Improved Methods for the Use of Psychedelics

Abstract

Improved methods are provided for treating psychological disorders in a subject, comprising administering to a subject an amount of psilocybin or psilocin sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and thereafter maintaining an average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during a therapeutic window. TIFF2024510637000009.tif103170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 161,070, entitled "IMPROVED METHODS FOR THE USE OF PSYCHEDELICS," filed March 15, 2021, the contents of which are incorporated by reference in their entirety.

[0002] Field The present technology relates to formulations and improved methods for the use of psilocybin, psilocin and other psychedelic compounds in the treatment of psychological disorders. [Background technology]

[0003] background Psilocybin (4-phosphoroyloxy-N,N-dimethyltryptamine) is a tryptamine psychedelic with effects similar to dimethyltryptamine (DMT), lysergic acid diethylamide (LSD) and mescaline that produce psychotropic effects. Psilocybin is being investigated as a treatment for certain mental health conditions. However, improved methods and compositions are needed to overcome challenges such as the potential for addiction, and difficulties in controlling doses and pharmacokinetic parameters. Methods and compositions that meet such needs are provided herein. Summary of the Invention

[0004] overview Provided herein are methods of treating a psychological disorder in a subject involving administration of a psychedelic. In some of any of the provided embodiments, the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0005] In some of any of the provided embodiments, the methods involve administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and thereafter maintaining an average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during a therapeutic window, where the psychedelic is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof.

[0006] In some of the optional embodiments, the methods also involve obtaining non-invasive measurements of brain activity from the subject to determine when the subject enters a dissociated state.

[0007] Also provided herein are methods of inducing a dissociative state involving administration of a psychedelic. In some of any of the provided embodiments, the methods involve administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject; and obtaining non-invasive measurements of brain activity from the subject to determine when the subject enters the dissociative state, where the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0008] Also provided herein is a method of inducing a dissociative state in a subject having a psychological disorder, comprising administering to the subject a psychedelic in an amount sufficient to induce a dissociative state in the subject; and obtaining electroencephalography (EEG) measurements from the subject to determine when the subject enters the dissociative state, where the psychedelic is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof.

[0009] Also provided herein are methods of determining a therapeutically effective dose of a psychedelic. In some of any of the provided embodiments, the methods involve administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject; obtaining a non-invasive measurement of brain activity from the subject to determine whether the subject has entered a dissociative state; and if the subject has entered a dissociative state, determining the amount of psychedelic as a therapeutically effective dose, where the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0010] Also provided herein are methods of maintaining a dissociated state in a subject with a psychological disorder. In some of any of the provided embodiments, the methods involve administering to the subject a psychedelic in an amount sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and obtaining an electroencephalography (EEG) measurement from the subject to determine when the subject enters the dissociated state; and thereafter maintaining an average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during a therapeutic window, wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0011] Also provided herein are methods of treating a psychological disorder. In some of any of the provided embodiments, the methods involve performing any of the methods provided herein and maintaining the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window; thereby treating the psychological disorder.

[0012] Also provided herein are methods of treating phantom limb pain in a subject. In some of any of the provided embodiments, the methods involve administering to a subject having phantom limb pain a psychedelic in an amount sufficient to induce a dissociative state in the subject, where the psychedelic is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof.

[0013] In some of any of the provided embodiments, administration of the psychedelic is by intravenous administration.

[0014] In some of the embodiments, the dissociated state is induced in the subject within less than, or less than about, 15, 30, 60, 90, or 120 minutes after administration, or within a range defined by any of the foregoing. In some of the embodiments, the dissociated state is induced in the subject within less than, or less than about, 30 minutes after administration.

[0015] In some optional embodiments, the methods also involve maintaining the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window.

[0016] In some of the optional embodiments, the non-invasive measurement of brain activity is selected from among electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), and optoencephalography (OEG). In some of the optional embodiments, the non-invasive measurement of brain activity is EEG.

[0017] In some of the optional embodiments, the non-invasive measurement of brain activity is a questionnaire-based assessment of the experience. In some of the optional embodiments, the questionnaire-based assessment of the psychedelic experience is selected from one or more of the Mystical Experiences Questionnaire (MEQ30) assessment, the Challenging Experiences Questionnaire (CEQ) assessment, the Psychological Insight Questionnaire (PIQ) assessment, a qualitative written assessment, and / or the Monitor Rating Scale (MRS) questionnaire.

[0018] In some of the optional embodiments, the method also involves obtaining additional non-invasive measurements of brain activity from the subject to monitor the dissociated state during the treatment window. In some of the optional embodiments, the method also involves obtaining additional measurements of EEG from the subject to monitor the dissociated state during the treatment window.

[0019] In some of the optional embodiments, the EEG measurements are analyzed as expressed by Lempel-Ziv Complexity (LZC).

[0020] In some optional embodiments, non-invasive measurements of brain activity are obtained before, during and / or after administration. In some optional embodiments, EEG measurements are obtained before, during and after administration.

[0021] In some optional embodiments, non-invasive measurements of brain activity after administration indicate the end of the dissociative state. In some optional embodiments, measurements of EEG after administration indicate the end of the dissociative state.

[0022] In some of the embodiments, the dissociated state is induced within or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes after administration. In some of the embodiments, the dissociated state is induced within or about 5 minutes after administration.

[0023] In some of the optional embodiments, the therapeutic window is at or about 0.5, 1, 2, 3, 4, 5, or 6 hours. In some of the optional embodiments, the therapeutic window is at or about 0.5 hours to at or about 4 hours.

[0024] In some of any of the provided embodiments, the methods also involve terminating administration of the psychedelic to terminate the dissociative state.

[0025] In some of any of the embodiments, the end of the dissociative state occurs within, or within about, 30, 60, 90, 120, or 180 minutes, or within a range defined by any of the foregoing, of the end of administration of the psychedelic. In some of any of the embodiments, the end of the dissociative state occurs within, or within about, 60 minutes, of the end of administration of the psychedelic.

[0026] In some of the optional embodiments, the psychedelic provides a predetermined C within or about 30 to 120 minutes after the start of administration. max In some of the optional embodiments, the psychedelic is administered to produce a predetermined C within or about 45-90 minutes after the start of administration. max In some of the optional embodiments, the psychedelic produces a predetermined C within or about 1-10 minutes of administration. max is administered to produce

[0027] In some of the optional embodiments, C max In some of the optional embodiments, C is between 1 μg / L and 50 μg / L or between about 1 μg / L and 50 μg / L. max In some of the optional embodiments, C is between 1 μg / L and 20 μg / L or between about 1 μg / L and 20 μg / L. max is between 10 μg / L and 20 μg / L or about 10 μg / L to 20 μg / L. max is between 10 μg / L and 15 μg / L or about 10 μg / L to 15 μg / L.

[0028] In some optional embodiments, the dissociative state is induced by intravenous administration of a loading dose of a psychedelic.

[0029] In some of the optional embodiments, the loading dose comprises administration of an initial bolus of the psychedelic, hi some of the optional embodiments, the initial bolus is at or about 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.

[0030] In some of the embodiments, the loading dose of the psychedelic is administered over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or a range defined by any of the foregoing. In some of the embodiments, the loading dose of the psychedelic is administered over a period of 3 minutes or about 3 minutes.

[0031] In some optional embodiments, the initial bolus of psychedelic is at a dose of at or about 0.02 mg / kg to at or about 0.2 mg / kg.

[0032] In some optional embodiments, the dissociative state is induced by intravenous administration of an initial bolus of a psychedelic at a dose of about 0.1 mg / kg to about 0.2 mg / kg.

[0033] In some optional embodiments, the average plasma concentration of the psychedelic is maintained at a predetermined value during the therapeutic window by administration of a maintenance dose of the psychedelic.

[0034] In some of the optional embodiments, the maintenance dose of the psychedelic is administered by continuous or intermittent administration of the psychedelic. In some of the optional embodiments, the continuous or intermittent administration is via an intravenous route.

[0035] In some of the optional embodiments, the maintenance dose is administered by intravenous infusion.

[0036] In some optional embodiments, the maintenance dose of the psychedelic is administered by intermittent administration of the psychedelic, wherein the intermittent administration is via subcutaneous, oral, transdermal, intramuscular, intranasal, intranasal / pharyngeal, or buccal routes.

[0037] In some optional embodiments, the maintenance dose is administered by intravenous infusion of the psychedelic at a rate of at or about 0.2 mg / min to at or about 1 mg / min.

[0038] In some of the optional embodiments, the continuous administration of the psychedelic is at a rate of from at or about 0.1 mg / min to at or about 1 mg / min.

[0039] Also provided herein are methods of treating a psychological disorder in a subject. In some of any of the provided embodiments, the methods involve administering to a subject having a psychological disorder a loading dose of a psychedelic by intravenous administration of an initial bolus in an amount of at or about 1 mg to at or about 5 mg; and continuously administering a maintenance dose of the psychedelic thereafter by intravenous infusion at a rate of at or about 0.02 mg / min to at or about 1 mg / min to maintain an average plasma concentration during the therapeutic window, wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0040] Also provided herein are methods of treating a psychological disorder in a subject. In some of any of the provided embodiments, the methods involve administering to a subject having a psychological disorder a loading dose of a psychedelic by intravenous infusion at a rate of at or about 0.5 mL / min to at or about 2.0 mL / min over a period of at or about 5 minutes to at or about 20 minutes; and thereafter continuously administering a maintenance dose of the psychedelic by intravenous infusion at a rate of at or about 0.1 mL / min to at or about 2.0 mL / min over a period of at or about 30 minutes to at or about 120 minutes to maintain an average plasma concentration during the therapeutic window, wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof.

[0041] In some of the embodiments, the loading dose of the psychedelic is administered at a rate of at or about 0.1 mL / min to at or about 2.0 mL / min. In some of the embodiments, the loading dose of the psychedelic is administered at a rate of at or about 1.0 mL / min.

[0042] In some of the embodiments, the maintenance dose is administered at a rate of 0.1 mL / min to 1.0 mL / min or about 1.0 mL / min. In some of the embodiments, the maintenance dose is administered at a rate of 0.5 mL / min or about 0.5 mL / min.

[0043] In some of the embodiments, the maintenance dose is administered for a period of at or about 30, 60, 90 or 120 minutes, or a range defined by any of the foregoing. In some of the embodiments, the maintenance dose is administered for a period of at or about 60 minutes. In some of the embodiments, the maintenance dose is administered for a period of at or about 120 minutes. In some of the embodiments, the therapeutic window is at or about 30 minutes to at or about 120 minutes.

[0044] In some optional embodiments, the therapeutic window is at or about 60 minutes. In some optional embodiments, the therapeutic window is at or about 120 minutes.

[0045] In some of the embodiments, the total amount of psychedelic administered to the subject is at most, or about, 1.0 mg, 1.5 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg per subject, or a range defined by any of the foregoing. In some of the embodiments, the total amount of psychedelic administered to the subject is at most, or about, 2.5 mg. In some of the embodiments, the total amount of psychedelic administered to the subject is at most, or about, 5 mg. In some of the embodiments, the total amount of psychedelic administered to the subject is at most, or about, 10 mg.

[0046] In some of the optional embodiments, the psychedelic is psilocin, a cocrystal, coformer, or a salt thereof. In some of the optional embodiments, the psychedelic is psilocin.

[0047] In some of the optional embodiments, the psychedelic is psilocybin, a cocrystal, coformer, or a salt thereof. In some of the optional embodiments, the psychedelic is psilocybin.

[0048] In some of the optional embodiments, the psychedelic is psilocin, the total amount of psilocin administered to the subject is at or about 2.5 mg, and the administration of psilocin is carried out over a period of at or about 60 minutes.

[0049] In some of the optional embodiments, the psychedelic is psilocybin, the total amount of psilocybin administered to the subject is at or about 5 mg, and the administration of the psilocybin is carried out over a period of at or about 60 minutes.

[0050] In some of the optional embodiments, the predetermined value of the average plasma concentration of the psychedelic is between 1 and 50 μg / L or between about 1 and 50 μg / L. In some of the optional embodiments, the predetermined value of the average plasma concentration of the psychedelic is between 10 and 20 μg / L or between about 10 and 20 μg / L. In some of the optional embodiments, the predetermined value of the average plasma concentration of the psychedelic is between 10 and 15 μg / L or between about 10 and 15 μg / L.

[0051] In some optional embodiments, the methods also involve providing psychological support to the subject during the treatment window.

[0052] In some of the optional embodiments, the method also includes the step of: 2A This involves removing the subject from the dissociated state at the end of the treatment window by administering a receptor antagonist.

[0053] In some of the optional embodiments, the psychological disorder is selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, fibromyalgia, neuropathic pain, phantom limb pain, hypothalamic-induced obesity, Prader-Willi syndrome, and binge eating disorder. In some of the optional embodiments, the psychological disorder is selected from the group consisting of hypothalamic-induced obesity, Prader-Willi syndrome, binge eating disorder, and fibromyalgia.

[0054] In some of the embodiments, the psychological disorder is nociceptive pain disorder. In some of the embodiments, the psychological disorder is fibromyalgia. In some of the embodiments, the psychological disorder is phantom limb pain. In some of the embodiments, the psychological disorder is complex regional pain syndrome.

[0055] In some of the optional embodiments, the methods also involve discontinuing administration if the subject experiences an adverse event.

[0056] In some optional embodiments, the psychedelic is administered with at least one additional therapeutic agent.

[0057] In some optional embodiments, the method results in induction of a dissociated state in at least 70%, 80%, 90% or 95% of subjects administered the psychedelic.

[0058] In some optional embodiments, the method results in maintenance of average plasma levels of the psychedelic in at least 70%, 80%, 90% or 95% of the subjects being administered the psychedelic.

[0059] In a first aspect, there is provided a method of treating a psychological disorder in a subject, comprising: administering to the subject an amount of a psychedelic sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. A method is provided, comprising:

[0060] In one embodiment, the dissociated state is induced within less than 1, 2, 3, 4, 5, 6, 7, 8, 9, about 10, about 15, about 20, about 25, or about 30 minutes. The therapeutic window can be about 0.5, 1, 2, 3, 4, 5, or 6 hours.

[0061] In one embodiment, the psychedelic C max occurs within 1 to 10 minutes of administration. max can be from 1 to at least about 50 μg / L.

[0062] In some embodiments, the dissociative state is induced by an initial administration of a bolus of the psychedelic administered intravenously at a dose of about 0.01 to 0.2 mg / kg.

[0063] In some embodiments, the dissociative state is induced by administration of an initial intravenous bolus of psilocybin or psilocin. The initial intravenous dose of psilocybin, psilocin, or a combination thereof can be about 1, 2, 3, 4, or 5 mg. Alternatively, the initial intravenous dose of psilocybin can be about 0.01-0.2 mg / kg, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or about 0.1 mg / kg.

[0064] In some embodiments, the dissociative state is induced by administration of an initial oral dose of psilocybin, psilocin, or a combination thereof, which may be 0.1-1.0 mg / kg, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / kg. Alternatively, the initial oral dose of psilocybin, psilocin, or a combination thereof may be 10-40 mg, e.g., 10, 15, 20, 25, 30, 35, or 40 mg.

[0065] After the initial dose, the average plasma concentration of the psychedelic is maintained at a predetermined value during the therapeutic window by continuous or intermittent administration of the psychedelic. For example, the psychedelic may be administered continuously intravenously at a rate of 0.02 mg / min to 1 mg / min. In some embodiments, the psychedelic may be administered continuously transdermally. Alternatively, the psychedelic may be administered intermittently, for example, intravenously or orally.

[0066] In an embodiment, the predetermined plasma concentration of the psychedelic is between about 1 μg / L and 50 μg / L.

[0067] In one embodiment, the psychedelic is psilocybin, psilocin or a combination thereof and is administered intravenously to maintain an average plasma concentration of the psychedelic at a predetermined value.

[0068] The intravenous dose of psilocybin, psilocin or a combination thereof can be about 1, 2, 3, 4, or 5 mg. Alternatively, the intravenous dose of psilocybin can be about 0.01-0.2 mg / kg, e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or about 0.1 mg / kg, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 mg / kg.

[0069] In one embodiment, psilocybin, psilocin or a combination thereof is administered orally.

[0070] Oral doses of psilocybin, psilocin or combinations thereof can be from about 2 mg to at least about 15 mg, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or at least about 15 mg. Alternatively, oral doses of psilocybin can be about 0.05-0.2 mg / kg, e.g., 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 mg / kg.

[0071] The method further includes providing psychological support to the subject during the treatment window.

[0072] The method further comprises administering a 5HT monotherapy such as risperidone, olanzapine, mirtazapine, or mianserin at the end of the treatment window or if the patient experiences an adverse event. 2A The method may further include removing the subject from the dissociated state by administering a receptor antagonist.

[0073] The psychological disorder may be selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, fibromyalgia, neuropathic pain, phantom limb pain, hypothalamic-induced obesity, and Prader-Willi syndrome, binge eating disorder. Preferably, the psychological disorder is hypothalamic-induced obesity, Prader-Willi syndrome, binge eating or fibromyalgia.

[0074] In some embodiments, the psychedelic is psilocybin, psilocin, or a combination thereof.

[0075] In some embodiments, the psychedelic is administered with at least one additional therapeutic agent for a psychological disorder.

[0076] In a preferred embodiment, the psychedelic is administered intravenously.

[0077] In some embodiments, the psychedelic is administered concomitantly or sequentially with another pharmaceutical agent.

[0078] In a second aspect, there is provided a method for determining a therapeutically effective dose of a psychedelic for treating a psychological disorder in a subject, comprising: administering to a subject an amount of psilocybin or psilocin sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and obtaining an EEG from the subject to determine when the subject enters a dissociated state; Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. A method is provided, comprising:

[0079] In some embodiments, the method may further include obtaining an additional EEG from the subject to monitor the dissociation state during the treatment window.

[0080] In some of the embodiments, provided herein is a psychedelic that is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof, for use in any of the embodiments described herein, including methods of treating a psychological disorder, methods of inducing a dissociative state, methods of determining a therapeutically effective dose of a psychedelic, and methods of maintaining a dissociative state in a subject with a psychological disorder, and methods of treating phantom limb pain in a subject. In some of the embodiments, provided herein is a psychedelic that is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof, for use in any of the embodiments described herein, including methods of treating a psychological disorder, methods of inducing a dissociative state, methods of determining a therapeutically effective dose of a psychedelic, and methods of maintaining a dissociative state in a subject with a psychological disorder, and methods of treating phantom limb pain in a subject. In some of the optional aspects, provided herein is the use of a psychedelic that is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for use according to any of the aspects described herein, including methods of treating a psychological disorder, methods of inducing a dissociative state, methods of determining a therapeutically effective dose of a psychedelic, and methods of maintaining a dissociative state in a subject with a psychological disorder, and methods of treating phantom limb pain in a subject. [Brief description of the drawings]

[0081] [Figure 1A]Figures 1A and 1B show plasma psilocin concentrations in three rats during and after a 1-hour intravenous infusion of 10 mg / kg psilocin (Figure 1A) or psilocybin (Figure 1B). [Figure 1B] Figures 1A and 1B show plasma psilocin concentrations in three rats during and after a 1-hour intravenous infusion of 10 mg / kg psilocin (Figure 1A) or psilocybin (Figure 1B). [Diagram 2] Figures 2A and 2B show estimates of normalized temporal Lempel-Ziv complexity (LZCN) as determined based on electroencephalography (EEG) in three rats before, during, and after a 1-hour intravenous infusion of 10 mg / kg psilocybin. Figure 2A shows the individual temporal LZCN values. Figure 2B shows the box plot distribution of temporal LZCN values. [Diagram 3] FIG. 3 shows plasma psilocin concentrations in rats following a 3-minute intravenous infusion of 10 mg / kg psilocybin, with rats either receiving (ISO+) or not (ISO-) isoflurane anesthesia prior to infusion of psilocybin. [Figure 4A] Figures 4A and 4B show Von Frey Assay (VFA) withdrawal thresholds in a formalin-induced rat pain model (formalin is injected into the hind paw of the rat) and either 10 mg / kg psilocybin or saline via intravenous infusion. Figure 4A shows the withdrawal threshold for the injected paw. [Figure 4B] Figures 4A and 4B show Von Frey Assay (VFA) withdrawal thresholds in a formalin-induced rat pain model (formalin injected into the hind paw of the rat) and either 10 mg / kg psilocybin or saline via intravenous infusion. Figure 4B shows the withdrawal threshold for the contralateral paw. [Diagram 5] FIG. 5 shows the formalin-induced rat pain model (formalin is injected into the hind paw of the rat) and hot plate assay (HPA) withdrawal latencies from a 52.5° C. hot plate with either 10 mg / kg psilocybin or saline via intravenous infusion. [Figure 6]FIG. 6 shows exemplary estimated plasma psilocin concentrations in human subjects over 360 minutes following oral (PO) or intravenous administration of psilocin or psilocybin. The plot includes observed plasma concentrations as described in Brown et al. (2017). Clin Pharmacokinet. 56(12):1543-1554. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] Detailed Description Provided herein are methods of inducing a dissociative or psychedelic state and methods of treatment involving administration of a psychedelic, such as psilocin or psilocybin, by intravenous administration. In some aspects, methods of determining a therapeutically effective dose of a psychedelic, such as for a method of treatment or treatment regimen, are also provided. Provided herein are methods for treating or ameliorating psychological disorders, such as diseases with a psychological component, and certain pain-related disorders, such as nociceptive pain disorders. In some aspects, provided methods involve administering a psychedelic, such as psilocin or psilocybin, for example, via intravenous administration. In some aspects, provided herein are methods of administering a psychedelic, such as psilocin or psilocybin, for treating or ameliorating psychological disorders or one or more symptoms thereof, and uses thereof, such as therapeutic or prophylactic uses. In some aspects, provided are methods involving monitoring a subject's dissociative or psychedelic state before, during, or after administration of a psychedelic. In some aspects, provided methods involve monitoring by one or more non-invasive measures of brain activity, such as electroencephalography (EEG). In some aspects, methods for determining a therapeutically effective dose of a psychedelic, e.g., for a treatment method or treatment regimen, are also provided. In some aspects, the methods and uses provided lead to an improvement, e.g., clinical improvement, or recovery, of the psychological disorder.

[0083] In some embodiments, psychedelics (e.g., psilocin or psilocybin) and compositions comprising psychedelics are useful in a variety of therapeutic, diagnostic, and prophylactic applications. For example, the compositions are useful for treating a variety of diseases and disorders, such as psychological disorders, in a subject. Such methods and uses include therapeutic methods and uses, e.g., those involving administration of a psychedelic to a subject having a disease, condition, or disorder, such as a psychological disorder or disease. In some embodiments, the psychedelic (e.g., psilocin or psilocybin) is administered in an effective amount to cause treatment of the disease or disorder. Uses include use of the compositions in such methods and treatments, and in the preparation of medicaments for carrying out such therapeutic methods. In some embodiments, the methods are carried out by administering a psychedelic (e.g., psilocin or psilocybin) to a subject having or suspected of having a disease or condition, such as a psychological disorder. In some embodiments, the methods thereby treat a disease, condition, or disorder in the subject.

[0084] Also provided herein are the uses of psychedelics, such as psilocin or psilocybin, in such methods and treatments, and in the preparation of medicaments for carrying out such methods. In some embodiments, the methods and uses thereby improve, ameliorate and / or treat a psychological disorder or one or more symptoms thereof in a subject. In some embodiments, the therapeutic methods and uses provided involve administration, for example, intravenous administration of a psychedelic, such as psilocin or psilocybin, to a subject having, exhibiting or suffering from one or more symptoms of a psychological disorder, in an amount sufficient to rapidly induce a dissociative or psychedelic state in the subject, and / or in an amount effective to improve or ameliorate one or more symptoms of the psychological disorder.

[0085] Psilocybin (4-phosphoroyloxy-N,N-dimethyltryptamine) is a tryptamine psychedelic with effects similar to those of dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and mescaline. These agents produce psychotropic effects that have been characterized as producing a profound dream-like state with sensations including colorful optical illusions, changes in hearing, touch, smell, taste, and movement perception, altered spatial and temporal perception, changes in body image, and ego disorganization, as well as profound mood changes ranging from feelings of wonder and bliss to sadness and grief.

[0086] Psilocybin administered in a properly supervised and supported setting can have long-lasting positive psychological effects, and long-term positive effects indicating reduction in depression and anxiety symptoms as well as abstinence from addictive substances have been observed in clinical trials.

[0087] The general mechanism of action of psychedelics (including psilocybin) is via the serotonergic (5-HT) pathway. Psilocybin is a potent 5-HT 2A Not only receptor agonists, but also 5-HT 1A and 5-HT 2C It is a prodrug of psilocin, a moderate agonist of the 5-HT receptor in the thalamus (a brain region that relays sensory information). 2A Activation of the receptors reduces thalamic activity, leading to the altered perceptions commonly referred to as hallucinations. 2A The receptor agonist properties not only increase sensitivity to the environment, but also facilitate emotional relief, which is hypothesized to be therapeutically powerful when combined with psychological support. That is, due to the ability of psilocybin to alter perception and serotonergic activity, it has been extensively studied as a treatment for mental health conditions characterized by perceptual abnormalities, such as major depressive disorder, treatment-resistant depression, anxiety or anxiety-related disorders. Psilocybin is also being studied for use in substance abuse disorders.

[0088] Psilocybin is a prodrug that is converted in vivo to active psilocin by alkaline phosphatase activity. The psilocybin threshold for intoxication is approximately 0.20 mg / kg body weight, and the hallucinogenic effects following oral administration typically begin within the first 60-90 minutes of use and end within 3-6 hours thereafter, although there is considerable inter-subject variability, which raises questions about the traditional use of psychedelic substances to treat psychological disorders. Specifically, following administration of psychedelics such as psilocybin, there is wide inter-subject variability in the area under the plasma concentration-time curve, and C max and T max Thus, there is a large inter-subject variability in the time to induction of dissociative states and the duration of dissociative states (required for effective treatment). That is, due to the wide inter-subject variability in the pharmacokinetic parameters of psilocybin and other psychedelics, it is difficult to predict or control the therapeutic window for psilocybin, psilocin, and other psychedelics. Thus, typical doses of psilocybin, especially when administered orally, may result in patients achieving plasma concentrations that are either too high and may lead to psychosis ("bad trips"), or too low and dissociative states are not achieved.

[0089] Another problem with treatments using psychedelic substances such as psilocybin and LSD is that the subject must be with two therapists for a minimum of 8-10 hours. The therapists must be with the patient prior to administration of the psychedelic, which can result in a lag time of up to 3 hours before the patient enters a dissociative state, which can last up to an additional 6 hours, far beyond the useful therapeutic window.

[0090] The inventors have developed formulations and methods that allow for controlled dosing of psilocin, psilocybin and other psychedelics, allowing for more effective therapeutic use of psychedelics. Compositions, methods and uses are provided that can address the difficulties and limitations of existing methods of administering psychedelics.

[0091] The provided embodiments, including methods, allow the treating physician to control one or more of the following parameters: Time to onset of dissociation Duration of dissociative state C for psychedelic max .

[0092] The provided embodiments, including methods, also allow the treating physician to monitor and control one or more of the following parameters: Time to dissociation Getting out of a dissociative state Average plasma concentration of psychedelics Duration of administration Termination of treatment if an adverse event occurs.

[0093] Controlling these parameters provides several advantages, including avoiding high plasma concentrations of psychedelics that may lead to subjects experiencing psychotic episodes or placing them at high risk of experiencing adverse events such as psychotic episodes. In some aspects, high plasma concentrations are associated with adverse events or side effects that are cardiovascular in nature, such as increases in blood pressure, heart rate and risk of tachycardia or arrhythmia, and the embodiments provided that allow for control of plasma levels and avoidance of high plasma concentrations improve therapeutic intervention with psychedelics while minimizing adverse effects. Additionally, controlling these parameters can be used to avoid undesirable effects of psychedelics, such as one or more of elevated blood pressure, tachycardia, panic attacks, hallucinogen persistent perception disorder (HPDD), unpleasant emotional reactions ("bad trips"), and the like. Thus, embodiments including the methods disclosed herein provide various advantages, such as the ability to monitor dissociative states, determine therapeutically effective doses, and assess, adjust and specialize therapeutic treatments according to the subject's response.

[0094] In some aspects, the embodiments provided are based on the observations described herein that intravenous administration of psychedelics, such as psilocin or psilocybin, results in reproducible and consistent pharmacokinetic and pharmacodynamic profiles in various subjects. In some aspects as described herein, intravenous administration of psychedelics, such as intravenous infusion, results in rapid and consistent plasma levels of the psychedelic accompanied by entering a dissociative state measured using non-invasive measurements of brain activity, such as EEG. In some aspects, a rapid decrease in plasma levels and a simultaneous exit from the dissociative state are also observed upon termination of administration. The observations also support the utility of various exemplary non-invasive measurements of brain activity, such as EEG or behavioral observations, to monitor the subject's dissociative state and allow control and variation of pharmacokinetic parameters, such as the dose of the psychedelic, and the plasma concentration and / or exposure of the psychedelic.

[0095] In some aspects, the provided embodiments are also based on the observation that intravenous administration of psychedelics has shown beneficial effects on nociception in animal models of pain associated with pain-related diseases and indications, such as nociceptive pain. In some aspects, the demonstrated effects of intravenous administration of psychedelics on nociception in the uninjected limb, which extend for several weeks after administration, support the utility of the provided embodiments in treating pain-related disorders, such as nociceptive pain disorders, e.g., fibromyalgia, phantom limb pain, or complex regional pain syndrome. In some aspects, the observations support the benefits of the provided embodiments.

[0096] In some aspects, the treatment also involves psychotherapy. In some aspects, the methods and uses provided also involve psychotherapy, for example in one or more clinical sessions. In some embodiments, the therapeutic methods and uses provided involve administration of a psychedelic to a subject, for example, in combination with psychotherapy.

[0097] All publications, including patent documents, scientific articles and databases, referenced in this application are incorporated by reference in their entirety for all purposes to the same extent as if each publication was individually incorporated by reference. To the extent that the definitions set forth herein are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications, published applications and other publications incorporated herein by reference, the definitions set forth herein take precedence over the definitions incorporated herein by reference.

[0098] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0099] I. Methods of Treatment and Uses Involving Administration of Psychedelic Compounds Methods and uses involving administration of psychedelics, such as psilocin or psilocybin, are provided herein. In some aspects, the embodiments provided involve intravenous administration of psychedelics. In some aspects, the embodiments provided involve intravenous administration of one or more doses of psychedelics, such as one or more doses of psilocin or one or more doses of psilocybin. In some aspects, the embodiments provided involve intravenous administration over a period of time, such as intravenous infusion of psychedelics. In some aspects, the embodiments provided involve administering psychedelics to the subject in an amount sufficient to induce a dissociative state. In some embodiments, the individual also undergoes psychotherapy, for example, in one or more clinical sessions, in combination with or in conjunction with administration of psychedelics.

[0100] The methods disclosed herein involve the administration of a psychedelic, such as psilocin or psilocybin, to a subject to treat or prevent psychological disorders. Typically, the methods involve intravenous administration of the psychedelic to avoid hepatic first-pass metabolism. Other routes of administration that avoid hepatic first-pass effects, such as intranasal, intranasal / pharyngeal, and oral routes, transdermal, are also contemplated. Parenteral administration via subcutaneous and intramuscular routes is also contemplated. The methods also require the provision of psychological support to the subject by a therapist, psychiatrist, psychotherapist, or other qualified health professional.

[0101] The methods require the subject to enter a "psychedelic" or "dissociative state", characterized by effects that fall into three categories: Perceptual effects: altered shapes and colors (often appearing brighter, clearer and more intense); visual distortions; visual hallucinations (open and closed-eye vision); optical illusions; ocular blurring; synesthesia. Mental Effects: Mood alterations (from ecstatic euphoria to panic); time distortion; thought alterations (difficulty concentrating; strange concepts, ideas, or associations; increased creativity); dream-like feelings; depersonalization; sense of "expanded" consciousness. Physical Effects: Dizziness; tremors; nausea; drowsiness; blurred vision.

[0102] The relative prominence of particular effects can depend strongly on the particular drug, dosage, and setting in which the drug is used, but in the case of psilocybin and psilocin, dissociative states are characterized by an unconstrained form of cognition in which the flow of conscious experience appears more fluid and dynamic, and novel neural states are explored by the subject.

[0103] A. Medication In some aspects, methods of treatment and uses are provided that involve administering a psychedelic, such as psilocin or psilocybin, to a subject in an amount of the psychedelic sufficient to induce a dissociated state in the subject. In some aspects, the amount of the psychedelic is sufficient to induce a dissociated state in the subject within less than 15, 30, 60, 90, or 120 minutes, or within less than about 15, 30, 60, 90, or 120 minutes, or within a range defined by any of the above, after administration. In some aspects, the amount of the psychedelic is sufficient to induce a dissociated state in the subject within less than 30 minutes or less than about 30 minutes after administration (e.g., less than or less than 30 minutes after the start of administration of the psychedelic, or less than or less than 30 minutes after the end of administration of the psychedelic). In some aspects, embodiments also involve maintaining the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window.

[0104] In some aspects, the psychedelic is administered by intravenous administration. In some aspects, the psychedelic is administered by an initial intravenous bolus injection. In some embodiments, the psychedelic is administered by intravenous infusion, e.g., continuous infusion and / or delivery of a constant rate of the psychedelic. In some aspects, both an initial bolus injection and an intravenous infusion are administered.

[0105] In some aspects, the methods provided involve administration, e.g., by intravenous administration, of a psychedelic in an amount sufficient to induce a dissociative state in a subject. In some aspects, the amount of the psychedelic, which is psilocybin or psilocin, is sufficient to induce a dissociative state in a subject less than, or less than about, 15, 30, 60, 90, or 120 minutes after administration, or a range defined by any of the foregoing, e.g., less than, or less than about, 30 minutes after administration.

[0106] In some aspects, provided embodiments also involve maintaining the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. In some aspects, pharmacokinetic parameters of the administered psychedelic or its metabolites (e.g., psilocin) are assessed and / or monitored in the subject. In some aspects, provided embodiments achieve a plasma concentration, such as an average plasma concentration, of the psychedelic at a predetermined value. In some aspects, the predetermined value is sufficient to maintain the psychedelic state during the therapeutic window. In some aspects, the amount or dose of the psychedelic is determined as a therapeutically effective dose when the subject enters a dissociated state.

[0107] In some aspects, the pharmacokinetic parameter is the plasma level of the psychedelic or its metabolites. In some aspects, the plasma concentration of psilocin is measured. In some embodiments, the maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max ), and / or area under the curve (AUC) are determined as pharmacokinetic parameters. In some embodiments, the dosage, rate or timing of administration is individualized, customized, altered or adjusted based on the determined pharmacokinetic parameters.

[0108] Exemplary pharmacokinetic (PK) parameters used to assess pharmacological drug response and bioavailability are C max , T max , and AUC (Bialer et al, J Pharm Sci 1995;84(10):1160-3). These parameters can be used to determine the extent and rate of absorption of immediate release pharmaceuticals. PK analysis can involve a blood draw where plasma is obtained and subsequently analyzed for drug metabolite levels (e.g., a psychedelic such as psilocin or its metabolites). In some aspects, pharmacokinetic parameter analysis provides the plasma concentration of a metabolite (e.g., psilocin) at a given time during the treatment window.

[0109] C maxis defined as the maximum concentration of a drug in plasma, or in the use of other biological material for analysis (e.g., blood, cerebrospinal fluid, or target organs) after a dose is administered. As a drug is processed (i.e., absorbed, distributed, metabolized, and excreted), the subject's plasma concentration fluctuates and the maximum concentration (C) of the drug is reached after administration of the drug. max ) takes T max It is. max is governed by the rates of drug absorption and drug elimination.

[0110] The area under the plot of drug plasma concentration versus time after dosing (i.e., area under the curve or AUC), which can be expressed in units of mg*h / L, is related to the degree of drug exposure and clearance from the body (Scheff et al., Pharm Res 2011;28(5):1081-9). Time integration provides a more accurate estimate of overall drug exposure compared to relying on individual concentration measurements. Furthermore, these measurements are useful for assessing the net pharmacological response to a given drug dose (Krzyzanski and Jusko, J Pharm Sci 1998;87(1):67-72).

[0111] For AUC, this parameter can be calculated as AUC(0-t) or AUC(0-∞). Generally, AUC(0-t) is defined as the area under the concentration-time curve from dosing at time=0 to time=t. AUC(0-t) can be calculated for multiple values ​​of t=time to obtain a better understanding of the PK drug profile. In some cases, the duration of the assay is always finite, so AUC(0-∞) is the AUC curve extrapolated to infinite time. AUC(0-∞) is calculated from AUC(0-t) by adding a constant (Clast / λz), where Clast is the last observed quantifiable concentration and λz is the terminal phase rate constant. AUC values ​​are often calculated using a computer due to the complexity and large number of variables involved in tracking drug metabolism.

[0112] In some embodiments, the pharmacokinetic parameters, such as plasma concentration, Cmax or AUC, are indicative of or related to the entry and / or exit from the dissociated state. In some aspects, the pharmacokinetic parameters are indicative of or related to one or more non-invasive measures of brain activity, such as EEG.

[0113] Peak plasma levels of psilocin after a single oral dose of psilocybin at 0.225 mg / kg occurred after 105 + / - 37 minutes representing a mean concentration of 8.2 + / - 2.8 ng psilocin / ml plasma, and the estimated absolute bioavailability of psilocin after oral administration of psilocybin is 52.7 + / - 20% (Hasler et al, Pharm Acta Helv. 1997 Jun;72(3):175-84).

[0114] In contrast, in some embodiments, the methods disclosed herein utilize a dose of psilocin or psilocybin to achieve a plasma psilocin concentration of 1-20 μg / L to induce a dissociated state.

[0115] In some embodiments, the psychedelic is at or about 1 μg / L to at or about 50 μg / L, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 μg / L, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 μg / L, or a range defined by any of the foregoing. max In some aspects, a given C max is 1 to 20 μg / L. For example, maxis approximately 1μg / L, 2μg / L, 3μg / L, 4μg / L, 5μg / L, 6μg / L, 7μg / L, 8μg / L, 9μg / L, 10μg / L, 11μg / L, 12 It can be μg / L, 13 μg / L, 14 μg / L, 15 μg / L, 16 μg / L, 17 μg / L, 18 μg / L, 19 μg / L, or about 20 μg / L.

[0116] In some embodiments, the psychedelic induces a given C occurring at or about 1 minute to within at or about 120 minutes after the start of administration, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 minutes, or within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 minutes after the start of administration, or within a range defined by any of the foregoing. max In some aspects, the psychedelic is administered to produce a predetermined C within or about 30 to 120 minutes after the start of administration. max In some aspects, the psychedelic is administered to produce a predetermined C within or about 45-90 minutes after the start of administration, e.g., within or about 60 minutes after the start of administration. max In some aspects, the psychedelic is administered to produce a predetermined C within or about 1-10 minutes after the start of administration. max In some embodiments, the psychedelic is administered to produce a predetermined C that occurs within 1-10 minutes of administration. max In some aspects, the psychedelic is administered to produce a predetermined C within or about 1-10 minutes after the start of administration. max is administered to produce

[0117] In some embodiments, a dissociative state can be induced and a suitable therapeutic window can be created with a single dose of about 0.01 mg / kg, about 0.02 mg / kg to about 0.5 mg / kg of the psychedelic. Suitable single doses include about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, or about 0.5 mg / kg.

[0118] Induction of a dissociated state in a subject marks the beginning of a therapeutic window, which relates to the range of plasma concentrations of the psychedelic compound within which treatment is effective without negative effects (such as psychotic episodes or tachycardia). In some aspects, the therapeutic window is the period during which the average plasma concentration of the psychedelic is maintained at a predetermined value to maintain the dissociated state. In some aspects, the therapeutic window is from or about 15 minutes to or about 12 hours, e.g., 0.5, 1, 2, 3, 4, 5, or 6 hours, or about 0.5, 1, 2, 3, 4, 5, or 6 hours, or a range defined by any of the foregoing. In some embodiments, the therapeutic window is from or about 0.5 to or about 4 hours, e.g., 1 hour or about 1 hour, or 2 hours or about 2 hours.

[0119] In some of any of the provided embodiments, the dissociative state is induced by administration of a loading dose (e.g., an initial dose) of the psychedelic. In some aspects, the loading dose of the psychedelic is administered by intravenous administration. In some aspects, the loading dose comprises administration of an initial bolus injection of the psychedelic. In some aspects, the loading dose comprises continuous intravenous administration, such as an intravenous drip. In some aspects, the loading dose is administered by an intravenous drip at an initial drip rate to maintain blood levels, followed by a slower rate. In some aspects, the loading dose of the psychedelic is administered over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or a range defined by any of the foregoing. In some aspects, the loading dose of the psychedelic is administered over a period of 3 minutes or about 3 minutes.

[0120] In some aspects, an exemplary loading dose of a psychedelic, such as psilocybin, psilocin, or a combination thereof, is from at or about 0.1 mg to at or about 10 mg, e.g., 1, 2, 3, 4, or 5 mg, or about 1, 2, 3, 4, or 5 mg, or a range defined by any of the foregoing. In some aspects, the loading dose is an initial bolus of the psychedelic, the initial bolus being from at or about 0.02 mg / kg to at or about 0.2 mg / kg, e.g., 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.6 0.6, 0.17, 0.18, 0.19, or 0.2 mg / kg or about 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 mg / kg, or a range defined by any of the foregoing.

[0121] In some embodiments, the dissociated state is from 0.01 mg / kg or about 0.01 mg / kg to 0.2 mg / kg or about 0.2 mg / kg, or from 0.02 mg / kg or about 0.02 mg / kg to 0.2 mg / kg or about 0.2 mg / kg, e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16 , 0.17, 0.18, 0.19, or 0.2 mg / kg, or about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 mg / kg, or a range defined by any of the foregoing. In some aspects, the dissociative state is induced by intravenous administration of an initial bolus of a psychedelic at a dose of about 0.1 mg / kg to about 0.2 mg / kg. In some embodiments, the initial intravenous dose of psilocybin, psilocin, or a combination thereof is at or about 5 mg / kg to 15 mg or about 15 mg / kg.

[0122] In some aspects, the loading dose of the psychedelic is administered by continuous administration, such as an intravenous infusion at an initial rate. In some aspects, an exemplary initial rate of infusion is at or about 0.1 mL / min to at or about 2.0 mL / min, such as 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mL / min, or at or about 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mL / min, or a range defined by any of the foregoing. In some aspects, the loading dose of the psychedelic is administered at a rate of at or about 1.0 mL / min.

[0123] In some embodiments, the provided methods and uses lead to achieving a dissociative or psychedelic state in a subject more rapidly than by other methods (e.g., by oral administration). In some aspects, the dissociative state is induced within 30 minutes or about 30 minutes of administration of the psychedelic, for example within 30 minutes or about 30 minutes of starting administration of the psychedelic. In some aspects, the dissociative state is induced within 1 or about 1 to 30 minutes or about 30 minutes of administration of the psychedelic, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes of administration of the psychedelic, e.g., within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes of administration of the psychedelic, e.g., of the onset of administration of the psychedelic, or within a range defined by any of the foregoing. In some aspects, the dissociated state is induced within or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes of administration. In some embodiments, the dissociated state is induced within or about 5 minutes of administration.

[0124] In another embodiment, C maxOnce the therapeutic window is reached and the dissociated state is induced, the administration rate of the psychedelic can be maintained or altered to maintain the therapeutic window. For example, in aspects where the psychedelic is administered by intravenous infusion, the psychedelic may be continuously infused into the subject, or the infusion rate can be reduced to keep the plasma concentration of the psychedelic just high enough to maintain the dissociated state. An appropriate infusion rate will depend on the concentration of the psychedelic in the infusion solution and can be determined by one of skill in the art, for example to maintain a predetermined plasma concentration of the psychedelic (i.e., a predetermined value of the average plasma concentration of the psychedelic), which can be from 1 μg / L or about 1 μg / L to 50 μg / L or about 50 μg / L, for example, from 1 μg / L or about 1 μg / L to 20 μg / L or about 20 μg / L, for example, 1 μg / L, 2 μg / L, 3 μg / L, 4 μg / L, 5 μg / L, 6 μg / L, 7 μg / L, 8 μg / L, 9 μg / L, 10 μg / L, 12 μg / L, 14 μg / L, 16 μg / L, 17 μg / L, 18 μg / L, 19 μg / L, 20 μg / L, 21 μg / L, 22 μg / L, 23 μg / L, 24 μg / L, 25 μg / L, 26 μg / L, 27 μg / L, 28 μg / L, 29 μg / L, 30 μg / L, 31 μg / L, 32 μg / L, 33 μg / L, 34 μg / L, 35 μg / L, 36 μg / L, 37 μg / L, 38 μg / L, 39 μg / L, 40 μg / L, 41 μg / L, 42 μg / L, 43 μg / L, 44 μg / L, 45 μg / L, 46 μg / L, 47 μg / L, 48 μg / L, 49 μg / L, 50 μg / L, 10μg / L, 11μg / L, 12μg / L, 13μg / L, 14μg / L, 15μg / L, 16μg / L, 17μg / L, 18μg / L, 19μg / L, or 20μg / L, or about 1μg / L, 2μg / L, 3μg / L, 4μg / L, 5μ g / L, 6 μg / L, 7 μg / L, 8 μg / L, 9 μg / L, 10 μg / L, 11 μg / L, 12 μg / L, 13 μg / L, 14 μg / L, 15 μg / L, 16 μg / L, 17 μg / L, 18 μg / L, 19 μg / L, or 20 μg / L.In some embodiments, the predetermined value for the average plasma concentration of the psychedelic is from at or about 1 μg / L to at or about 50 μg / L, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, or 50 μg / L, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 μg / L, or a range defined by any of the foregoing. In some aspects, the predetermined value for the average plasma concentration of the psychedelic is 10-20 μg / L or about 10-20 μg / L, such as 10-20 μg / L or about 10-20 μg / L, or 10-15 μg / L or about 10-15 μg / L.

[0125] In some aspects, embodiments involve maintaining the dissociated state in the subject, for example by maintaining the average plasma concentration of the psychedelic at a predetermined value, during the therapeutic window. In some aspects, the average plasma concentration of the psychedelic is maintained at a predetermined value during the therapeutic window by administration of a maintenance dose of the psychedelic.

[0126] In some aspects, the maintenance dose of the psychedelic is administered by intravenous or continuous infusion, or intermittent administration of the psychedelic. In some aspects, the maintenance dose is administered by intravenous infusion. In some aspects, the continuous or intermittent administration is via an intravenous route. In some aspects, the maintenance dose is administered by intermittent administration. In some aspects, the intermittent administration is via a subcutaneous, oral, transdermal, intramuscular, intranasal, intranasal / pharyngeal, or buccal route.

[0127] In some embodiments, the maintenance dose is administered at a rate of at or about 0.1 mL / min to at or about 1.0 mL / min, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mL / min, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mL / min, or a range defined by any of the foregoing. In some embodiments, the maintenance dose is administered by intravenous infusion of the psychedelic at a rate of at or about 0.1 mL / min to at or about 1.0 mL / min, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mL / min, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mL / min, or a range defined by any of the foregoing. In some aspects, the maintenance dose is administered by intravenous infusion at a rate of at or about 0.5 mL / min.

[0128] In some embodiments, the maintenance dose is administered at a rate of at or about 0.2 mg / min to at or about 1.0 mg / min, e.g., 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / min, or at or about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / min, or a range defined by any of the foregoing. In some aspects, the maintenance dose is administered by intravenous infusion of the psychedelic at a rate of at or about 0.2 mg / min to at or about 1.0 mg / min, e.g., 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / min, or at or about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / min, or a range defined by any of the foregoing. In some aspects, the continuous administration of the psychedelic is at a rate of at or about 0.1 mg / min to at or about 2 mg / min, e.g., 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, or 2.0 mg / min, or 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, or 2.0 mg / min, or a range defined by any of the foregoing.

[0129] In some embodiments, the continuous administration of the psychedelic is at a rate of at or about 0.1 mL / kg / h to at or about 5 mL / kg / h at a dose of at or about 0.01 to at or about 0.2 mg / kg. In some embodiments, the continuous administration of the psychedelic is at a rate of 5 mL / kg / h at 10 mg / kg.

[0130] In some aspects, the maintenance dose is administered over a period of time from or about 10 minutes to or about 120 minutes, such as 10, 20, 30, 40, 45, 50, 60, 90 or 120 minutes, or about 10, 20, 30, 40, 45, 50, 60, 90 or 120 minutes, or a range defined by any of the above. In some embodiments, the maintenance dose is administered over a period of time of 30, 60, 90 or 120 minutes, or about 30, 60, 90 or 120 minutes, or a range defined by any of the above. In some embodiments, the maintenance dose is administered over a period of time of up to or about 60 minutes. In some embodiments, the maintenance dose is administered over a period of up to or about 120 minutes. In some aspects, the maintenance dose is administered over a period of 40 minutes or about 40 minutes. In some aspects, the maintenance dose is administered over a period of 45 minutes or about 45 minutes. In some aspects, the maintenance dose is administered over at or about 50 minutes. In some aspects, the maintenance dose is administered over at or about 55 minutes.

[0131] In some embodiments, both the loading dose and the maintenance dose are administered by intravenous infusion. In some aspects, the loading dose has a higher infusion rate than the maintenance dose, for example when administered by intravenous infusion. In some aspects, the loading dose is administered by intravenous infusion at a rate of 0.5 mL / min or about 0.5 mL / min to 2.0 mL / min or about 2.0 mL / min, for example 1.0 mL / min or about 1.0 mL / min; and the maintenance dose is administered by intravenous infusion at a rate of 0.1 mL / min or about 0.1 mL / min to 1.0 mL / min or about 1.0 mL / min, for example 0.5 mL / min or about 0.5 mL / min.

[0132] In some aspects, the loading dose is administered as an initial bolus injection and the maintenance dose is administered by continuous administration, such as by intravenous infusion. In some aspects, the loading dose of the psychedelic in an amount of at or about 1 mg to at or about 5 mg, e.g., at or about 1 mg, by intravenous administration of an initial bolus, and the maintenance dose are administered by intravenous infusion at a rate of at or about 0.02 mg / min to at or about 1 mg / min.

[0133] In some embodiments, the methods and uses provided involve administration of a loading dose of the psychedelic in an amount of at or about 1 mg to at or about 5 mg via an initial bolus intravenous administration. In some aspects, the loading dose is an amount of the psychedelic sufficient to induce a dissociative state in the subject. In some aspects, the loading dose is at or about 1 mg. In some embodiments, a maintenance dose of the psychedelic is subsequently administered by intravenous infusion, e.g., at or about 0.02 mg / min to at or about 1 mg / min to maintain the average plasma concentration during the therapeutic window. In some aspects, the maintenance dose is administered at a rate of at or about 0.5 mg / min.

[0134] In some embodiments, the methods and uses involve administering to a subject with a psychological disorder a loading dose of a psychedelic (e.g., psilocybin, psilocin, cocrystals, coformers, or salts thereof, or combinations thereof) via an initial bolus intravenous administration in an amount of at or about 1 mg to at or about 5 mg; and subsequently administering a maintenance dose of the psychedelic via intravenous infusion at a rate of at or about 0.02 mg / min to at or about 1 mg / min to maintain an average plasma concentration during the therapeutic window. In some aspects, the maintenance dose is administered at a rate of at or about 0.5 mg / min.

[0135] In some embodiments, the methods and uses provided involve administration of a loading dose of the psychedelic via intravenous infusion at a rate of at or about 0.5 mL / min to at or about 2.0 mL / min over a period of at or about 5 minutes to at or about 20 minutes. In some aspects, the loading dose is an amount of the psychedelic sufficient to induce a dissociative state in the subject. In some aspects, the loading dose is administered via intravenous infusion at a rate of at or about 1.0 mL / min over a period of at or about 10 minutes. In some embodiments, a maintenance dose of the psychedelic is subsequently administered, e.g., by intravenous infusion, at a rate of 0.1 mL / min to 1.0 mL / min or about 1.0 mL / min for 30 minutes or about 30 minutes to 120 minutes or about 120 minutes, e.g., 30, 40, 45, 50, 60, 70, 80, 90, 100, 110, or 120 minutes, or about 30, 40, 45, 50, 60, 70, 80, 90, 100, 110, or 120 minutes, or a period of time within a range defined by any of the foregoing. In some aspects, the maintenance dose is administered at a rate of 0.5 mL / min or about 0.5 mL / min for 60 minutes or about 60 minutes.

[0136] In some aspects, the methods and uses provided involve administering to a subject with a psychological disorder a loading dose of a psychedelic (e.g., psilocybin, psilocin, cocrystals, coformers, or salts thereof, or combinations thereof) by intravenous infusion at a rate of at or about 0.5 mL / min to at or about 2.0 mL / min over a period of at or about 5 minutes to at or about 20 minutes; and thereafter continuously administering a maintenance dose of the psychedelic by intravenous infusion at a rate of at or about 0.1 mL / min to at or about 2.0 mL / min over a period of at or about 30 minutes to at or about 120 minutes to maintain an average plasma concentration during the therapeutic window. In some aspects, the maintenance dose is administered for at or about 60 minutes at a rate of at or about 0.5 mL / min.

[0137] In some aspects, the therapeutic window is at or about 30 minutes to at or about 120 minutes. In some aspects, the therapeutic window is at or about 60 minutes. In some aspects, the therapeutic window is at or about 120 minutes.

[0138] In some aspects, the total amount of psychedelic administered to the subject is at or about 1.0 mg to at or about 20 mg per subject, e.g., 1.0 mg, 1.5 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg per subject, or at or about 1.0 mg, 1.5 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg per subject, or a range defined by any of the foregoing. In some embodiments, the total amount of psychedelic administered to the subject is at or about 2.5 mg. In some embodiments, the total amount of psychedelic administered to the subject is at or about 5 mg. In some embodiments, the total amount of psychedelic administered to the subject is at or about 10 mg.

[0139] In some embodiments, the psychedelic is psilocin, and the total amount of psilocin administered to the subject is at or about 1 mg, to at or about 10 mg, e.g., at or about 2.5 mg, and the administration of psilocin is carried out over a period of at or about 30 minutes, to at or about 120 minutes, e.g., at or about 60 minutes.

[0140] In some embodiments, the psychedelic is psilocybin, and the total amount of psilocin administered to the subject is at or about 1 mg, to at or about 10 mg, e.g., at or about 5 mg, and the administration of psilocybin is carried out over a period of at or about 30 minutes, to at or about 120 minutes, e.g., at or about 60 minutes.

[0141] Termination of administration of the psychedelic to terminate the dissociative state. In some aspects, the step of terminating administration involves discontinuing intravenous administration, e.g., discontinuing an intravenous infusion. In some aspects, termination of the dissociative state occurs within 30, 60, 90, 120, or 180 minutes, or within about 30, 60, 90, 120, or 180 minutes, or within a range defined by any of the foregoing, of termination of administration of the psychedelic. In some aspects, termination of the dissociative state occurs within 60 minutes, or within about 60 minutes, of termination of administration of the psychedelic. In some aspects, termination of the dissociative state can be measured or observed using one or more non-invasive measures of brain activity, e.g., any of those described herein, e.g., EEG, and / or pharmacokinetic parameters, e.g., plasma concentration, Cmax, or AUC.

[0142] In some embodiments, one or more non-invasive measurements of brain activity, such as any of those described herein, e.g., EEG, and / or pharmacokinetic parameters, e.g., plasma concentration, Cmax or AUC, are indicative of or associated with entering and / or exiting a dissociated state. In some aspects, one or more non-invasive measurements of brain activity, such as EEG, and / or pharmacokinetic parameters, can be used to monitor entering and exiting a dissociated state, and can also be used to individualize, customize, change or adjust the dosage, rate or timing of administration based on the measurements.

[0143] Thus, intravenous administration of psychedelics results in a rapid and controllable transition to dissociated state in as little as 10 minutes after administration of the first dose. This is in contrast to oral administration of psilocybin, which does not control the plasma levels of psilocybin or psilocin after oral administration. This contributes to significant inter-subject variability. Thus, the methods provided herein, particularly those involving inducing a dissociated state and then maintaining a predetermined plasma concentration of psychedelics, allow for minimizing or avoiding adverse events and controlling the plasma levels of psychedelics, thereby increasing the safety and reproducibility of the method.

[0144] Conventional treatments using psychedelics involve a delay of up to three hours before the subject enters a dissociative state, which can last up to an additional six hours, well beyond the useful therapeutic window. Thus, being able to more quickly initiate the dissociative state and bring the subject out of the dissociative state has the advantage of allowing the treating physician to control the treatment window, thereby minimizing the total treatment time.

[0145] In some aspects, by tightly controlling the level of psychedelic administered to the subject, the methods can avoid some of the adverse effects of psychedelic use associated with high plasma concentrations of the psychedelic, such as psychosis, negative emotional experiences ("bad trips") or tachycardia, increased blood pressure, vasoconstriction, vasospasm, transient, delayed headaches, rhabdomyolysis, transient renal failure or dysfunction, transient loss or reduction of vision, "flashbacks," sweating, combativeness, and hallucinogen persistent perception disorder (HPPD).

[0146] In some embodiments, the methods described herein reduce the incidence of adverse effects by up to 100% as compared to conventional treatment with oral psychedelics. For example, the methods can reduce the incidence of adverse effects by or about 5%, 10%, 15%, 20%, 15%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% as compared to conventional treatment. Adverse effects include psychosis, elevated blood pressure, tachycardia, nausea, vomiting, ataxia, muscle weakness, increased anxiety, panic, paranoia, feeling threatened, or the subject reporting a "bad trip."

[0147] Dissociative state can be subjectively assessed, for example, by a therapist providing psychological support. In some embodiments, monitoring entering into dissociative state and / or duration of dissociative state uses techniques for non-invasive measurement of brain activity, such as electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), optoencephalography (OEG). In some aspects, any of the non-invasive measurements of brain activity described herein can be used to assess and monitor entering into, being in and / or leaving dissociative state. Preferably, EEG is used.

[0148] Psychological support is provided to the subject after inducing dissociative state.In the context of the methods described herein, psychological support is any form of support that aims to help the subject to improve mental health and cognitive, emotional and behavioral well-being.Typically, psychological support is provided by therapists, psychiatrists, or other qualified medical professionals, preferably therapists who are specifically trained in the administration of psychedelics.

[0149] In some embodiments, once psychological support has been provided, the therapeutic window can be closed by removing the subject from the dissociative state. This can be done by discontinuing administration of psychedelics or by administering 5-HT 2A This can be achieved in several ways, such as by discontinuing administration of the psychedelic along with administration of a 5-HT R antagonist. 2A R antagonists include ketanserin, ritanserin, setoperone, olanzapine, mirtazapine, and mianserin. Dopamine and 5-HT antagonists such as risperidone 2A Compounds combining R antagonist activity may be used.

[0150] Methods for determining the rate and amount of psychedelic to be administered to a subject to tailor a dosing regimen for an individual subject are also provided.

[0151] The method includes administering a therapeutically effective dose of a psychedelic (such as psilocybin or psilocin) sufficient to induce a dissociative state in the subject, preferably within at least 10 minutes of administration. An EEG is then obtained from the subject to confirm that the subject enters the dissociative state. In some embodiments, EEG monitoring may begin before or at about the same time that the psychedelic is administered.

[0152] EEG monitoring can then be continuous or intermittent to allow monitoring of the subject while further doses of the psychedelic are administered to maintain the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window.

[0153] B. Psychological support In some embodiments, the provided methods and uses involve providing psychological support, e.g., psychotherapy, in addition to or in conjunction with administration of a psychedelic, such as psilocin or psilocybin. In some aspects, the methods or uses involve administration of a psychedelic and psychological support or mental health support, e.g., psychotherapy, to a subject, e.g., a human subject. In some aspects, the methods or uses involve administration of a psychedelic and psychotherapy to an individual in need thereof. In some aspects, the methods or uses involve administration of a psychedelic and talk therapy to an individual in need thereof. In some embodiments, the psychological support or mental health support occurs in person and / or remotely, e.g., by telephone or video conference. In some embodiments, the psychotherapy occurs in person and / or remotely, e.g., by telephone or video conference. In some embodiments, the talk therapy occurs in person and / or remotely, e.g., by telephone or video conference.

[0154] In some embodiments, the psychological support includes psychotherapy and / or talk therapy. In some embodiments, the psychological support is therapist-initiated or initiated by one or more persons other than the individual. In some embodiments, the psychological support is self-administered. In some embodiments, the psychological support is therapist-initiated or self-administered. In some embodiments, the psychological support precedes administration of the psychedelic, e.g., during a preparation session. In some embodiments, the psychological support precedes administration of the psychedelic. In some embodiments, the psychological support is concomitant with administration of the psychedelic. In some embodiments, the psychological support follows or occurs after administration of the psychedelic, e.g., during an integration session. In some embodiments, the psychological support follows administration of the psychedelic.

[0155] In some embodiments, the method or use involves the psychological support being provided in an individual session, where an individual meets with one or more therapists.In some embodiments, the method or use involves the psychological support being provided in an individual session, where an individual meets with two or more therapists.In some embodiments, the method or use involves the psychological support being provided in a group session, where more than one individual meets with one or more therapists.In some embodiments, one or more of the individual's family members or friends can attend one or more pre-administration psychological support sessions.In some embodiments, one or more psychological support sessions are provided in person or remotely, for example by telephone or video conference.

[0156] Due to the psychotropic properties of psychedelics, testing psychedelics within a "set and setting" protocol can increase subject safety in clinical trials (Lyons and Carhart-Harris, J Psychopharmacol 2018;32(7):811-19). In some aspects, the "set" refers to one or more of the subject's affective state, cognitive state, behavioral state, mindset, and expectations prior to, e.g., immediately prior to, psychedelic administration. In some aspects, the "setting" refers to the physical environment in which administration of the psychedelic occurs. By addressing the set and setting of the experience, the risk of an individual reporting a distressing event or self-harming can be reduced. In some embodiments, this approach includes three components: 1) psychological support prior to psychedelic administration (e.g., preparation), 2) administration, and 3) post-administration psychological support to consolidate the experience of the classical hallucinogen (e.g., integration).

[0157] In some embodiments, prior to administration, the subject undergoes a pre-exposure preparation session, including rapport building with the therapist who will be present during the drug administration session. In some embodiments, prior to the first dose, the subject undergoes a pre-exposure preparation session, including identifying personal themes and conflicts that may be particularly likely to affect the session experience. In some embodiments, the drug administration session itself is conducted by one therapist. In some embodiments, the drug administration session itself is conducted by two therapists, such as a male and female therapist who will be present throughout the session. In some embodiments, the session is typically conducted in a room that is designed to be quiet, comfortable, and aesthetically pleasing. In some embodiments, the subject is encouraged to wear eyeshades and listen to music programs through headphones during the drug administration session to help focus their attention internally.

[0158] In some embodiments, the method or use involves supervising the individual until the observer determines that the psychedelic effects have completely subsided. In some embodiments, the method or use involves discharge criteria. In some embodiments, the individual must meet one criterion to be discharged. In some embodiments, the individual must meet more than one criterion to be discharged. In some embodiments, all criteria must be met to be discharged. In some embodiments, the discharge criteria include one or more of: whether a responsible friend or family member is available to accompany the individual home; whether the individual's blood pressure and heart rate have returned to pre-drug levels; whether the individual is deemed by the observer to be free of any acute drug effects; whether the individual believes he or she has returned to physiological baseline; whether the observer determines that it is safe to discharge the individual; and whether the individual has expressed that he or she is ready to go home.

[0159] II. Monitoring the dissociation state In some aspects, provided herein are methods of inducing a dissociative state and / or treating a psychological disorder in a subject by administration of a psychedelic, for example by intravenous administration, which also involve monitoring a dissociative state, such as entering or exiting a dissociative state, using one or more non-invasive measurements of brain activity. In some aspects, the one or more non-invasive measurements of brain activity are indicative of or associated with entering and / or exiting a dissociative state. In some aspects, the one or more non-invasive measurements of brain activity can be used to monitor entering and exiting a dissociative state, and can also be used to individualize, tailor, vary or adjust the dosage, rate or timing of administration based on the measurements. In some aspects, the methods also relate to methods of treating psychological disorders, diseases with significant psychological components, and / or diseases or symptoms related to pain or pain sensation.

[0160] In some aspects, methods of inducing a dissociative state are provided that involve administering to a subject an amount of a psychedelic (e.g., psilocin or psilocybin) sufficient to induce a dissociative state in the subject; and obtaining a non-invasive measurement of brain activity from the subject to determine when the subject enters the dissociative state. In some aspects, methods of inducing a dissociative state are provided that involve administering to a subject an amount of a psychedelic (e.g., psilocin or psilocybin) sufficient to induce a dissociative state in the subject; and obtaining an electroencephalography (EEG) measurement from the subject to determine when the subject enters the dissociative state.

[0161] Also provided in some aspects is a method of determining a therapeutically effective dose of a psychedelic (e.g., psilocin or psilocybin) that involves administering to a subject an amount of a psychedelic sufficient to induce a dissociative state in the subject; obtaining a non-invasive measurement of brain activity (e.g., EEG) from the subject to determine if the subject enters the dissociative state; and determining the amount of psychedelic as a therapeutically effective dose if the subject enters the dissociative state. In some aspects, the therapeutically effective dose is determined based on the non-invasive measurement of brain activity (e.g., EEG).

[0162] In some aspects, methods are also provided for maintaining a dissociated state in a subject, involving administering to the subject a psychedelic (e.g., psilocin or psilocybin) in an amount sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and obtaining an electroencephalography (EEG) measurement from the subject to determine when the subject enters the dissociated state; and thereafter maintaining an average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during a therapeutic window.

[0163] In some embodiments, non-invasive measurements of brain activity are obtained before, during and / or after administration. In some aspects, provided embodiments also involve obtaining additional non-invasive measurements of brain activity from the subject to monitor the dissociated state during the treatment window. In some aspects, additional EEG measurements are obtained from the subject to monitor the dissociated state during the treatment window. In some aspects, the non-invasive measurements of brain activity after administration indicate the end of the dissociated state.

[0164] A. Non-invasive measurement of brain activity Provided herein are methods involving non-invasive measurement of brain activity for monitoring dissociative states in patients administered psychedelics (e.g., psilocin or psilocybin). In some embodiments, the non-invasive measurement of brain activity is performed using electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), and optoencephalography (OEG), quantitative sensory testing (QST), proton magnetic resonance spectroscopy (QST), and other techniques. 1 The non-invasive measurement of brain activity includes one or more of 1H-MRS, diffusion tensor imaging (DTI), questionnaire assessment of psychedelic experience, and combinations thereof. In some embodiments, the non-invasive measurement of brain activity includes one or more of electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), and optoencephalography (OEG). In some embodiments, the non-invasive measurement of brain activity includes electroencephalography (EEG). In some embodiments, the non-invasive measurement of brain activity includes questionnaire assessment of psychedelic experience.

[0165] In some aspects, exemplary non-invasive methods for measuring brain activity, such as electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), or optoencephalography (OEG), can be used to monitor and assess subjects and their entry into and / or exit from dissociative or psychedelic states by the methods and uses provided. In some aspects, other exemplary non-invasive methods for measuring brain activity include quantitative sensory testing (QST), proton magnetic resonance spectroscopy ( 1 H-MRS), diffusion tensor imaging (DTI), and combinations thereof.

[0166] In some aspects, non-invasive methods have been used to measure brain-specific changes during development, aging, learning, disease, and in response to acute stimuli, including small molecule compounds and / or 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). Non-invasive measurements of brain activity can be used to more closely assess, monitor and control dissociative states and psychedelic experiences and psychedelic-based interventions, for example, by the embodiments provided, to measure changes and / or improvements during psychedelic interventions (e.g., administration of psilocin or psilocybin). In some aspects, the non-invasive measurements of brain activity are behavioral observations.

[0167] In some embodiments, exemplary parameters measured by non-invasive measurements of brain activity include assessment of burst synchrony, power spectral analysis, default mode network analysis, functional connectivity and activation analysis, glutamine and glutamate measurements, GABA measurements, and assessment of gray matter volume.

[0168] 1. Electroencephalography (EEG) In some of any of the provided embodiments, brain activity is measured to monitor entering and / or exiting dissociative states using non-invasive methods such as electroencephalography (EEG). EEG is a tool for non-invasive research on neurological disorders (Neto and Rosa, Neurosci Biobehav Rev 2019;105:83-93). EEG is convenient and effective for neurological research. EEG analysis measures electrical signals directly through the scalp, providing millisecond timescale information compared to the seconds and minutes required by other methodologies to record high-resolution temporal brain activity (Michel and Brunet, Front Neurol 2019;10:325). EEG data can be collected from multiple different states (e.g., resting, tonic cuff pressure, visual stimulation) to capture objective response signals and changes in brain activity. Although EEG is limited to measuring the top layers of the brain, when paired with other brain activity measurements (e.g., fMRI), EEG provides important data to generate a comprehensive view and quantitative assessment of brain activity (Abreu et al., Front Hum Neurosci 2018;12:29). EEG data is often used to diagnose neurological disorders such as seizures, epilepsy, head trauma, brain tumors, and insomnia.

[0169] In some aspects, EEG data represents electrical activity measured at the brain surface, recorded as waveforms of different frequencies (Hertz, Hz), amplitudes (microvolts, μV) and shapes. The physical location of the electrodes used for recording is an important factor for the interpretation of EEG data. The most common EEG waveform frequencies are delta, theta, alpha, beta, or gamma, measured as cycles per second or Hertz (Hz). While many features of the EEG are rhythmic, other features are transient, including spikes, sharp waves, parietal waves, and sleep spindles. The rhythmicity of these waves, as well as the presence and absence of different wave frequencies in various parts of the brain, can be used to diagnose neurological disorders and monitor ongoing treatments in psychopharmacology (e.g., administration of psychedelics such as psilocin or psilocybin).

[0170] In some embodiments, for example, according to the embodiments provided, EEG is utilized to evaluate the activity of psychedelics (e.g., psilocin or psilocybin) in inducing dissociative or psychedelic states and / or treating psychological disorders. In some aspects, exemplary indices measured with EEG include burst synchronization and power spectral analysis (frequency bands) of network activity at rest.

[0171] In some aspects, analytical methods and tools for analyzing, quantifying and interpreting EEG data can be used to determine when a subject enters a dissociated state. Exemplary tools and methods include, for example, those described in Burns et al., Version 1. F1000Res. 2015; 4: 137. Although the analysis of EEG data can be complex due to variations in stimuli (e.g., therapeutic interventions) and patient-specific differences (e.g., epilepsy, depression, Alzheimer's disease), it has been found to be beneficial to account for the complexity measures (i.e., various patterns in the EEG signal) during data interpretation. Exemplary measures of complexity that can be used include Lempel-Ziv complexity (Lempel and Ziv, IEEE Trans Inform Theory 1976; 22(1):75-81), fractal dimension estimation (FD), permutation entropy (PE), Wiener entropy (WE), and spectral structure variability (SSV) (see, e.g., Burns et al., Version 1. F1000Res. 2015; 4: 137). Lempel-Ziv complexity (LZC) is an algorithm-based measure and a surrogate for neural signal diversity.

[0172] In some scenarios, LZC is the number of distinct identified substrings encountered when iteratively viewing a binary sequence (e.g., a preprocessed EEG signal) as a stream. LZC calculates the number of different patterns present in a sequence of symbols. If a large number of different patterns exist, the sequence is considered complex and may be difficult to compress. LZC is obtained by dividing the number of different patterns by the maximum complexity of a sequence of length N (Hornero et al., Philos Trans A Math Phys Eng Sci 2009;367(1887):317 - 36). To determine LZC, the time series is first reduced to a list of symbols. The EEG signal is converted into a binary sequence s = s(1), s(2),..., s(N), where, for example, as described in Hornero et al., Philos Trans A Math Phys Eng Sci 2009;367(1887):317 - 36, s(i) = 0 if x(i) < Td and s(i) = 1 otherwise. The threshold Td is chosen as the median of x because the latter is robust to outliers. In some scenarios, EEG measurements are analyzed as expressed by the Lempel - Ziv complexity (LZC).

[0173] 2. Functional magnetic resonance imaging (fMRI) In some aspects, non-invasive measurements of brain activity include functional magnetic resonance imaging (fMRI). In some aspects, fMRI detects changes in blood flow in the brain, where these changes correspond to regional and site-specific changes in activity. In certain aspects, fMRI can be used to assess entering and / or exiting dissociated states. In some aspects, functional connectivity MRI (fMRI) focuses on the default mode network (DMN) and the salience network (SLN). The DMN is a set of brain regions engaged in self-referential cognition, which are "deactivated" during external focus tasks (Buckner and Vincent, Neuroimage 2007;37(4):1091-99; Fox and Raichle Nat Rev Neurosci 2007;8(9):700-11). In some aspects, subjects with more central pain show increased connectivity between the DMN and the insular cortex (SLN region), which decreases with successful treatment (Napadow et al., Arthritis Rheum 2012;64(7):2398-2403). To obtain a baseline measurement of functional brain connectivity, a whole-brain BOLD functional image is acquired while the subject rests comfortably in the scanner with eyes closed for approximately 8 minutes at the beginning of the scanning session. Immediately afterwards, the subject undergoes an fMRI scan with a sensory stimulus (e.g., pain) to assess functional brain connectivity response to the stimulus.

[0174] 3. Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) 1H-MRS is a non-invasive neuroimaging technique that allows for the detection, identification, and quantification of metabolites and biochemical compounds in brain tissue (Castillo et al., AJNR Am J Neuroradiol 1996;17(1):1-15; Sidek et al., Eur Radiol 2016;26(12):4404-12). In some cases, proton magnetic resonance spectroscopy ( 1In relation to pain-related indices using H-MRS, reports have shown that changes in glutamine and glutamate (Glx) and gamma aminobutyric acid (GABA) levels in specific regions of the brain (e.g., posterior and anterior insular cortex) are strongly correlated with improvements in pain symptoms, with reductions in clinical pain being associated with reduced Glx and increased GABA levels (Mawla et al., Arthritis Rheumatol 2021;73(7):1318-28; Harris et al., Arthritis Rheum 2009;60(10):3146-52; Harris et al., Arthritis Rheum 2008;58(3):903-7). 1 H-MRS provides an assessment metric that can be used for longitudinal studies, where high-resolution anatomical scans isolate the same brain structures within an individual over time, minimizing errors that would otherwise occur due to small differences in voxel location from one assessment to the next. 1 H-MRS was directed to the right posterior insular cortex both before and after stimulation. Individuals undergoing treatment: 1 The subjects were asked to rest between H-MRS sessions, during which one or more 1 H-MRS assessment is integrated into the fMRI neuroimaging workflow.

[0175] 4. Diffusion Tensor Imaging (DTI) Diffusion tensor imaging (DTI) is a method for anatomical mapping and characterization of microstructures in the brain (Alexander et al., Neurotherapeutics 2007;4(3):316-29), making it useful for bridging the gap between EEG and fMRI data, collectively enhancing the value of neurological datasets. DTI leverages the fMRI platform and is used to characterize small changes in brain structure during neuropathology and treatment (Alexander et al., Neurotherapeutics 2007;4(3):316-29; Soares et al., Fron Neurosci 2013;7:31). DTI data is collected during fMRI neuroimaging procedures and can aid in the spatial mapping of EEG data. A unique structural brain network is generated for each individual undergoing treatment to better inform pre- and post-mortem EEG analysis. In some embodiments, DTI assessments are utilized to complement or enhance other neuroimaging results to assess the effects of psychedelics in entering and exiting dissociative states.

[0176] 5. Quantitative Sensory Testing (QST) Quantitative sensory testing (QST) is a psychophysical testing approach that involves the determination of thresholds or stimulus-response curves for sensory processing under normal and pathological conditions (e.g., psychological disorders such as pain-related disorders), in which stimuli are quantified and used to measure perception (Yarnitsky and Granot, Handb Clin Neurol 2006;81:397-409). Although QST is a semi-subjective (e.g., assessing subjective responses) technique, responses are derived using known stimulus inputs, providing an objective framework for assessing individuals (e.g., before, during, or after a therapeutic intervention, such as the administration of psychedelics). Examples of stimulation modalities include electrical, thermal, immersion thermal, mechanical, chemical, and optical contact, where pain measurements may include pain threshold / tolerance, time loading, conditioned stimulus pain modulation, pain ratings, pain region mapping, brain responses (e.g., EEG, fMRI, PET), or muscle reflexes (Uddin and MacDermid, Pain Med 2016;17(9):1694-703). All QST procedures have been evaluated for safety and are well tolerated by subjects with pain (Petersen et al., Pain 2015;156(1):55-61; Goodin et al., J Pain 2009;10(2):180-90; Weissman-Fogel et al., J Pain 2009;10(6):628-36; Price et al., Pain 2002;99(1-2):49-59).

[0177] 6. Questionnaire-based assessment of psychedelic experiences In some aspects, the embodiments provided use questionnaires to assess the entry and exit of dissociative states, psychedelic experiences, and associated clinical effects before, during, and / or after administration of psychedelics. In some aspects, to assess the psychedelic experiences and associated clinical effects for an individual undergoing treatment with the embodiments provided, the individual is subjected to one or more questionnaire assessments to assess the psychedelic experiences and clinical activity in response to treatment (Davis et al., J Psychopharmacol 2021;35(4):437-46). In some embodiments, exemplary questionnaire assessments to assess the psychedelic experiences and clinical activity in response to treatment include one or more of the Mystical Experiences Questionnaire (MEQ30) assessment, the Challenging Experiences Questionnaire (CEQ) assessment, the Psychological Insight Questionnaire (PIQ) assessment, a qualitative written assessment, and / or a Monitor Rating Scale (MRS) questionnaire. In some embodiments, questionnaire-based assessment of psychedelic experience is utilized to monitor dissociative states and psychedelic experiences in individuals receiving psychedelic administration. In some embodiments, the questionnaire-based assessment of psychedelic experience is selected from one or more of the Mystical Experiences Questionnaire (MEQ30) assessment, the Challenging Experiences Questionnaire (CEQ) assessment, the Psychological Insight Questionnaire (PIQ) assessment, a qualitative written assessment, and / or the Monitor Rating Scale (MRS) questionnaire.

[0178] a. Mystical Experiences Questionnaire (MEQ30) The Mystical Experiences Questionnaire (MEQ or MEQ30; an abbreviated version derived from the MEQ43) is an assessment completed by patients that includes four factors: mystical (e.g., internal cohesion, external cohesion, intellectual qualities, and sacredness scales), positive mood, transcendence of time and space, and ineffability (Barrett et al., J Psychopharmacol 2015;29(11):1182-90). The MEQ30 predicts lasting therapeutic benefits (e.g., changes in attitudes, behaviors, and well-being) resulting from psychedelic experiences and serves as the primary measure of an individual's mystical experiences. There are 30 items included in the MEQ30 assessment distributed across four factors, each rated on a 0-5 point scale, where 0 is "none; not at all," 1 is "too slight to be certain," 2 is "slight," 3 is "moderate," 4 is "strong (equivalent in degree to any previous strong experience or expectation of this description)," and 5 is "extreme (stronger than 4 ever in my life)." Across these 30 items, four factors or sub-categories contain different items, where mystical consists of items 4-6, 9 14-16, 18, 20, 21, 23-26, and 28; positive mood consists of items 2, 8, 12, 17, 27, and 30; space / time consists of items 1, 7, 11, 13, 19, and 22; and ineffability consists of items 3, 10, and 29. Within a subcategory or across the entire MEQ30 set, item-by-item scores are summed together and converted to a percentage by dividing by the corresponding total points. A "complete experience" is defined by a MEQ30 score of 60% or greater (combined) across all four subcategories, where a complete experience correlates with a more meaningful and / or expanded therapeutic benefit.

[0179] b. Challenging Experiences Questionnaire (CEQ) Due to the powerful experiences induced by classical hallucinogens (e.g., psilocybin), patients undergoing treatment may have one or more acute adverse psychological reactions (i.e., bad trips, or challenging experiences). In some aspects, evidence supports that symptoms may occur, including affective (panic, depressed mood), cognitive (confusion, feeling of going crazy), and somatic (nausea, heart palpitations) (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). Understanding the range and severity of symptoms is useful in individualizing patient care and anticipating the patient's needs during future treatment sessions. The Challenging Experiences Questionnaire (CEQ) addresses seven salient factors (grief, fear, death, insanity, isolation, physical pain, and paranoia) and provides a phenomenological profile of the challenging aspects a patient may have or experience during treatment (Barrett et al., J Psychopharmacol 2016;30(12):1279-95). There are 26 items included in the CEQ assessment, with each response having a numerical value ranging from 0 to 5, where 0 is "none; never at all" and 5 is "extreme (never in my life)". Across these 26 items, seven factors or sub-categories contain different items, where grief consists of items 2, 6, 9, 11, 23, and 25; fear consists of items 4, 7, 14, 21, and 26; death consists of items 16 and 20; insanity consists of items 8, 13, and 19; isolation consists of items 1, 10, and 24; physical pain consists of items 3, 5, 15, 17, and 18; and paranoia consists of items 12 and 22. Within each sub-category, responses are summed and converted to a percentage of the full score. Additionally, responses for all items are summed and converted to a percentage of the full score.

[0180] c. Psychological Insight Questionnaire (PIQ) In the context of psychedelic treatment, existing measures of insight fail to capture the sharp insights associated with psychedelic-induced experiences. To address this need, a new tool to assess the intensity of a wide range of sharp insights was created: the Psychological Insight Questionnaire (PIQ) (Davis et al., J Psychopharm 2021;35(4):437-46). The PIQ is a 23-item assessment that includes two subscales, one assessing insight into avoidance and maladaptive patterns (AMP) and the other assessing goal and adaptive patterns (GAP) (Davis et al., J Psychopharm 2021;35(4):437-46). Items 1, 3, 5, 7, 9, 10, 12, 14, 15, 17-19, 21, and 23 relate to the AMP subscale, whereas items 2, 4, 6, 8, 11, 13, 16, 20, and 21 relate to the GAP subscale. Individuals respond to each item using a 6-point scale from 0 to 5, where 0 is "none, not at all," 3 is "moderate," and 5 is "extreme (never in my life)." Responses are summed and averaged for each and across subscales, with higher scores for each corresponding to higher levels of insightful experiences. PIQ, AMP, and GAP scores correlate well with increases in psychological flexibility, well-being, and long-term positive outcomes.

[0181] d. Monitor Rating Scale (MRS) The Monitor Rating Scale (MRS) questionnaire is completed by the clinician and involves rating and scoring dimensions of the subject'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), with some dimensions assigned a numerical value ranging from 0 to 4, where 0 is "none; no effect" and 4 is "peak effect; occurs often." For other dimensions, a score is assigned as the total duration (in minutes over a given time frame) observed for the patient behavior (e.g., the entire conversation or utterance with the clinician).

[0182] e. Qualitative (written) evaluation A subjective narrative description of a psychedelic experience can provide insight into the unique aspects, needs and concerns of a particular individual during and / or after completion of treatment. A narrative description is completed after each treatment administration session (e.g., first or second administration). After the final dosing session, the individual participates in a treatment integration session (e.g., weekly, one hour) during which consideration of one or more narrative descriptions helps the individual gain insight and understanding from their experience. The narrative description is also used to study common themes related to this treatment. In some cases, the individual is asked open-ended questions during a three-month follow-up to measure lasting changes in behavior, thought patterns, and emotions in response to receiving treatment.

[0183] 7. Behavioral Responses In some aspects, the non-invasive measurement of brain activity comprises observing the behavioral aspects of the subject.Exemplary behaviors that can be observed include behaviors similar to head-turning response (HTR), as observed in animals such as rodents.Exemplary HTR observations include those described in, for example, Zhuk et al., Toxins 2015, 7, 1018-1029; Halberstadt et al., J Psychopharmacol. 2011 25(11): 1548-1561.

[0184] III. Psychedelic Compounds and Compositions In some aspects, provided embodiments involve administration of a psychedelic. In some aspects, the psychedelic is psilocybin, psilocin, co-crystals, coformers, or salts thereof, or combinations thereof. In some aspects, the psychedelic is psilocin, co-crystals, coformers, or salts thereof. In some aspects, the psychedelic is psilocin. In some aspects, the psychedelic is psilocybin, co-crystals, coformers, or salts thereof. In some aspects, the psychedelic is psilocybin.

[0185] As used herein, the terms "psychedelic compound," "psychedelic drug," "psychedelic substance," and "psychedelic" are used interchangeably and refer to the action of a psychedelic compound on the serotonin 2A receptor (5-HT 2A R) agonist. 2A There is a strong positive correlation between a psychedelic's affinity for R and its psychedelic potency.

[0186] Psychedelics suitable for use in the methods described herein include baeocystin, norbaeocystin, N,N-dimethyltryptamine, 5-hydroxytryptamine (serotonin), 5-hydroxytryptophan, psilocybin, psilocin, their precursors and direct derivatives. Synthetic or natural prodrugs, congeners and analogs of psilocybin, psilocin, baeocystin and norbaeocystin may also be used.

[0187] Homologues are chemical compounds related to each other in origin, structure, or function. An analog (or analogue or structural mimetic) is a compound that has a similar structure to another, but differs from it with respect to certain substituents, in which one or more atoms or functional groups are replaced by other atoms or groups or substituents.

[0188] Psilocybin, psilocin and analogs that may also be useful include those with modified hydroxyl groups or modified methyl groups at the terminal amine nitrogen. Examples of hydroxyl group substituents include alkyl ethers and esters and aryl ethers and esters, such as methoxy ethers and ethoxy ethers and acetyl esters, halogens including fluoro-, chloro- and bromo-substituents, and thio groups such as methylthio or benzothio. Examples of nitrogen group substituents include one or both methyl groups replaced with ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, amyl or allyl groups and N-trimethyl analogs. The corresponding phosphate esters, i.e., psilocybin analogs, may also prove useful. The same may be true for analogs in which one or more hydrogen atoms are replaced by fluorine, chlorine, or bromine.

[0189] In some embodiments, the typically more stable salts of the compounds are used, such as the hydrochloride, fumarate, maleate, picrate, oxalate, tartrate, and sulfate salts. The salts can be in zwitterionic form, particularly the zwitterionic forms of phosphate esters and quaternary ammonium compounds.

[0190] Examples of suitable analogs are: 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT or O-acetylsyrosine), an acetylated form of syrosine (4-OH-DMT), a compound which (like other 4-alkyl-esters) is a potential prodrug of syrosine and has greater stability and a longer shelf life than syrosine; 4-acetoxy-N-methyl-N-ethyltryptamine (4-AcO-MET), a syrosine analog substituted at R4 of its indole heterocycle with an acetoxy (AcO or CH3COO-) functional group and which also contains a methyl group and an ethyl chain attached to the terminal amine nitrogen of its tryptamine backbone. 4-AcO-MET is the acetate analogue of 4-OH-MET and the N-substituted ethyl homologue of 4-AcO-DMT; 4-acetoxy-N,N-diethyltryptamine (4-AcO-DET); 4-acetoxy-N-methyl-N-propyltryptamine (4-AcO-MPT); 4-acetoxy-N-methyl-N-isopropyltryptamine (4-AcO-MIPT); 4-acetoxy-N,N-dipropyltryptamine (4-AcO-DPT) and 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DI PT); 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET, metocin, or methylcybin), a 4-hydroxy N-substituted structural analog of psilocin and having methyl and ethyl groups attached to the terminal amine nitrogen of the tryptamine structure; 4-hydroxy-N-methyl-N-propyltryptamine (4-OH-MPT); 4-hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MI PT); 4-hydroxy-N,N-diethyltryptamine (4-OH-DET); 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT); 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DI PT); and 4-hydroxy-N,N-diallyltryptamine (4-OH-DALT);Analogs in which the 4-OH group has been removed, such as N,N-dimethyltryptamine (DMT), N-methyl-N-ethyltryptamine (MET), N-methyl-N-propyltryptamine (MPT), N,N-diethyltryptamine (DET), N,N-dipropyltryptamine (DPT), N,N-isopropyltryptamine (DIPT), N-methyl-N-isopropyltryptamine (MIPT), α-methyltryptamine (AMT), N-ethyl-N-isopropyltryptamine (EIPT), N-methyl-N-butyl-tryptamine (MBT), or substituted at other positions, Analogs of the compounds that have been used include, for example, N,N-dimethyl-5-hydroxytryptamine (5-OH-DMT or bufotenin), 5-methoxy-α-methyltryptamine (5-MeO-aMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 5-methoxy-N,N-diethyltryptamine (5-MeO-DET), 5-methoxy-N,N-dipropyltryptamine (5-MeO-DPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N-ethyl-N-isopropyltryptamine (5-MeO-EI PT), 2,α-dimethyltryptamine (2,α-DMT), α,N-dimethyltryptamine (α,N-DMT), α-ethyltryptamine (α-ET), 2-methyl-N,N-dimethyltryptamine (2-Me-DMT), 2-methyl-N,N-diethyltryptamine (2-Me-DET), 1-methylpsilocine, and ibogaine (complex tryptamines);

[0191] In some embodiments, an equimolar amount of psilocin or a psilocybin analog may be used in place of psilocybin and / or psilocybin, or an amount that produces an equivalent functional effect may be used.

[0192] In one embodiment, the psychedelic is psilocybin.Psilocybin is a natural psychedelic compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms.After being administered to a subject, psilocybin is metabolized by endogenous alkaline phosphatase to psilocin, which then acts on serotonin receptors in the brain.In a preferred embodiment, the psychedelic is psilocin.

[0193] Psilocybin is also known as [3-(2-dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate and has been given the CAS number 520-52-5. Psilocin (also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), psilocine, psilocyn, or psilotsin) has been given the CAS number 520-53-6.

[0194] Co-crystals are multi-component systems in which two components, an active pharmaceutical ingredient and a conformer, are present in a stoichiometric ratio and are bound together in the crystal lattice by hydrogen bonds, pi-pi interactions, and van der Waals forces. In some embodiments, the conformer and the active can be bound by non-covalent bonds, such as halogen bonds.

[0195] Examples of suitable coformers are acetamide, benzamide, (+ / -)-limonene, 1-(phenylazo)-2-naphthylamine, 1,2,6-hexanetriol, 1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)), 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), Glycerol), 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,5-naphthalene-disulfonic acid, 1-hydroxy-2-naphthoic acid, 1-o-tolylbiguanide, 2-ethyl-1,6-hexanediol, 4-aminobenzoic acid, 4-aminopyridine, 4-aminosalicylic acid, 4-chlorobenzene-sulfonic acid, 4-ethoxyphenylurea, 7-oxo-dhea, gum arabic, gum arabic mucilage, gum arabic syrup, acesulfame, acesulfame potassium, acetohydroxamic acid, acetone sodium bisulfite, acesulfame Cetyl lanolin alcohol, acetylated monoglyceride, acetyl cysteine, acetyl tributyl citrate, acrylic acid copolymer, acrylic acid-isooctyl acrylate copolymer, adenine, adipic acid, alanine, aggregated albumin, colloidal albumin, human albumin, albumins, alginic acid, alkyl ammonium sulfonate betaine, sodium alkylaryl sulfonate, allantoin, allopurineol, allyl alpha-ionone, alpha-terpineol, alpha-tocopherol, alginate acetate Pha-tocopherol, sodium aminobenzoate, amyl acetate, anethole, anhydrous citric acid, anhydrous glucose, anhydrous lactose, anhydrous trisodium phosphate, anhydrous trisodium citrate, arginine, aracel, asafetida, ascorbic acid, ascorbyl palmitate, asparagine, aspartame, aspartic acid, bacteriostatic sodium chloride injection, barium sulfate, benzalkonium chloride, benzenesulfonic acid, benzethonium chloride, benzododecinium bromide, benzoic acid, benzyl acetate, benzyl alcohol, benzyl benzoate,Benzyl chloride, beta-carotene, beta-naphthol, betose, bivapsitide, bismuth subcarbonate, bismuth subgallate, boric acid, brominated nitrate, butyl stearate, butyl hydroxyanisole, butyl hydroxytoluene, butylparaben, butyric acid, C-11-1-aminocyclohexane carboxylic acid, C12-15 alkyl lactate, caffeine, calcobutrol, sodium cardiamide, trisodium caroxetate, calcium cartelidol, camphoric acid, capric acid, captan, captisol, carboxypolymethylcellulose Carmine, Carnauba Wax, Carnauba Yellow Wax, Carrageenan, Calcium Carrageenan, Carrageenan Salt, Sodium Carrageenan, Ceresin, Ceteareth-12, Ceteareth-15, Ceteareth-30, Cetearyl Alcohol / Ceteareth-20, Cetearyl Ethylhexanoate, Ceteth-10, Ceteth-2, Ceteth-20, Ceteth-23, Cetostearyl Alcohol, Cetrimonium Chloride, Cetyl Alcohol, Cetyl Esters Wax, Cetyl Palmitate, Cetylpyridinium Chloride, Chlorocresol, Chloroxylenol, Cholesterol, Chrysin, Katsura Cinnamic aldehyde, cinnamic acid, citrate, citric acid, citric acid monohydrate, clemizole, cocamide ether sulfate, cocamine oxide, coco-betaine, coco-diethanolamide, coco-monoethanolamide, coco-caprylic acid, coco-glyceride, creatine, creatinine, cresol, copper(II) sulfate, cyclamic acid, cyclomethicone, cyclomethicone 5, cysteine, dalfampridine, decyl methyl sulfoxide, dehydroacetic acid, denatonium benzoate, deoxycholic acid, dextran, dextran 40, dextrate, dextrin, bromide Dough sugar, dextrose monohydrate, diacetylated monoglyceride, diatrizoic acid, disodium hydrogen phosphate anhydrous, disodium hydrogen phosphate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, diethyl pyrocarbonate, diethyl sebacic acid, diethylaminoethyl stearamidophosphate, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylhexyl phthalate, diisopropyl adipate,Diisopropyl Dilinoleate, Diisopropyl Benzothiazyl-2-Sulfenamide, Dimethicone Pharmaceutical Solution 360, Dimethyl Isosorbide, Dimethyl Phthalate, Dimethyl Sulfoxide, Dimethyl Dioctadecyl Ammonium Bentonite, Dimethyl Glycine, Dimethyl Siloxane / Methyl Vinyl Siloxane Copolymer, Dinoseb-Ammonium, Dipropylene Glycol, Disodium Cocoamphodiacetate, Disodium Hydrogen Citrate, Disodium Laureth Sulfosuccinate, Disodium Lauryl Sulfosuccinate, Monoethanolamine Oleamide Sulfoco Disodium citrate, disodium sulfosalicylate, disofenin, dl-a350 lactic acid, dl-acetyltryptophan, dl-alpha-tocopherol, dl-alpha-tocopherol acetate, dl-dipalmitoylphosphatidylglycerol, dl-distearoylphosphatidylcholine, dl-glutamic acid, dl-tartaric acid, d-mannose, dmdm hydantoin, docosanol, sodium docusate, d-ribose, calcium disodium edetate, disodium edetate, sodium edetate, edetic acid, egg phosphatidylglycerol Roll, egg phospholipids, entufon, entufon sodium, epilactose, epitetracycline hydrochloride, erythorbic acid, erythritol, ethanolamine hydrochloride, ethyl maltol, ethyl oleate, ethyl vanillate, ethyl vanillin, ethylenediamine dihydrochloride, ethylhexyl hydroxystearate, ethylparaben, eucalyptol, eugenol, exercisethazime, fatty acid esters, fatty acid glycerides, fatty acid pentaerythritol esters, fatty acids, fatty alcohol citrate esters, fatty alcohols, ferric chloride, ferric oxide, tetrahydrofuran. Ferrous oxide, ferrous fumarate, ferrous oxide, fluorescein, fructose, fumaric acid, fumaryl diketopiperazine, gadolinium oxide, galactaric acid, galactose, gamma cyclodextrin, genistein, gentisic acid, gentisic acid ethanolamide, gentisic acid ethanolamine, sodium gluceptate, gluconic acid, gluconolactone, glucosamine, glucose, glucuronic acid, glutamic acid, glutamic acid hydrochloride, glutamine, glutaric acid, glutathione, glyceryl caprylate, glyceryl dibehenate, glyceryl distearate,Glyceryl Isostearate, Glyceryl Laurate, Glyceryl Monostearate, Glyceryl Oleate, Glyceryl Palmitate, Glyceryl Palmitostearate, Glyceryl Ricinoleate, Glyceryl Stearate, Glyceryl Stearate-Laureth-23, Glyceryl Stearate / PEG Stearate, Glyceryl Stearate / PEG-100 Stearate, Glyceryl Stearate / PEG-40 Stearate, Glyceryl Stearate-Stearamidoethyl Diethylamine, Triolein Glyceryl Acetate, Glycine, Glycine Hydrochloride, Glycol Distearate, Glycol Stearate, Glycolic Acid, Glycyrrhizin, Guanidine Hydrochloride, Hexylresorcinol, Hippuric Acid, Histidine, Sodium Hyaluronate, Hydrocortisone, Hydroquinone, Citric Acid Hydrate, Hydroxyethylpiperazine Ethanesulfonic Acid, Hydroxyoctacosanyl Hydroxystearate, Hydroxyprogesterone Caproate, Hydroxypropyl Beta-Cyclodextrin, Histylene, Illicium anisatum, imidazole, imidurea, sodium indigotine disulfate, iodoxamic acid, iofetamine hydrochloride, ipriflavone, isoleucine, isopropyl isostearate, isopropyl myristate, isopropyl myristate-myristyl alcohol, isopropyl palmitate, isopropyl stearate, isostearic acid, isostearyl alcohol, lactate, lactitol monohydrate, lactobionic acid, lactose, landalgine, lanolin, lauralkonium chloride, lauramine oxide, laureth sulfate, lauric acid, lauric acid Diethanolamide, lauric myristic diethanolamide, lauroyl sarcosine, lauryl lactate, lauryl sulfate, lecithin, leucine, levomenthol, levulinic acid, lidofenine, sodium I-lactate, lysine, maleic acid, malic acid, malonic acid, maltitol, maltodextrin, maltol, maltose anhydride, mandelic acid, mannitol, maprofix, mebrofenin, medium chain triglycerides, disodium medronate, medronic acid, menthol, metacresol, methionine, methyl salicylate, methyl stearate, methylchloroisothiazolinone,Methylisothiazolinone, methylparaben, sodium methylparaben, myripyrium chloride, mono- and diglycerides, monosodium phosphate, monosodium phosphate anhydrous, monosodium phosphate dihydrate, monosodium phosphate monohydrate, monoglyceride citrate, monoglycerides, monosodium citrate, monosodium glutamate, monostearyl citrate, monothioglycerol, myristic acid, myristyl alcohol, myristyl lactate, niacinamide, nicotinamide, nicotinic acid, N-methylglucamine , octanoic acid, oleth-20, oleyl alcohol, oleyl oleate, orotic acid, oxalic acid, disodium oxidronate, oxyquinoline, palmitamine oxide, palmitic acid, pamoic acid, pentadecalactone, pentaerythritol cocoate, pentasodium pentetate, calcium trisodium pentetate, pentetic acid, phenol, phenonip, phenoxyethanol, phenylalanine, phenylethyl alcohol, phospholipids, piperazine, piperazine hexahydrate, procaine, product w wat), proline, propenyl guaethol, propyl gallate, propylene carbonate, propylene glycol, propylene glycol-lecithin, propylene glycol alginate, propylene glycol diacetate, propylene glycol dicaprylate, propylene glycol monolaurate, propylene glycol monopalmitostearate, propylene glycol palmitostearate, propylene glycol ricinoleate, propylene glycol / diazolidinyl urea / methylparaben / propylparaben, propylparaben, sodium propylparaben, p-toluol. Enesulfonic acid, pyridoxamine, pyridoxine (4-pyridoxic acid), quercetin, resveratrol, riboflavin, saccharin, saccharin calcium, saccharin sodium, sodium saccharin anhydrous, salicylic acid, saturated fatty acid esters, sebacic acid, serine, sodium 1,2-ethanedisulfonate, sodium 2-naphthalenesulfonate, sodium acetate, sodium acetate anhydrous, sodium alginate, sodium alkyl sulfate, sodium aluminum silicate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium bisulfate,Sodium Bisulfate Acetone, Sodium Bisulfite, Potassium bitartrate, sodium borate, sodium borate decahydrate, sodium carbonate, sodium carbonate decahydrate, sodium carbonate monohydrate, sodium carboxymethyl beta-glucan (ds 065-085), sodium caseinate, sodium cellulose, sodium cetostearyl sulfate, sodium chlorate, sodium chloride, sodium chloride injection, sodium cholesteryl sulfate, sodium citrate, sodium citrate hydrate, sodium cocoyl sarcosinate, sodium cyclamate, sodium desoxycholate, sodium dithionite, sodium dodecylbenzenesulfonate, sodium ethylparaben, sodium formaldehyde sulfoxylate, sodium gluconate, sodium hydroxide, sodium hypochlorite, sodium iodide, sodium lactate, la Sodium ureth-2 sulfate, sodium laureth-3 sulfate, sodium laureth-5 sulfate, sodium lauroyl sarcosinate, sodium lauryl sulfate, sodium lauryl sulfoacetate, sodium metabisulfite, sodium nitrate, sodium oleate, sodium phosphate, sodium phosphate dihydrate, sodium phosphite, sodium polyacrylate, sodium polyacrylate (2,500,000 MW), sodium polymetaphosphate, sodium propionate, sodium pyrophosphate, sodium pyrrolidone carboxylate, sodium starch glycolate, sodium starch glycolate type A corn, sodium starch glycolate type A potato, sodium starch glycolate type B potato, sodium stearate, sodium stearyl fumarate, sodium succinate hexahydrate, sodium sulfate, sodium sulfate anhydrous, sodium sulfate decahydrate, sodium sulfite, sodium sulfosuccinated undecyclenic acid monoalkylolamidemonoalkylolamide), sodium tartrate, sodium thioglycolate, sodium thiomalate, sodium thiosulfate, sodium thiosulfate anhydrous, sodium trimetaphosphate, sodium tripolyphosphate, sodium xylenesulfonate, sorbic acid, sorbitan, sorbitan isostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitol, squalane, 2-ethylhexanoate, stearalkonium chloride, stearalkonium hectorite / propylene carbonate, stearamidoethyl diethylamine, stearate, stearic acid, stearic acid diethanolamide, stearoxytrimethylsilane, stearyl alcohol, succinic acid, sucralose, sucrose, sucrose distearate, sucrose laurate, sucrose palmitate, sucrose polyester, sucrose stearate Sucrose syrup, sodium sulfacetamide, sulfobutyl ether beta-cyclodextrin, tagatose, tartaric acid, tegacid, tert-butylhydroquinone, tetrofosmin, theophylline, thimerosal, threonine, thymol, tocopherol, tocophersolan, tragacanth, triacetin, trisodium phosphate, trisodium phosphate monohydrate, tribehenin, tricaprylin, triceteareth-4 phosphate, triethanolamine lauryl sulfate, citric acid. Contains triethyl ester, trihydroxystearin, trilaneth-4 phosphate, trilaureth-4 phosphate, trimyristin, tris, trisodium citrate dihydrate, trisodium hedta, tristearin, trolamine, tromantadine, tromethamine, tryptophan, tyloxapol, tyrosine, undecylenic acid, urea, urethane, ursodiol, valine, vanillin, versetamide, viscarin, vitamin E, vitamin E acetate, vitamin K5, xylitol, and zinc sulfate.

[0196] Since the formation of co-crystals can control the solubility, water adsorption, dissolution rate, and other physicochemical properties of drugs, many studies on drug co-crystals have been conducted to improve the efficacy of drugs. Drug co-crystals can be produced and can improve the drug properties such as solubility, stability, and processability of poorly soluble drugs.

[0197] Psilocybin and psilocin are used in powder form, which is characterized by the active ingredient of the psilocybin formulation and low stability during storage.Therefore, psilocybin or psilocinco crystals with improved stability and solubility are provided.A method for producing psilocybin or psilocinco crystals is also provided.

[0198] The psilocybin and psilocincocrystals described herein can form supramolecular synthons with psilocybin molecules, including at least one conformer. The formation of these supramolecular synthons allows for the formation of cocrystals.

[0199] In one aspect, the coformer has a carboxylate moiety that can form an acid amide heterosynthon with a nitrogen atom in the psilocybin or psilocin molecule, while in another aspect, the coformer molecule forms a heterosynthon with the phosphate moiety of psilocybin.

[0200] Also provided is a method for preparing psilocybin or psilocin cocrystals, which comprises providing at least one coformer molecule to a psilocybin or psilocin molecule. The psilocybin or psilocin and the at least one conformer are mixed to prepare a mixed solution. Cocrystals can be formed from the mixed solution by evaporative crystallization, cooling crystallization, reaction crystallization, and isothermal crystallization.

[0201] Evaporative co-crystallization involves the nucleation and growth of co-crystals from a mixed solution with supersaturation provided by removing solvent from the solution via evaporation. To ensure recovery of clean crystals, individual co-crystals or bulk crystal samples should be collected before the solution is evaporated to dryness.

[0202] Co-crystals can also be formed by solid state grinding, a method in which the solid materials resulting in a co-crystal are mixed in stoichiometric amounts and crushed with a mortar and pestle, ball mix, or other grinding type millery.

[0203] Liquid-assisted grinding is a variant of solid-state grinding by the addition of a small amount of solvent during the grinding process, which is used to enhance supramolecular selectivity, both polymorphic and stoichiometric, in crystalline systems. This method enhances the rate of co-crystallization, since some co-crystals have shown poor performance in co-crystal formation under solid-state grinding conditions.

[0204] Cooling crystallization can be used to prepare co-crystals with supersaturation provided by the temperature reduction.

[0205] In another aspect, co-crystals can be formed by isothermal slurry conversion. This involves suspending psilocybin or psilocin and the conformer in a solvent, always leaving a solid fraction in excess. Typically, this involves adding psilocybin or psilocin to a solution or suspension of the coformer in a solvent. Although this is a solution-based method, the mixed solution does not need to contain completely dissolved psilocybin or psilocin and the conformer.

[0206] Alternatively, co-crystals can be obtained by supercritical fluid methods, for example using supercritical carbon dioxide (CO2). In these methods, supercritical CO2 is used to suspend psilocybin or psilocin and a coformer as a slurry in liquid or supercritical CO2. By controlling the thermodynamic conditions of CO2 (e.g., temperature, pressure), it is possible to fine-tune its density and dissolving power, thereby providing control over the co-crystallization between the co-crystal components.

[0207] In one aspect, the co-crystals can be obtained by using a non-solvent that is different from the solvent used to prepare the mixed solution.

[0208] In some aspects, the psilocybin or psilocinco crystals have improved solubility, stability, or both, as compared to psilocybin or psilocin alone.

[0209] The method may utilize psychedelics, pharma- ceutically acceptable salts thereof. The term "pharma- ceutically acceptable salt" refers to salts that are suitable for use in contact with human and animal tissues, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. SM Berge et al. provide a detailed description of pharma- ceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66:1-19. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharma- ceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Suitable pharma- ceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucoronic acid, fumaric acid, maleic acid, pyruvic acid, alkylsulfonic acid, arylsulfonic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, amboic acid, pamoic acid, pantothenic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, algenic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid.Suitable pharma- ceutically acceptable base addition salts of the compounds of the present invention include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine, etc. Alternatively, suitable pharma- ceutically acceptable base addition salts of the compounds of the present invention include organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, quaternary salts such as ammonium salts, tetramethylammonium salts, amino acid addition salts, such as salts with glycine and arginine. For compounds that are solids, it will be understood by those skilled in the art that compounds, agents and salts may exist as different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention.

[0210] The psychedelic compounds, salts thereof, or co-crystals described herein may be administered as formulations or compositions that include a pharma- ceutical effective amount of the compound in association with one or more pharma- ceutical acceptable excipients, including carriers, vehicles, and diluents, chemical stabilizers, e.g., antioxidants. The term "excipient" herein means any substance that is not itself a therapeutic agent, but is used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject, or is added to a pharmaceutical composition to improve its handling or storage characteristics, or to enable or facilitate the formation of a dosage form, such as a solution or suspension, suitable for parenteral administration, such as by intravenous, intramuscular, intradermal, or subcutaneous, nasal, or buccal application.

[0211] Suitable salts include any pharma- ceutically acceptable salts that can be prepared from inorganic or organic acids. Such inorganic acid salts are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, boric, sulfamic, and phosphoric. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, butyric, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, edetic, hydroxymaleic, pyruvic, alkylsulfonic, arylsulfonic, aspartic, glutamic, benzoic, and benzoic acids. The following acids are preferred: benzoic acid, palmitic acid, oleic acid, lauric acid, valeric acid, benzenesulfonic acid, oxalic acid, anthranilic acid, mesylic acid, methanesulfonic acid, toluenesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, amboic acid, pamoic acid, pantothenic acid, tannic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, arginic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid. Suitable pharma- ceutically acceptable base addition salts of the compounds of the present invention include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine, and the like. Alternatively, suitable pharma- ceutically acceptable base addition salts of the compounds of the invention include organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, quaternary salts such as ammonium salts, alkylammonium, tetramethylammonium salts, amino acid addition salts, e.g., salts with glycine and arginine. Basic nitrogen-containing groups may also be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl sulfate and diethyl sulfate. Metal salts can be prepared by reaction of the psychedelic with a metal hydroxide. Acid salts can be prepared by reacting the appropriate acid with the psychedelic.

[0212] Excipients can include, by way of example and not limitation, diluents, wetting agents, polymers, lubricants, glidants, stabilizers, and substances added to improve the appearance of the composition. Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, magnesium carbonate, talc, gelatin, gum arabic, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulosic materials such as cellulose esters and cellulose alkyl esters of alkanoic acids, low melting point waxes, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycol, and other pharma-ceutically acceptable substances. Examples of excipients and their uses are described in Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0213] In some embodiments, the composition or formulation comprises an antioxidant such as pyruvate, ascorbate, or tartrate.

[0214] The compounds and pharmaceutical compositions of the present invention may be formulated for injection, nasal, parenteral, subcutaneous, intravenous, or intramuscular delivery. Non-limiting examples of specific formulation types include powders, granules, injections, ampoules, vials, ready-to-use solutions, suspensions, or lyophilized materials.

[0215] For parenteral administration, including intravenous, intramuscular, or subcutaneous administration, liquid unit dosage forms can be prepared by combining the psychedelic with a sterile vehicle, typically a sterile aqueous solution that is preferably isotonic with the subject's blood. Depending on the vehicle and concentration used, the psychedelic can be suspended or dissolved in the vehicle or other appropriate solvent. In preparing a solution, the psychedelic may be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as preservatives and buffers can be dissolved in the vehicle. To enhance stability, the composition may be frozen after filling into the vial and the water removed under reduced pressure. The lyophilized powder is then sealed in the vial and an accompanying vial of water for injection or other suitable liquid can be supplied to reconstitute the liquid prior to use.

[0216] The total liquid volume before lyophilization can be less than, equal to, or greater than the final reconstitution volume of the lyophilized formulation. The lyophilization process is well known to those skilled in the art and typically involves subliming water from the frozen formulation under controlled conditions. Lyophilized formulations can typically be stored at a wide range of temperatures. For example, lyophilized formulations can be stored below 25°C, e.g., refrigerated at 2-8°C, or at room temperature (e.g., about 25°C). Preferably, lyophilized formulations are stored below about 25°C, more preferably at about 20°C; below about 4°C; or below about 0°C.

[0217] The lyophilized formulation is preferably reconstituted with a solution consisting essentially of water (e.g., USP WFI, or water for injection) or bacteriostatic water (e.g., USP WFI with 0.9% benzyl alcohol). Alternatively, a solution containing buffers and / or excipients and / or one or more pharma- ceutically acceptable carriers may be used. The liquid to be subjected to freeze-drying or lyophilization preferably contains all the desired components in the final reconstituted liquid formulation.

[0218] In some aspects, a kit for use in the method is provided, the kit comprising a lyophilized formulation, optionally a solution for reconstitution of the lyophilized formulation, and instructions for use.

[0219] The terms "combination therapy" or "adjunctive therapy" in the definition of the use of a psychedelic and one or more other pharmaceutical agents are intended to encompass the sequential administration of each agent in a regimen that provides the beneficial effect of the drug combination, as well as the substantially simultaneous co-administration of these agents, e.g., in a single formulation having a fixed ratio of the active agents or in multiple, separate formulations of each agent.

[0220] According to various embodiments of the present invention, one or more psychedelics may be formulated or administered in combination with one or more other therapeutic agents, such as an NSAID or palmitoylethanolamide (PEA). Thus, according to various embodiments of the present invention, one or more psychedelics may be included in a combination treatment regimen with other known therapeutic or prophylactic agents.

[0221] Alternatively, the subject may be pre-treated with one or more other therapeutic agents, such as an NSAID or palmitoylethanolamide (PEA), for example, during an initial psychotherapy session, which may begin several weeks prior to administration of the psychedelic agent. In some embodiments, treatment with one or more other therapeutic agents, e.g., an NSAID, continues after psychedelic administration.

[0222] A combination regimen may involve administering the active agents together, sequentially, or at intervals, as appropriate. Combinations of active agents, including compounds of the present invention, may be synergistic.

[0223] Co-administration of the compounds of the invention may be effected by the psychedelic being in the same unit dose as another active agent, or the compound and one or more other active agents may be in individual and separate unit doses administered at the same time or at similar times or at different times according to a dosing regimen or schedule. Sequential administration may be in any order as needed, and may require that the physiological effect of the first or initial compound is currently ongoing when the second or subsequent compound is administered, particularly where a cumulative or synergistic effect is desired.

[0224] For example, when the methods described herein are used to treat fibromyalgia administration, it is expected that not only will an analgesic (NSAID) be administered to reduce pain, but also reduce potential CNS inflammation that may contribute to providing a positive environment that may be reinforced during dissociative states. That is, in some embodiments, there is a "pretreatment period" to prepare the subject for administration of the psychedelic to enhance the impact of the psychedelic and induce a longer-lasting effect that may otherwise fade due to CNS inflammation.

[0225] In some embodiments, there is a "pretreatment period" during which therapeutic agents appropriate for the procedure are used to prepare the brain for psychedelic intervention and enhance the effects of psychedelics to induce longer-lasting effects that do not fade away due to CNS inflammation.

[0226] In some embodiments, a psychedelic (e.g., psilocybin or psilocin) can be administered with one or more of orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide, phentermine, benzphetamine, diethylpropion, phendimetrazine, and SGLT2 inhibitors (glifozina). These combinations can be useful for treating eating disorders such as hypothalamic obesity, ROHHAD (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation), binge eating, hyperphagia, anorexia, pica, rumination disorder, avoidant / restrictive food intake disorder (ARFID), purging disorder, night-eating syndrome, and orthorexia.

[0227] In some embodiments, the psychedelic (e.g., psilocybin or psilocin) can be administered with one or more of analgesics, antidepressants and anticonvulsants for the treatment of fibromyalgia. In this regard, suitable analgesics such as acetaminophen, ibuprofen or naproxen sodium may be beneficial. Gabapentin or pregabalin may also be used.

[0228] Suitable antidepressants include duloxetine, and milnacipran (Sabella) may help reduce the pain and fatigue associated with fibromyalgia. Suitable anticonvulsants include carbamazepine, clobazam, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, sodium valproate, topiramate, lacosamide, and zonisamide.

[0229] In connection with the treatment of fibromyalgia, psychedelics (e.g., psilocybin or psilocin) may alternatively or additionally be co-administered with a muscle relaxant such as cyclobenzaprine, or may be co-administered with transcranial magnetic stimulation.

[0230] IV. Psychological Disorders and Indications for Treatment The methods and uses disclosed herein can be useful for the treatment or prevention of any psychological disorder or disease that has a significant psychological component. In some aspects, psychological disorders or diseases that have a psychological component also include diseases or symptoms related to pain or pain sensation.

[0231] Examples of psychological disorders that may be treated or prevented by the methods disclosed herein include PTSD, alcohol and drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety (e.g., associated with a terminal illness such as cancer), eating disorders, fibromyalgia, neuropathic pain, phantom limb pain, hypothalamic-induced obesity (HO) and Prader-Willi syndrome (PWS), anorexia, bulimia, and binge eating disorder. In some aspects, an exemplary psychological disorder that can be treated by the provided embodiments includes algesic pain.

[0232] In a preferred embodiment, the methods described herein are used to treat hypothalamic induced obesity (HO), Prader-Willi syndrome (PWS), binge eating or fibromyalgia.

[0233] Other examples of psychological disorders that may be treated or prevented by the methods disclosed herein include psychotic disorders, schizophrenia, schizophreniform disorders (acute schizophrenic episodes); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder with or without psychotic features (psychotic depression); delusional disorder (paranoia); shared psychotic disorder (shared paranoid disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizoid personality disorder; schizotypal personality disorder, anxiety disorder, panic disorder, panic attacks, agoraphobia, and attention deficit syndrome.

[0234] In some aspects, the disorder or disease includes a pain-related disorder, e.g., a pain-related disorder that is a psychological disorder or disease that has a psychological component. In some aspects, the pain-related disorder includes a pain-related disease that is associated with or has characteristics of nociopathic pain. In some aspects, the disease or disorder, e.g., a psychological disorder, to be treated by the provided embodiments includes an nociopathic pain disorder.

[0235] In some aspects, nocio-modulated pain is not associated with signs of neuropathic disorders and is characterized by hypersensitivity in apparently normal tissue. In some aspects, nocio-modulated pain is due to altered nociception without obvious evidence of actual or threatened tissue damage or evidence of pathology or disease. In some aspects, nocio-modulated pain is chronic. Exemplary types of nocio-modulated pain include fibromyalgia, irritable bowel syndrome, phantom limb pain, complex regional pain syndrome, and non-specific chronic low back pain. In some aspects, nocio-modulated pain is mechanistically distinct from nociceptive pain caused by ongoing tissue inflammation and tissue damage, and neuropathic pain caused by nerve damage. The mechanisms underlying nocio-modulated pain are not fully understood, but may involve enhanced central nervous system (CNS) pain and sensory processing and altered pain regulation. Exemplary symptoms observed in algesic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. Algesic pain can occur in isolation, as in fibromyalgia or tension headaches, or as part of a mixed pain state with ongoing nociceptive or neuropathic pain, as can occur in chronic low back pain (see, e.g., Fitzcharles et al. 2021 Lancet 397(10289):2098-2110).

[0236] In some embodiments, the psychological disorder or nociomorphic pain disorder is fibromyalgia. In some embodiments, the psychological disorder or nociomorphic pain disorder is phantom limb pain. In some embodiments, the psychological disorder or nociomorphic pain disorder is complex regional pain syndrome.

[0237] In some aspects, animal models of nociceptive pain can be used to assess the activity and effect of administration of psychedelics, for example as described herein. In some examples, rats with pain induced by injection of formalin are used as animal models of nociceptive pain. The formalin pain model is a translational animal model for chronic nociceptive pain, including fibromyalgia, phantom limb pain, or complex regional pain syndrome (Vanini G., Sleep 2016;39(1):133-42). In the formalin pain model, in addition to experiencing extra pain in the limb injected with formalin, animals experience increased pain sensation (i.e., hyperalgesia) in the limb that is not injected with formalin (e.g., the contralateral limb compared to the limb injected with formalin). To assess the activity of psychedelics in nociceptive pain disorders, pain sensation was measured in the contralateral limb.

[0238] It will be appreciated by those skilled in the art that numerous variations and / or modifications may be made to the present invention as shown in the specific embodiments, without departing from the spirit or scope of the invention as broadly described. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

[0239] V. Definition Unless otherwise defined, all terminology, notation, and other technical and scientific terms or terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having 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 representing a substantial difference from what is commonly understood in the art.

[0240] C max means the peak concentration achieved by a drug in serum or plasma.

[0241] Throughout this specification, unless the context clearly requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" are understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0242] Throughout this specification the term "consisting of" means consisting solely of.

[0243] The term "consisting essentially of" means the inclusion of the stated elements, integers, or steps, but may also include other elements, integers, or steps that do not materially alter or contribute to the operation of the invention.

[0244] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is merely for the purpose of providing a context for the present technology, and should not be taken as an admission that any or all of such matter formed part of the prior art base or was common general knowledge in the art relevant to the present technology by virtue of existing prior to the priority date of each claim herein.

[0245] Unless the context requires otherwise or specifically states to the contrary, any integer, step, or element of the present technology described herein as a singular integer, step, or element clearly encompasses both the singular and the plural of the described integer, step, or element.

[0246] In the context of this specification, the terms "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of an article. By way of example, a reference to "an element" means one element or more than one element.

[0247] In the context of this specification, the term "about" means that reference to a figure or value should not be taken as an absolute figure or value, but includes a margin of variation that includes a typical margin of error or risk limit above or below the figure or value in question, consistent with what one of ordinary skill in the art would understand in the art. In other words, use of the term "about" is understood to refer to a range or approximation that one of ordinary skill in the art would consider equivalent to the recited value in relation to achieving the same function or result.

[0248] The terms "treating," "treatment," and "therapy" are used herein to refer to curative, prophylactic, palliative, and preventative therapies. Thus, in the context of this disclosure, the term "treating" encompasses curing, ameliorating, or reducing the severity of one or more of the psychological conditions or their associated symptoms.

[0249] The term "therapeutically effective amount" or "pharmacologically effective amount" or "effective amount" refers 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 be appropriate for the amount of each agent that achieves the goal of improvement in disease severity and / or incidence over the treatment of each agent itself, while preferably avoiding or minimizing adverse side effects, including those typically associated with other therapeutic approaches.

[0250] "Pharmaceutical carriers, diluents or excipients" include, but are not limited to, suitable water-soluble organic carriers, solvents, dispersion media, bulking agents, carriers, coating agents, antibacterial and antifungal agents, any physiological buffered (i.e., about pH 7.0-7.4) medium containing isotonic and absorption retarding agents. Suitable water-soluble organic carriers include, but are not limited to, saline, glucose, corn oil, dimethyl sulfoxide. Other additives include lactose, mannitol, corn starch, potato starch, binders such as crystalline cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, arabio gum, gelatin, solubilizers such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.

[0251] A "subject" includes any human.

[0252] In the context of this specification, the term "administering" and variations of this term including "administer" and "administration" include contacting, applying, delivering, or providing a compound or composition of the invention to a subject by any suitable means.

[0253] Those skilled in the art will recognize that the technology described herein is susceptible to variations and modifications other than those specifically described.It should be understood that this technology includes such variations and modifications.For the avoidance of doubt, this technology also includes all of the steps, features and compounds mentioned or shown herein, individually or collectively, and any and all combinations of any two or more of said steps, features and compounds.

[0254] In order that the present technology may be more clearly understood, preferred embodiments will now be described with reference to the following descriptions.

[0255] VI. Illustrative Embodiments Aspects provided include: 1. A method for treating a psychological disorder in a subject, comprising: administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject less than 30 minutes after administration; and Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; method. 2. The method of embodiment 1, further comprising the step of obtaining non-invasive measurements of brain activity from the subject to determine when the subject enters a dissociated state. 3. administering to a subject suffering from a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject; and obtaining non-invasive measurements of brain activity from the subject to determine when the subject enters a dissociated state. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; Methods for inducing a dissociated state. 4. administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject; and obtaining electroencephalography (EEG) measurements from the subject to determine when the subject enters a dissociative state. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; Methods for inducing a dissociated state. 5. administering to a subject having a psychological disorder a psychedelic in an amount sufficient to induce a dissociative state in the subject; obtaining a non-invasive measurement of brain activity from the subject to determine whether the subject has entered a dissociated state; and If the subject has entered a dissociated state, determining the amount of psychedelic as a therapeutically effective dose. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; A method for determining a therapeutically effective dose of a psychedelic. 6. A method of maintaining a dissociative state in a subject having a psychological disorder, comprising: administering to the subject a psychedelic in an amount sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and obtaining electroencephalography (EEG) measurements from the subject to determine when the subject enters a dissociated state; and Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; method. 7. Carrying out the method of any one of aspects 1 to 6; and maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window; thereby treating a psychological disorder. A method for treating psychological disorders. 8. Administering to a subject with phantom limb pain a psychedelic in an amount sufficient to induce a dissociative state in the subject. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; A method of treating phantom limb pain in a subject. 9. The method of any one of aspects 1-8, wherein administration of the psychedelic is by intravenous administration. 10. The method of any one of aspects 1-5 and 7-9, wherein the dissociated state is induced in said subject within less than 15, 30, 60, 90 or 120 minutes, or within about less than 15, 30, 60, 90 or 120 minutes, or within a range defined by any of the foregoing, after administration. 11. The method of any one of aspects 1-5 and 7-10, wherein the dissociated state is induced in the subject within less than or about 30 minutes after administration. 12. The method of any one of aspects 3-5 and 8-11, further comprising maintaining the average plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. 13. The method of any one of aspects 2, 3, 5, 7, and 9-12, wherein the non-invasive measurement of brain activity is selected from among electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), and optoencephalography (OEG). 14. The method of any one of aspects 2, 3, 5, 7, and 9-13, wherein the non-invasive measurement of brain activity is an EEG. 15. The method of any one of aspects 2, 3, 5, 7, and 9-12, wherein the non-invasive measurement of brain activity is a questionnaire-based assessment of experience. 16. The method of embodiment 15, wherein the questionnaire-based assessment of the psychedelic experience is selected from among one or more of the Mystical Experiences Questionnaire (MEQ30) assessment, the Challenging Experiences Questionnaire (CEQ) assessment, the Psychological Insight Questionnaire (PIQ) assessment, a qualitative written assessment, and / or a Monitor Rating Scale (MRS) questionnaire. 17. The method of any one of aspects 2, 3, 5, 7, and 9-16, further comprising obtaining additional non-invasive measurements of brain activity from the subject to monitor the dissociation state during the therapeutic window. 18. The method of any one of aspects 4, 6-12, and 14, further comprising obtaining additional EEG measurements from the subject to monitor the dissociation state during the treatment window. 19. The method of any one of aspects 4, 6-12, 14, and 18, wherein the EEG measurements are analyzed as expressed by Lempel-Ziv Complexity (LZC). 20. The method of any one of aspects 2, 3, 5, 7, and 9-17, wherein non-invasive measurements of brain activity are obtained before, during and / or after administration. 21. The method of embodiment 20, wherein non-invasive measurement of brain activity following administration indicates termination of the dissociated state. 22. The method of any one of aspects 4, 6-12, 14, 18, and 19, wherein EEG measurements are obtained before, during, and after administration. 23. The method of embodiment 22, wherein EEG measurements following administration indicate termination of the dissociative state. 24. The method of any one of aspects 1-23, wherein the dissociated state is induced within, or within about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes after administration. 25. The method of any one of aspects 1-24, wherein the dissociated state is induced within 5 minutes or within about 5 minutes after administration. 26. The method of any one of embodiments 1, 6, 7, and 9-25, wherein the therapeutic window is at or about 0.5, 1, 2, 3, 4, 5, or 6 hours. 27. The method of any one of aspects 1, 6, 7, and 9-26, wherein the therapeutic window is from at or about 0.5 hours to at or about 4 hours. 28. The method of any one of aspects 1-27, further comprising terminating administration of the psychedelic to terminate the dissociative state. 29. The method of embodiment 28, wherein end of the dissociative state occurs within, or within about, 30, 60, 90, 120, or 180 minutes, or within a range defined by any of the foregoing, of end of administration of the psychedelic. 30. The method of embodiment 28 or 29, wherein termination of the dissociative state occurs within 60 minutes or within about 60 minutes of termination of administration of the psychedelic. 31. The psychedelic produces a given C within or about 30-120 minutes after the start of administration. max The method of any one of embodiments 1-30, wherein the antibody is administered to produce 32. The psychedelic produces a given C within or about 45-90 minutes after the start of administration. max The method of any one of embodiments 1-31, wherein the antibody is administered to produce 33. Psychedelics produce a given C within or about 1-10 minutes of administration. max The method of any one of embodiments 1-30, wherein the antibody is administered to produce 34. C max is between or about 1 μg / L and 50 μg / L. 35. C max The method of any one of aspects 30-34, wherein the concentration is between 10 μg / L and 20 μg / L or about 10 μg / L to 20 μg / L. 36. C max is between 10 μg / L and 15 μg / L or about 10 μg / L to 15 μg / L. 37. The method of any one of aspects 1-36, wherein the dissociative state is induced by intravenous administration of a loading dose of a psychedelic. 38. The method of embodiment 37, wherein the loading dose comprises administration of an initial bolus of the psychedelic. 39. The method of embodiment 37 or 38, wherein the initial bolus dose is at or about 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. 40. The method of any one of aspects 37-39, wherein the loading dose of the psychedelic is administered over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, or a range defined by any of the foregoing. 41. The method of any one of aspects 37-40, wherein the loading dose of the psychedelic is administered over a period of 3 minutes or about 3 minutes. 42. The method of any one of aspects 38-41, wherein the initial bolus of the psychedelic is at a dose of at or about 0.02 mg / kg to at or about 0.2 mg / kg. 43. The method of any one of aspects 1-42, wherein the dissociative state is induced by intravenous administration of an initial bolus of the psychedelic at a dose of about 0.1 mg / kg to about 0.2 mg / kg. 44. The method of any one of aspects 1, 6, 7, and 9-43, wherein the average plasma concentration of the psychedelic is maintained at a predetermined value during the therapeutic window by administration of a maintenance dose of the psychedelic. 45. The method of embodiment 44, wherein the maintenance dose of the psychedelic is administered by continuous or intermittent administration of the psychedelic. 46. ​​The method of embodiment 45, wherein the continuous or intermittent administration is via an intravenous route. 47. The method of any one of aspects 44-46, wherein the maintenance dose is administered by intravenous infusion. 48. The method of embodiment 45, wherein the maintenance dose of the psychedelic is administered by intermittent administration of the psychedelic, and the intermittent administration is via a subcutaneous, oral, transdermal, intramuscular, intranasal, intranasal / pharyngeal, or buccal route. 49. The method of any one of aspects 45-47, wherein the maintenance dose is administered by intravenous infusion of the psychedelic at a rate of at or about 0.2 mg / min to at or about 1 mg / min. 50. The method of any one of aspects 45-47, wherein the continuous administration of the psychedelic is at a rate of from at or about 0.1 mg / min to at or about 1 mg / min. 51. A method of treating a psychological disorder in a subject, comprising: administering to a subject having a psychological disorder a loading dose of a psychedelic via intravenous administration of an initial bolus in an amount of at or about 1 mg to at or about 5 mg; and thereafter continuously administering a maintenance dose of the psychedelic by intravenous infusion at a rate of at or about 0.02 mg / min to at or about 1 mg / min to maintain an average plasma concentration during the therapeutic window. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; method. 52. A method of treating a psychological disorder in a subject, comprising: administering a loading dose of a psychedelic to a subject with a psychological disorder by intravenous infusion at a rate of at or about 0.5 mL / min to at or about 2.0 mL / min over a period of at or about 5 minutes to at or about 20 minutes; and thereafter continuously administering a maintenance dose of the psychedelic by intravenous infusion at a rate of from, or about, 0.1 mL / min to, or about, 2.0 mL / min over a period of, or about, 30 minutes to, or about, 120 minutes to maintain an average plasma concentration during the therapeutic window. wherein the psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; method. 53. The method of any one of aspects 37-52, wherein the loading dose of the psychedelic is administered at a rate of from at or about 0.1 mL / min to at or about 2.0 mL / min. 54. The method of any one of aspects 37-53, wherein the loading dose of the psychedelic is administered at a rate of 1.0 mL / min or about 1.0 mL / min. 55. The method of any one of aspects 44-54, wherein the maintenance dose is administered at a rate of 0.1 mL / min to 1.0 mL / min or about 1.0 mL / min. 56. The method of any one of aspects 44-55, wherein the maintenance dose is administered at a rate of 0.5 mL / min or about 0.5 mL / min. 57. The method of any one of aspects 44-56, wherein the maintenance dose is administered over a period of 30, 60, 90, or 120 minutes, or about 30, 60, 90, or 120 minutes, or a range defined by any of the foregoing. 58. The method of any one of aspects 44-57, wherein the maintenance dose is administered over a period of up to or about 60 minutes. 59. The method of any one of aspects 44-58, wherein the maintenance dose is administered over a period of up to or about 120 minutes. 60. The method of any one of aspects 1, 6, 7, and 9-59, wherein the therapeutic window is from at or about 30 minutes to at or about 120 minutes. 61. The method of any one of aspects 1, 6, 7, and 9-60, wherein the therapeutic window is 60 minutes or about 60 minutes. 62. The method of any one of aspects 1, 6, 7, and 9-60, wherein the therapeutic window is at or about 120 minutes. 63. The method of any one of aspects 1-62, wherein the total amount of psychedelic administered to the subject is at most, or about, 1.0 mg, 1.5 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg per subject, or a range defined by any of the foregoing. 64. The method of any one of aspects 1-63, wherein the total amount of psychedelic administered to the subject is up to or about 2.5 mg. 65. The method of any one of aspects 1-63, wherein the total amount of psychedelic administered to the subject is up to or about 5 mg. 66. The method of any one of aspects 1-63, wherein the total amount of psychedelic administered to the subject is up to or about 10 mg. 67. The method of any one of aspects 1-66, wherein the psychedelic is psilocin, a cocrystal, coformer, or a salt thereof. 68. The method of any one of aspects 1-67, wherein the psychedelic is psilocin. 69. The method of any one of aspects 1-66, wherein the psychedelic is psilocybin, a cocrystal, coformer, or a salt thereof. 70. The method of any one of aspects 1-66 and 69, wherein the psychedelic is psilocybin. 71. The method of any one of aspects 1-68, wherein the psychedelic is psilocin and the total amount of psilocin administered to the subject is at or about 2.5 mg, and the administration of psilocin is carried out over a period of at or about 60 minutes. 72. The method of any one of aspects 1-66, 69, and 70, wherein the psychedelic is psilocybin, and the total amount of psilocybin administered to the subject is at or about 5 mg, and the administration of psilocybin is carried out over a period of at or about 60 minutes. 73. The method of any one of aspects 1, 2, 6, 7, and 12-72, wherein the predetermined value of the mean plasma concentration of the psychedelic is between 1 and 50 μg / L or between about 1 and 50 μg / L. 74. The method of any one of aspects 1, 2, 6, 7, and 12-73, wherein the predetermined value of the mean plasma concentration of the psychedelic is 10-20 μg / L or about 10-20 μg / L. 75. The method of any one of aspects 1, 2, 6, 7, and 12-74, wherein the predetermined value of the mean plasma concentration of the psychedelic is 10-15 μg / L or about 10-15 μg / L. 76. The method of any one of aspects 1-75, further comprising the step of providing psychological support to the subject during the treatment window. 77. 5HT 2A The method of any one of embodiments 1-76, further comprising the step of removing said subject from the dissociated state at the end of the treatment window by administering a receptor antagonist. 78. The method of any one of aspects 1-7 and 9-77, wherein the psychological disorder is selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, fibromyalgia, neuropathic pain, phantom limb pain, hypothalamic-induced obesity, Prader-Willi syndrome, and binge eating disorder. 79. The method of any one of aspects 1-7 and 9-78, wherein the psychological disorder is selected from the group consisting of hypothalamic induced obesity, Prader-Willi syndrome, binge eating disorder, and fibromyalgia. 80. The method of any one of aspects 1-7 and 9-77, wherein the psychological disorder is an algesic pain disorder. 81. The method of any one of aspects 1-7 and 9-80, wherein the psychological disorder is fibromyalgia. 82. The method of any one of aspects 1-7 and 9-80, wherein the psychological disorder is phantom limb pain. 83. The method of any one of aspects 1-7 and 9-80, wherein the psychological disorder is complex regional pain syndrome. 84. The method of any one of aspects 1-83, further comprising the step of discontinuing said administration if the subject experiences an adverse event. 85. The method of any one of embodiments 1-84, wherein the psychedelic is administered with at least one additional therapeutic agent. 86. The method of any one of aspects 1-85, resulting in induction of a dissociative state in at least 70%, 80%, 90%, or 95% of subjects administered the psychedelic. 87. The method of any one of aspects 1-86, resulting in maintenance of average plasma levels of the psychedelic in at least 70%, 80%, 90%, or 95% of the subjects being administered the psychedelic. 88. The method of any one of aspects 1 to 87, wherein the subject is a human. 89. Administering to a subject an amount of psilocybin or psilocin sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. 4. A method for treating a psychological disorder in a subject, comprising: 90. The method of embodiment 89, wherein the dissociated state is induced within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes. 91. The method of embodiment 89 or 90, wherein the therapeutic window is 0.5, 1, 2, 3, 4, 5, or 6 hours. 92. C for psychedelic maxoccurs within 1 to 10 minutes of administration. 93. C max is about 1 μg / L to 50 μg / L. 94. The method of any one of embodiments 89-93, wherein the dissociative state is induced by intravenous administration of an initial bolus of the psychedelic at a dose of about 0.1 mg / kg to about 0.2 mg / kg. 95. The method of any one of aspects 89-94, wherein the average plasma concentration of the psychedelic is maintained at a predetermined value during the therapeutic window by continuous or intermittent administration of the psychedelic. 96. The method of embodiment 95, wherein the continuous or intermittent administration is via an intravenous route. 97. The method of embodiment 95, wherein the intermittent administration is via subcutaneous, oral, transdermal, intramuscular, intranasal, intranasal / pharyngeal, or buccal routes. 98. The method of embodiment 95 or 96, wherein the psychedelic is administered continuously at a rate of 0.1 mg / min to 1 mg / min. 99. The method of any one of aspects 89-98, wherein the predetermined plasma concentration of the psychedelic is 1-50 μg / L. 100. Any one of the methods of 89-99, further comprising the step of providing psychological support to the subject during the treatment window. 101. 5HT 2A The method of any one of embodiments 89-100, further comprising removing the subject from the dissociated state at the end of the treatment window by administering a receptor antagonist. 102. The method of any one of aspects 89 to 101, wherein the psychological disorder is selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, fibromyalgia, neuropathic pain, phantom limb pain, hypothalamic-induced obesity and Prader-Willi syndrome, binge eating. 103. The method of aspect 102, wherein the psychological disorder is hypothalamic induced obesity, Prader-Willi syndrome, binge eating or fibromyalgia. 104. The method of any one of aspects 89-103, wherein the psychedelic is psilocybin, a cocrystal, coformer, or salt thereof, psilocin, or a combination thereof. 105. The method of embodiment 104, wherein the psychedelic is psilocin, a cocrystal, coformer, or a salt thereof. 106. The method of any one of embodiments 89-105, wherein the psychedelic is administered with at least one additional therapeutic agent. 107. Administering to a subject an amount of psilocybin or psilocin sufficient to induce a dissociated state in the subject less than 30 minutes after administration; and obtaining an EEG from the subject to determine when the subject enters a dissociated state; Thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window. A method for determining a therapeutically effective dose of a psychedelic for treating a psychological disorder in a subject, comprising: 108. The method of embodiment 107, further comprising obtaining an additional EEG from the subject to monitor the dissociation state during the treatment window. 109. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in the method of any one of embodiments 1-108. 110. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method for treating a psychological disorder, the method comprising any one of the methods of embodiments 1-108. 111. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method of inducing a dissociative state, the method comprising the method of any one of embodiments 1-108. 112. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method for determining a therapeutically effective dose of a psychedelic, the method comprising any one of the methods of embodiments 1 to 108. 113. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method of maintaining a dissociated state in a subject having a psychological disorder, the method comprising any one of the methods of embodiments 1-108. 114. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method of treating phantom limb pain. 115. A psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for use in a method for treating phantom limb pain, the method comprising the method of any one of embodiments 1-108. 116. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for use in the method of any one of embodiments 1 to 108. 117. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for treating a psychological disorder by the method of any one of embodiments 1 to 108. 118. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for inducing a dissociative state by the method of any one of embodiments 1 to 108. 119. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for determining a therapeutically effective dose of a psychedelic by the method of any one of embodiments 1 to 108. 120. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for maintaining a dissociated state in a subject having a psychological disorder by the method of any one of embodiments 1 to 108. 121. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for treating phantom limb pain. 122. Use of a psychedelic that is psilocybin, psilocin, a co-crystal, coformer, or salt thereof, or a combination thereof, in the manufacture of a medicament for treating phantom limb pain by the method of any one of embodiments 1-108. 123. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, in the method of any one of embodiments 1 to 108. 124. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, for treating a psychological disorder by the method of any one of embodiments 1 to 108. 125. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, to induce a dissociative state by the method of any one of embodiments 1 to 108. 126. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, to determine a therapeutically effective dose of the psychedelic by the method of any one of embodiments 1 to 108. 127. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, to maintain a dissociated state in a subject having a psychological disorder by the method of any one of embodiments 1 to 108. 128. Use of a psychedelic that is psilocybin, psilocin, their cocrystals, coformers, or salts, or combinations thereof, to treat phantom limb pain. 129. Use of a psychedelic that is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof, to treat phantom limb pain by the method of any one of embodiments 1 to 108. EXAMPLES

[0256] VII. Working Examples The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0257] Example 1 : Pharmacokinetics and pharmacodynamics of intravenous infusion of psychedelics in rats. This example describes the pharmacokinetic and pharmacodynamic responses in animals following intravenous infusion of psychedelics over a period of time. During the study, plasma concentrations of psilocin following a 1-hour intravenous infusion of psilocybin or psilocin were assessed, as well as indices of dissociation or a psychedelic state as determined by recorded head twitching movements.

[0258] Three male Sprague Dawley rats were administered a 10 mg / kg intravenous infusion (IV) over one hour (60 minutes) of either psilocin or psilocybin as described in Table E1. Psilocybin or psilocin was administered over 60 minutes into the femoral vein catheter via an IV infusion set attached to a syringe pump.

[0259] Plasma psilocin concentration, maximum plasma concentration (C maxPharmacokinetic parameters, including pharmacokinetics (PA), and pharmacodynamic parameters, including incidence of head-shaking behavior as an index of dissociative state, were assessed over time. All animals were 7 to 12 weeks old and weighed 250 to 400 grams, and pre-study health assessments were acceptable. All animals were acclimated to the laboratory environment for 1 day prior to the study. Animals were observed daily for signs of clinical changes.

[0260] Table E1. Intravenous administration of psilocin or psilocybin in rats TIFF2024510637000002.tif16165

[0261] A. Pharmacokinetics After the infusion began, serial blood samples of approximately 0.5 mL each were collected from each animal via the jugular catheter at several time points, including 0.25, 0.5, 1, 2, 4, 6, and 8 hours after the infusion began. Immediately prior to each blood collection time point, a volume of blood slightly larger than the void volume of the catheter tubing was withdrawn and discarded. A syringe with a blunt needle was used to obtain a 0.5 mL blood sample from the jugular catheter. The blood sample was immediately transferred to a chilled blood collection tube containing anticoagulant and chilled. The chilled blood sample was centrifuged at 3000 RPM for 10 minutes at 4°C to collect the plasma. The plasma samples were stored at -70°C until ready for analysis.

[0262] For each of the three rats that received an IV infusion of psilocin (Table E2; Figure 1A) or psilocybin (Table E4; Figure 1B), the plasma psilocin levels determined at each time point, as well as the maximum plasma concentration (C max ), the time to reach maximum plasma concentration (Tmax), and T calculated based on the formula below. max Area under the curve (AUC T ) (including the assumption that at time T=0, concentration (ng / mL)=0): Pharmacokinetic parameters were determined, including TIFF2024510637000003.tif12128. As shown, mean plasma concentrations and C at each time point in both psilocin-treated animals (Tables E2 and E3) and psilocybin-treated animals (Tables E4 and E5).max was remarkably similar for each animal, with small standard deviations. As shown in Tables E3 and E5, AUC T was also remarkably similar between different animals. The results also showed a consistent and rapid decrease in drug plasma concentrations after the 1-hour infusion was completed (see the decrease in plasma psilocin concentrations at hours 2, 4, 6, and 8 in Figures 1A and 1B).

[0263] The results demonstrate consistent plasma concentrations and exposure in different individual animal subjects during intravenous infusion of psilocybin or psilocin, and that plasma concentrations decline rapidly and reproducibly following completion of the infusion.

[0264] Table E2. Plasma concentrations of psilocin (ng / mL) during and after a 1-hour IV infusion of psilocin TIFF2024510637000004.tif55169

[0265] Table E3: Pharmacokinetic parameters following IV infusion of psilocin TIFF2024510637000005.tif55157

[0266] Table E4. Psilocybin plasma concentrations (ng / mL) during and after a 1-hour IV infusion of psilocybin TIFF2024510637000006.tif55170

[0267] Table E5. Pharmacokinetic parameters following IV infusion of psilocybin TIFF2024510637000007.tif55157

[0268] B. Pharmacodynamics / behavioral To assess the pharmacodynamics (PD) of psychedelic infusions, head shaking of animals was recorded as an indicator of achieving dissociative state. Head shaking response (HTR) is used as a surrogate PD marker for animals achieving or on their way to achieving dissociative or psychedelic state (e.g., Zhuk et al., Toxins 2015, 7, 1018-1029; Halberstadt et al., J Psychopharmacol. 2011 25(11): 1548-1561). HTR was also used to determine when the end of dissociative state occurred after cessation of IV infusion.

[0269] To assess HTR, a video monitoring system was used to record the animals in the study from the cessation of infusion until the final collection time (1 hour after infusion). The camera was positioned to allow a top-down view of the animals. Records were kept for review, detailing the time of head-shaking behavior observed, the duration of observed behavior, and any atypical observations.

[0270] The number of head-shaking events observed within 60 minutes following the 1-hour IV infusion of each of three rats receiving psilocin or psilocybin was determined from video recordings. Head-shaking was observed in two of three rats receiving IV infusions of psilocin and two of three rats receiving IV infusions of psilocybin, with each animal experiencing between two and six head-shaking events during the 60 minutes following the 1-hour IV infusion. Of note, for rats receiving psilocin, no head-shaking was observed beyond 16 minutes following the end of the infusion in any of the animals, which correlated with a rapid and controlled return from the psychedelic or dissociative state. For rats receiving psilocybin, head-shaking was observed for up to 50 minutes following the end of the infusion. Once the IV infusion of either psilocin or psilocybin was terminated, the head-shaking activity subsided within 50 minutes, supporting a rapid termination of dissociation or psychedelics compared to previously reported termination of the dissociative state following oral administration of psilocybin.

[0271] The oral route of administration of psychedelics does not provide a mechanism for blood level control, and it is not easy to control the duration of the dissociative state or psychedelic experience, or the ability to terminate or recede adverse events. After a 25 mg oral capsule, the onset of dissociation of the psychedelic state begins 1-2 hours after administration and can last 6-8 hours, making it impossible to manipulate or terminate the experience (see, e.g., Hasler et al., (1997) Pharm Acta Helv, 72(3), 175-184). As evidenced by the rapid decline in blood levels and pharmacodynamic markers of dissociation or the psychedelic state, intravenous administration allows the duration of the dissociative state or psychedelic experience to be controlled, and in the case of adverse events, the experience to be terminated.

[0272] The results demonstrated that intravenous infusion of a psychedelic (psilocin or psilocybin) over a period of time, such as 1 hour, results in rapid achievement of effective concentrations to induce a dissociative state, and a more consistent and reproducible decrease in plasma levels after the end of the infusion, consistent with reproducible plasma levels. This contrasts with previous reports of plasma levels after oral administration, which have been shown to result in wide variability between subjects (see, e.g., Brown et al. (2017). Clin Pharmacokinet. 56(12):1543-1554). As demonstrated herein, intravenous administration provides a method of administration that allows for a more rapid and controlled entry into the dissociative state depending on the rate of administration, the ability to control the duration in the dissociative state based on the duration of administration, and provides for a more rapid termination of the dissociative state should an adverse event occur. The results also support the ability to monitor and maintain the average plasma concentration of a psychedelic, such as the active metabolite psilocin, during the therapeutic window.

[0273] The results support the usefulness of intravenous infusion as a method of administration to achieve consistent and controllable plasma concentrations of psilocin (active pharmacological agent). The results also support the usefulness of monitoring psilocin plasma levels as a means of assessing dissociation state and correlating with target plasma levels of psilocin, and monitoring the maintenance of the average plasma concentration of psychedelics to a specific value during the therapeutic window. The results support the usefulness of intravenous administration, including intravenous infusion, and monitoring behavior, such as head-shaking behavior, in rats. Head-shaking behavior can generally be translated to dissociation state or psychedelic effects in humans, as an exemplary non-invasive measurement of brain activity during and after administration to monitor entering and leaving dissociation state, as well as the pharmacodynamics of administered psychedelics.

[0274] Example 2 : Monitoring dissociative states before, during, and after intravenous infusion of psychedelics using electroencephalography (EEG) This example describes another exemplary non-invasive measurement of brain activity using electroencephalography (EEG) in animals receiving an intravenous infusion of a psychedelic over a period of time.

[0275] Before, during and after 60 minutes of 10mg / kg intravenous infusion (IV) of either psilocybin or psilocin, rats were assessed for changes in neurophysiological complexity and brain response to psilocybin or psilocin infusion.Sprague Dawley rats were subjected to 60 minutes of IV infusion of psilocybin or psilocin, generally as described in Example 1.Changes in EEG were monitored before, during and after infusion.In addition, the incidence of head-shaking response was assessed before, during and after infusion as an additional indicator of pharmacodynamic response.

[0276] To prepare the animals for IV drug infusion and EEG monitoring, rats were first anesthetized using standard techniques and operated on for IV cannulation. An indwelling cannula was inserted into the jugular vein and exteriorized at the base of the skull for IV infusion of psilocin or psilocybin. The exteriorized cannula was attached to an infusion port, which allowed for IV infusion into freely moving, conscious animals.

[0277] For EEG electrode implantation, rats were anesthetized and placed in a stereotaxic apparatus (Model 963, David Kopf Instruments, Tujunga, CA). The stereotaxic apparatus allowed 3D positioning of the electrodes to precise regions of the rat brain. The skull was exposed and burr holes (30) were drilled to implant stainless steel screw electrodes (B000FN89DM, Small Parts, Logansport, IN) for recording EEG through the cortex. A screw electrode was implanted in the superior nasal sinus to serve as a reference electrode and another screw electrode was implanted in the superior cerebellum as a ground electrode. The electrodes were interfaced with a pedestal and the entire assembly, along with an infusion port for intravenous catheter infusion, was firmly fixed in place with dental acrylic (methyl methacrylate).

[0278] For EEG recording and data acquisition, unipolar EEG data were acquired from each rat using a 32-channel Cereplex μ-headstage (Blackrock Microsystems, Salt Lake City, UT). Signals were digitized at 1 kHz and band-pass filtered between 0.1 and 1 kHz using the Cereplex Direct system paired with Cereplex Direct Software.

[0279] Prior to IV drug administration, a baseline EEG was recorded for 20 min under freely moving, normal behavioral conditions. Immediately after baseline recording, a continuous intravenous infusion of psilocybin (10 mg / kg at a rate of 5 mL / kg / h) was initiated. The infusion continued for 60 min, during which time EEG data were recorded. Post-infusion EEG data was also collected for 120 min for each animal.

[0280] After collecting EEG results, raw EEG signals were exported to MATLAB (version 2021a; MathWorks, Inc., Natick, MA) and downsampled to 500 Hz. Seven 5-min artifact-free EEG epochs were extracted from 1) the baseline period, 2) the beginning, middle, and end of the psilocybin or psilocin infusion period, and 3) the recovery period after psilocybin / psilocin infusion. Prior to analysis, signals were detrended using a local linear regression method in Chronux analysis software with a 10-s window and a 5-s step size (Mitra & Bokil, Observed Brain Dynamics; Oxford University Press, NY, 2008). Line noise (60 Hz) and its harmonics were identified and removed via a multitaper regression approach, while background signal distortion was minimized using the CleanLine EEGLAB plugin (Mullen T., Neuroimaging Informatics Tools Resource, Clear, San Diego:2012). Signals were low-pass filtered at 30 Hz through an order 5 Butterworth filter and divided into non-overlapping 2-second windows for analysis.

[0281] Lempel-Ziv complexity (LZC), a surrogate for neural signal diversity, was used to analyze EEG complexity before, during, and after psilocybin infusion (Lempel and Ziv, IEEE Trans Inform Theory 1976; 22(1):75-81). LZC analysis was performed as previously described (Schartner et al., PLoS One 2015; 10(8):e0133532; Schartner et al., Sci Rep 2017;7:46421; Schartner et al., Neuroscie Conscious 2017;2017(1):niw022; Li and Mashour, Neuroimage 2019;196:32-40; Pal et al., J Neurosci 2020;40(3):605-18).

[0282] After preprocessing, for each 2-s window, we calculated the instantaneous amplitude from the Hilbert transform of the signal, which was then binarized using its average value as the threshold per channel. The LZC values ​​were then averaged over each 5-min epoch. We normalized the original LZC by using the average of the LZC values ​​from n=50 surrogate time series generated by randomly shuffling the binary sequences; this yields the maximum value for a fixed-length binary sequence.

[0283] To investigate whether the complexity as reflected by LZC can be dissociated from the spectral content of the signal, we applied an additional control measure that compared the time-shuffled LZC (above) with LZC normalized by phase randomization; this was obtained from surrogate data in which the power spectrum of the signal was preserved. The resulting normalized LZC measure (LZC N The LZC and LZC N Both LZC and LZC per channel are reported in arbitrary units. N was calculated separately and then averaged across the channels.

[0284] As shown in Figure 2A and Figure 2B, for animals receiving a 60 min psilocybin infusion, the time LZC N Estimation showed an increase in the complexity of the 1-30 Hz signal 5 min after the start of the infusion, which persisted for the duration of the infusion. After the end of the infusion period, the time LZC N The LZC rapidly returned to pre-infusion baseline levels. These changes were consistently observed across the three rats (Figure 2A: individual rats G, H and I; Figure 2B: average). These results support the temporal LZC in human magnetoencephalography (MEG) data. N This is consistent with the observations of others, indicating that psilocybin infusion has similar effects on brain network dynamics in humans and rats.

[0285] In another study, unrestrained rats were infused with 10 mg / kg psilocybin over a 60-minute period, and head-twitch responses (HTRs) were recorded before, during, and after IV administration. In all rats tested, HTRs were consistently observed within 5 minutes of the start of the infusion and persisted throughout the 60-minute infusion period. HTRs ceased immediately after the end of the infusion, typically within 30 minutes after the end of the infusion. HTR results supported a more rapid attainment of dissociative or psychedelic state, which coincided with an increase in systemic plasma psilocin levels, and a rapid exit from the dissociative or psychedelic state after the end of the infusion (e.g., as assessed in Example 1).

[0286] The results demonstrated that IV administration of psychedelics, such as psilocybin or psilocin, resulted in rapid entry into a dissociated state, which could be maintained over the continuous infusion period, as evidenced by changes in EEG measurements. Furthermore, at the end of the IV infusion, the subjects rapidly returned from the dissociated state to baseline EEG measurements. The results demonstrated that IV administration of psychedelics could achieve rapid entry into, maintenance of, and exit from a dissociated state, as shown by EEG, an exemplary non-invasive measurement of brain activity. In addition, the results of head-shake response (HTR) measurements and pharmacokinetic parameters also supported rapid entry into, maintenance of, and exit from a dissociated state.

[0287] The results support the utility of administering psychedelics via intravenous administration, including intravenous infusion, which, in addition to consistent, reproducible and controllable pharmacokinetics and pharmacodynamics, as opposed to oral administration, which has been shown to result in wide variability between subjects, can also be used to rapidly and precisely control the dissociative state in a subject. The results also support the utility of using non-invasive measures of brain activity, such as EEG, to monitor the dissociative state and, depending on the subject's response, determine a therapeutically effective dose, as well as assess, adjust and individualize therapeutic treatment.

[0288] Example 3 : Pharmacokinetics of psychedelics following intravenous bolus administration Plasma psilocin concentrations were assessed over time following an intravenous bolus administration of psilocybin.

[0289] Rats receiving isoflurane anesthesia (ISO+) or not receiving isoflurane anesthesia (ISO-) were administered an intravenous bolus of 10 mg / kg psilocybin administered over 3 minutes. Plasma psilocin concentrations were measured generally as described in Example 2 above. Three minutes after the bolus administration, blood samples were collected periodically over a period of approximately 40 minutes.

[0290] Plasma psilocin levels following a bolus infusion of psilocybin in animals receiving isoflurane anesthesia (ISO+) or not receiving isoflurane anesthesia (ISO-) are shown in Figure 3. The results show a constant plasma concentration and blood levels sufficient to achieve a psychedelic state for at least 40 minutes following intravenous bolus administration.

[0291] Example 4 : Effect of intravenous psychedelics on pain-related disorders This example describes the effects of intravenous administration of psychedelics in animal models of pain on nociception and disorders associated with pain, such as nociceptive pain.

[0292] Chronic pain was induced in rats by injection of formalin into the hind paw. Rats were then administered psilocybin intravenously and assessed for changes in pain sensation over time. The formalin pain model is a translational animal model for chronic nociceptive pain, including fibromyalgia, phantom limb pain, or complex regional pain syndrome (Vanini G., Sleep 2016;39(1):133-42). In the formalin pain model, in addition to experiencing extra pain in the limb injected with formalin, animals experience increased pain sensation (i.e., hyperalgesia) in limbs that have not been injected with formalin (e.g., the contralateral hind paw compared to the formalin-injected hind paw). To assess the potential benefits of psychedelics in nociceptive pain disorders, pain sensation was measured in the contralateral limb. Reduction in pain sensation and duration of pain reduction were investigated after an intravenous bolus of 10 mg / kg psilocybin administered over 3 minutes.

[0293] Two types of pain sensation were measured. First, the Von Frey assay (VFA) was used to measure pain due to pressure applied to the paw (i.e., mechanical allodynia). Specifically, the VFA employed seven filaments: 1, 2, 4, 6, 8, 10, and 15 g. Each filament was applied in ascending order to the plantar surface of the rat's hind paw until it bent. When the filament bent, it was held in place for 5 seconds until the rat withdrew its paw. If the rat was walking, grooming, or sniffing, no stimulation was applied. Stimuli were applied to the injected and contralateral hind paws in five trials each, with at least 30 seconds of rest between stimulations. The minimum amount of force required to elicit a paw withdrawal response in each trial was determined to be the minimum withdrawal threshold for that animal trial. After five trials per paw, the minimum amount of force required to elicit a paw withdrawal response was averaged across all trials to calculate the average minimum withdrawal threshold for each paw.

[0294] The second pain measurement was based on the hot plate assay (HPA). This assay measures withdrawal latency at temperatures that register a painful response (i.e., thermal hyperalgesia). The HPA was started 15-20 min after the completion of the VFA. The hot plate was preheated to a temperature of 52.5 °C. After heating, each animal was placed in a cylindrical tube on the hot plate and the latency to lick the hind paw or observed overt escape behavior (e.g., attempting to jump out of the cylinder) was recorded (Ingram et al., Neruopsychopharmacology 2007;32(3):600-6; Gunn et al., J Pain 2011;12(2):222-7; Hestehave et al., Lab Anim 2016;51(3):264-72). For safety purposes, the maximum time that the rats were on the hot plate was limited to 30 s. After a 15 min rest, the exercise was repeated once more.

[0295] The entire pain study lasted for 30 days for each animal, as described in Table E6 below.

[0296] (Table E6) Inspection Procedures and Schedule TIFF2024510637000008.tif105165

[0297] Figures 4A and 4B show results for VFA comparing the effects of psilocybin or saline injection on withdrawal thresholds (i.e., mechanical allodynia). Withdrawal thresholds for both groups were initially high at baseline (BL) and substantially reduced after formalin injection (FBL). After psilocybin or saline injection on the second day, a significant and acute difference in withdrawal thresholds was observed in both the formalin-injected paw (Figure 4A) and the contralateral paw (Figure 4B), indicating the analgesic properties of psilocybin administration. For other analgesics (e.g., NSAIDs, opioids), this response disappears quickly after drug clearance from the circulation. Rats administered intravenous psilocybin showed reduced pain sensitivity for at least 2 weeks after a single psilocybin administration in both the injected paw (Figure 4A) and the contralateral paw (Figure 4B). In the contralateral paw, a statistically significant increase in withdrawal thresholds was observed for 3 weeks after a single psilocybin administration.

[0298] Similar results were observed for heat sensitivity as indicated by the HPA results, as shown in Figure 5. Following the acute recovery response in withdrawal latency following psilocybin administration, the improved pain sensitivity response persisted for at least 4 weeks compared to saline controls.

[0299] The results demonstrated acute and sustained effects of intravenous administration of psychedelics such as psilocybin or psilocin on mechanical and thermal pain sensitivity. The results showed long-lasting improvements in pain sensitivity, at least up to 4 weeks in an animal model of nociceptive pain. Importantly, effects were also observed in the non-injected contralateral limb, which is closely associated with nociceptive pain. The results support the utility of administering psychedelics by intravenous administration to treat and ameliorate diseases and disorders related to pain sensation, including nociceptive pain disorders, such as fibromyalgia, phantom limb pain, or complex regional pain syndrome.

[0300] Example 5 : Intravenous Administration and Monitoring of Psilocin or Psilocybin in Human Subjects Psychedelics such as psilocin and psilocybin are administered intravenously to human subjects, for example to human subjects with psychological disorders or diseases with psychological components. Monitoring and assessing the entry and exit into dissociative or psychedelic states and the plasma levels of psychedelics. In some aspects, intravenous administration allows the induction of a dissociative state in the subject in less than 30 minutes after administration, and the plasma concentration of psychedelics is maintained at a predetermined value to maintain the dissociative state during the therapeutic window.

[0301] Adult human subjects not concurrently taking any medications that have a primary centrally acting serotonergic effect (e.g., selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs)) are administered one of the following doses of a psychedelic: (1) 2.5 mg of psilocin administered over 60 minutes by intravenous infusion; (2) 5 mg of psilocybin administered over 60 minutes by intravenous infusion; (3) 25 mg of psilocybin administered orally; (4) 2.5 mg of psilocybin administered over 60 minutes by intravenous infusion; (5) 2.5 mg of psilocybin administered orally; (4) 10 mg total psilocin administered as a loading dose at a rate of 1 ml / min infusion for the first 10 or 15 minutes of the infusion, then adjusted to a maintenance dose at a rate of 0.5 ml / min infusion for the remainder of the total infusion time up to 120 minutes; (5) 10 mg total psilocybin administered as a loading dose at a rate of 1 ml / min infusion for the first 10 or 15 minutes of the infusion, then adjusted to a maintenance dose at a rate of 0.5 ml / min infusion for the remainder of the total infusion time up to 120 minutes. In most cases, the total amount of psilocybin or psilocin administered intravenously will be up to about 10 mg / subject.

[0302] In some aspects, the initial dose (i.e., loading dose) is sufficient to induce a dissociated state in the subject within 30 minutes of initiating administration. In some aspects, the maintenance dose is sufficient to maintain the mean plasma concentration of the psychedelic at a predetermined value to maintain the dissociated state during the therapeutic window.

[0303] Subject is monitored before, during and after administration.Subject's vital signs, such as blood pressure (BP), pulse and heart rate (HR), as well as dissociation state, are monitored during and after administration, such as before administration and at one or more of 30, 60, 90, 120, 180, 240, 300 and 360 minutes after administration.Session monitor completes Monitor Rating Scale (MRS) form, which involves rating or scoring several dimensions of subject's behavior and mood, such as the presence / intensity of behavior, signs and reported symptoms, such as calm, yawning, nausea / vomiting, amount of speech, anxiety, drowsiness, crying, restlessness, visual changes, euphoria and unreal feeling.

[0304] In some aspects, blood samples are collected before administration and at one or more of 5, 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after the start of administration, and the plasma concentration of psilocybin and psilocin is determined at these time points.In some aspects, subject is monitored by exemplary non-invasive measurement of brain activity, such as by electroencephalography (EEG).In the case of EEG, subject is monitored before, during and after infusion.

[0305] 6 shows exemplary projected plasma psilocin concentrations in human subjects over 360 minutes following administration of 2.5 mg psilocin administered by intravenous infusion over 60 minutes; 5 mg psilocybin administered by intravenous infusion over 60 minutes; 15 mg oral psilocybin or 25 mg oral psilocybin. The plot also includes plasma concentrations observed from administration of 0.6 mg / kg oral psilocybin as described in Brown et al. (2017). Clin Pharmacokinet. 56(12):1543-1554.

[0306] Subjects are also monitored and evaluated for safety, outcomes related to entering and exiting dissociative states, and treatment outcomes, eg, treatment of psychological disorders or diseases that have a psychological component.

[0307] The present invention is not intended to be limited in scope to the specific disclosed embodiments, which are provided, for example, to illustrate various aspects of the present invention. Various modifications to the described compositions and methods will become apparent from the descriptions and teachings herein. Such variations can be made without departing from the true scope and spirit of the present disclosure and are intended to fall within the scope of the present disclosure.

Claims

1. A pharmaceutical composition for use in a method for treating a psychological disorder in a subject, comprising: The method comprises: administering to a subject having a psychological disorder an intravenous loading dose of a psychedelic, the loading dose comprising a sufficient amount of the psychedelic to induce a dissociative state in the subject less than 30 minutes after administration; and thereafter, maintaining the mean plasma concentration of the psychedelic at a predetermined value by intravenous administration of a maintenance dose of the psychedelic to maintain the dissociated state during the therapeutic window. Including; The psychedelic is psilocybin, psilocin, a cocrystal, coformer, or salt thereof, or a combination thereof; Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the method further comprises obtaining a non-invasive measurement of brain activity from the subject to determine when the subject enters a dissociated state.

3. 3. The pharmaceutical composition of claim 2, wherein the non-invasive measurement of brain activity is selected from electroencephalography (EEG), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), magnetoencephalography (MEG), and optoencephalography (OEG).

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the dissociated state is induced within approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes after the start of administration of the loading dose.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the method further comprises administering a psychedelic to produce a predetermined plasma concentration during administration of the intravenous loading dose or within or about 30 to 120 minutes after the start of administration of the intravenous loading dose.

6. The pharmaceutical composition of claim 5, wherein the predetermined plasma concentration is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 μg / L or a range defined by any of the above, preferably the predetermined plasma concentration is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 μg / L.

7. 7. The pharmaceutical composition of any one of claims 1-6, wherein the intravenous loading dose of the psychedelic is administered over a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 minutes, or a range defined by any of the foregoing.

8. The pharmaceutical composition of any one of claims 1-7, wherein the maintenance dose is administered by intravenous infusion of the psychedelic at a rate of at or about 0.02 mg / min to at or about 1 mg / min.

9. The intravenous loading dose of the psychedelic is administered as a bolus containing about 1 mg to 10 mg of the psychedelic; The pharmaceutical composition of any one of claims 1 to 8, wherein an intravenous maintenance dose of the psychedelic is thereafter continuously administered by infusion at a rate of about 0.02 mg / min to about 1 mg / min to maintain average plasma concentrations during the therapeutic window.

10. A pharmaceutical composition described in any one of claims 1 to 8, wherein the loading dose of the psychedelic is administered at a rate of about 0.1 mL / min to about 2.0 mL / min.

11. A pharmaceutical composition described in any one of claims 1 to 10, wherein the maintenance dose is administered over a period of at least 30, 60, 90, or 120 minutes, or over a period of about 30, 60, 90, or 120 minutes, or over a range defined by any of the foregoing.

12. The intravenous loading dose of the psychedelic is administered by infusion at a rate of about 0.1 mL / min to about 2.0 mL / min over a period of about 1 minute to about 20 minutes; and The pharmaceutical composition of any one of claims 1 to 8, wherein an intravenous maintenance dose of the psychedelic is thereafter continuously administered by infusion at a rate of about 0.1 mL / min to about 2.0 mL / min over a period of about 30 minutes to about 120 minutes to maintain an average plasma concentration during the therapeutic window.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the therapeutic window is from about 30 minutes to about 120 minutes, or is about 60 minutes, or is about 120 minutes.

14. The pharmaceutical composition of any one of claims 1-13, wherein the total amount of psychedelic administered to the subject is up to about 1.0 mg, 1.5 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg per subject, or a range defined by any of the foregoing.

15. 15. The pharmaceutical composition of any one of claims 1-14, wherein the psychedelic is psilocin and the total amount of psilocin administered to the subject is at or about 20 mg, and wherein psilocin is administered as a loading dose over a period of at or about 30 minutes and as a maintenance dose over a period of at or about 180 minutes.

16. A pharmaceutical composition described in any one of claims 1 to 15, wherein the method further comprises a step of providing psychological support to the subject during the treatment window.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the psychological disorder is selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, fibromyalgia, algesic pain, phantom limb pain, hypothalamic-induced obesity, Prader-Willi syndrome, binge eating disorder, anorexia, and irritable bowel syndrome.

18. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the psychological disorder is selected from the group consisting of PTSD, alcohol addiction, drug addiction, treatment-resistant depression, anxiety, end-of-life anxiety, eating disorders, nociceptive pain, phantom limb pain, Prader-Willi syndrome, binge eating disorder, fibromyalgia, and complex regional pain syndrome.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the psychedelic is administered together with at least one additional therapeutic agent.

Images