve self-awareness, increase confidence, and result in reduced depression and a sense of well-being, lack of overeating cravings, weight loss, and improvement in eating behavior. Table 1 DSM-IV and DSM-5 Diagnostic Criteria for Binge Eating Disorder (BED) JPEG2025521221000002.jpg197138

[0073] Specific treatment recommendations for BED are available (see, e.g., Association AP., American Psychiatric Association, Am J Psychiatry. 2006 Jul;163(7 Suppl):4-54; Yager et al., American Psychiatric Association; 2012. p. 1-18; National Institute for Health and Care Excellence (NICE), 2004; Aigner et al., World J Biol Psychiatry. 2011;12(6):400-43; Ozier and Henry, J Am Diet Assoc. 2011;111(8):1236-41). Such treatment guidelines generally include the use of cognitive behavioral therapy and selective serotonin reuptake inhibitors (Berkman et al., Comparative Effectiveness Reviews, No. 160., Rockville (MD): Agency for Healthcare Research and Quality (US), 2015; 8-9). In addition, lisdexamfetamine, second-generation antidepressants, and topiramate have been found to remit BED in adults (Brownley et al., Ann Intern Med. 2016;165(6):409-420). However, available treatments are of limited efficacy and may be associated with side effects.

[0074] In some aspects, silibinin or its active metabolite can be used to treat one or more behaviors or symptoms associated with BED, such as those described herein. For example, behaviors or symptoms treated according to the described embodiments that involve administration of silibinin or its active metabolite include, in particular with respect to food, anxiety about food, preoccupation, and repetitive and intrusive thoughts about food. In some aspects, one or more of the indicators described herein are related to measuring or evaluating one or more BED symptoms, dissociative states, treatment outcomes, and safety, and / or are related to the subject. In some aspects, the methods and uses provided herein include measuring or evaluating one or more BED symptoms before and after administration of silibinin or its active metabolite.

[0075] B. Administration of Psychedelic Drugs In some embodiments, the provided methods of treatment and uses include the administration of a psychedelic drug compound, such as psilocybin or its active metabolite. In some embodiments, the administration of the psychedelic drug is conducted in combination with one or more clinical sessions, such as one or more preparatory sessions or integration sessions for psychotherapy. In some embodiments, the methods and uses include the oral administration of psilocybin or its active metabolite to a subject suffering from the symptoms of one or more BEDs one or more times. In some embodiments, when the subject is selected or identified for treatment with psilocybin or its active metabolite, the subject is orally administered psilocybin or its active metabolite one or more times.

[0076] Psychedelic drugs (drugs that “reveal the mind”) are a class of compounds that have been used to treat certain mental disorders, such as depression, addiction, anxiety, and PTSD (Nutt et al., Cell 2020;181(1):24-8), and exhibit a remarkable safety profile (REF).

[0077] Psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate; 4-phosphoryloxy-N,N-dimethyltryptamine) is a natural product produced by many species of psilocybin mushrooms and is manufactured for clinical use to control potency and purity. It is a tryptamine derivative, and in humans, the phosphate group is rapidly enzymatically degraded to produce psilocin. Psilocin is an agonist of various serotonin receptors, in this case 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 non-specific esterases to produce the active metabolite psilocin (Dinis-Oliveraira R, Drug Metab Rev 2017;49(1): 84-91). Psilocin is an agonist of multiple serotonin receptors including the 5-hydroxytryptamine (5-HT)2A receptor (Carhart-Harris et al., Front Hum Neurosci 2014;8:20; Nichols D, Pharmacol Ther 2004;101(2):131-81). Psilocybin causes significant changes in perception, emotion, thought, and self-awareness, characterized by marked alterations in all mental functions including perception, mood, volition, cognition, and self-experience (Geyer & Vollenweider, Trends Pharmacol Sci. 2008;29(9):445-53; Studerus et al., J Psychopharmacol. 2011;25(11):1434-52). These significant changes are often referred to as mystical experiences.The scale of the mystical experiences that occur during psilocybin treatment has been repeatedly observed to predict subsequent effects on behavior and emotions, such as the reduction of depressive and anxiety symptoms (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 by forming intense dream-like states with richly colored visual illusions, changes in hearing, touch, smell, taste, kinesthetic sensations, changes in the perception of time and space, changes in body image, sensations such as ego dissolution, and intense mood swings ranging from surprise and bliss to sadness and lamentation.

[0078] In some aspects, psilocybin causes significant changes in perception, emotion, thought, and self-awareness, characterized by marked changes in all mental functions, including perception, mood, volition, cognition, and self-experience (Geyer & Vollenweider, Trends Pharmacol Sci. 2008;29(9):445-53;Studerus et al., J Psychopharmacol. 2011;25(11):1434-52). These significant changes have often been referred to as mystical experiences that have been repeatedly observed to predict subsequent effects on behavior and emotions, such as the reduction of depressive and anxiety symptoms (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).

[0079] In some embodiments, the effects of psilocybin are mainly related to the activation of 5-HT2A receptors. In tests in animals and some tests in humans, 5-HT2A receptors are associated with hypersensitivity. Stimulation of 5-HT2A receptors in the paraventricular nucleus of the hypothalamus reduces neuropeptide Y-induced hyperphagia via the activation of corticotropin-releasing factor (Grignaschi et al., 1996, Brain Res, 708(1-2), 173-176). The 5-HT2C / 2B receptor agonist m-chlorophenylpiperazine inhibited 2-deoxy-D-glucose-induced hyperphagia in rats (Sugimoto et al., 2001, Biological and Pharmaceutical Bulletin, 24(12), 1431-1433). Some conflicting results have also been shown regarding the association between 5-HT2A receptor gene polymorphisms and eating disorders (Serretti et al., 2007, Curr Med Chem, 14(19), 2053-2069). Studies using positron emission tomography with 5-HT-specific radioligands and single photon emission computed tomography have consistently shown changes in 5-HT(1A) and 5-HT(2A) receptors and 5-HT transporters in the cortex and limbic system in anorexia nervosa and bulimia nervosa, which may be related to anxiety, behavioral inhibition, and distorted body image. In some embodiments, being overweight has been reported to be associated with increased 5-HT2A binding in most regions of the human cortex (Erroitze et al., 2009, Neuroimage, 46(1):23-30).

[0080] The bioavailability of oral silibinin is approximately 50%, and silosine can be detected 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 plasma half-life of silosine is 2 to 3 hours. Generally, a marked psychoactive effect develops within 1 hour after administration and reaches a peak at about 2 hours. This marked effect usually disappears at about 6 hours after administration. Based on this time course, observations in clinical trials are set up to 8 hours after administration. Furthermore, the exposure after a 25 mg oral dose is related to both the nearly maximal occupancy of the neocortical serotonin 5-HT2A receptor and the subjective intensity assessment of the elements of the psychedelic experience that are repeatedly associated with the long-term therapeutic effect (Madsen et al., Neuropsychopharmacology. 2019;44(7):1328-1334).

[0081] In non-clinical trials, as in humans, when silybin is orally administered to rats, it is rapidly dephosphorylated by alkaline phosphatase and non-specific esterase in the intestinal mucosa to become silybin, and it has been reported that approximately 50% of the total amount of silybin is absorbed from the digestive tract (Kalberer et al., Biochem Pharmacol. 1962;11:261-9). The maximum plasma level is 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., not via the intestine), the initial metabolism of silybin is carried out by tissue phosphatases, and in in vitro tests, the kidney has been shown to be one of the most active metabolic organs (Horita & Weber, Biochem. Pharmacol. 1961;7(1):47-54). The highest concentrations of silybin were found in the neocortex, hippocampus, and thalamus across the species tested (Hopf & Eckert, Act Nerv Super (Praha) 1974;16(1):64-6). In several trials, silybin has been shown to reduce responses to symptoms such as obsessive-compulsive disorder (OCD), substance use disorder, depression, and anxiety. Overall, silybin has shown good tolerance at the doses examined in clinical trials.

[0082] In tests in rats, the breakdown of silibinin is similar to that in humans, with approximately 50% of total silicic acid being absorbed from the gastrointestinal tract (Kalberer et al., Biochem Pharmacol 1962;11:261-9), and it has been demonstrated that the highest concentration is reached in plasma 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., not via the intestine), the initial metabolism of silibinin is carried out by tissue phosphatases, and in in vitro tests, the kidney has been shown to be one of the most active metabolic organs (Horita & Weber, Biochem. Pharmacol. 1961;7(1):47-54). Furthermore, the highest concentrations of silicic acid have consistently been found in the neocortex, hippocampus, and thalamus (Hopf & Eckert, Act Nerv Super (Praha) 1974;16(1):64-6).

[0083] In a clinical setting, administration of silibinin has been reported to improve specific symptoms of cancer-related mental stress, depression and anxiety, nicotine and alcohol dependence, obsessive-compulsive disorder (OCD) (Nutt et al., Cell 2020;181(1):24-8), and anorexia nervosa (a state where intrusive thoughts cause maladaptive and life-threatening behaviors and treatment resistance is common) (Foldi et al., 2020, Frontiers in Neuroscience, 14). Silibinin showed good tolerance at the doses examined in clinical trials. Furthermore, it has been shown that a single dose of silibinin improved the reported depression score in patients after one week, and that improvement persisted for up to six months (Carhart-Harris et al., Psychopharmacol 2018;235(2):399-408). Since then, silibinin has received fast track designation from the FDA as a treatment for depression. In any of the provided embodiments, a reference to administration of silibinin may include administration of active metabolites of silibinin such as silicic acid.

[0084] 1. Administration In some embodiments, the methods and uses include a sirolimus dosing regimen for treating a subject suffering from BED. In some embodiments, a sirolimus dosing regimen for treating a patient or subject diagnosed with BED, or suffering from BED, or exhibiting one or more symptoms of BED is provided herein. In some embodiments, a method for treating a subject includes administering to the subject a therapeutically effective dose of sirolimus one or more times.

[0085] In some embodiments, the subject is administered sirolimus one or more times. In some embodiments, the subject is administered sirolimus 1, 2, 3, 4, or 5 times. In some embodiments, sirolimus is administered once. In some embodiments, the subject is administered sirolimus two or more times. In some embodiments, sirolimus is administered twice.

[0086] In some embodiments, subsequent non-first administrations can be optionally administered after the first or initial administration and the subject is administered at least twice. In some embodiments, subsequent non-first administrations can be optionally administered after the first or initial administration and the subject is administered two or more times. In some embodiments, subsequent non-first administrations can be the second, third, or fourth sirolimus administration.

[0087] In some embodiments, when silibinin is administered two or more times, the dosing interval between the previous dose and the subsequent dose, for example, between the first dose and the second dose, is about 1 week to 4 weeks. In some embodiments, the second dose of silibinin is administered about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks after the first dose. In some aspects, the dosing interval, for example, the time between the first dose and the second dose, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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, or approximately those times. In some embodiments, the second dose of silibinin is administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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 after the first dose, or approximately those number of days after.

[0088] In some embodiments, the dose of silibinin is administered to a subject such as a subject suffering from BED. In some aspects, the dose of silibinin is a therapeutically effective dose. In some aspects, the dose of silibinin is effective and / or sufficient to induce a dissociative state. In some aspects, the therapeutically effective dose is based on the route of administration.

[0089] In some embodiments, the dosage of silibinin is a constant or fixed dosage. In some embodiments, the dosage of silibinin administered is 5 mg or about 5 mg to 50 mg or about 50 mg. In some embodiments, the dosage of silibinin administered is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, or approximately those amounts. In some aspects, the dosage of silibinin is administered orally. In some aspects, for oral administration, the dosage of silibinin administered is 5 mg or about 5 mg to 50 mg or about 50 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, or approximately those amounts. In some embodiments, the dosage of silibinin administered by oral administration or the like is 25 mg or about 25 mg. In some embodiments, the dosage of silibinin administered by oral administration or the like is 50 mg or about 50 mg.

[0090] In some aspects, silibinin is administered one or more times. In some embodiments, the one or more dosages are the same. In some embodiments, the one or more dosages are different. In some embodiments, a first dosage and a second dosage are administered to the subject, and the first dosage and the second dosage are the same or substantially the same. In some embodiments, the first dosage is greater than the second dosage. In some embodiments, the second dosage is greater than the first dosage.

[0091] In some embodiments, for oral administration, the first dose of silybin administered is 5 mg or about 5 mg to 50 mg or about 50 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, or approximately those amounts. In some embodiments, the first dose of silybin administered, such as by oral administration, is 25 mg or about 25 mg. In some embodiments, the first dose of silybin administered, such as by oral administration, is 50 mg or about 50 mg.

[0092] In some embodiments, the dose is determined according to body weight. In some embodiments, the first dose is determined according to body weight. In some embodiments, exemplary doses based on body weight include 0.1 mg / kg, 0.15 mg / kg, 0.25 mg / kg, 0.35 mg / kg, 0.45 mg / kg, 0.55 mg / kg, 0.65 mg / kg, 0.75 mg / kg, 0.85 mg / kg, 0.95 mg / kg, or 1.0 mg / kg, or approximately these amounts. In some embodiments, a subject with a body weight less than 100 kg (≤ 100 kg) is administered a dose of 25 mg or about 25 mg of silybin. In some embodiments, a subject with a body weight greater than 100 kg and less than or equal to 117 kg (> 100 kg and ≤ 117 kg) is administered a dose of 30 mg or about 30 mg of silybin. In some embodiments, a subject with a body weight greater than 117 kg (> 117 kg) is administered a dose of 35 mg or about 35 mg of silybin.

[0093] In some embodiments, subsequent doses of silybin are determined according to body weight. In some embodiments, the subsequent dose is increased by 0.1 mg / kg or about 0.1 mg / kg to 1 mg / kg or about 1 mg / kg, for example, 0.1 mg / kg, 0.15 mg / kg, 0.25 mg / kg, 0.35 mg / kg, 0.45 mg / kg, 0.55 mg / kg, 0.65 mg / kg, 0.75 mg / kg, 0.85 mg / kg, 0.95 mg / kg, or 1.0 mg / kg, or approximately those amounts, compared to the first dose, the initial dose. In some embodiments, the subsequent dose is increased by 0.15 mg / kg, 0.25 mg / kg, 0.35 mg / kg, 0.45 mg / kg, 0.55 mg / kg, 0.65 mg / kg, 0.75 mg / kg, 0.85 mg / kg, or about 0.95 mg / kg, or approximately those amounts, compared to the first dose, the initial dose.

[0094] In some embodiments, a subsequent dose of about 30 mg of silybin is administered to a subject with a body weight of less than 80 kg (≤80 kg). In some embodiments, a subsequent dose of about 35 mg of silybin is administered to a subject with a body weight greater than 80 kg and less than or equal to 90 kg (>80 kg and ≤90 kg). In some embodiments, a subsequent dose of about 40 mg of silybin is administered to a subject with a body weight greater than 90 kg and less than or equal to 100 kg (>90 kg and ≤100 kg). In some embodiments, a subsequent dose of about 45 mg of silybin is administered to a subject with a body weight greater than 100 kg and less than or equal to 112 kg (>100 kg and ≤112 kg). In some embodiments, a subsequent dose of about 50 mg of silybin is administered to a subject with a body weight greater than 112 kg (>112 kg).

[0095] In some embodiments, sirolimus is administered orally. In some embodiments, sirolimus is administered in the form of tablets. In some embodiments, sirolimus is administered in the form of capsules. In some embodiments, one or more 5 mg sirolimus capsules are administered to meet the desired dosage level of the subject. In some embodiments, one or more 25 mg sirolimus capsules are administered to meet the desired dosage level of the subject. In some embodiments, sirolimus is administered in capsules containing one or more of gelatin, hydroxypropyl methylcellulose (HPMC) or hypromellose, and pullulan. In some embodiments, sirolimus is administered in capsules containing hydroxypropyl methylcellulose (HPMC) or hypromellose.

[0096] In some embodiments, when sirolimus is administered to the subject one or more times or repeatedly, the amount of the first administration is the same as the amount of one or more subsequent administrations. In some embodiments, when sirolimus is administered to the subject one or more times or repeatedly, the amount of the first administration is different from the amount of one or more subsequent administrations. In some embodiments, when sirolimus is administered to the subject one or more times or repeatedly, the amount of the first administration is less than the amount of one or more subsequent administrations. In some embodiments, when sirolimus is administered to the subject one or more times or repeatedly, the amount of the first administration is more than the amount of one or more subsequent administrations.

[0097] In some embodiments, sirolimus is administered twice, and the first and second doses are the same. In some embodiments, sirolimus is administered twice, and the first and second doses are different. In some embodiments, sirolimus is administered twice, and the first dose is the same amount as the second dose. In some embodiments, sirolimus is administered twice, and the first dose is less than the second dose. In some embodiments, sirolimus is administered twice, and the first dose is less than the second dose. In some embodiments, sirolimus is administered twice, and the second dose is more than the first dose.

[0098] In some embodiments, the methods and uses also include providing psychological support and / or psychotherapy in addition to the administration of sirolimus. In some aspects, the psychological support and / or psychotherapy is as described, for example, in section C of part I.

[0099] C. Psychological support In some aspects, the provided embodiments involve providing psychological support or mental health support to a subject in addition to or in conjunction with the administration of sirolimus or its active metabolite. In some aspects, the provided embodiments involve the administration of sirolimus or its active metabolite to a subject and psychotherapy.

[0100] In some embodiments, the psychological support includes psychotherapy and / or talk therapy. In some embodiments, the psychological support is led by someone other than the therapist or the subject. In some embodiments, the psychological support is self-administered, for example, for adjunct administration of subsequent or maintenance doses. In some embodiments, the psychological support is led and self-administered by the therapist. In some aspects, the embodiments provided involve administration of psilocybin to the subject and talk therapy. In some embodiments, the psychological support or mental health support is provided in-person and / or remotely, such as by telephone or video. In some embodiments, the psychotherapy is provided in-person and / or remotely, such as by telephone or video. In some embodiments, the talk therapy is provided in-person and / or remotely, such as by telephone or video. In some embodiments, the psilocybin is self-administered and the psychological support or mental health support is provided remotely, such as by telephone or video.

[0101] In some embodiments, the psychological support precedes the administration of psilocybin, such as during a preparation session. In some embodiments, the psychological support does not precede the administration of psilocybin. In some embodiments, the psychological support is conducted concurrently with the administration of psilocybin. In some embodiments, the psychological support is conducted after the administration of psilocybin, such as during an integration session.

[0102] In some embodiments, the provided embodiments involve providing psychological support and / or psychotherapy in one or more sessions, such as one or more preparatory sessions or integration sessions. In some embodiments, the psychological support is provided in one or more sessions. In some embodiments, the psychological support and / or psychotherapy is provided prior to the administration of psilocybin, such as during a preparatory session. In some embodiments, the psychological support is conducted along with the administration of psilocybin. In some embodiments, the psychological support and / or psychotherapy is provided after the administration of psilocybin, such as during an integration session. In some embodiments, the psychological support and / or psychotherapy is provided before, during, and after the administration of psilocybin, where psilocybin is administered at least once, at least twice, at least three times, or at least four times. An example schedule of sessions of psychological support according to the provided embodiments is shown in Table 2. Table 2 Exemplary Sessions of Psychological Support JPEG2025521221000003.jpg163110 * One or more therapists or facilitators of psychological support provide the above treatment.

[0103] In some embodiments, the psychological support and / or psychotherapy is implemented in a single-subject session where one subject meets with one or more therapists. In some embodiments, the psychological support and / or psychotherapy is implemented in a single-subject session where one subject meets with two or more therapists. In some embodiments, the psychological support and / or psychotherapy is implemented in a group session where one or more subjects meet with one or more therapists. In some embodiments, one or more of the subject's family members or friends may attend the pre-administration psychological support session. In some embodiments, one or more psychological support sessions conducted prior to the administration of psilocybin are conducted in person or remotely, such as by phone or video.

[0104] 1. Psychological support before psilocybin administration In some embodiments, one or more sessions of psychological support and / or psychotherapy, such as one or more preparatory sessions, are provided prior to the first or initial administration of psilocybin. In some embodiments, two or more sessions of psychological support, such as three, four, five, or more sessions of psychological support and / or psychotherapy, are provided prior to the first or initial administration of psilocybin.

[0105] In some embodiments, the subject participates in at least one session of psychological support, such as a preparatory session, prior to administration of psilocybin. In some embodiments, the pre-administration psychological support session is provided within about one month prior to administration of psilocybin, such as four weeks, three weeks, two weeks, or one week prior, or approximately prior to these periods. In some embodiments, the subject participates in at least one session of psychological support, such as a preparatory session, prior to administration of psilocybin. Or in some of these embodiments, the pre-administration psychological support session is provided within about one week prior to administration of psilocybin, such as seven days, six days, five days, four days, three days, two days, or one day, or approximately on these days.

[0106] In some embodiments, one or more sessions of psychological support are conducted prior to administration of psilocybin. In some aspects, two sessions of psychological support are provided prior to administration of psilocybin. In some embodiments, two sessions of psychological support, such as two preparatory sessions, are provided prior to the session of the first administration of psilocybin. In some aspects, two sessions of psychological support are provided prior to administration of psilocybin, the first session is one week or about one week prior to that administration, and the second session is one to three days or about one to three days prior to that administration, such as two days or about two days prior to that administration.

[0107] In some embodiments, one or more psychological support sessions conducted prior to the administration of psilocybin are conducted in person or remotely, such as by telephone or video.

[0108] In some embodiments, breathing techniques can be provided, demonstrated, and / or practiced for the purpose of promoting relaxation and / or alleviating anxiety. In some embodiments, the breathing techniques include instructing the subject to focus on their breath and / or sensations related to breathing throughout the body. In one example, the subject may be instructed to inhale while counting to four, hold their breath for a short time, and then exhale while counting to eight. In some embodiments, the therapist and the subject may discuss the most helpful support methods in case emotional distress occurs during the psilocybin session. In some embodiments, the therapist may assist in motivating the subject for the psilocybin session. In some embodiments, the subject is provided with access (such as online access) to materials regarding the safety and mechanism of action of psilocybin.

[0109] In some embodiments, the psychological support and / or psychotherapy conducted prior to the administration of psilocybin includes the pursuit of 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, addressing concerns, and demonstrating and practicing self-directed exploration and experiential processing. In some embodiments, the pre-administration psychological support session includes a discussion of the reliable and / or potential effects of psilocybin. In some embodiments, in the pre-administration psychological support session, through practicing appropriate therapeutic techniques to reduce avoidance behaviors and anxiety, eliciting appropriate treatment goals, building trust, and / or establishing therapeutic alliance, the subject is prepared for psilocybin administration. In some embodiments, the pre-administration psychological support session includes interviewing the subject about overeating, anxiety, guilt, treatment history, etc. and understanding the most prominent patterns of psychological immobility. In some embodiments, the pre-administration psychological support session includes psychological education regarding the psilocybin 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 the administration of psilocybin.

[0110] 2. Psychological Support Associated with Psilocybin Administration In some embodiments, the psychological support is provided during the psilocybin administration session. In some aspects, the provided embodiments include administering psilocybin to the subject in a controlled environment, and psychological support is provided to the subject. In some aspects, the provided embodiments include administering psilocybin to the subject one or more times, such as an initial administration and one or more subsequent administrations, or a first administration and a second administration, in a controlled environment, where psychological support is provided to the subject.

[0111] In some embodiments, in a controlled environment, a therapeutically effective dose of psilocybin is administered to the subject, where the subject is provided with psychological support. In some embodiments, one or more administrations of psilocybin, such as a first administration and one or more subsequent administrations, or a first administration and a second administration, are performed on the subject in a controlled environment, where the subject is provided with psychological support. In some embodiments, the provider of psychological support does not provide significant acceptance and commitment therapy (ACT) intervention or feedback. In some embodiments, the provider of psychological support newly listens to events, records cases of psychological immobility and mobility, especially momentary recognition, avoidance, and values, and the ACT-based clinical dosing is continued.

[0112] 3. Psychological Support after Psilocybin Administration In some embodiments, one or more sessions of psychological support and / or psychotherapy are provided after one or more administrations of psilocybin, such as a first administration of psilocybin. In some embodiments, one or more sessions of psychological support and / or psychotherapy are provided as one or more integrated sessions. In some aspects, the one or more integrated sessions are provided to the subject after recovery from a dissociative state due to one or more administrations of psilocybin.

[0113] In some embodiments, the one or more integrated sessions, e.g., two, three, four, or more integrated sessions, are provided after each administration of psilocybin. In some embodiments, two integrated sessions are provided after each administration of psilocybin. In some aspects, two integrated sessions are provided after the first administration of psilocybin. In some aspects, two integrated sessions are provided after a subsequent administration of psilocybin, e.g., after the second administration. In some aspects, the integrated sessions include psychological support, psychotherapy, and / or talk therapy. In some embodiments, the psychological support is led by a therapist or someone other than the subject. In some embodiments, the psychological support is self-administered. In some embodiments, the manner of psychological support is led by a therapist and self-administered.

[0114] In some embodiments, two psychological support sessions, e.g., two integrated sessions, are provided after the first and / or subsequent administrations of psilocybin. In some embodiments, the two integrated sessions are provided within two weeks after the psilocybin administration. In some embodiments, the two integrated sessions are provided within one week after the psilocybin administration. In some embodiments, the first of the two integrated sessions is provided one day or about one day after the psilocybin session. In some embodiments, the second of the two integrated sessions is provided about one week after the psilocybin session. In some embodiments, the second of the two integrated sessions is provided 7 days or about 7 days, or 14 days or about 14 days after the psilocybin session. In some embodiments, the second of the two integrated sessions is provided about 7 days after the psilocybin session. In some embodiments, the second of the two integrated sessions is provided 14 days after the psilocybin session. In some embodiments, the second of the two integrated sessions is provided about two weeks after the psilocybin session.

[0115] In some embodiments, during one or more post - administration sessions, or one or more integration sessions, it includes listening to all of the subject's experiences during the psilocybin session. In some embodiments, the post - administration session or integration session includes intensive acceptance - commitment therapy (ACT) - based clinical activities related to momentary contact, defusion, or acceptance based on clinical dosing. In some embodiments, the post - administration session or integration session includes reflecting on the subject's psilocybin experience, including emotional, mental, or lifestyle changes that occurred after the dosing session.

[0116] 4. Set and Setting In some aspects, considering the psychoactive effects of psilocybin and testing psilocybin within the "set and setting" protocol improves the safety of subjects administered psilocybin (Lyons & Carhart - Harris, J Psychopharmacology 2018;32(7):811 - 819). This may be due to the psychoactive effects of psilocybin. In some aspects, "set" relates to one or more of the subject's emotional, cognitive, behavioral states, thoughts, and expectations before psilocybin administration, for example, immediately before administration. In some aspects, the "set" is addressed by the therapist in a pre - dosing psychotherapy session. In some aspects, "setting" relates to the physical environment in which psilocybin is administered. In some aspects, by addressing the context and situation of the experience, the risk that the subject reports distressing events or harms themselves can be reduced. In some embodiments, this approach consists of three elements: 1) psychological support (preparation, etc.) before psilocybin administration, 2) administration, and 3) post - administration psychological support (integration, etc.) for integrating the classic hallucinogenic experience.

[0117] In some embodiments, prior to the administration of psilocybin, the subject undergoes pre-exposure preparation sessions that include building a relationship of trust with the therapist who will be present during the psilocybin administration. In some embodiments, prior to the administration of psilocybin, the subject undergoes pre-exposure preparation sessions that include identifying personal themes and conflicts that may particularly affect the session experience. In some embodiments, the administration of psilocybin itself is performed by one therapist. In some embodiments, the psilocybin administration is performed by two therapists, for example, one male therapist and one female therapist who are present throughout the session. In some embodiments, the session is typically conducted in a room designed to be quiet, comfortable, and aesthetically pleasing. In some embodiments, to focus attention on oneself, it is recommended that the subject wear an eye shade and listen to a music program through headphones during the administration of psilocybin.

[0118] In some embodiments, the subject is monitored until the observer determines that the effects of psilocybin have fully subsided. In some embodiments, the subject may be discharged when the discharge criteria are met. In some embodiments, to be discharged, the subject needs to meet one criterion. In some embodiments, to be discharged, the subject needs to meet two or more criteria. In some embodiments, to be discharged, the subject needs to meet all the criteria. In some embodiments, the discharge criteria include the following: whether a responsible friend or family member can accompany the subject home, whether the subject's blood pressure and heart rate have returned to pre-dosing levels or normal levels, whether the supervisor determines that the subject has no acute effects of the medication, whether the subject believes they have returned to psychological criteria, whether the observer determines it is safe to discharge the subject, and whether the subject indicates that they are ready to go home.

[0119] D. Examples of Treatment Regimens Examples of treatment regimens according to the provided embodiments are described. In one example of a treatment regimen, a subject undergoes screening, preparatory treatment sessions, dosing, integrative treatment sessions, and up to 12 weeks of follow-up after psilocybin administration. The total period of participation in the study is approximately 5 months in total.

[0120] During the psilocybin administration session, 25 mg of psilocybin capsules are administered orally in a single dose. Session monitors are trained to reassure the subject if they experience acute anxiety, agitation, delusions, or panic.

[0121] After the psilocybin administration session, the subject participates in an in-person integrative session the day after dosing. Approximately 7 days after dosing, another integrative session is conducted, either via video or in person. All therapists involved in this process are trained by an independent group, and a psychotherapy manual regarding all stages of the process is provided to subjects receiving the psychedelic drug. Follow-up sessions are provided to evaluate and assess one or more parameters or metrics, as described in some aspects such as Section II, at various times after the administration session. An example schedule of treatment and evaluation according to the provided embodiments is shown in FIG. 1.

[0122] II. Treatment Outcomes, Observer-Assessed and Subject-Reported Parameters, and Measurement of Clinical Metrics In some aspects, the present disclosure provides methods and the use of psilocybin or its active metabolite for treating binge eating disorder (BED), which involves measuring one or more parameters or metrics related to or indicative of one or more symptoms, signs, or behaviors of BED, dissociative states, treatment outcomes, and safety, and / or related to the subject. In some aspects, an individual undergoing treatment according to the provided embodiments receives one or more evaluations before, during, and after treatment. In some aspects, the one or more metrics include parameters of observer assessment, parameters of subject report, and / or clinical metrics.

[0123] In some embodiments, the assessment of the individual undergoing treatment includes measurement of one or more physical scales of effectiveness, observer evaluations and subject-reported outcomes, quantification of clinical metrics, and combinations thereof. In some embodiments, the assessment of the individual undergoing treatment includes analysis of observer evaluations and / or subject reports, which includes evaluation of eating behavior, evaluation of response to treatment, psychological evaluation, evaluation of psychostimulant experience, and / or evaluation of clinical activity.

[0124] In some embodiments, the evaluation includes measurement of effectiveness or therapeutic effect. In some aspects, the evaluation includes, but is not limited to, indices of physique and weight, such as changes from criteria of body mass index (BMI), waist circumference, body weight, blood pressure, and blood lipid levels. In some embodiments, the evaluation of an individual undergoing treatment includes analysis of observer evaluation and / or subject self-report, for example, evaluation of eating behavior, evaluation of response to treatment, psychological evaluation, evaluation of psychostimulant experience, evaluation of clinical activities including binge eating evaluation, evaluation of the Binge Eating Scale (BES), impression of the primary therapist, daily binge eating episodes, food-related anxiety, depression related to eating behavior, depression related to weight management, and / or daily food diary, evaluation of the Clinical Global Impression - Improvement (CGI-I), evaluation of the Patient Global Impression - Improvement (PGI-I), evaluation of the Hospital Anxiety and Depression Scale (HADS), evaluation of the Emotion Breakthrough Inventory (EBI), questionnaire on acceptance and action (AAQ-II), questionnaire on mystical experience (MEQ30), questionnaire on difficult experience (CEQ), and / or evaluation of the Monitor Rating Scale (MRS). In some embodiments, the evaluation of an individual undergoing treatment includes quantitative measurement of clinical indicators. In some embodiments, the evaluation of an individual undergoing treatment includes quantitative measurement of neurological clinical indicators and metabolic biomarkers, including, but not limited to, brain morphology, brain activity, functional activation and / or functional connectivity, leptin concentration, adiponectin concentration, ghrelin concentration, glucose concentration, insulin concentration, and homeostasis model assessment of insulin resistance. In some embodiments, the clinical indicators are related to the metabolism of the individual undergoing treatment and include, but are not limited to, regulation of hunger and satiety, glucose metabolism, and glucose regulation by insulin.

[0125] In some aspects, due to the subjective nature and general difficulty of psychedelic intervention, it is difficult to objectively quantify the results in patients administered with psilocybin or its active metabolites. Exemplary approaches for quantifying treatment outcomes and safety can include observer evaluations and subject-reported results conducted in the form of time-limited surveys.

[0126] In some aspects, for example, one or more metrics associated with BED can include the frequency of binge eating episodes, improvement in overall clinical impression (CGI-I), waist circumference, and body mass index (BMI). In some aspects, the one or more metrics can include interest in the intake of trigger foods. In some aspects, the one or more metrics can include an evaluation of the Binge Eating Scale (BES). In some aspects, the one or more metrics can include a daily food diary.

[0127] In some aspects, the one or more metrics are related to the subject's response to treatment (e.g., change from baseline) and / or psychological state, psychedelic experience. In some aspects, the one or more metrics can include the Emotional Breakthrough Inventory (EBI), Mystical Experience Questionnaire (MEQ30), Challenging Experience Questionnaire (CEQ), Monitor Rating Scale (MRS), Hospital Anxiety and Depression Scale (HADS), and / or Acceptance and Action Questionnaire (AAQ-II).

[0128] In some aspects, an individual receiving treatment according to the provided embodiments undergoes one or more evaluations before, during, and after treatment. In some embodiments, the evaluation of the individual receiving the treatment includes physical measurements of treatment outcomes, observer evaluations and subject-reported results, quantification of clinical metrics, and combinations thereof.

[0129] In some embodiments, the evaluation includes measurement of treatment outcomes that are indicators of physique and / or weight. In some embodiments, the indicators of physique and / or weight are changes from the criteria of body mass index. In some embodiments, the indicators of physique and / or weight are changes from the criteria of waist circumference. In some embodiments, the indicators of physique and / or weight are changes from the criteria of body weight. In some embodiments, the indicators of physique and / or weight are changes from the criteria of blood lipid levels.

[0130] In some embodiments, the subject shows remission of one or more indicators between the baseline measurement and the outcome measurement. In some aspects, the subject shows improvement or remission of any of the described indicators related to BED and / or psychedelic experience. In some embodiments, the improvement is observed over a period of time after administration of a psychedelic, such as psilocybin or its active metabolite. In some aspects, the improvement (e.g., treatment effect) is durable and persistent even after a single administration of psilocybin or its active metabolite. In some embodiments, the improvement is observed for at least 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 improvement is observed for at least about 4 weeks. In some embodiments, the improvement is observed for at least about 8 weeks. In some embodiments, the improvement is observed for at least about 10 weeks. In some embodiments, the improvement is observed for at least about 12 weeks. In some embodiments, the improvement is observed for at least about 14 weeks. In some embodiments, the improvement is observed for at least about 16 weeks.

[0131] A. Parameters of Observer Evaluation and Subject Report In some embodiments, one or more metrics include parameters of observer assessment and subject reporting related to, for example, one or more symptoms or behaviors associated with BED, treatment outcomes, and / or experience of administration of psilocybin or its active metabolites (such as the subject's psychedelic experience). In some embodiments, the parameters of observer assessment and subject reporting indicate the treatment effect of the provided embodiments, such that, as a result, one or more symptoms, signs, or behaviors associated with BED are improved according to the provided methods and uses.

[0132] 1. Assessment of Eating Behavior Examples of parameters related to eating behavior and changes in eating behavior are evaluated before, during, and after treatment in an individual undergoing treatment according to the provided embodiments. In some embodiments, such parameters include the results of observer assessment and subject reporting.

[0133] a. Frequency of Binge Eating The assessment of binge eating frequency (FBE) is a 3-item patient-reported survey derived from the Eating Disorder Questionnaire (Fairburn and Beglin, Int J Eat Disorder 1994;16(4):363 - 70) and is used to quantify the frequency of binge eating episodes and similar behaviors that occurred in the past 4 weeks. Each item is answered with a numerical value that is totaled and compared to a control and / or "normal" FBE score. In some embodiments, changes from the criteria in FBE are utilized to evaluate the treatment of BED. In some embodiments, FBE is evaluated based on the subject's response to the following questionnaire (or its grammatical variations): "How many days in the past 28 days did such binge eating episodes (i.e., consuming an abnormally large amount of food and having a sense of loss of control at that time) occur?"

[0134] In some embodiments, the embodiments provided herein include assessing a change from a criterion in the assessment of the frequency of binge eating (FBE). In some embodiments, the assessment of the FBE is at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0135] In some embodiments, the FBE score of the individual undergoing treatment decreases during and / or after treatment. For example, the FBE score decreases by at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, or at least 30 points compared to the criterion. In some embodiments, the FBE of the individual undergoing treatment decreases during and / or after treatment. For example, the FBE decreases by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately by these degrees compared to the FBE in the criterion. In some embodiments, the improvement in the FBE is observed for at least about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks of administration. In some embodiments, the improvement in the FBE is observed for at least about 4 weeks. In some embodiments, the improvement in the FBE is observed for at least about 8 weeks. In some embodiments, the improvement in the FBE is observed for at least about 10 weeks.

[0136] b. Binge Eating Scale (BES) The Binge Eating Scale (BES) is a 16-item questionnaire that assesses specific binge eating behaviors that may indicate an eating disorder (Gormally et al., Addict Behav 1982;7(1):47-55). Specifically, the BES assesses both the manifestation of the behavior (e.g., eating large amounts of food) and the thought / feeling state surrounding the binge eating episode (e.g., guilt, fear of being unable to stop eating). Previous studies have validated the BES assessment, showing that response scores are appropriately discriminated among individuals judged by trained interviewers to have no binge eating disorder, moderate binge eating disorder, or severe binge eating disorder. Individuals undergoing treatment are scored on a scale of 0-64, with 0 indicating no problem with binge eating and 64 indicating severe binge eating disorder. In some embodiments, the BES is utilized to evaluate the treatment of BED.

[0137] In some aspects, the embodiments provided herein include assessing changes from the criteria in the Binge Eating Scale (BES) assessment. In some aspects, the BES assessment is completed at one or more time points after one or more administrations of psilocybin, for example, 2 to 20 weeks after one or more administrations of psilocybin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0138] In some embodiments, the BES score of an individual undergoing treatment decreases during and / or after treatment, for example, the BES 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, 12 points or more, 16 points or more, 20 points or more, 24 points or more, 36 points or more, 48 points or more, or 60 points or more.

[0139] c. Interest in trigger foods In some embodiments, the one or more metrics include a particular food that induces an overeating episode, an interest in consuming a triggering food, such as an overdesire for the triggering food or other foods.

[0140] In some embodiments, the embodiments provided herein include an assessment of whether a subject has an interest in consuming a triggering food. In some embodiments, the interest in consuming a triggering food is evaluated at one or more time points after one or more administrations of psilocybin, for example, 2 to 20 weeks after one or more administrations of psilocybin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0141] d. Overeating episodes per day In some embodiments, the number of overeating episodes per day is evaluated in the subject. In some embodiments, the number of overeating episodes per day is evaluated before the start of psychotherapy and / or before the administration of psilocybin. In some embodiments, the number of overeating episodes per day is evaluated both before the start of psychotherapy and before the administration of psilocybin. In some embodiments, two different evaluations of the number of overeating episodes per day account for past overeating behavior and the most recent overeating behavior immediately before starting the methods and uses according to the provided embodiments. In some embodiments, a change from a baseline in the number of overeating episodes per day is utilized to evaluate the treatment of BED. In some embodiments, the number of overeating episodes per day is evaluated based on the subject's response to the following question (or a grammatical variation thereof): "In the past 24 hours, how many times did you eat an amount of food that (considering the circumstances) would be considered an abnormally large amount by others?"

[0142] In some embodiments, the embodiments provided herein include evaluating a change from a baseline of the number of binge eating episodes per day. In some embodiments, the number of binge eating episodes per day is evaluated at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately at these time points.

[0143] In some embodiments, the score of the number of binge eating episodes per day of the individual undergoing treatment decreases during and / or after treatment. In some embodiments, the score of the number of binge eating episodes per day of the individual undergoing treatment decreases during and / or after treatment, for example, the number of binge eating episodes per day decreases by at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 points. In some embodiments, the score of the number of binge eating episodes per day of the individual undergoing treatment decreases during and / or after treatment, for example, the score of the number of binge eating episodes per day decreases by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately these degrees, compared to the score of the number of binge eating episodes per day in the baseline. In some embodiments, the score of the number of binge eating episodes per day decreases by at least 70% or about 70% compared to the score of the number of binge eating episodes per day in the baseline. In some embodiments, the score of the number of binge eating episodes per day decreases by at least 80% or about 80% compared to the score of the number of binge eating episodes per day in the baseline.

[0144] e. Loss of control and hyperphagia In some embodiments, the one or more metrics include the frequency of the sense of loss of control over eating. In some embodiments, the frequency of the sense of loss of control over eating indicates or is associated with hyperphagia. In some embodiments, the frequency of the sense of loss of control over eating is measured using an eating-related questionnaire. In some embodiments, the frequency of the sense of loss of control over eating is measured daily. The number of times the subject has a sense of loss of control over eating (loss of control score) per day is evaluated. In some aspects, the loss of control per day is evaluated before the start of psychotherapy and / or before the administration of psilocybin. In some aspects, the loss of control per day is evaluated both before the start of psychotherapy and before the administration of psilocybin. In some aspects, the two different evaluations of the loss of control per day account for the past sense of loss of control and the most recent sense of loss of control immediately before starting the methods and uses according to the provided embodiments. In some aspects, the change from the baseline in the sense of loss of control per day is utilized to evaluate the treatment of BED. In some aspects, the number of times the subject has a sense of loss of control over eating per day is evaluated based on the subject's response to the following question (or its grammatical variants): “How many times did you have a sense of loss of control over eating (during a meal)?”.

[0145] In some aspects, the embodiments provided herein include evaluating a change from a baseline in the loss of control per day. In some aspects, the loss of control per day is evaluated at one or more time points after one or more administrations of psilocybin, such as 2 to 20 weeks, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after the one or more administrations of psilocybin, or approximately at these time points.

[0146] In some embodiments, the score of loss of control per day for an individual undergoing treatment decreases during and / or after treatment. In some embodiments, the score of loss of control per day for an individual undergoing treatment decreases during and / or after treatment. For example, the score of loss of control per day decreases by at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 points. In some embodiments, the score of loss of control per day for an individual undergoing treatment decreases during and / or after treatment. For example, the score of loss of control per day decreases by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately these degrees, compared to the score of loss of control per day at the baseline. In some embodiments, the score of loss of control per day decreases by at least 70% or about 70% compared to the score of loss of control per day at the baseline. In some embodiments, the score of loss of control per day decreases by at least 80% or about 80% compared to the score of loss of control per day at the baseline.

[0147] 2. Response to Treatment Evaluation and Psychological Evaluation In some aspects, to evaluate an individual undergoing treatment according to the provided embodiments, the individual is subjected to one or more evaluations to determine the response to treatment and / or the psychological state (e.g., change from the baseline). In some embodiments, the evaluations for determining the response to treatment and / or the psychological state include, for example, evaluation of the Clinical Global Impression - Improvement (CGI - I), evaluation of the Patient Global Impression - Improvement (PGI - I), evaluation of the Hospital Anxiety and Depression Scale (HADS), and / or evaluation of the Emotional Breakthrough Inventory (EBI).

[0148] In some embodiments, one or more evaluations are completed at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2, 4, 6, 8, 10, 12, 14, and / or 16 weeks after said administration, or approximately after these time points.

[0149] a. Improvement in general clinical impression (CGI-I) The evaluation of the improvement in general clinical impression (CGI-I) is an assessment by a clinician of the change in the health status of an individual receiving treatment, where the individual is sometimes compared to a baseline state within the past 7 days (Guy W., Manual of Psychopharmacological Evaluation (Revised Edition) 1976: 217-21). The individual receiving treatment is evaluated on a scale of 1 to 7 for the baseline state, where 1 means not ill at all and 7 means the most severely ill patient. The individual receiving treatment is then evaluated on a scale of 1 to 7 for the current state, where 1 means "much improved" from the baseline (start of treatment), 4 means no change in state from the baseline, and 7 means "much worsened" compared to the baseline. In some embodiments, the change from the baseline in the CGI-I scale is utilized to evaluate the treatment of BED.

[0150] In some embodiments, the methods provided herein include a change from the baseline in the evaluation of the improvement in general clinical impression (CGI-I). In some aspects, the evaluation of said CGI-I is completed at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2, 4, 6, 8, 10, 12, 14, and / or 16 weeks after said administration, or approximately after these time points.

[0151] In some embodiments, the CGI-I score of the individual undergoing treatment improves during and / or after treatment. For example, 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 or more. In some aspects, the CGI-I related improvement includes reducing the score of the baseline state and reducing the score of the current state.

[0152] b. Degree of improvement in the patient's global impression (PGI-I) Similar to CGI-I, the degree of improvement in the patient's global impression (PGI-I) is what the patient reports regarding the effectiveness of treatment (Guy W., Psychopharmacology Evaluation Manual (Revised Edition) 1976: 217 - 21). The individual undergoing treatment evaluates their baseline state on a scale of 1 - 7, where 1 means not ill at all and 7 means the most severe illness experienced. The individual then evaluates their current state on a scale of 1 - 7, where 1 means "very improved" from the baseline (start of treatment), 4 means no change in state from the baseline, and 7 means "very deteriorated" compared to the baseline. In some embodiments, the PGI-I scale is utilized to evaluate the treatment of BED.

[0153] In some embodiments, the methods provided herein include an evaluation of the degree of improvement in the patient's global impression (PGI-I). In some aspects, the evaluation of the PGI-I is completed at one or more time points after one or more administrations of silodosin, for example, 2 weeks to 20 weeks after one or more administrations of silodosin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0154] In some embodiments, the PGI-I score of the individual undergoing treatment decreases during and / or after treatment. For example, the PGI-I score decreases by 1 point or more, 2 points or more, 3 points or more, 4 points or more, or 5 - 7 points or more. In some aspects, the improvement related to PGI-I includes reducing the score of the current state compared to a baseline. In some aspects, the PGI-I score is improved by at least 1 point, 2 points, or 3 points, or approximately those numbers of points, compared to a baseline.

[0155] c. Hospital Anxiety and Depression Scale (HADS) The assessment of the Hospital Anxiety and Depression Scale (HADS) aims to measure psychological distress, anxiety, and depression using a 14-item questionnaire. Among them, 7 items are designated for the subscale related to depression (HADS-Depression), and the other 7 items are designated for the subscale related to anxiety (HADS-Anxiety) (Zigmond and Snaith, Acta Psychiatr Scand 1983;67(6):361 - 70). The part related to depression focuses particularly on anhedonia, that is, the ability to feel pleasure, while the part related to anxiety addresses common symptoms shared by many anxiety disorders. As an assessment method, each item of HADS is scored on a response scale with 4 options from 0 to 3. Next, the responses are summed to obtain a total score for each of the two subscales. An individual is evaluated as normal 0 - 7, borderline abnormal (case) 8 - 10, or abnormal (case) 11 - 21. It is generally considered best practice to interpret using a cut-off score of 8 or more for both the HADS-Anxiety and HADS-Depression subscales.

[0156] In some embodiments, the embodiments provided herein include evaluating a change from a criterion in the evaluation of the Hospital Anxiety and Depression Scale (HADS). In some embodiments, the evaluation of the HADS is performed at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0157] In some embodiments, the HADS is utilized to evaluate the treatment of BED. In some embodiments, the HADS score of the individual receiving the treatment decreases during and / or after the treatment. For example, the HADS score decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, or 8 points, or more points, or approximately those numbers of points. In some embodiments, the HADS score of the individual receiving the treatment decreases during and / or after the treatment. For example, the HADS score decreases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately those extents, compared to the HADS score in the criterion. In some embodiments, the HADS score decreases by at least 50% or approximately 50% compared to the HADS score in the criterion.

[0158] In some embodiments, the HADS anxiety score is utilized to evaluate the treatment of BED. In some embodiments, the HADS anxiety score of the individual undergoing treatment decreases during and / or after treatment. For example, the HADS anxiety score decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, or more points, or approximately those numbers of points. In some embodiments, the HADS anxiety score of the individual undergoing treatment decreases during and / or after treatment. For example, the HADS anxiety score decreases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately those percentages compared to the HADS anxiety score at baseline. In some embodiments, the HADS anxiety score decreases by at least 50% or approximately 50% compared to the HADS anxiety score at baseline. In some aspects, the improvement is observed for at least about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after administration.

[0159] In some embodiments, the HADS depression score is utilized to evaluate the treatment of BED. In some embodiments, the HADS depression score of the individual undergoing treatment decreases during and / or after treatment. For example, the HADS depression score decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, or more points, or approximately those numbers of points. In some embodiments, the HADS depression score of the individual undergoing treatment decreases during and / or after treatment. For example, the HADS depression score decreases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or approximately those extents, compared to the HADS depression score at the baseline. In some embodiments, the HADS depression score decreases by at least 50% or approximately 50% compared to the HADS depression score at the baseline. In some aspects, the improvement is observed at least about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after administration.

[0160] d. Questionnaire on acceptance and behavior (AAQ-II) The evaluation of the Questionnaire on Acceptance and Behavior (AAQ-II) is a scale of psychosocial flexibility that is broadly defined as the ability to fully engage with the present moment and the thoughts and feelings contained therein without unnecessary defensiveness (Hayes et al., Psychological Record 2004;54:553-78; Bond et al., Behav Ther 2011;42(4):676-88). The evaluation of the AAQ-II includes 7 items. Each answer is assigned a numerical value from 1 to 7, where 1 means not at all applicable, 4 means sometimes applicable, and 7 means always applicable. The answers to each item are totaled, and the total score is interpreted to determine the individual's psychological flexibility. Note that the range of 24-28 has generally been noted to be associated with depression, anxiety, and / or related symptoms. In some embodiments, it is utilized to evaluate the treatment of one or more symptoms, signs, or behaviors associated with BED, such as depression, anxiety, and / or symptoms related to food and eating.

[0161] In some aspects, the embodiments provided herein include evaluating changes from criteria in the assessment of the Acceptance and Action Questionnaire (AAQ-II). In some aspects, the assessment of the AAQ-II is completed at one or more time points after one or more administrations of psilocybin, for example, 2 to 20 weeks after one or more administrations of psilocybin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0162] In some embodiments, the AAQ-II score of the individual undergoing treatment decreases during and / or after treatment. For example, the AAQ-II score decreases by at least 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, or 45 points, or approximately by those numbers of points.

[0163] 3. Evaluation of Psychedelic Experience and Clinical Activity In some aspects, to evaluate the psychedelic experience and related clinical effects of an individual undergoing treatment according to the provided embodiments, the individual is subjected to one or more evaluations to assess the psychedelic experience and clinical activity in response to the treatment.

[0164] In some aspects, one or more parameters or metrics related to the psychedelic experience can measure or evaluate the dissociative effects and states in subjects suffering from BED during or after the administration of psilocybin or its active metabolite. In some embodiments, the relationship between clinical activity or treatment outcome (e.g., measured by one or more parameters or metrics related to the psychedelic experience) and the intensity of the psychedelic experience can be evaluated.

[0165] In some embodiments, the assessment for evaluating the psychedelic experience and clinical activity for treatment includes, for example, assessment of the Mystical Experience Questionnaire (MEQ30), assessment of the Challenging Experience Questionnaire (CEQ), and / or the Monitor Rating Scale (MRS) questionnaire. In some embodiments, one or more psychedelic assessments are completed at one or more time points, such as one day or about one day after one or more administrations of psilocybin or its active metabolite.

[0166] a. Mystical Experience Questionnaire (MEQ30) A questionnaire regarding mystical experiences (derived from MEQ43, a shortened MEQ or MEQ30) is an assessment completed by the patient, which includes four elements: mysticism (e.g., scales of inner unity, outer unity, perceptual quality, sacredness), positive mood, transcendence of time and space, and ineffability (Barrett et al., J Psychopharmacol 2015;29(11):1182 - 90). MEQ30 predicts the sustained therapeutic effects of psychedelic experiences (e.g., changes in attitude, behavior, and well - being) and functions as an important scale for an individual's mystical experiences. The MEQ30 assessment includes 30 items spanning the four elements, and each item is rated on a scale of 0 - 5. Here, 0 is "none, not at all", 1 is "very slight and indistinguishable", 2 is "slight", 3 is "moderate", 4 is "strong (equivalent to a strong past experience or expectation regarding this description)", and 5 is "extreme (the strongest in one's life and stronger than 4)". Across these 30 items, the four elements, i.e., sub - categories, include different items. Mysticism is composed of items 4 - 6, 9, 14 - 16, 18, 20, 21, 23 - 26, and 28. Positive mood is composed of items 2, 8, 12, 17, 27, and 30. Space / time is composed of items 1, 7, 11, 13, 19, and 22. And ineffability is composed of items 3, 10, and 29. The scores of each item within a sub - category or across the entire MEQ30 set are summed and divided by the corresponding total points and converted to a percentage. A "complete experience" is defined as having an MEQ30 score of 60% or more in total across all four sub - categories, and the complete experience correlates with more significant and / or long - term therapeutic effects.

[0167] In some aspects, the embodiments provided herein include assessing changes from the criteria in the MEQ30 assessment. In some aspects, the MEQ30 assessment is completed at one or more time points, such as one day after one or more administrations of psilocybin.

[0168] b. Emotional Breakthrough Inventory (EBI) The Emotion Breakthrough Inventory (EBI) is a 6-item assessment that evaluates emotional breakthroughs during psychedelic experiences and is considered an important factor and key mediator of long-term psychological changes (Roseman et al., J Psychopharmacol 2019;33(9):1076-87). The EBI score appears to be dose-dependent as predicted and is complementary to other established and widely used assessments such as the Mystical Experience Questionnaire (MEQ) and the Challenging Experience Questionnaire (CEQ). The items within the EBI assessment are evaluated using a Visual Analogue Scale (VAS) (0-100, increment unit is 1), where 0 is defined as "no, not more than usual" and 100 is defined as "yes, all or completely".

[0169] In some aspects, the embodiments provided herein include evaluating a change from a criterion in the assessment of the Emotion Breakthrough Inventory (EBI). In some aspects, the evaluation of the EBI is completed at one or more time points after one or more administrations of psilocybin, such as 2 to 20 weeks after one or more administrations of psilocybin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0170] c. Challenging Experience Questionnaire (CEQ) Due to the powerful experiences induced by conventional hallucinogens (e.g., psilocybin), patients undergoing treatment can endure one or more acute adverse psychological reactions (i.e., extremely unpleasant or difficult experiences). Case reports and anecdotal evidence suggest that symptoms such as emotional symptoms (panic, depression), cognitive symptoms (confusion, a sense of losing one's mind), and physical symptoms (nausea, palpitations) can occur (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). Understanding the range and severity of symptoms helps to tailor patient care and predict patient needs during future treatment sessions. The Challenging Experience Questionnaire (CEQ) takes up seven major elements (sadness, fear, death, psychosis, isolation, physical pain, delusions) and provides a phenomenological profile of the challenging aspects that patients experience or may experience during treatment (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). The CEQ assessment includes 26 items. Each answer is assigned a numerical value from 0 to 5, where 0 is "none, not at all" and 5 is "extreme (the most in one's life so far)". Across these 26 items, the seven elements or subcategories are composed of various items. Here, "sadness" is composed of items 2, 6, 9, 11, 23, and 25, "fear" is composed of items 4, 7, 14, 21, and 26, "death" is composed of items 16 and 20, "psychosis" is composed of items 8, 13, and 19, "isolation" is composed of items 1, 10, and 24, "physical pain" is composed of items 3, 5, 15, 17, and 18, and "delusions" is composed of items 12 and 22. The answers are summed within each subcategory and converted to a percentage of the total possible points. Further, the answers for all items are summed and converted to a percentage of the total possible points.

[0171] In some aspects, the embodiments provided herein include evaluating changes from the criteria in the assessment of the Challenging Experience Questionnaire (CEQ). In some aspects, the CEQ assessment is completed at one or more time points, such as one day after one or more administrations of psilocybin.

[0172] d. Monitor-based Rating Scale (MRS) The questionnaire for the monitor-based rating scale (MRS) is completed by a clinician and involves assessing and scoring dimensions of the participant's behavior and / or mood during the treatment session (Griffiths et al., Psychopharmacology Berl 2006;187(3):268-83). The MRS assessment includes 20 items (or dimensions). Some dimensions are assigned numerical values from 0 to 4, where 0 is "none, no effect" and 4 is "peak effect, occurring frequently". For other dimensions, the score is assigned as the total duration (in minutes, within a defined time frame) of the period during which the patient's behavior (e.g., conversation with the clinician or total speech) was observed. The dimension scores are summed within each subcategory or across all dimensions.

[0173] In some aspects, the embodiments provided herein include evaluating a change from a criterion in the assessment of the monitor-based rating scale (MRS) questionnaire. In some aspects, the evaluation of the MRS is completed at one or more time points, such as one day after one or more administrations of silibinin.

[0174] In some embodiments, the MRS score of the individual undergoing treatment improves during and / or after treatment. For example, 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.

[0175] B. Clinical indicators In some aspects, one or more indicators include clinical indicators such as one or more indicators that can be measured in a clinic, e.g., metabolic biomarkers or neurological indicators.

[0176] 1. Metabolic biomarkers In some embodiments, BED may be caused by excessive and unhealthy eating habits, leading to obesity and weight-related health disorders (e.g., diabetes). A person may experience dysfunctional or uncontrollable hunger and lack of satiety after eating, which may lead to excessive intake beyond the current body's energy requirements (Heymsfield et al., Obesity (Silver Spring) 2014;22(01):S1-S17). The regulation of hunger and satiety, and the metabolism and regulation of glucose can be evaluated by quantifying important metabolites involved in these pathways.

[0177] In some embodiments, the embodiments provided herein include evaluating changes from criteria in the assessment of metabolic biomarkers. In some embodiments, an individual undergoing treatment according to the provided embodiments undergoes measurement of metabolic biomarkers. In some embodiments, exemplary measurements include quantification of plasma levels of important metabiolites, including ghrelin, leptin, adiponectin, glucose, and insulin, and / or assessment of the homeostasis model of insulin resistance. In some embodiments, the measured values of the metabolic biomarkers are collected using one or more quantitative analysis techniques, such as mass spectrometry, liquid chromatography, antibody-based detection and quantification, immunoassay, activity-based assay, or other methods for detecting metabolites and analytes.

[0178] In some embodiments, the quantification of plasma levels of one or more of important metabolic biomarkers, such as ghrelin, leptin, adiponectin, glucose, and insulin, and / or the assessment of the homeostasis model of insulin resistance, is performed at one or more time points before one or more administrations of silibinin and at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2, 4, 6, 8, 10, 12, 14, and / or 16 weeks after said administration, or approximately at these time points.

[0179] a. Regulation of hunger and satiety Hunger is a strong desire or physical need for food, and satiety is the feeling that persists after eating (Smith and Ferguson, Dev Disabil Res Rev 2008;14:96-104). These are two important elements in the regulation of normal eating habits, and dysregulation can lead to weight-related problems such as overeating and obesity (Benelam B, Nutr Bull 2009;34:126-73). The regulation of hunger and satiety is extremely complex and depends on multiple signaling pathways both inside and outside the central nervous system (CNS) (Graaf et al., Am J Clin Nutr 2004;79(6):946-61). This regulation includes a temporal aspect in which some biomolecules (e.g., ghrelin) are involved in short-term regulation and other molecules (e.g., leptin and adiponectin) are involved in long-term hunger regulation. As a characteristic of normal metabolism and its deviation, the quantification of these metabolic biomolecules (or biomarkers) is an important element for understanding the physiological state of individuals suffering from metabolic disorders including BED. In some embodiments, changes from a standard in one or more aspects of the regulation of hunger and satiety are utilized to evaluate the treatment of BED. In some embodiments, aspects of the regulation of hunger and satiety include, for example, the level of ghrelin, the level of leptin, and / or the level of adiponectin.

[0180] (i) Ghrelin Ghrelin is a short peptide hormone that functions as an important regulator of nutrient sensing, meal initiation, and appetite. Ghrelin is often referred to as the "hunger hormone" because its levels increase in association with increased hunger and food consumption (Davis, J Brain Res 2018;1693(Pt B):154-158). Ghrelin plays an important regulatory role throughout the body and is an important factor in the development of obesity, insulin resistance, and diabetes (Pradhan et al., Curr Opin Clin Nutr Metab Care 2013;16(6):619-24). In some embodiments, changes from a baseline in ghrelin levels are utilized to evaluate the treatment of BED. In some embodiments, the quantification of ghrelin is performed at one or more time points before one or more administrations of silodosin and at one or more time points after one or more administrations of silodosin, for example, 2 to 20 weeks after one or more administrations of silodosin, or approximately after this period, for example, 2, 4, 6, 8, 10, 12, 14, and / or 16 weeks after said administration, or approximately after these time points. In some embodiments, the level of ghrelin decreases in the patient being treated, for example, the decrease in the level of said ghrelin is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to the baseline.

[0181] (ii) Leptin Leptin plays an important role in the regulation of energy balance and metabolic homeostasis. Impairment of leptin signaling is deeply involved in the development of obesity and metabolic diseases (e.g., diabetes and cardiovascular diseases) (Obradovic et al., Front Endocrinol (Lausanne) 2021;12:585887). Leptin functions to suppress appetite, reduce food intake, and promote mitochondrial oxidation and thermogenesis (Liu et al., Adv Exp Med Biol 2018;1090:123-144). In some embodiments, changes from a baseline level of leptin are utilized to evaluate the treatment of BED. In some embodiments, the quantification of leptin is performed at one or more time points before one or more doses of silibinin and at one or more time points after one or more doses of silibinin, e.g., 2 to 20 weeks after one or more doses of silibinin, or approximately after this period, e.g., 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points. In some embodiments, the level of leptin increases in the patient receiving the treatment, e.g., the increase in the level of said leptin is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to the baseline.

[0182] (iii) Adiponectin Adiponectin (a 30 kDa adipocyte complement-related protein, or Acrp30) is an adipokine endocrine factor synthesized and released from adipose tissue. Adiponectin is the most abundant peptide secreted from adipocytes, and its decrease plays a central role in obesity-related diseases including type 2 diabetes and cardiovascular diseases (Achari and Jain, Int J Mol Sci 2017;18(6):1321). In some embodiments, changes from a baseline in the level of adiponectin are utilized to evaluate the treatment of BED. In some embodiments, the quantification of adiponectin is performed at one or more time points before one or more administrations of silibinin and at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2, 4, 6, 8, 10, 12, 14, and / or 16 weeks after said administration, or approximately after these time points. In some embodiments, the level of adiponectin increases in the patient receiving the treatment, for example, the increase in the level of said adiponectin is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to the baseline.

[0183] b. Glucose metabolism and regulation Inappropriate glucose metabolism and regulation are characteristic features of diseases most frequently associated with type 2 diabetes (Roden and Shulman, Nature 2019;576(7785):51-60). Abnormal glucose regulation and / or insulin sensitivity are known to have a genetic origin but are also strongly influenced by environmental and lifestyle factors. Understanding the state of glucose metabolism and regulation in individuals suffering from BED is essential for a comprehensive assessment. In some embodiments, changes from criteria in glucose metabolism and regulation are utilized to evaluate the treatment of BED. In some embodiments, glucose quantification is performed at one or more time points before one or more doses of silibinin and at one or more time points after one or more doses of silibinin, for example, 2 to 20 weeks after one or more doses of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0184] (i) Glucose In some embodiments, glucose levels are utilized to evaluate the treatment of BED. In the case of an average adult, normal blood glucose levels are defined as less than 100 mg / dL fasting before meals; less than 140 mg / dL two hours after meals, elevated blood glucose levels are defined as 100 - 125 mg / dL fasting before meals; 140 - 199 mg / dL two hours after meals, and hyperglycemic levels are defined as greater than 126 mg / dL fasting before meals; greater than 200 mg / dL two hours after meals.

[0185] In some embodiments, the quantification of glucose is performed at one or more time points before one or more administrations of silibinin and at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points. In some embodiments, the level of glucose is reduced in the patient being treated, for example, the reduction of said glucose level is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to a reference.

[0186] (ii) Insulin Insulin is a hormone secreted from the pancreatic β-cells (islets of Langerhans) in response to food consumption and energy availability, and directs an increase in glucose uptake and storage to lower and / or maintain blood glucose levels. Insulin regulates complex metabolic changes associated with changes in metabolic pathways, energy management, immune function, and other important aspects essential for a healthy life. Lifestyle, environmental, and genetic factors can lead to insulin resistance, i.e., overeating, unhealthy eating habits, and lack of physical activity, or a generally sedentary lifestyle. Insulin resistance is a major risk factor for developing one or more disease states including, but not limited to, diabetes, metabolic syndrome, heart disease, liver disease, polycystic ovary syndrome, cancer, and cognitive decline (PCOS) (Wilcox G., Clin Biochem Rev 2005;26(2):19-39). In the case of an average adult, insulin levels are defined as normal when they are less than 25 μU / L fasting, 30 - 230 μU / L 30 minutes after glucose administration, 18 - 276 μU / L 1 hour after glucose administration, and 16 - 166 μU / L 2 hours after glucose administration.

[0187] In some embodiments, the insulin quantification is performed at one or more time points before one or more administrations of silibinin and at one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0188] (iii) Insulin resistance Insulin resistance is a term that indicates a certain degree of dysfunction and / or impairment with respect to the effects of insulin on glucose uptake, storage, and metabolism (Kahn and Flier J Clin Ivest 2000;106(4):473-81; Wilcox G., Clin Biochem Rev 2005;26(2):19-39). Since insulin and appropriate insulin sensitivity play important roles in maintaining proper health, insulin resistance is a major risk factor for developing one or more disease states including, but not limited to, diabetes, metabolic syndrome, heart disease, liver disease, polycystic ovary syndrome, cancer, and cognitive decline (PCOS). The homeostasis model assessment of insulin resistance (HOMA-IR) is a common analytical strategy for evaluating the spectrum of insulin sensitivity and resistance, and HOMA-IR is defined by the formula of multiplying fasting plasma glucose (mmol / L) by fasting serum insulin (mU / L) and dividing by 22.5 (Matthews et al., Diabetologia 1985;28:412-19). In the case of an average adult, insulin sensitivity is defined as normal or high insulin sensitivity when the HOMA-IR score is less than 1.0, insulin resistance when the HOMA-IR score exceeds 1.9, and significant insulin resistance when the HOMA-IR score is less than 2.9. In some embodiments, insulin resistance is measured using the HOMA-IR approach. In some embodiments, HOMA-IR is measured at one or more time points before one or more administrations of silibinin and at one or more time points after one or more administrations of silibinin, for example, 2 weeks to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.In some embodiments, the HOMA-IR score decreases in the subject undergoing treatment. For example, the decrease in the HOMA-IR score is at least 0.1 point, at least 0.2 point, at least 0.3 point, at least 0.4 point, at least 0.5 point, at least 1 point, at least 1.5 points, or more than 2 points less compared to the baseline.

[0189] 2. Neurophysiological Clinical Indicators Neurophysiological clinical indicators such as brain morphology, connectivity, and functionality can be measured by various methodologies, technological advancements, and rapidly evolving neuroinformatics, which are important elements in the subsequent analysis of large datasets from population-scale 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 indicators can be used to more quantitatively measure brain-specific changes during development, aging, learning, disease, and in response to acute stimuli such as small molecule compounds and biomolecules (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). Using such indicators, changes and improvements during and after administration of a psychoactive compound such as psilocybin can be measured according to the provided embodiments.

[0190] In some embodiments, an individual undergoing treatment according to the provided embodiments undergoes measurement of one or more neurophysiological clinical metrics such as voxel-based morphometry, multi-state functional connectivity and activation analysis based on functional magnetic resonance imaging (fMRI), and / or electroencephalogram (EEG) analysis. In some cases, an individual undergoing treatment according to the provided embodiments is made to undergo one or more neurophysiological clinical metric measurements to quantify, for example, the morphology of the brain including the volume and structure of the gray matter, and the brain activity including resting EEG activity and multi-state functional connectivity and activation patterns.

[0191] a. Brain morphology In some embodiments, the morphology of the brain, including the volume and structure of the gray matter, can be evaluated (Dolz et al., Comput Med Imaging Graph 2020;79:101660; Shofty et al., World Neurosurg 2020;134:e1l43-e1l47). Gray matter, which occupies most of the nerve cell bodies in the brain (Lee et al., Sci Total Environ 2020;707:135603; Chiao et al., Methods Mol Biol 2020;2092:65-75), is related to appropriate cognitive abilities, and a decrease in the volume of gray matter corresponds to 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). Voxel-based morphometry (VBM) is a neuroimaging technique that quantifies local differences in the anatomical structure of the brain, and images of the central components in the brain (e.g., gray matter, white matter, and cerebrospinal fluid) are anatomically normalized and processed according to various computational algorithms and statistics (Wright et al., Schizophr Res 1999;35(1):1-14; Ashburner and Friston Neuroimage 2000;11(6 Pt 1):805-21). Thus, VBM enables global and local volume comparisons between different groups (Andujar et al., Brain Sci 2021;11(8):999).

[0192] In some embodiments, changes from the baseline in VBM are utilized to evaluate the brain morphology of the individual undergoing treatment. In some embodiments, resting-state VBM is performed before and after treatment. In some embodiments, resting-state VBM is performed approximately one week prior to the start of treatment and approximately four weeks and / or eight weeks after one or more administrations of silibinin, for example, approximately four weeks after. In some embodiments, the volume of gray matter of the individual undergoing treatment increases during and / or after treatment. For example, the volume of gray matter increases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or at least 10% compared to the baseline.

[0193] b. 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 in milliseconds through the scalp, and the recorded signals represent the macroscopic activity of the brain. fMRI detects blood flow changes in the brain, and these changes correspond to local and site-specific changes in activity. In some embodiments, the measurement of brain activity is performed approximately one week prior to the start of treatment and approximately four weeks and / or eight weeks after one or more administrations of silibinin, for example, approximately four weeks after. In some embodiments, brain activity is utilized to evaluate the treatment of BED, for example, using fMRI and / or EEG analysis.

[0194] (i) Functional activation and / or connectivity In some embodiments, functional connectivity and activation are often characterized by functional magnetic resonance imaging (fMRI) analysis, using arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) to measure changes in blood flow and functional connectivity in various brain regions at various time points (such as before treatment, during treatment, and / or after treatment, etc.) (Soares et al., Front Neurosci 2016;10:515). In some embodiments, changes from a baseline in functional connectivity and / or activation are utilized to evaluate the treatment of BED.

[0195] In some embodiments, exemplary metrics measured by fMRI include functional connectivity (resting state, feeding and fasting), functional activation (food cue-responsive tasks, feeding and fasting), functional connectivity (food cue-responsive tasks, feeding and fasting), and / or voxel-based morphometry (gray matter volume / structure).

[0196] In some embodiments, the assessment of functional connectivity is completed in the resting state, where the individual undergoing treatment is in either a fed or fasted state. In some embodiments, the assessment of functional connectivity and / or activation is completed in a task-related state, where the individual undergoing treatment exhibits food cue responsiveness to a given task and is in either a fed or fasted state. In some embodiments, resting-state functional connectivity fMRI is performed before and after treatment. In some embodiments, task-related functional activation and connectivity fMRI are performed before and after treatment. In some embodiments, resting-state functional connectivity fMRI is performed approximately 1 week before the start of treatment and approximately 4 weeks and / or 8 weeks after one or more administrations of silodosin, for example, approximately 4 weeks after. In some embodiments, task-related functional activation and connectivity fMRI are performed approximately 1 week before the start of treatment and approximately 4 weeks and / or 8 weeks after one or more administrations of silodosin, for example, approximately 4 weeks after.

[0197] In some embodiments, the embodiments provided herein include assessing a change from a baseline in the analysis of functional magnetic resonance imaging (fMRI). In some embodiments, fMRI is performed at one or more time points after one or more administrations of psilocybin, for example, 2 to 20 weeks after one or more administrations of psilocybin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or approximately after these time points.

[0198] In some embodiments, the fMRI data of the individual undergoing treatment change during and / or after treatment.

[0199] (ii) Electroencephalogram (EEG) EEG is less spatially sensitive but convenient and effective for recording high-resolution transient brain activity (Michel and Brunet, Front Neurol 2019;10:325). By directly measuring the scalp electrically, information on a millisecond time scale is provided as compared to the seconds or minutes required for other preferred methods. EEG is limited to measuring the uppermost layer of the brain, but when combined with other brain activity measurements (e.g., fMRI), EEG provides important data for a comprehensive view and quantitative assessment of brain activity (Abreu et al., Front Hum Neurosci 2018;12:29). In some embodiments, changes from a baseline in EEG are utilized to evaluate the treatment of BED.

[0200] In some embodiments, examples of metrics measured using EEG include explosive synchronization of resting network activity and power spectrum analysis (frequency bands).

[0201] In some embodiments, resting EEG is performed before and after treatment. In some embodiments, resting EEG is performed approximately one week before the start of treatment and approximately four weeks and / or eight weeks after one or more administrations of silibinin, for example, approximately four weeks after. In some aspects, the embodiments provided herein include evaluating changes from a baseline in electroencephalogram (EEG) analysis. In some aspects, EEG is performed at one or more time points after one or more administrations of silibinin, for example, two to twenty weeks after one or more administrations of silibinin, or approximately after this period, for example, two weeks, four weeks, six weeks, eight weeks, ten weeks, twelve weeks, fourteen weeks, and / or sixteen weeks after said administration, or approximately after these time points, for example, four weeks or approximately four weeks after administration.

[0202] In some embodiments, the resting EEG data of the individual undergoing treatment changes during and / or after treatment.

[0203] C. Indicators Related to Body and Weight and Clinical Examination Parameters In some aspects, the one or more indicators include indicators related to body and weight and various clinical examination parameters, such as vital signs, hematological parameters, and blood chemistry parameters. Indicators related to body and weight are convenient and typical measurement criteria for inferring the health and medical risks of a subject, and these include, but are not limited to, body mass index (BMI) and waist circumference (USPSTF Ann Intern Med 2003;139(11):930 - 2; Barton M., Pediatrics 2010;125(2):361 - 7). In some embodiments, the indicators related to body and weight are changes from the criteria of BMI, waist circumference, and / or weight.

[0204] 1. Body Mass Index (BMI) The body mass index (BMI) is calculated by dividing the weight in kilograms by the square of the height in meters and is a convenient way to screen for individuals with a high degree of obesity, who are likely to be overweight or nearly overweight (Gallegher et al., Am J Epidemiol 1996;143(3):228-39). In extreme cases, it can lead to obesity or morbid obesity, and weight-related health complications can be severe and life-threatening. People with high BMI levels have an increased risk of mortality (all causes of death), high blood pressure, elevated cholesterol levels, elevated triglyceride levels, diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and other respiratory complications, chronic inflammation, certain types of cancer, decreased quality of life, depression, anxiety, increased pain, decreased physical function, etc. (NHLBI 2013 Management of Overweight and Obesity in Adults: A Systematic Evidence Review by an Obesity Expert Panel; Bhaskaran et al., Lancet 2014;384(9945):755-65). In adults, a BMI of 18.5-24.9 is considered a healthy weight, less than 18.5 is considered underweight, 25.0-29.9 is considered overweight, and 30.0 or higher is considered obese. Although BMI does not take into account athletic body types or people with a lot of muscle mass, athletes represent a very small portion of the population. For most people, BMI and other weight-related indicators are very accurate (Garrow and Webster Int J Obes 1985;9(2):147-53; Freedman et al., Am J Clin Nutr 2013;98(6):1417-24; Wohlfahrt-Veje et al., Eur J Clin Nutr 2014;68(6):664-70; Flegal and Graubard Am J Clin Nutr 2009;89(4):1213-19), and using them in combination (e.g., BMI and waist circumference) is even more effective (Zhang et al., Circulation 2008;117(13):1658-67; Ross et al., Nat Rev Endocrinol 2020;16(3):177-89). In some embodiments, in these embodiments, changes from the criteria in BMI are utilized to evaluate the treatment of BED.

[0205] In some embodiments, the embodiments provided herein include evaluating the maximum change from a criterion in post-treatment BMI. In some embodiments, the evaluation includes one or more time points after one or more administrations of silibinin, for example, 2 to 20 weeks after one or more administrations of silibinin, or approximately after this period, for example, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or one or more BMI evaluations at approximately these time points.

[0206] In some embodiments, the BMI of the individual undergoing treatment decreases during and / or after treatment, for example, the BMI decreases by at least 1, at least 2, at least 3, at least 4, at least 5, or at least 10 compared to the criterion.

[0207] 2. Waist circumference The waist circumference is a physical characteristic used to determine abdominal fat accumulation and general obesity (Ross et al., Nat Rev Endocrinol 2020;16(3):177 - 89). The waist circumference correlates well with BMI, and similarly, a large waist size is associated with serious and life-threatening health complications related to weight. In the case of adult men, a waist circumference exceeding 40 inches is considered obese. In the case of adult women, a waist circumference exceeding 35 inches is considered obese. In some embodiments, the change from a criterion of waist circumference is utilized to evaluate the treatment of BED.

[0208] In some embodiments, the embodiments provided herein include evaluating the maximum change from a baseline in the waist circumference after treatment. In some embodiments, the evaluation includes one or more time points after one or more administrations of silibinin, for example, 1 to 36 months after one or more administrations of silibinin, or after approximately this period, for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months after said administration, or evaluating one or more waist circumferences at approximately these time points.

[0209] In some embodiments, the waist circumference of the individual undergoing treatment decreases during and / or after treatment, for example, the waist circumference decreases by at least 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 15 cm, 20 cm, 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, or 50 cm, or approximately to these extents, compared to the baseline.

[0210] 3. Body weight Weight gain, along with measurements of BMI and waist circumference, is strongly correlated with adverse health effects and outcomes, as described in the above section. In extreme cases, an individual may become obese or morbidly obese, and weight-related health complications can be severe and life-threatening. People with increased weight are at higher risk of mortality (from all causes), high blood pressure, elevated cholesterol levels, elevated triglyceride levels, diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and other respiratory complications, chronic inflammation, certain types of cancer, decreased quality of life, depression, anxiety, increased pain, decreased physical function, etc. (NHLBI 2013 Management of Overweight and Obesity in Adults: A Systematic Evidence Review by the Obesity Expert Panel; Bhaskaran et al., Lancet 2014;384(9945):755-65). In some cases, for an adult of average height, a weight of 125 - 174 pounds is considered normal, 175 - 204 pounds is overweight, and over 204 pounds is considered obese. In some embodiments, changes from the weight criteria are utilized to evaluate the treatment of BED.

[0211] In some aspects, embodiments provided herein include evaluating the maximum change from the criteria in post-treatment weight. In some aspects, the evaluation includes one or more time points after one or more administrations of silibinin, e.g., 2 - 20 weeks after one or more administrations of silibinin, or approximately after this period, e.g., 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, and / or 16 weeks after said administration, or one or more weight evaluations at approximately these time points.

[0212] In some embodiments, the weight of an individual undergoing treatment decreases during and / or after treatment, e.g., the weight decreases by at least 1 kg, 2 kg, 3 kg, 4 kg, 5 kg, 6 kg, 7 kg, 8 kg, 9 kg, 10 kg, 12.5 kg, 15 kg, 17.5 kg, or 20 kg, or approximately to these extents, compared to the baseline.

[0213] D. Examples of Monitoring and Evaluation Table 3 summarizes examples of an evaluation schedule including physical measurements of treatment results, observer evaluations and subject reports, quantification of clinical indicators, and combinations thereof, as described in the method of the present invention. Table 3 Examples of Monitoring and Evaluation Schemes JPEG2025521221000004.jpg219149JPEG2025521221000005.jpg191149 1. As described in this specification 2. Psychiatric history evaluated by PI and research psychologists 3. Vital signs (heart rate and blood pressure) in full sitting position at screening and at clinical admission on the dosing day. Evaluate simple vital signs before capsule administration, 30, 60, 90, 120, 180, 240, 300, and 360 minutes after capsule administration, and on the next day. Evaluate simple vital signs in full sitting position for each in-person follow-up visit. 4. Measure 12-lead ECG three times at screening, before dosing, and 60, 120, and 360 minutes after capsule administration. Also obtain ECG for early terminators. 5. Before dosing on the dosing day, perform a chemistry panel (Na + , K + , Cl - , HCO3 - , Ca ++ , Mg ++ , P, BUN, creatinine, glucose, total bilirubin, albumin, ALT, AST, GGT, CK, LDH, alkaline phosphatase). 6. Before dosing on the dosing day, perform a CBC including white blood cell differential and platelet count. 7. Urinalysis includes examination of pH, specific gravity, protein, occult blood, glucose, ketones, and microscopic examination of sediment for RBC, WBC, epithelial cells, casts, crystals, and bacteria. 8. Urine drug testing is for 14 standard items (AMP, BUP, BZO, COC, mAMP, MDMA, MOP, MTD, OXY, THC, ETG, FTY, TRA, K2). 9. Before administration on the administration date, urine drug screening and alcohol breath testing are performed. 10. Pregnancy testing is performed before administration on the dosing date for women of reproductive potential. 11. Further details regarding treatment sessions are described herein. 12. fMRI and EEG are performed only at the 6-week visit. 13. Complete before administration on the administration date and before discharge. During follow-up, if there are psychiatric concerns, the C-SSRS can be performed weekly along with the HADS. 14. Perform during vital signs monitoring during the administration session. 15. Fill in daily only on weeks 4, 5, and 6. 16. Fill in once, 4 weeks before screening. 17. Fill in once only at weeks 10 and 14. 18. Medical events that occur before the baseline visit and after obtaining explanation and consent are recorded as part of the medical history, not as adverse events. 19. Fill in before administration and before discharge on the dosing date.

[0214] III. Definitions Unless otherwise defined, all technical terms, notations, and other technical or scientific terms used herein are intended to have the same meaning as commonly understood by a person of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as being materially different from what is commonly understood in the art.

[0215] In some aspects, the term "comprising" or variations thereof is understood to mean that the recited element, integer, step, or group of elements, integers, or steps is included, but is not meant to exclude any other element, integer, step, or group of elements, integers, or steps.

[0216] Any discussion of documents, acts, materials, devices, articles, etc. included in this specification is for the sole purpose of providing a background to the present technology. None of these matters should be construed as an admission that any or all of these formed part of the prior art base or were common general knowledge in the relevant field of the present technology that existed before the priority date of each claim of this specification.

[0217] In some aspects, a technical integer, step, or element described herein as a singular integer, step, or element clearly encompasses both the singular and plural forms of the recited integer, step, or element.

[0218] In some contexts, the term "a" is used to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, a reference to "an element" means one element or two or more elements.

[0219] In some contexts, the term "about" means that a reference to a number or value should not be construed as an absolute number or value, but includes the range of variation above and below the number or value that would be understood by a person skilled in the art, including within the normal error range or the limitations of the equipment. In some cases, "about" is understood to refer to a range or approximation that a person or a person skilled in the art would consider equivalent to the recited value in the context of achieving the same function or result.

[0220] In some contexts, the terms "treatment," "therapy," and "remedy" refer to curative therapies, prophylactic therapies, palliative therapies, and preventive therapies. Thus, in the context of the present disclosure, the term "treatment" encompasses curing, improving, or alleviating the severity of one or more of a psychological state or its associated symptoms. Desirable effects of treatment include, but are not limited to, prevention or recurrence of disease, alleviation of symptoms, reduction of the direct or indirect pathological effects of the disease, reduction of the rate of disease progression, improvement or alleviation of the medical condition, and remission or improvement of prognosis. These terms do not mean complete cure of the disease or complete elimination of symptoms or effects for all symptoms or outcomes.

[0221] In some contexts, the terms "therapeutically effective amount," "pharmacologically effective amount," or "effective amount" refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in a subject being treated. These terms are synonymous and are intended to identify the amount of each agent that achieves the goal of improving the severity and / or frequency of onset of a disease compared to treatment with each agent alone and that avoids or minimizes adverse side effects, including those normally associated with other therapeutic methods.

[0222] In some contexts, "pharmaceutical carrier," "diluent," or "excipient" includes, but is not limited to, a physiologically buffered medium (i.e., pH of about 7.0 - 7.4) that includes a suitable water-soluble organic carrier, a common solvent, a dispersion medium, a filler, a carrier, a coating agent, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents.

[0223] "Subject" includes any human.

[0224] In some contexts, the terms "administering" and its variations "administer" or "administration" include contacting, applying, delivering, or providing a compound or composition of the invention to a subject by suitable means.

[0225] IV. Exemplary Embodiments Among the provided embodiments are the following: 1. A method for treating binge eating disorder (BED), comprising: orally administering once or more times to a subject suffering from one or more symptoms of BED, psilocybin or its active metabolite effective to induce a dissociative state; after recovery from the dissociative state, providing to the subject one or more integration sessions; and evaluating the subject for one or more metrics before and / or after administering psilocybin or its active metabolite one or more times. The method includes: wherein the one or more metrics are related to one or more symptoms of BED, dissociative state, treatment outcome, and safety, and / or are related to the subject. 2. A method for treating binge eating disorder (BED), including evaluating a subject suffering from one or more symptoms of BED for one or more metrics before, after, or both before and after one or more administrations of psilocybin or its active metabolite, wherein one or more integration sessions are provided after recovery from a dissociative state induced by one or more oral administrations of psilocybin or its active metabolite effective to induce a dissociative state, and wherein the one or more metrics related to one or more symptoms of BED, dissociative state, treatment outcome, and safety, and / or related to the subject are evaluated in the subject before and / or after one or more administrations of psilocybin or its active metabolite. 3. The method according to embodiment 1 or 2, wherein the one or more metrics are selected from the frequency of binge eating episodes, Binge Eating Scale (BES), binge eating episodes per day, food-related anxiety, depressive state related to eating behavior, depressive state related to weight management, Clinical Global Impression - Improvement (CGI-I), interest in the intake of trigger foods, waist circumference, Body Mass Index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, genuine well-being, binge eating craving, weight, eating behavior, Hospital Anxiety and Depression Scale (HADS) for anxiety or depressive state related to hospitalization, Patient Global Impression - Improvement (PGI-I), and Acceptance and Action Questionnaire - II (AAQ-II). 4. A method for treating binge eating disorder (BED), comprising: orally administering once or more times to a subject suffering from one or more BED symptoms, psilocybin or its active metabolite effective to induce a dissociative state; providing to the subject one or more integration sessions after recovery from the dissociative state; and evaluating the subject for one or more indicators before and / or after administering psilocybin or its active metabolite one or more times. The method includes: wherein the one or more indicators are selected from the frequency of binge eating episodes, Binge Eating Scale (BES), binge eating episodes per day, food-related anxiety, depressive state related to eating behavior, depressive state related to weight management, Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, waist circumference, body mass index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, sense of genuine well-being, binge eating craving, weight, eating behavior, Hospital Anxiety and Depression Scale (HADS) for anxiety or depression related to hospitalization, Patient Global Impression - Improvement (PGI - I), and Acceptance and Action Questionnaire - II (AAQ - II). 5. A method for treating binge eating disorder (BED), comprising: evaluating the subject for one or more indicators before, after, or both before and after administering psilocybin or its active metabolite one or more times, in a subject suffering from one or more BED symptoms, in whom one or more integration sessions are provided after recovery from a dissociative state induced by one or more oral administrations of psilocybin or its active metabolite effective to induce a dissociative state. The method, wherein the one or more indicators are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, food-related anxiety, depressive state related to eating behavior, depressive state related to weight management, the Clinical Global Impression-Improvement (CGI-I), interest in the intake of trigger foods, waist circumference, body mass index (BMI), general anxiety, food-related anxiety, self-awareness, confidence, genuine well-being, binge eating desire, weight, eating behavior, the Hospital Anxiety and Depression Scale (HADS) for anxiety or depressive state related to hospitalization, the Patient Global Impression-Improvement (PGI-I), and the Acceptance and Action Questionnaire-II (AAQ-II). 6. A method for treating binge eating disorder (BED), comprising orally administering once or more times to a subject suffering from one or more symptoms of BED, psilocybin or an active metabolite thereof effective to induce a dissociative state; and providing one or more integration sessions to the subject after recovery from the dissociative state. 7. A method for treating binge eating disorder (BED), comprising providing one or more integration sessions after recovery from a dissociative state induced by orally administering once or more times to a subject suffering from one or more symptoms of BED, psilocybin or an active metabolite thereof effective to induce a dissociative state. 8. The method according to embodiment 6 or 7, further comprising evaluating the subject for one or more indicators before and / or after administering psilocybin or an active metabolite thereof once or more times. 9. The method according to embodiment 8, wherein the one or more indicators are related to one or more symptoms of BED, dissociative state, treatment outcome, and safety, and / or related to the subject. 10. Before administering psilocybin or an active metabolite thereof once or more times, the subject is evaluated for the following parameters: (1) Risk of suicide, (2) Vital signs, (3) Incidence of cardiovascular disease, (4) Incidence of gastrointestinal disease, (5) Incidence of epilepsy, (6) Incidence of schizophrenia spectrum or other psychotic disorders, (7) Family history of mental illness, (8) Moderate or severe alcohol or drug use disorder, (9) Side effects due to past psilocybin or its active metabolites, and (10) Use of previous medications or concomitant medications The method according to any one of Embodiments 1 to 9, further comprising evaluating one or more of. 11. The method according to Embodiment 10, further comprising identifying a subject for treatment with psilocybin or its active metabolite when the subject meets the criteria for the one or more parameters. 12. A method for identifying a subject for treating binge eating disorder (BED) with psilocybin or its active metabolite, comprising: (a) A subject suffering from one or more symptoms of BED is evaluated for the following parameters: (1) Risk of suicide, (2) Vital signs, (3) Incidence of cardiovascular disease, (4) Incidence of gastrointestinal diseases, (5) Incidence of epilepsy, (6) Incidence of schizophrenia spectrum or other psychotic disorders, (7) Family history of mental illness, (8) Moderate or severe alcohol or drug use disorder, (9) Side effects due to past psilocybin or its active metabolites, and (10) Use of previous medications or concomitant medications evaluating one or more of, and (b) identifying a subject for treatment by one or more administrations of psilocybin or its active metabolite when the subject meets the criteria for the one or more parameters A method comprising. 13. A method for identifying a subject for treating binge eating disorder (BED) with one or more administrations of psilocybin or its active metabolite, wherein a subject suffering from one or more symptoms of BED has the following one or more parameters evaluated in the subject: (1) The risk of suicide, (2) Vital signs, (3) The incidence of cardiovascular diseases, (4) The incidence of gastrointestinal diseases, (5) The incidence of epilepsy, (6) The incidence of schizophrenia spectrum or other psychotic disorders, (7) Family history of mental illness, (8) Moderate or severe alcohol or drug use disorders, (9) Side effects due to past psilocybin or its active metabolites, and (10) Use of past medications or concomitant medications A method comprising identifying a subject for treatment with psilocybin or its active metabolite when the subject meets the criteria of 14. Orally administering to the identified subject a dose of psilocybin or its active metabolite effective to induce dissociative states one or more times, and After the subject has recovered from the dissociative state, providing the subject with one or more integration sessions The method according to embodiment 12 or 13, further comprising 15. The method according to any one of embodiments 6 to 14, further comprising evaluating the subject for one or more indicators before and / or after administering psilocybin or its active metabolite one or more times. 16. The method according to embodiment 15, wherein the one or more indicators are related to one or more symptoms of BED, dissociative states, treatment outcomes, and safety, and / or relate to the subject. 17. The method according to any one of embodiments 1, 2, 8 to 11, 15, and 16, wherein the one or more indicators include parameters of observer evaluation, parameters of subject reporting, and / or clinical indicators. 18. The method according to embodiments 1 to 17, wherein the one or more indicators are evaluated as reference measurement values before administration and as result measurement values after administration. 19. The method according to embodiment 18, wherein the change between the reference measurement value and the result measurement value is measured. 20. The method according to embodiment 19, wherein the subject shows improvement between the measured value of the reference of the one or more indicators and the measured value of the result. 21. The method according to any one of embodiments 1, 2, 8 to 11, and 15 to 20, wherein the one or more indicators are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, anxiety about food, depression related to eating behavior, depression related to weight management, the Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, waist circumference, body mass index (BMI), general anxiety, anxiety about food, self - awareness, confidence, genuine well - being, binge eating desire, weight, eating behavior, the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression related to hospitalization, the Patient Global Impression - Improvement (PGI - I), and the Acceptance and Action Questionnaire - II (AAQ - II). 22. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 21, wherein the one or more indicators are selected from the frequency of binge eating episodes, the Binge Eating Scale (BES), the number of binge eating episodes per day, anxiety about food, depression related to eating behavior, depression related to weight management, the Clinical Global Impression - Improvement (CGI - I), interest in the intake of trigger foods, waist circumference, and body mass index (BMI). 23. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 22, wherein the one or more indicators include the frequency of binge eating episodes. 24. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 23, wherein the frequency of the binge eating episodes is measured using the questionnaire regarding eating. 25. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 24, wherein the frequency of the binge eating episodes is measured daily. 26. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 22, wherein the one or more indicators include the number of binge eating episodes per day. 27. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 22, wherein the one or more indicators include interest in the intake of trigger foods. 28. The method according to any one of embodiments 1-5, 8-11, and 15-22, wherein the one or more indicators are selected from the Emotional Breakthrough Inventory (EBI), the Acceptance and Action Questionnaire-II (AAQ-II), the Patient Global Impression of Improvement (PGI-I), and the Hospital Anxiety and Depression Scale (HADS). 29. The method according to any one of embodiments 1-5, 8-11, and 15-22, wherein the one or more indicators are one or more neurophysiological biomarkers selected from resting-state functional connectivity (during feeding and fasting) by functional magnetic resonance imaging (fMRI), task-related functional activation and connectivity (during feeding and fasting) during a food cue reactivity task by fMRI, voxel-based morphometry (gray and white matter volume / structure) by fMRI, and resting electroencephalogram (EEG). 30. The method according to any one of embodiments 1-5, 8-11, and 15-22, wherein the one or more indicators are one or more metabolic biomarkers selected from ghrelin, leptin, adiponectin, insulin, glucose, and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance). 31. The method according to any one of embodiments 1-5, 8-11, and 15-22, wherein the one or more indicators are selected from the Monitor Rating Scale (MRS), the Mystical Experience Questionnaire (MEQ30), and the Challenging Experience Questionnaire (CEQ). 32. The method according to any one of embodiments 1-5, 8-11, and 15-31, wherein the one or more indicators are measured during one or more of the integration sessions. 33. The method according to any one of embodiments 1-5, 8-11, and 15-22, wherein the one or more indicators are selected from vital signs, blood chemistry and hematology tests, urine tests, electrocardiogram (ECG), and the Columbia Suicide Severity Rating Scale (C-SSRS). 34. The blood chemistry and hematology tests include Na + , K + , Cl - , HCO3 - , Ca ++ , Mg ++、P, BUN, creatinine, glucose, total bilirubin, albumin, ALT, AST, GGT, CK, LDH, alkaline phosphatase, complete blood count, white blood cell differential count, and platelet count, the method according to embodiment 33, comprising measuring one or more levels thereof. 35. The method according to embodiment 33, wherein the urine test includes one or more of the measurement of pH, specific gravity, protein, occult blood, glucose, and ketone, and the microscopic examination of the sediment of RBC, WBC, epithelial cells, casts, crystals, and bacteria. 36. When the parameter is the presence of gastrointestinal diseases and the subject does not suffer from a gastrointestinal disease that may interfere with the absorption of silibinin or its active metabolite orally administered to the subject, the subject meets the criteria of the parameter, the method according to any one of embodiments 11 to 35. 37. When the parameter is the incidence rate of epilepsy and the subject does not suffer from epilepsy, the subject meets the criteria of the parameter, the method according to any one of embodiments 11 to 36. 38. When the parameter is the incidence rate of schizophrenia spectrum or other psychotic disorders, and the subject does not suffer from a schizophrenia spectrum or other psychotic disorder, a major depressive disorder with psychotic features, or a bipolar type I or bipolar type II disorder that meets the DSM-5 criteria, the subject meets the criteria of the parameter, the method according to any one of embodiments 11 to 37. 39. When the parameter is a family history of mental illness and the subject does not have a family history of mental illness, the subject meets the criteria of the parameter, the method according to any one of embodiments 11 to 38. 40. When the parameter is moderate or severe alcohol use disorder or drug use disorder, and the subject does not suffer from a moderate or severe alcohol use disorder or drug use disorder that meets the DSM-5 criteria, the subject meets the criteria of the parameter, the method according to any one of embodiments 11 to 39. 41. If the parameter is an adverse effect caused by past silibinin or its active metabolite, and the subject has not suffered from an adverse effect caused by past silibinin or its active metabolite, the method according to any one of embodiments 11 to 40, wherein the subject meets the criteria of the parameter. 42. If the parameter is the use of a previous drug or concomitant drug, and the subject has not used any of the following previous drugs or concomitant drugs: UGT1A9 inhibitor, 1A10 inhibitor, regorafenib, rifampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, itraconazole, deferasirox, Korean ginseng, aldehyde or alcohol dehydrogenase inhibitor, disulfiram, amphetamine, buprenorphine, benzodiazepine, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoid (K2), psychoactive prescription drug (used regularly), opioid, tramadol, or benzodiazepine; antidepressant (used in combination); drug having a central serotonergic effect (used regularly), monoamine oxidase inhibitor (MAOI), or selective serotonin reuptake inhibitor (SSRI), or serotonergic dietary supplement, 5-hydroxytryptophan, St. John's wort, the method according to any one of embodiments 11 to 41, wherein the subject meets the criteria of the parameter. 43. If the subject meets all the criteria of the parameters (1) to (10), the method according to any one of embodiments 11 to 42, wherein the subject is identified for treatment with silibinin or its active metabolite. 44. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 43, wherein the one or more indicators are measured at about 4 weeks and about 12 weeks after one or more administrations of silibinin or its active metabolite. 45. The method according to any one of embodiments 1 to 5, 8 to 11, and 15 to 44, wherein the one or more indicators are measured at about 4 weeks, about 8 weeks, and about 12 weeks after one or more administrations of silibinin or its active metabolite. 46. The method according to any one of embodiments 1-5, 8-11, and 15-45, wherein the one or more indicators are measured at about 4 weeks after one or more administrations of silibinin or its active metabolite. 47. The method according to any one of embodiments 1-46, wherein in a subject undergoing treatment, improvement of one or more symptoms of BED is shown, or one or more symptoms of BED are alleviated. 48. In a subject undergoing treatment, a decrease in the frequency of binge eating episodes, a decrease in the binge eating scale (BES), a decrease in the number of binge eating episodes per day, a decrease in the frequency of the sense of loss of meal control per day, a reduction in food-related anxiety, a reduction in food-related depression, a reduction in depression related to eating behavior, a reduction in depression related to weight management, an improvement in the Clinical Global Impression - Improvement (CGI-I), a reduction in interest in the intake of trigger foods, a decrease in waist circumference, a reduction in body mass index (BMI), a reduction in general anxiety, a reduction in food-related anxiety, an improvement in self-awareness, an improvement in confidence, an improvement in depression and a sense of well-being from the heart, a lack of overeating desire, weight loss, an improvement in eating behavior, a reduction in the scale of anxiety or depression related to hospitalization (HADS), a reduction in HADS - anxiety, a reduction in HADS - depression, an improvement in the Patient Global Impression - Improvement (PGI-I), and an improvement in the questionnaire response related to acceptance and behavior (AAQ-II), and one or more improvements selected therefrom are shown. The method according to any one of embodiments 1-47. 49. The method according to any one of embodiments 1-48, wherein in a subject undergoing treatment, a decrease in the frequency of binge eating episodes, a decrease in the binge eating scale (BES), a decrease in the number of binge eating episodes per day, a reduction in food-related anxiety, a reduction in depression related to eating behavior, a reduction in depression related to weight management, an improvement in the Clinical Global Impression - Improvement (CGI-I), a reduction in interest in the intake of trigger foods, a decrease in waist circumference, a reduction in body mass index (BMI), a reduction in the scale of anxiety or depression related to hospitalization (HADS), an improvement in the Patient Global Impression - Improvement (PGI-I), and an improvement in the questionnaire response related to acceptance and behavior (AAQ-II), and one or more improvements selected therefrom are shown. 50. In a subject undergoing treatment, one or more improvements selected from reduction of general anxiety, reduction of food-related anxiety, improvement of self-awareness, improvement of confidence, improvement of depressive state and heartfelt well-being, absence of hyperphagia, weight loss, and improvement of eating behavior are shown, the method according to any one of Embodiments 1 to 48. 51. The method according to any one of Embodiments 1 to 50, wherein the administration of the one or more times of silibinin or its active metabolite comprises administration of silibinin or its active metabolite once, twice, three times, four times, or five times. 52. The method according to any one of Embodiments 1 to 51, wherein the administration of the one or more times of silibinin or its active metabolite comprises administration of silibinin or its active metabolite once. 53. The method according to any one of Embodiments 1 to 51, wherein the administration of the one or more times of silibinin or its active metabolite comprises administration of silibinin or its active metabolite twice. 54. The method according to any one of Embodiments 1 to 53, wherein the dose is 10 mg or about 10 mg to 50 mg or about 50 mg of silibinin or its active metabolite. 55. The method according to Embodiment 54, wherein the dose is 25 mg and about 25 mg of silibinin or its active metabolite. 56. The method according to any one of Embodiments 1 to 55, wherein the one or more integrated sessions comprise one, two, three, four, or five integrated sessions. 57. The method according to any one of Embodiments 1 to 56, wherein the one or more integrated sessions comprise one integrated session. 58. The method according to any one of Embodiments 1 to 56, wherein the one or more integrated sessions comprise two integrated sessions. 59. The method according to any one of Embodiments 1 to 58, wherein the integrated session is provided 1 day or about 1 day after administration of the dose of silibinin or its active metabolite. 60. The method according to any one of Embodiments 53 to 59, further comprising providing one or more additional integrated sessions. 61. The method of embodiment 60, wherein the one or more additional integration sessions are provided between about 6 days and 9 days or about 9 days after administration of the dose of sirolimus or its active metabolite. 62. The method of embodiment 60 or 61, wherein the one or more additional integration sessions are provided at or about 7 days after administration of the dose of sirolimus or its active metabolite.

[0226] V. EXAMPLES The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0227] Example 1: Administration of silibinin and psychotherapy in subjects with binge eating disorder (BED) In this example, an open-label clinical trial for evaluating the safety and efficacy of oral sirolimus and treating human subjects with binge eating disorder (BED) will be described. BED is typically characterized by severe impairment in the control of binge eating behavior and strong anxiety about food. Also, BED is associated with comorbidities such as obesity, depression, impulse control disorders, and obsessive-compulsive disorder. This example supports that sirolimus can be useful in the treatment of BED through various mechanisms, such as alleviating general anxiety, food-related anxiety, rumination, and repetitive and intrusive thoughts about food.

[0228] A. STUDY DESIGN Subjects were orally administered a single dose of 25 mg of sirolimus. The safety and efficacy of sirolimus and psychotherapy were evaluated over 12 weeks after a single administration of sirolimus. The primary endpoint was 4 weeks after administration. Subjects were screened and baseline measurements were taken before two preparatory sessions preceding the administration session. Two integration sessions followed after administration, and treatment and safety follow-up evaluations were completed 12 weeks after the administration session.

[0229] B. INCLUSION AND EXCLUSION CRITERIA Subjects who met the criteria for Binge Eating Disorder (BED) in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) were eligible to participate in this study. Scheduled subjects were excluded from the study based on various criteria, such as physiological and psychological conditions, specific medical histories and / or concurrent treatments, diagnostic evaluations conducted during subject screening or criterion assessment, family history of mental illness, etc.

[0230] Exemplary inclusion criteria include the following: 1. Meeting the criteria for Binge Eating Disorder (BED) in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). 2. Being 18 years of age or older and 64 years of age or younger. 3. Presenting a signed and dated informed consent form. 4. Indicating the intention to comply with all study procedures and responses during the study period. 5. Being medically stable as determined by the principal investigator of the clinical trial based on measurements from normal clinical tests, including screening medicine, physical examination, electrocardiogram, blood tests, and urine tests. 6. For women of reproductive potential: Using a highly effective method of contraception for at least 1 month before screening and agreeing to use such a method during the study participation and for an additional 4 weeks after administration of silodosin. Appropriate methods of contraception include intrauterine devices, injections, implants, vaginal, or transdermal hormonal methods, oral hormones and barrier contraception, abstinence, a partner who has had a vasectomy, or a double-barrier method of contraception. 7. For men of reproductive potential: Using a condom or other method for effective contraception with a partner for 90 days after administration. 8. Agreeing to consume a caffeinated beverage (such as coffee, tea, etc.) in approximately the same amount as consumed in the normal morning before arriving at the research unit on the morning of the dosing session. If the participant does not normally consume caffeinated beverages, they must agree not to consume any on the day of the dosing session. 9. Agreeing to refrain from using any psychotropic medications, including alcoholic beverages, starting at least 1 week before drug administration. 10. Agree to refrain from taking over-the-counter medications, dietary supplements, herbal supplements, or prescription medications as needed (PRN), including on the morning of the session, one week prior to the drug treatment session, except as approved by the study investigator. Exceptions are evaluated by the study investigator and include acetaminophen, non-steroidal anti-inflammatory drugs, and typical doses of vitamins and minerals, and birth control pills.

[0231] Exemplary exclusion criteria include the following: 1. A significant suicide risk as defined by any of the following: suicidal ideation recognized on item 4 or 5 of the C-SSRS within the past year, at screening, or at baseline; a suicide attempt within the past year; or a clinical assessment of significant suicide risk during the subject's interview. The C-SSRS is a questionnaire designed to distinguish between the areas of suicidal ideation and suicide attempts through four components: severity of suicidal ideation, intensity of suicidal ideation, action subscale, and lethality subscale (Posner et al., American Journal of Psychiatry, 2011;168(12):1266-1277). 2. Currently participating in another concurrent clinical trial or having participated in another clinical trial within the past month. 3. Pregnant women, women planning to become pregnant during the study period, or women currently breastfeeding. 4. Mean vital signs measured three times within 15 minutes with systolic blood pressure (BP) > 139 mmHg, diastolic blood pressure BP > 89 mmHg, or heart rate > 90 bpm. 5. Having any of the following cardiovascular diseases: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, myocardial ischemia, congestive heart failure, past myocardial infarction, tachycardia, artificial heart valve; QTc > 450 milliseconds at screening; other clinically significant screening ECG abnormalities; or other significant cardiovascular diseases. 6. Having a gastrointestinal disease that may interfere with the absorption of orally administered silibinin. 7. Having epilepsy. 8. Meeting the DSM-5 criteria for schizophrenia spectrum or other psychotic disorders (including major depressive disorders with psychotic features, or bipolar type I or bipolar type II disorders). 9. Having a family history of psychosis. 10. Meeting the DSM-5 criteria for moderate or severe alcohol or substance use disorders. 11. Being positive on urine drug screening or alcohol breath test at the time of screening. Retesting can be performed at the time of screening or one day prior at the discretion of the principal investigator or designee of the clinical trial. 12. Having had previous side effects due to psilocybin. 13. Currently taking or expected to require UGT1A9 or 1A10 inhibitors (e.g., regorafenib, rifampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, itraconazole, deferasirox, Korean ginseng), and aldehyde or alcohol dehydrogenase inhibitors (e.g., disulfiram) prior to the dosing session. 14. Taking abused drugs such as amphetamine, buprenorphine, benzodiazepine, cocaine, methamphetamine, ecstasy (MDMA), morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, synthetic cannabinoid (K2), etc., or having a positive reaction on urine drug testing. 15. Regularly (e.g., daily) taking drugs with major central serotonergic effects, including SSRIs, MAOIs, or serotonergic dietary supplements (such as 5-hydroxytryptophan and St. John's wort). For those who use such drugs intermittently or PRN, the dosing session will not be performed until 5 times the half-life of the drug has elapsed since the last dose. 16. fMRI subjects: Having contraindications to fMRI procedures in accordance with the facility's policy.

[0232] C. Screening and Criterion Measurement The subjects received at least one examination for screening. During the screening period (-5th week and -4th week), hematology, blood chemistry, urine drug screen, physical examination, and other safety evaluations to assess medical inclusion criteria were included. During this period, responses to questionnaires including the C-SSRS, binge eating scale (BES), questionnaire on eating (Fairbun and Beglin, Int J Eat Disord, 1994;16(4):363-370), clinical global impression of improvement (CGI-I), patient global impression of improvement (PGI-I), anxiety and depression scale for hospitalization (HADS), and acceptance and action questionnaire (AAQ-II) were collected. The evaluations conducted during the screening period were regarded as reference values for determining the change from baseline (CFB).

[0233] Daily binge eating episodes (e.g., the number of binge eating episodes per day) were evaluated daily (-3rd week and -2nd week) over a two-week period using a two-item dietary questionnaire. Daily binge eating episodes (e.g., the number of binge eating episodes per day) were evaluated before the start of psychotherapy and before the administration of silibinin. As an example, the following questions were used to ask the subjects to record the number of binge eating episodes once a day. 1. "How many times in the past 24 hours did you eat an amount of food that others would consider unusually large (considering the situation)?", and 2. "How many of those times did you feel that you lost control of your eating (during the meal)?". These evaluations were regarded as reference values for determining the CFB in binge eating frequency.

[0234] During the week before the preparation session, reference electroencephalogram (EEG) and fMRI were measured to measure CFB (Week 1, Day 1). Resting EEG with eyes open and eyes closed was acquired for 10 minutes each in a balanced order. For fMRI imaging, the subject was placed headfirst in an MRI scanner equipped with a 64-channel head coil in a supine position. The subject evaluated their current level of hunger using a 100-point visual analog scale (VAS) ranging from "not at all hungry" to "as hungry as imaginable". First, a blood oxygenation level-dependent (BOLD) resting functional scan was performed for approximately 9 minutes. The subject was instructed to stay as still as possible, let their mind wander, fixate on the central cross displayed on the monitor, and try not to move as much as possible. Next, the subject completed a cue-reactivity task during the acquisition of the BOLD functional images. During this task, the subject viewed images of highly processed foods such as pizza, images of minimally processed foods such as apples, and photographs with neutral value of household items such as light bulbs. The subject was instructed to consider how much they desired each item. After completion of the task, the subject was removed from the MRI bore and given a small meal. After completion, the subject was placed back inside the MRI and the hunger VAS, resting scan, and cue-reactivity task were repeated. The order of the resting scan and cue-reactivity task was balanced. Thereafter, a high-resolution T1-weighted image (approximately 4 minutes) was collected as a structural image of the brain.

[0235] D. Preparation Session The two preparatory sessions were conducted with the therapist during the week prior to the dosing session. The preparatory sessions were designed to build a trusting relationship with the therapist who would be present during the psilocybin session and to identify personal themes and conflicts that could affect the session experience. In the first preparatory session, conducted approximately one week before the dosing session, the therapist aimed to establish a therapeutic alliance by building trust, listening to the subject's stories about overeating, anxiety, guilt, and treatment history, and understanding the most prominent patterns of psychological flexibility. The therapist provided psychological education about acceptance and commitment therapy (ACT), a therapeutic approach aimed at promoting psychological flexibility through the psilocybin experience and practicing acceptance and mindfulness (Zhang et al., Front Psychol. 2018 Jan 11;8:2350).

[0236] The second preparatory session was conducted 1 - 3 days before the dosing session. In this session, the therapist taught grounding techniques such as breathing methods. The boundaries of the treatment, such as contact and safety measures, were discussed. The subject received support regarding motivation for the psilocybin session. The two preparatory sessions were conducted either in person or via video.

[0237] E. Psilocybin Administration The subjects were instructed to consume a low - fat breakfast at least one hour before the dosing session in which they would receive a single oral dose of 25 mg of psilocybin (Usona Institute). On the dosing day, vital signs such as heart rate and blood pressure were evaluated before psilocybin administration and at 30, 60, 90, 120, 180, 240, 300, and 360 minutes after administration. A 12 - lead ECG was performed three times each, before dosing and at 60, 120, and 360 minutes after capsule administration. C - SSRS responses were reported before and after dosing. Throughout the session, the therapist followed a supportive stance and did not provide significant ACT interventions or feedback. Based on ACT, clinical administration continued while the therapist listened to emerging stories and recorded examples of psychological flexibility and inflexibility, particularly examples of present - moment awareness, avoidance, and values.

[0238] The session monitor was trained to provide support when the subject experienced acute anxiety, excitement, delusions, or panic. However, in case of an AE, consult a physician. AEs include psychiatric emergencies, hypertension, acute chest pain, and headache. Oral benzodiazepines (such as lorazepam) were available for the treatment of panic and anxiety. Oral antipsychotics (such as risperidone) were available for the treatment of psychosis and severe excitement. When the subject experienced hypertension, i.e., when the systolic blood pressure exceeded 200 mmHg or the diastolic blood pressure exceeded 110 mmHg in four consecutive readings and this state persisted for more than 15 minutes, the subject was transported to the emergency treatment room regardless of the presence or absence of symptoms. Labetalol or similar drugs were available for the treatment of hypertension. When the subject newly developed chest pain, the physician in charge of the trial directly examined the subject and determined whether the pain was cardiovascular pain, musculoskeletal pain, or reflected acute panic / anxiety. Vital signs and ECG were monitored and compared with reference measurements to find evidence of acute ischemia. Ibuprofen or similar drugs were available for the treatment of headache.

[0239] F. Integrated Session After the dosing session, the subject participated in two integrated sessions. The first integrated session was conducted in person on the day after administration, while the second integrated session was conducted via video or in person approximately 7 days after administration. In these integrated sessions, intensive ACT-based clinical activities related to contact, defusion, or acceptance with the current moment based on the clinical administration were practiced. Also, the subject's psilocybin experience and emotional, mental, or lifestyle changes after the dosing session were examined and reflected.

[0240] G. Follow-up Session The initial treatment follow-up session was conducted approximately two weeks (week 4) after the silibinin administration session. During this follow-up session, the therapist continued to explore and reinforce insights gained from the silibinin experience while evaluating changes in psychological flexibility. The subject and the therapist reviewed how each ACT process became apparent during the dosing and therapy sessions and whether any successful behavioral changes or firm actions were taken. The therapist led a discussion regarding the subject's plan for follow-up care, discussing the practice of acceptance and specific ways to translate this trial experience into lasting change.

[0241] Safety follow-up was conducted at week 4, day 5, week 8, and week 12 (2, 3, 6, and 10 weeks after the administration session). The safety follow-up session included an assessment of overeating behavior, such as the use of the C-SSRS and eating questions. In-person follow-up examinations were scheduled at week 6, week 10, and week 14 (4, 8, and 12 weeks after dosing). During the in-person follow-up examinations, several evaluations were performed, including physical examinations such as measurements of height, weight, BMI, and waist circumference, and assessments of vital signs and metabolic indicators. fMRI and EEG were also performed. Responses to the C-SSRS, BES, eating questionnaires (daily and over a four-week period), CGI-I, PGI-I, HADS, and AAQ-II were also evaluated. H. Endpoints of the trial

[0242] Regarding the analysis and presentation of the collected data, continuous data were summarized by the number of subjects (n) without missing data, mean, median, SD, minimum, and maximum values. For categorical variables, the number and percentage of each category were displayed. The indicators or biomarkers were set to be analyzed using statistical methods appropriate for the specific endpoint type and purpose.

[0243] The endpoints included determining the effect of silibinin on the indicators of clinical activity in the BED population throughout the trial, and evaluating the relationship between clinical activity and the intensity of the psychotropic experience. The indicators were measured using various evaluations, including the assessment of binge-eating behavior, physical examinations, subject-reported outcomes, neurophysiological indicators, and metabolic indicators. Exploratory analyses included the CFB at all tested time points for such parameters.

[0244] For example, binge-eating behavior, such as binge-eating episodes, was evaluated using questionnaires such as those regarding eating. The observer-reported CGI-I, which is a 7-point scale for clinicians to assess how much a subject's illness has improved or worsened compared to the baseline state, was also performed, and among other factors, the severity of symptoms and response to treatment were measured. Using the questionnaires reported by the subjects, several other indicators, such as BES, PGI-I, EBI, HADS, and AAQ-II, were evaluated at 4, 8, and 12 weeks after dosing.

[0245] The safety evaluation for a single administration of silibinin to BED subjects was planned during the dosing session and up to 12 weeks (week 14) after dosing. To determine safety, several evaluations were performed, including assessment of the nature and severity of AEs, physical examinations of the subjects, monitoring of changes in electrocardiogram (ECG) and vital signs (such as blood pressure and heart rate), measurement of clinical laboratory parameters (such as hematology and blood chemistry), and evaluation of the response to C-SSRS over 12 weeks after dosing.

[0246] Vital signs such as BP and heart rate were recorded at the dosing session, the day after dosing, and at weeks 6, 10, and 14 (4, 8, and 12 weeks after the dosing session). Physical examinations were reported at screening, the day after dosing, and at weeks 6, 10, and 14. ECG, blood chemistry, and hematological data were aggregated at screening, at the time of dosing, at the first integration session, and at weeks 6, 10, and 14. Blood chemistry tests included Na + , K + , Cl - , HCO3 - , Ca 2+ , Mg2+ Measurement of P, blood urea nitrogen (BUN), creatinine, glucose, total bilirubin, albumin, ALT, AST, GGT, CK, LDH, and alkaline phosphatase is included. Hematological evaluation includes CBC including white blood cell fraction and platelet count. Urinalysis includes microscopic examination of sediment for RBC, WBC, epithelial cells, casts, crystals, and bacteria in addition to evaluation of pH, specific gravity, protein, occult blood, glucose, and ketones.

[0247] Throughout the trial, adverse events (AE) were monitored. An AE can be an unfavorable, unintended sign or disease that is temporarily related to the use of the drug. Use of this term does not imply a causal relationship determination. AEs are classified into degrees from mild to severe. Mild AEs require minimal treatment or no treatment and do not interfere with the subject's daily activities. Moderate AEs cause inconvenience or concern with low-level treatment measures. However, moderate events can cause some impairment of function. Severe AEs interrupt the subject's normal daily activities and may require systemic drug therapy or other treatment. Severe events usually threaten life or make it impossible to live normally.

[0248] Other endpoints include the evaluation of one or more indicators related to the state of mental expansion, for example, the evaluation of the feasibility of inducing a state of mental expansion by psilocybin in the BED patient population, the determination of the frequency of binge-eating episodes and other weight-related indicators in the BED patient population up to 4 weeks after administration (i.e., the 6th week), and the preliminary clinical activities and effects of the combination of psilocybin and psychotherapy. The magnitude and duration of the dissociative effects induced by psilocybin in subjects suffering from BED were evaluated using the Mystical Experience Questionnaire - 30 items (MEQ30) and the Monitor Rating Scale (MRS). The criteria levels of the frequency of binge-eating episodes, CGI-I, waist circumference, and body mass index (BMI) were compared with the measured values at 4 weeks after dosing to determine CFB. The relationship between clinical activities such as clinical response to psilocybin and the intensity of the experience of the psychedelic drug was evaluated. The intensity of the experience of the psychedelic drug, such as the magnitude and duration of the dissociative effect, was evaluated using various questionnaires including MEQ30, the Questionnaire on Difficult Experiences (CEQ), the Emotional Breakthrough Inventory (EBI), and MRS.

[0249] Physical examinations included, for example, measuring waist circumference and BMI at 8 weeks and 12 weeks after administration. The determination of metabolic indicators included, for example, the evaluation of ghrelin, leptin, adiponectin, insulin, glucose, and HOMA-IR (homeostatic model assessment of insulin resistance) at 4, 8, and 12 weeks after administration. The evaluation of neurophysiological indicators included various fMRI evaluations including resting-state functional connectivity (during feeding and fasting), task-related functional activation and connectivity during food cue reactivity tasks (during feeding and fasting), voxel-based morphometry (volume / structure of gray matter), and EEG (such as after 4 weeks of administration, explosive synchronization of resting-state network activity, power spectrum analysis (frequency band)).

[0250] I. Results In a certain subject, immediate changes were observed after the administration of psilocybin. The subject showed a reduced interest in eating, resistance to trigger foods, and the disappearance of an anxious expression (e.g., continuous wrinkling between the eyebrows). Improvements such as a reduction in general anxiety related to BED-related symptoms or behaviors, a reduction in anxiety related to food, an improvement in self-awareness, an increase in confidence, an improvement in depressive state and a sense of well-being from the heart, the absence of hyperphagia, weight loss, and an improvement in eating behavior were observed.

[0251] Table 4 shows the changes in BMI (kg / m 2 ) and waist circumference (cm) in the subjects treated as described. As shown, in the subject, the BMI and waist circumference decreased on the 27th day after the administration of psilocybin. Table 4 Changes in BMI and Waist Circumference JPEG2025521221000006.jpg22134

[0252] The score of the subject's binge eating scale (BES) was 13 on the -42nd day and 5 on the 27th day. The range of BED is 0 - 46, and the higher the score, the more related to binge eating symptoms.

[0253] Table 5 shows the changes in the scores of the Hospital Anxiety and Depression Scale (HADS) for the subject's anxiety about hospitalization and depressive state. As shown, both the scores for the depressive state and anxiety decreased on the 13th day or the 27th day after the administration of psilocybin, which is consistent with the reduction in general depressive state and anxiety. Table 5 Changes in HADS JPEG2025521221000007.jpg33134

[0254] The improvement degree of the patient's overall impression (PGI-I) was measured for the past 7 days (including the examination day and the period between examinations) compared with the state the patient felt at the baseline examination. The patient evaluated the state based on the following criteria: 1. Very improved from the baseline (treatment start), 2. Very improved, 3. Slightly improved, 4. No change from the baseline, 5. Slightly deteriorated, 6. Significantly deteriorated, 7. Very deteriorated from the baseline. In the case of this subject, the PGI-I on the -42nd day (42 days before silodosin administration) was set to 4 as the baseline. The subject reported a score of 1 on the 13th day and a score of 1 on the 27th day after silodosin administration. This indicates that the patient is experiencing improvement in symptoms.

[0255] The scores of the questionnaire on acceptance and behavior (AAQ-II) were 13 on the -42nd day, 10 on the 13th day, and 10 on the 27th day after silodosin administration. The higher the AAQ-II score, the lower the psychological well-being. This result was consistent with the improvement in overall psychological well-being.

[0256] The questionnaire on daily eating included the following: Question 1 (Q1) "In the past 24 hours, considering the situation, how many times did you eat an amount of food that others would consider an unusually large amount?"; Question 2 (Q2) "Among those times, how many times did you feel that you lost control over your eating during the meal?"; and Question 3 (Q3) "In the past 28 days, how many days did such episodes of overeating (i.e., consuming an unusually large amount of food and feeling out of control at that time) occur?"

[0257] As shown in Figure 2A (Q1) and Figure 2B (Q2), the answers to Q1 and Q2 generally decreased after silodosin administration.

[0258] The scores of the questionnaire on difficult experiences (reported on the day after dosing) were as follows: Fear: 0.16 Sadness: 0 Physical pain: 0.24 Madness: 0 Isolation: 0 Death: 0 Delusion: 0 Total score: 0.06

[0259] The range of CEQ is from 0.000 to 1.000, and a high score corresponds to a severe and harmful acute psychological reaction to the drug (a "terribly unpleasant experience" or a "difficult experience").

[0260] The scores of the questionnaire on mystical experiences (MEQ30) reported on the first day after administration were as follows: Transcendence of time and space: 46.67% Positive mood: 93.33% Ineffability: 80% Mysteriousness: 45.33% Total score: 58.67%

[0261] The range of MEQ30 is from 0% to 100%, and a high score corresponds to a strong mystical experience.

[0262] No adverse events were observed during administration or during the integration session. No substantial changes were observed in heart rate or blood pressure.

[0263] In the results obtained from one subject, immediately after the integration session after administration and throughout the four weeks after administration with a psychotherapist, the subject showed a reduction in general anxiety, a reduction in anxiety related to food, a reduction in binge eating impulses, and an improvement in self-awareness and confidence.

[0264] For a total of five subjects, an evaluation after administration of psilocybin was performed at the time point of further clinical trial evaluation. The analysis of the additional four subjects was consistent with the clinical observations seen in the first subject described above.

[0265] As shown in FIGS. 3A (Questionnaire Q1 regarding eating) and 3B (Questionnaire Q2 regarding eating), after the administration of silibinin, the number of events per day (average) of Q1 and Q2 decreased in all subjects. In the five subjects as a whole, during the four-week measurement period after administration, the daily overeating episodes decreased by an average of 80.4% from the baseline, and all subjects reported that the daily overeating episodes decreased by at least 60% from the baseline. As shown in FIG. 3A, during the four-week measurement period after administration, four out of five subjects reported that the daily overeating episodes decreased by at least 75% from the baseline. As shown in FIG. 3B, during the four-week measurement period after administration, the average number of days when the subjects felt that they had lost control of their diet decreased by 81.6%, and four out of five subjects reported a decrease of more than 70%. As shown in FIG. 3C (Questionnaire Q3 regarding eating), the assessment of the frequency of binge eating (FBE), i.e., the number of days with binge eating episodes in the past 28 days, also substantially decreased in all subjects tested, and continued to decrease until more than 50 days after administration in all four subjects for whom data was available. In three subjects for whom data was available, it continued to decrease for more than 80 days.

[0266] In the analysis of the scores of anxiety (FIG. 4A) and depression (FIG. 4B) on the Hospital Anxiety and Depression Scale (HADS), a tendency for improvement related to the levels of anxiety and depression in the subjects was shown. During the four-week period after administration, no drug-related adverse events were reported by the subjects.

[0267] EEG- and fMRI-based neuroimaging analysis mainly focused on the changes in resting brain function and connectivity before and after treatment with psilocybin-assisted psychotherapy as described above. For EEG, moderate to high changes in resting connectivity across the entire brain were observed across the δ, θ, α, and β frequency bands. Specifically, a decrease in resting connectivity was mainly observed. Also, an increase in power at posterior electrodes from pre-treatment to post-treatment was observed in the δ, θ, and β frequency bands. Specifically, the spectral power in the δ band increased from pre-treatment to post-treatment in both the eyes-open and eyes-closed states (Figure 5A). Without being bound by theory, greater power within the slower spectral bands (δ and θ) is thought to be related to more effective emotion regulation. Thus, in some aspects, the greater power observed within the slower spectral bands is related to the beneficial effects of psilocybin-assisted psychotherapy on the emotional symptoms associated with BED described herein.

[0268] For fMRI, changes in connectivity within important resting brain networks (including the default mode network (DMN), salience network (SN), and executive control network (ECN)) before and after treatment were evaluated. Also, connectivity between these networks and the rest of the brain was evaluated both at rest and after presentation of cues for processed food, unprocessed food, and non-food. It was observed that the connectivity between brain regions constituting the SN increased from pre-treatment to post-treatment after presentation of cues for processed food and unprocessed food, and similarly, the connectivity between the ECN and SN, which has structures related to visual processing and memory function, also increased (Figure 5B). Before treatment, when cues for processed food were presented, the connectivity between nodes decreased more than for cues for unprocessed food. After treatment, the reverse pattern was observed.

[0269] In addition, the connectivity between these networks and other regions of the brain associated with the processing of resting bodily sensations and vision changed after treatment. Finally, the pattern of brain activation after the presentation of cues was also measured. Here, it was observed that, compared to before treatment, after the presentation of cues for processed foods after treatment, the activation of regions associated with cognitive control was higher (Figure 5C). When cues for processed foods were presented, although the activation was lower than that for cues for unprocessed foods before treatment, several clusters with increased activation were identified in the follow-up after treatment. These included (a) the left precentral gyrus, (b) the left supramarginal gyrus, and (c) the left angular gyrus. Overall, the above fMRI results suggest that psilocybin-assisted psychotherapy can change the functional activation and network connectivity related to the processing of cues for processed and unprocessed foods.

[0270] The above results showed that when psilocybin was used in combination with psychotherapy, several different symptoms and indicators related to BED, such as the frequency of binge-eating behavior, were significantly improved without adverse events. The above results showed that when a single dose of psilocybin was used in combination with psychotherapy, the symptoms of BED and the quality of life were substantially improved, and the magnitude of changes in binge-eating, anxiety, and depressive states in most subjects was dramatic. Such magnitudes are usually only observable after treatment based on evidence over a much longer period. In addition, the above results showed that the effect of improving the symptoms of BED lasted for more than 80 days after psilocybin administration, indicating that there is a persistent and lasting therapeutic effect even after a single dose of this psychotropic drug. The above results support the usefulness of methods and uses including the administration of psychotropic drugs such as psilocybin and psilocin in the treatment of BED.

[0271] The present invention is not intended to be limited, for example, to the specific disclosed embodiments provided to illustrate various aspects of the present invention. Various modifications to the described compositions and methods will become apparent from the description and teachings herein. Such modifications may 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. Use of one or more doses of psilocybin or its active metabolite effective in inducing a dissociative state in a subject for the treatment of bulimia edema (BED), wherein the use involves orally administering one or more doses of effective psilocybin or its active metabolite to a subject suffering from one or more symptoms of BED, and providing the subject with one or more integration sessions after recovery from the dissociative state. Includes, use.

2. Furthermore, the subjects shall be evaluated for one or more indicators before and / or after the administration of psilocybin or its active metabolite, once or multiple times. Includes, The use according to claim 1, wherein the one or more indicators relate to the symptoms, dissociative states, treatment outcomes, and safety of one or more BEDs and / or the subject.

3. The use according to claim 2, wherein one or more of the indicators are selected from the frequency of binge eating episodes, Binge Eating Scale (BES), Binge Eating Episodes per Day, Food Anxiety, Eating Behavior-Related Depression, Weight Management-Related Depression, Overall Clinical Impression Improvement-I, Interest in Induction of Trigger Foods, Waist Circumference, Body Mass Index (BMI), General Anxiety, Food Anxiety, Self-Perception, Confidence, Well-being, Binge Eating Cravings, Weight, Eating Behavior, Hospitalization Anxiety and Depression Scale (HADS), Patient's Overall Impression Improvement-I, and Acceptance and Behavior Questionnaire (AAQ-II).

4. The use according to claim 2 or 3, wherein the one or more indicators include parameters for observer evaluation, parameters for subject reporting, and / or clinical indicators.

5. The use according to any one of claims 2 to 4, wherein one or more of the indicators are evaluated as a reference measurement before administration, evaluated as a result measurement after administration, the change between the reference measurement and the result measurement is measured, and the subject shows improvement between the reference measurement and the result measurement of the one or more indicators.

6. The use according to any one of claims 3 to 5, wherein the frequency of the binge eating episodes is measured daily.

7. The use according to any one of claims 2 to 5, wherein the one or more indicators include the number of overeating episodes per day.

8. The use according to any one of claims 2 to 5, wherein the frequency of the binge eating episodes is measured over a 28-day period prior to the measurement day.

9. The use according to any one of claims 2 to 5, wherein the one or more indicators include the frequency of overeating episodes during the 28 days prior to the measurement day.

10. The use according to any one of claims 2 to 5, wherein the one or more indicators is the frequency of binge eating urges indicated by a sense of loss of eating control.

11. The use according to any one of claims 2 to 5, wherein the one or more indicators is the frequency of the feeling of loss of eating control per day.

12. The use according to any one of claims 2 to 11, wherein the one or more indicators include an interest in consuming induced foods.

13. The use according to any one of claims 2 to 12, wherein one or more of the indicators are measured using the dietary questionnaire.

14. The use according to any one of claims 2 to 13, wherein one or more indicators are selected from the Emotional Breakthrough Inventory (EBI), the Acceptance and Behavior Questionnaire II (AAQ-II), the Patient's Overall Impression Improvement-I (PGI-I), and the Hospitalization Anxiety and Depression Scale (HADS).

15. The use according to claim 14, wherein one or more of the indicators is HADS-anxiety.

16. The use according to claim 14, wherein one or more of the indicators is HADS-depressive state.

17. The one or more indicators are one or more neurophysiological biomarkers selected from resting-state functional connectivity (during feeding and fasting) by functional magnetic resonance imaging (fMRI), task-related functional activation and connectivity in a food cue responsiveness task by fMRI (during feeding and fasting), voxel-based morphometry (gray matter volume / structure) by fMRI, and resting-state electroencephalography (EEG). The one or more indicators are one or more metabolic biomarkers selected from ghrelin, leptin, adiponectin, insulin, glucose, and HOMA-IR (Hostasis Model Assessment of Insulin Resistance), and are selected from the Monitor Rating Scale (MRS), the Questionnaire on Mysterious Experiences (MEQ30), and the Questionnaire on Difficult Experiences (CEQ), or The use according to any one of claims 2 to 5, wherein the one or more indicators are selected from vital signs, blood chemistry and hematological tests, urinalysis, electrocardiogram (ECG), and the Columbia Suicide Severity Scale (C-SSRS).

18. The use according to any one of claims 2 to 17, wherein the one or more indicators are measured during one or more of the integrated sessions.

19. The one or more of the above indicators are measured approximately 4 weeks and approximately 12 weeks after one or more doses of psilocybin or its active metabolite. The one or more indicators described above are measured approximately 4 weeks, 8 weeks, and 12 weeks after one or more doses of psilocybin or its active metabolite, or The use according to any one of claims 2 to 18, wherein one or more of the indicators are measured approximately four weeks after one or more administrations of psilocybin or its active metabolite.

20. The use according to any one of claims 1 to 19, wherein the treated subjects exhibit one or more improvements selected from the following: a reduction in the frequency of binge eating episodes, a reduction in the Binge Eating Scale (BES), a reduction in the number of binge eating episodes per day, a reduction in the frequency of loss of dietary control per day, a reduction in food-related anxiety, a reduction in food-related depression, a reduction in eating behavior-related depression, a reduction in weight management-related depression, an improvement in overall clinical impression improvement (CGI-I), a reduction in interest in consuming trigger foods, a reduction in waist circumference, a reduction in body mass index (BMI), a reduction in overall anxiety, a reduction in food-related anxiety, an improvement in self-awareness, an increase in confidence, an improvement in depression and genuine well-being, a lack of binge eating cravings, weight loss, an improvement in eating behavior, a reduction in the Hospitalization Anxiety and Depression Scale (HADS), a reduction in HADS-anxiety, a reduction in HADS-depression, an improvement in overall patient impression improvement (PGI-I), and an improvement in acceptance and behavior questionnaire responses (AAQ-II).

21. The use according to any one of claims 1 to 20, wherein the one or more administrations of psilocybin or its active metabolite comprise one, two, three, four, or five administrations of psilocybin or its active metabolite.

22. The use according to any one of claims 1 to 21, wherein the dose is 10 mg or about 10 mg to 50 mg or about 50 mg of psilocybin.

23. The use according to claim 22, wherein the dose is 25 mg and about 25 mg of psilocybin.

24. The use according to any one of claims 1 to 23, wherein the one or more integrated sessions include one, two, three, four, or five integrated sessions.

25. The use according to any one of claims 1 to 24, wherein the integrated session is provided one day or about one day after administration of the dose of psilocybin or its active metabolite.

26. The use according to any one of claims 1 to 25, further comprising providing one or more further integrated sessions.

27. The use according to claim 26, wherein the one or more further integrated sessions are provided about 6 to 9 days or about 9 days after administration of the dose of psilocybin or its active metabolite.

28. The use according to claim 26 or 27, wherein the one or more further integrated sessions are provided 7 days or about 7 days after administration of the dose of psilocybin or its active metabolite.

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