24978-0935 PSILOCYBIN FOR TREATING PHANTOM PAIN CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Application No. 63/519,099, filed August 11, 2023, which is incorporated herein by reference. TECHNICAL FIELD [0002] The present invention relates to the therapeutic treatment of phantom pain. BACKGROUND [0003] Phantom limb pain (PLP) is a debilitating pain disorder experienced by up to 64% of the 356 million amputees worldwide
1,2. Chronic PLP symptoms are defined by persistent feelings of pain perceptually arising from a missing limb and are often severe, intractable, and unpredictable
3. In upwards of 70% of cases, PLP persists for over 25 years
4 with traumatic amputation being a predictor of pain outcomes
2. There are instances of PLP in individuals with congenital missing limbs
5 and following brachial plexus avulsion injury
6. Functional magnetic resonance imaging (fMRI) studies also point to centralized mechanisms by showing that PLP is facilitated by heightened activation of missing limb representations within the thalamus and primary motor and somatosensory (SI) cortices, and by aberrant processing of sensory inputs in brain regions supporting the sense of “self” (e.g., the default mode network (DMN))
7-13. Importantly, PLP greatly impairs quality of life
14 and current treatments, e.g., opioids and antidepressants, are chronically prescribed and ineffective with some studies reporting as low as 1% lasting benefits
4,15,16. These findings illustrate the dire need for new treatments for PLP. [0004] Literature also shows a moderately high correlation between residual limb pain, experienced in nearly 70% of amputees
41, and PLP. Amputees affected by PLP are more likely to experience residual limb pain than those without PLP
1,4,51. It is postulated that ectopic firing from stump neuromas contributes to central sensitization to sensory inputs and maintained representation of the missing limb in the somatosensory cortex
12. [0005] Upwards of 50% of individuals with PLP report it to be severe, such that it affects their quality of life, describing it with neuropathic qualities including burning, stabbing, and pricking
46. Current treatments for PLP include ketamine
47 and opioids
48,49, which have only
been found to acutely decrease phantom limb pain intensity, and antidepressants such as amitriptyline
50, which appear largely ineffective. Moreover, these treatments present with chronic side effects such as sedation, insobriety, and tachycardia. [0006] There is therefore a need for alternative treatments for phantom pain and PLP that are more effective in treating said pain and alleviating patient discomfort. SUMMARY OF THE INVENTION [0007] The present invention discloses psilocybin compositions and methods of use to prevent or treat phantom pain comprising administering to a subject in need thereof an effective amount of a composition comprising a psilocybin, or a derivative or an analog thereof, to prevent or treat phantom pain of the subject. In embodiments, the invention provides that the phantom pain is phantom limb pain. [0008] In embodiments, the invention provides that the effective amount of psilocybin is administered in doses of between 5 and 50 mg, or about 25 mg. In embodiments, the invention provides that the effective amount of psilocybin is administered as one single dose, or as multiple doses administered on different days. In embodiments, the invention provides that the effective amount of psilocybin is administered on two or more separate days within about 30 days. In embodiments, the invention provides that the effective amount of psilocybin is administered on two or more separate days within about one year. In embodiments, the invention provides that the psilocybin is administered orally. [0009] In embodiments, the invention provides a pharmaceutical composition comprising a psilocybin, or derivative thereof, and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is formulated and used to treat phantom pain. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG.1. Participant screening flowchart. Summary of the number of participants screened, excluded, and who completed all study sessions and data collection time points successfully to be included in analyses.
[0011] FIG. 2. Study design and timeline. Outline of study sessions and associated data collection time points. [0012] FIG. 3. Blood pressure and heart rate changes during dosing session. (Panel A) Systolic and (Panel B) diastolic blood pressure (BP), and (Panel C) heart rate changes across baseline (BL) to 360 minute post-dosing with 25 mg psilocybin (left) and 100 mg placebo niacin (right) at dosing Session 5. Mean is shown via the dashed black line, while individual scores are reported for each participant in color. [0013] FIG. 4. Changes in chronic pain outcomes. Changes in VAS ratings for (Panel A) phantom limb pain intensity and (Panel B) residual limb pain intensity, and brief pain inventory (BPI) (Panel C) severity and (Panel D) interference from baseline Session 1 (green) to the two- (purple) and four-week (orange) online follow-ups in the 25 mg psilocybin versus 100 mg placebo niacin groups. Mean and SEM are shown. Circles illustrate individual participant data points. [0014] FIG.5. Effectiveness of participation in the study. Self-reported effectiveness of participation in the study at the two- (purple) and 4-week (orange) online follow-up time points post-dosing, Circles illustrate individual participant data points. There were no significant differences between psilocybin and niacin groups as revealed by linear mixed models. [0015] FIG. 6. Five-dimensional altered states of consciousness (5D-ASC) ratings. Self-reported scores for 5D-ASC sub-scales immediately following dosing Session 5 just prior to discharge. Scores represent mean score on each of eleven subscales and are out of 100% total. One-way ANOVAs tested for between group differences on each subscale DETAILED DESCRIPTION [0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [0017] Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as commonly understood by one of ordinary skill in the art in the field of the invention. Although any methods and materials similar or equivalent to those
described herein can be used in the practice of the present invention, the exemplary methods, devices, and materials are described herein. [0018] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, 2
nd ed. (Sambrook et al., 1989); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Animal Cell Culture (R. I. Freshney, ed., 1987); Methods in Enzymology (Academic Press, Inc.); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987, and periodic updates); PCR: The Polymerase Chain Reaction (Mullis et al., eds., 1994); Remington, The Science and Practice of Pharmacy, 20
th ed., (Lippincott, Williams & Wilkins 2003), and Remington, The Science and Practice of Pharmacy, 22
th ed., (Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences 2012). [0019] Despite a growing body of evidence that psilocybin can safely relieve depression
19- 23, there have been comparatively fewer studies on its potential as a treatment for chronic pain
30,34. However, as described herein, psilocybin is a safe and feasibly means for reducing pain and discomfort associated with PLP, when coupled with psychological support. [0020] Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) is a classical psychedelic drug that elicits profound changes in sensory perception and the sense of self
17. Growing evidence supports that even a single dose of psilocybin may afford relief from trauma
18, depression
19-23 and body dysmorphia
24, refractory health conditions likewise defined by maladaptive sensory and self-referential processing. The DMN has been proposed as a mechanistic target for psilocybin and its ability to assuage symptoms associated with these disorders
17,25-27. [0021] Treating PLP with a compound (i.e., psilocybin) that has the capacity to modify egocentric appraisals of sensory inputs can be particularly effective given it is a pain condition that is not explicitly mediated by peripheral innervation or injury, but one that rather modifies centrally mediated processes
3. Preliminary preclinical
28, survey-based
29,30, and clinical/case studies
31-34 suggest that psilocybin may be effective at reducing pain and pain-related affective comorbidities.
[0022] As described herein, psilocybin was shown to be well-tolerated in patients, and no serious adverse events, episodes of suicidal ideation, or clinically significant changes in vitals were reported. The peak adverse drug effect was slight to moderate anxiety during dosing with psilocybin, but there were no between group differences on any adverse effect subscale. It was also shown that psilocybin treatment resulted in a 58.9% reduction in weekly phantom limb pain intensity scores as compared to only a 2.8% change in the control group. These findings represent encouraging qualitative evidence for the efficacy of psilocybin for treating PLP. [0023] In embodiments, the invention provides a method of preventing or treating phantom pain comprising administering to a subject in need thereof an effective amount of a psilocybin, or a derivative or analog thereof, to prevent or treat phantom pain of the subject. In embodiments, the invention provides that the phantom pain is phantom limb pain. [0024] In embodiments, the invention provides that the effective amount of psilocybin is administered in doses of between 5 and 50 mg, or about 25 mg. In embodiments, the invention provides that the effective amount of psilocybin is administered as one single dose, or as multiple doses administered on different days. In embodiments, the invention provides that the effective amount of psilocybin is administered on two or more separate days within about five to thirty days. In embodiments, the invention provides that the effective amount of psilocybin is administered on two or more separate days within about thirty days to one year. In embodiments, the invention provides that the effective amount of psilocybin is administered on two or more separate days within about one year to five years. In embodiments, the effective amount of psilocybin is administered repeatedly at periodic intervals, such as once every five years, once every four years, once every three years, once every two years, once every year, once every six months, once every five months, once every four months, once every three months, once every two months, once per month, twice per month, three times per month, or once per week. In embodiments, the invention provides that the psilocybin is administered orally. [0025] In embodiments, the invention provides a pharmaceutical composition comprising a psilocybin, or derivative thereof, and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is formulated and used to treat phantom pain. [0026] Psilocybin and related compounds have been isolated from more than 150 species of mushroom but are primarily found in the following genera: Psilocybe, Panaeolus,
Gymnopilus. The species most commonly referenced in the literature are: Psilocybe cubensis, Psilocybe mexicana, Psilocybe cyanescens, Psilocybe semilanceata; Panaeolus foenisecii; Gymnopilus spectabilis; Psathyrella foenisecii. The family of psilocybin-containing mushrooms grows in tropical and subtropical regions of South America, Mexico, and the United States. [0027] After administration to humans and other mammalian species, psilocybin is dephosphorylated to psilocin (4-hydroxy-N,N-dimethyltryptamine) by alkaline phosphatase and other enzymes in the gastrointestinal tract and other tissues. Psilocin is an active metabolite of psilocybin and is believed to represent the pharmacologically active species in the brain and peripheral tissues after oral or parenteral administration of psilocybin. Psilocybin is therefore believed to act as a prodrug for psilocin. Both psilocybin and psilocin are indole derivatives and are simple tryptamines with close structural and similarities to serotonin. [0028] In embodiments, the invention provides compositions and methods for the administration with effective amounts of psilocybin of between 5 and 50 mg, or about 25 mg. A 25 mg dose of psilocybin likely approximates the circulating levels of psilocin that occur when psilocybin is administered at a 0.3 mg/kg weight-based dose (Brown et al. 2017; Dahmane et al.2020). [0029] It would be understood that the methods of treatment disclosed herein, pertaining to administration of psilocybin to a subject experiencing phantom pain, include administering psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin for the treatment of phantom pain. The use of psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin in the manufacture of a medicament for the treatment of phantom pain, and the use of psilocybin, a prodrug of psilocybin, a metabolite of psilocybin, and/or a prodrug of a metabolite of psilocybin for the treatment of phantom pain is contemplated by the present disclosure. [0030] Without being bound by theory, the invention is believed to work by enhancing visualization and synesthesia which can temporarily relieve the discrepancy between visual and tactile sensory input that likely underlies the pain. In addition, psilocybin activates the 5- HT2A receptor and can induce neuroplasticity, potentially allowing the cortical abnormalities underlying phantom pain to be "re-wired", providing long-lasting relief of pain.
[0031] The invention contemplates the methods described herein using multiple forms of psilocybin, such as crystalline and microcrystalline psilocybin, and other agents that activate the 5-HT2A receptor, including psychedelics like LSD (ergolines), psilocin (tryptamines) and mescaline (phenethylamines), and derivatives and analogs thereof. [0032] In embodiments, the effective amount of psilocybin is between 1 mg to 100 mg. For example, the dose may be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In some embodiments, the dose of psilocybin is between 0.1 mg to 100 mg, 1 mg to 5 mg, or 5 mg to 30 mg. In some embodiments, the dose of psilocybin is 1 mg, 10 mg, or 25 mg. In some embodiments, the dose of psilocybin is in the between 0.001 mg to 1 mg. In some embodiment, the dose of psilocybin is between 100 mg to 250 mg. In some embodiments, the dose of psilocybin is 25 mg. [0033] In some embodiments, a first dose and a second dose of psilocybin are administered to the subject. In some embodiments, the first dose is about 1 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 10 mg. in some embodiments, the first dose is about 25 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 10 mg. In some embodiments, the first dose is about 1 mg and the second dose is about 25 mg. In some embodiments, the first dose is about 10 mg and the second dose is about 1 mg. In some embodiments, the first dose is about 25 mg and the second dose is about 1 mg. [0034] In some embodiments, the first dose or second dose of psilocybin are a “micro- dose”, such as between about 0.05 mg to about 2.5 mg psilocybin. [0035] In some embodiments, the second dose of psilocybin is administered from about one day to about 4 weeks after the first dose. In some embodiments, the second dose is administered about one week after the first dose, two weeks after the first dose, three weeks after the first dose, or four weeks after the first dose. [0036] In some embodiments, the second dose of psilocybin is administered from about one month to about 12 months after the first dose. In some embodiments, the second dose is administered about one month after the first dose, two months after the first dose, three months after the first dose, four months after the first dose, five months after the first dose, six months
after the first dose, seven months after the first dose, eight months after the first dose, nine months after the first dose, ten months after the first dose, eleven months after the first dose, or twelve months after the first dose. [0037] In some embodiments, the second dose of psilocybin is administered from about one year to about five years after the first dose. In some embodiments, the second dose is administered about one year after the first dose, two years after the first dose, three years after the first dose, four years after the first dose, or five years after the first dose. [0038] In some embodiments, multiple doses of psilocybin are administered to the subject. For example, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, or at least 50 doses of psilocybin may be administered to the subject. In some embodiments, the same dose of psilocybin is administered to a subject during each administration. In some embodiments, a different dose of psilocybin is administered to a subject during each administration. In some embodiments, the dose of psilocybin administered to the subject is increased over time. In some embodiments, the dose of psilocybin administered to the subject is decreased over time. [0039] In some embodiments, a method for treating a subject in need thereof includes administering to the subject a therapeutically effective dose of psilocybin. In some embodiments, a method for treating a subject in need thereof includes administering to the subject a therapeutically effective dose of psilocybin in a controlled environment, where the subject is also provided with psychological support. In some embodiments, a method for treating a subject in need thereof includes one or more of the following: (i) administering to the subject a therapeutically effective dose of psilocybin in a controlled environment, where the subject is provided with psychological support, (ii) having the subject participate in one or more pre-administration psychological support session(s); and/or (iii) having the subject participate in one or more post-administration psychological support session(s). [0040] The pre-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a monitor, therapist, or physician. In some embodiments, the psychological support sessions may be group sessions, where more than one subject meets with a single monitor, therapist, or physician. In some embodiments, the psychological support sessions may be group sessions, where more than one subject meets with multiple monitors, therapists, or physicians. In some embodiments, one or more of the subject's
family members or friends may be present at the pre-administration psychological support session(s). [0041] In some embodiments, the goals of the pre-administration psychological session include: (i) establishing a therapeutic relationship between the subject and the monitor, therapist, or physician; (ii) answering the subject's questions and addressing any concerns; and/or (iii) demonstrating and practicing the skills of self-directed inquiry and experimental processing. In some embodiments, the pre-administration psychological support sessions focus on discussion of possible psilocybin effects, and/or preparing subjects for the dosing session by practicing relevant therapeutic techniques, elicit relevant therapeutic goals, building rapport, and/or establishing a therapeutic relationship. During the psychological support session, skills of self-directed inquiry and experimental processing may be demonstrated and/or practiced. [0042] In some embodiments, the subject may be supervised by one or more trained monitors, therapists, or physicians during the course of treatment. The monitor, therapist, or physician supervising the subject during the psilocybin treatment session may be the same as or different from the subject's pre-administration psychological support session(s). The monitor(s), therapist(s), and physician(s) may provide psychological support to the subject as necessary. As used herein, the term "psychological support" refers to any measure(s) taken by the monitor, therapist, or physician during the subject's session(s) to ensure the safety of the subject and maximize the clinical effectiveness of the psilocybin session. For example, the psychological support may be anything done by the monitor, therapist, or physician to: (1) ensure the psychological and physical safety of the subject; (2) allow the subject's subjective experience to unfold naturally within the boundaries of the therapeutic intention set between the subject and the monitor, therapist, or physician; (3) maintain the subject's attention and awareness on the experience, allowing exposure and processing of the subject's emotions; and/or (4) to generate insights and solutions for the resolution of the subject's emotions. In some embodiments, support can be in the form of therapeutic touch, verbal reassurance, guided imagery, and/or relaxation or breathing exercises. In some embodiments, the support may include reminders, encouragement, or active guiding. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject's unique process. [0043] In some embodiments, the psychological support may comprise curious questioning. Curious questioning includes brief, but detailed, questioning of the subject to help the subject shift and sustain their attention towards different levels of cognition and emotions.
Due to the applicability across a range of mental states and within various settings, the technique of curious questioning can typically be used safely and consistently during the psilocybin session(s), regardless of the quality or intensity of the experience of each subject. [0044] In some embodiments, the level of psychological support will vary during the various stages of the subject's psilocybin experience. Because experiences involving ego- dissolution, mystical or spiritual experiences, or peak experiences have been shown to positively correlate with the magnitude and durability of some clinical responses to psilocybin and other psychedelic drugs, the therapist will, in some embodiments, attend to such states with particular care. [0045] In some embodiments, the subject may experience an altered sense of self during the psilocybin experience. In some embodiments, there is a disruption of ego-boundaries, reflecting an altered sense of self or self-awareness. In some embodiments, the disruption of ego-boundaries may reflect a blurring of the distinction between oneself and the outside world. In some embodiments, ego dissolution may occur, which may reflect a sense of unity with the environment or a loss of awareness of the self as an entity that is distinct from the outside world. In some embodiments, there is a non-dual experience, which is a state of consciousness in which the subject-object dichotomy in normal waking consciousness dissolves and is replaced by a unitary experience that is centerless and undivided. In some embodiments, an ego dissolution experience is a spontaneously occurring state of consciousness where there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a compromised sense of self. In some embodiments, a unitive experience is an experience characterized by a sense of unity that exceeds sensory or cognitive comprehension. [0046] In some embodiments, the monitor, therapist, or physician may encourage the subject to wear headphones and/or listen to music. In some embodiments, the headphones reduce outside noise (i.e., noise cancelling headphones). In some embodiments, the music is calming music such as instrumental (e.g., classical) music. In some embodiments, the music includes nature sounds and/or the sound of moving water (e.g., ocean sounds). In some embodiments, the music includes isochronic tones. In some embodiments, the music comprises moments of silence. In some embodiments, the music is emotionally evocative. In some embodiments, the music includes a playlist which mirrors the pharmacodynamics of a typical high-dose psilocybin session. In some embodiments, listening to the music helps the subject to focus on their internal experience.
[0047] During some stages of the psilocybin session, the monitor, therapist, or physician may encourage the subject to face and explore their experience. The monitors, therapists, or physicians may direct subjects to participate in self-directed inquiry and experiential processing to develop a different perspective on their personal challenges and conflicts, and to generate their own solutions. Such self-generated insights are not only therapeutic because of the emotional resolution, but also empowering to the subjects. [0048] As used herein, the term "self-directed inquiry" refers to directing attention to internal states. Subjects are encouraged to be curious about experiences in the present moment, including foreground and background thoughts, emotions, and physical sensations. During the preparation and integration stages, this inquiry may mean asking specific and detailed questions to help direct attention to internal states. However, during the period of drug action, inquiry might simply mean an attitude of openness to inner experiences. [0049] As used herein, the term "experiential processing" refers to a participant's ability to maintain full attention on the experiences that come into awareness through self-directed enquiry. This includes a willingness and ability to be with and/or move in and through even uncomfortable or challenging thoughts, feelings, sensations, or emotions, until discomfort is diminished or resolved. [0050] In some embodiments, the therapist may employ a transdiagnostic therapy. In some embodiments, the transdiagnostic therapy is a Method of Levels (MOL) therapy. In some embodiments, the MOL therapy comprises Self-Directed Enquiry and Experiential Processing. MOL may use brief, but detailed, curious questioning to help subjects shift and sustain their attention towards different levels of cognition and emotions. The emphasis within MOL is on identifying and working with a subject's underlying distress as opposed to just their symptoms. These MOL related methods and techniques can include: (1) self-directed enquiry – directing attention to internal states. Participants are encouraged to be curious about experiences in the present moment, including foreground and background thoughts, emotions, and physical sensations; during the preparation and integration stages, such enquiry can mean asking specific and detailed questions to help direct attention to internal states, although for some embodiments, during the period of drug action enquiry can refer to an attitude of openness to inner experiences; and (2) experiential processing – sustained focus on the experience; refers to a participant's ability to maintain full attention on the experiences that come into awareness through self-directed enquiry. This includes a willingness and ability to be with and/or move
in and through even uncomfortable or challenging thoughts, feelings, sensations, or emotions, until discomfort is diminished or resolved. [0051] In some embodiments, the psychological support includes mindfulness-based therapy or cognitive behavioral therapy (CBT). In some embodiments, the psychological support is informed by a functional theory of human behavior called Perceptual Control Theory. [0052] Occasionally, the subject may try to avoid certain subjective experiences, or will distract themselves while trying to regain cognitive control over the unusual state of their mind. Such distractions may take different forms. For example, the subject may want to engage in a conversation or prematurely describe in detail their experience, visions, or insights. When this occurs, the therapist may remain silent, thereby enabling the subject and their inner experience to direct the course of the psilocybin session. In some embodiments, the therapist may use active listening skills and prompts to encourage the subject to continue focusing attention on present experiences, particularly if the subject engages the therapist in conversation. In some embodiments, the subject may ask to use the restroom or have a drink of water. The sudden and urgent character of such a request may suggest that the subject is trying to avoid emerging in the experience. In such cases, the monitor, therapist, or physician may encourage the subject to stay with the experience by simply redirecting their attention. [0053] In some embodiments, spontaneous movements such as shaking, stretching, or dancing while engaging in the experience is accepted and encouraged, unless the movement appears to be a way to distract themselves from the experience. In some embodiments, if the subject continues to move around, reminders may periodically be given to return to a lying down or actively focused position. [0054] The monitor, therapist, or physician is not required to understand, support, or have an opinion about the nature or content of the subject's experiences, but the therapist may validate and convey openness towards the subject's own view without dismissing or pathologizing any experience. These experiences may provide the subject with a perspective that goes beyond identification with their personal narrative. In some embodiments, the therapist will validate one or more of the subject's experiences. In some embodiments, validation of the experiences simply means acknowledging the courage of opening up to the experience and the possibility that any experience will serve the intention of the session.
[0055] In some embodiments, the monitor, therapist, or physician provides psychological support for approximately 4-8 hours immediately after administration of the psilocybin. In some embodiments, the monitor, therapist, or physician uses guided imagery and/or breathing exercises to calm the subject and/or focus the subject's attention. In some embodiments, the monitor, therapist, or physician holds the subject's hand, arm, or shoulder. In some embodiments, the monitor, therapist, or physician counsels the subject to do one or more of the following: (1) to accept feelings of anxiety, (2) to allow the experience to unfold naturally, (3) to avoid psychologically resisting the experience, (4) to relax, and/or (5) to explore the subject's own mental space. [0056] In some embodiments, the monitor, therapist, or physician avoids initiating conversation with the subject, but may respond if the subject initiates conversation. Active intervention may be kept to a minimum during the treatment experience. In some embodiments, the subject is encouraged to explore their own mental space, and guided imagery may be used to assist relaxation. "Guided imagery" may refer to an exercise where the subject is asked to image a scene, for example, a scene that is calming or safe for the subject. [0057] In some embodiments, the subjects may be encouraged to participate in post- administration integration sessions with their therapist. Integration is a process that involves processing, or embodying, a psychedelic experience within a therapeutic context. The process initially begins by the subject verbalizing and reflecting upon any experience from the psilocybin treatment, and discussing it openly with the monitor, therapist, or physician. Successfully integration of a psilocybin experience accommodates for emotional changes and comprises of translating experiences into new insights, perspectives, and subsequently new behaviors that can be used to benefit the subject's quality of life. New perspectives may in turn influence the subject's current knowledge or values, and lead to new ways of relating to cognitions, emotions, behaviors, and physical experiences. [0058] In some embodiments, a post-administration psychological support session may be held the day after the psilocybin session, two days after the psilocybin session, three days after the psilocybin session, one week after the psilocybin session, two weeks after the psilocybin session, one month after the psilocybin session, three months after the psilocybin session, six months after the psilocybin session, or one year after the psilocybin session.
[0059] In some embodiments, the subject may participate in one, two, three, four, five, six, seven, or eight post-administration psychological support sessions. In some embodiments, the subject may participate in at least two, or at least three, post-administration psychological support sessions. [0060] In some embodiments, the psychological support sessions are individual sessions, where a subject meets one-on-one with a monitor, therapist, or physician. In some embodiments, the psychological support sessions may be group sessions, where more than one subject meets with a single monitor, therapist, or physician. In some embodiments, the psychological support sessions may be group sessions, where more than one subject meets with a multiple monitors, therapists, or physicians. In some embodiments, one or more of the subject's family members or friends may be present at the post-administration psychological support session(s). [0061] In some embodiments, psilocybin is administered to the subject in combination with one or more additional therapies. In some embodiments, the additional therapy administered in combination with psilocybin is mirror therapy, also known as mirror visual feedback. In mirror therapy, an intact limb or body part adjacent to an amputation is placed near or behind a mirror to generate a reflective illusion that the amputated body part is resurrected. In some embodiments, while mirror therapy is performed, the subject will have the experience that an amputated body part is resurrected and is moving. In some embodiments, while mirror therapy is performed, the subject will have the experience that an amputated body part is resurrected and they have regained control of the movement of the amputated body part. In some embodiments, while mirror therapy is performed, the subject will have the experience that an amputated body part is resurrected and they can move the resurrected body part from a painful position to a position that is less painful or pain free. In some embodiments, performing mirror therapy will reduce the signs and/or symptoms of phantom pain. In some embodiments, combining psilocybin and mirror therapy will enhance the ability of psilocybin to reduce the signs and/or symptoms of phantom pain. In some embodiments, combining psilocybin and mirror therapy will produce a greater reduction of the signs and/or symptoms of phantom pain then can be achieved by administering psilocybin alone or mirror therapy alone. [0062] In some embodiments, the invention further includes administering to the subject at least one additional therapeutic to reduce the signs and/or symptoms of phantom pain. In some embodiments, the at least one additional therapeutic is a selective serotonin reuptake inhibitor,
a serotonin and norepinephrine reuptake inhibitor, a norepinephrine uptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, an opioid analgesic, and opiate analgesic, a non-opioid analgesic, a cannabinoid or a cannabinoid receptor agonist, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist. In some embodiments, the at least one additional therapeutic is administered prior to the administration of psilocybin, on the same day as the administration of psilocybin, or after the administration of psilocybin. [0063] In some embodiments, the subject having phantom pain has an additional comorbidity or disorder. In some embodiments, the additional comorbidity or disorder is depression, an anxiety disorder, an obsessive-compulsive disorder, alcoholism, a personality disorder, a cardiovascular disease, a neurological disease, or cancer. In some embodiments, the subject has dementia, Alzheimer's Disease, or Parkinson's Disease. In some embodiments, reducing at least one sign or symptom of the phantom pain in the subject using the methods described herein prevents one or more comorbidities or disorders in the subject. [0064] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by,” or any other variation thereof, are intended to encompass a non-exclusive inclusion, subject to any limitation explicitly indicated otherwise, of the recited components. For example, a fusion protein, a pharmaceutical composition, and/or a method that “comprises” a list of elements (e.g., components, features, or steps) is not necessarily limited to only those elements (or components or steps), but may include other elements (or components or steps) not expressly listed or inherent to the fusion protein, pharmaceutical composition and/or method. [0065] As used herein, the transitional phrases “consists of” and “consisting of” exclude any element, step, or component not specified. For example, “consists of” or “consisting of” used in a claim would limit the claim to the components, materials or steps specifically recited in the claim except for impurities ordinarily associated therewith (i.e., impurities within a given component). When the phrase “consists of” or “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, the phrase “consists of” or “consisting of” limits only the elements (or components or steps) set forth in that clause; other elements (or components) are not excluded from the claim as a whole.
[0066] As used herein, the transitional phrases “consists essentially of” and “consisting essentially of” are used to define a fusion protein, pharmaceutical composition, and/or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of” occupies a middle ground between “comprising” and “consisting of”. [0067] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. [0068] The term “and/or” when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression “A and/or B” is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression “A, B and/or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination. [0069] It is understood that aspects and embodiments of the invention described herein include “consisting” and/or “consisting essentially of” aspects and embodiments. [0070] It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Values or ranges may also be expressed herein as “about,” from “about” one particular value, and/or to “about” another particular value. When such values or ranges are expressed, other embodiments disclosed include the specific value recited, from the one particular value, and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the
antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that there are a number of values disclosed therein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. In embodiments, “about” can be used to mean, for example, within 10% of the recited value, within 5% of the recited value, or within 2% of the recited value. [0071] As used herein, “patient” or “subject” means a human or animal subject to be treated. [0072] As used herein the term “pharmaceutical composition” refers to pharmaceutically acceptable compositions, wherein the composition comprises a pharmaceutically active agent, and in some embodiments further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may be a combination of pharmaceutically active agents and carriers. [0073] The term “combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where one or more active compounds and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals. In some circumstances, the combination partners show a cooperative, e.g., synergistic effect. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.
[0074] As used herein the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia, other generally recognized pharmacopoeia in addition to other formulations that are safe for use in animals, and more particularly in humans and/or non-human mammals. [0075] As used herein the term “pharmaceutically acceptable carrier” refers to an excipient, diluent, preservative, solubilizer, emulsifier, adjuvant, and/or vehicle with which one or more pharmaceutically active agents is administered. Such carriers may be sterile liquids, such as water, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride, buffers, or dextrose may also be a carrier. Methods for producing compositions in combination with carriers are known to those of skill in the art. In some embodiments, the language “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. See, e.g., Remington, The Science and Practice of Pharmacy, 20th ed., (Lippincott, Williams & Wilkins 2003). Except insofar as any conventional media or agent is incompatible with the active compound, such use in the compositions is contemplated. [0076] Sterile compositions are within the present disclosure, including compositions that are in accord with national and local regulations governing such compositions. Pharmaceutical compositions, alone or in combination with other active ingredient(s), described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. A glycosidase, alone or in combination with other active ingredient(s), described herein, and preferably in the form of a pharmaceutical composition, may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.
[0077] Exemplary methods of administering psilocybin include oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal diaphragm and/or cardiac muscle), intradermal, intrapleural, intracerebral, and intra-articular), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), inhalation (e.g., via an aerosol), rectal (e.g., via a suppository), transmucosal, intranasal, buccal (e.g., sublingual), vaginal, intrathecal, intraocular, transdermal, in utero (or in ovo), intralymphatic, and direct tissue or organ injection (e.g., to liver, skeletal muscle, cardiac muscle, diaphragm muscle, or brain). [0078] In some embodiments, the pharmaceutical composition is a parenteral dosage form. In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, more than one dosage form may be administered to the subject at substantially the same time. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be split among multiple tablets or capsules. [0079] For oral administration, psilocybin may be provided in a solid form, such as in a synthetic form of psilocybin, an extract containing psilocybin that is prepared from a natural product, or in the natural form of the dried fruiting body of a mushroom containing psilocybin. In embodiments, psilocybin contained within dried fungi may be provided in doses of from 0.1 to 3.0 grams dried fungi. In embodiments, psilocybin or analogs thereof, alone or in combination with another active ingredient or another active tryptamine derivative such as psilocin and baeocystin that occurs naturally in psilocybin-containing mushrooms, may be provided in a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, psilocybin or analogs thereof, alone or in combination with another active ingredient or another tryptamine derivative, may be formulated to yield a dosage of, e.g., from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and
calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. [0080] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. [0081] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, cyclodextrans, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. [0082] For parenteral use, including, intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, psilocybin, alone or in combination with other active ingredient(s), may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles can include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit- dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
[0083] For nasal, inhaled, or oral administration, psilocybin, alone or in combination with other active ingredient(s), may be administered using, for example, a spray formulation also containing a suitable carrier. [0084] For topical applications, psilocybin, alone or in combination with other active ingredient(s), are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, psilocybin, alone or in combination with other active ingredient(s), may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering a psilocybin, alone or in combination with other active ingredient(s), may utilize a patch formulation to effect transdermal delivery. [0085] One of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, psilocybin, alone or in combination with other active ingredient(s), may be modified to render them more soluble in water or other vehicle. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of the compositions, alone or in combination with other active ingredient(s), in order to manage the pharmacokinetics of the present compositions for maximum beneficial effect in a patient. [0086] As used herein, “therapeutically effective amount” refers to an amount of a pharmaceutically active compound(s) that is sufficient to treat or ameliorate, or in some manner reduce the symptoms associated with diseases and medical conditions. When used with reference to a method, the method is sufficiently effective to treat or ameliorate, or in some manner reduce the symptoms associated with diseases or conditions. For example, an effective amount in reference to diseases is that amount which is sufficient to block or prevent onset; or if disease pathology has begun, to palliate, ameliorate, stabilize, reverse or slow progression of the disease, or otherwise reduce pathological consequences of the disease. In any case, an effective amount may be given in single or divided doses. [0087] As used herein, the terms “treat,” “treatment,” or “treating” embraces at least an amelioration of the symptoms associated with diseases in the patient, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. a symptom associated with the disease or condition being treated. As such, “treatment” also includes situations where the disease, disorder, or pathological condition, or at least symptoms
associated therewith, are completely inhibited (e.g. prevented from happening) or stopped (e.g. terminated) such that the patient no longer suffers from the condition, or at least the symptoms that characterize the condition. [0088] As used herein, and unless otherwise specified, the terms "prevent," "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In certain embodiments, the terms refer to the treatment with or administration of a compound or dosage form provided herein, with or without one or more other additional active agent(s), prior to the onset of symptoms, particularly to subjects at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. In certain embodiments, subjects with familial history of a disease are potential candidates for preventive regimens. In certain embodiments, subjects who have a history of recurring symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment." [0089] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.. [0090] A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention. EXAMPLES [0091] Described herein is a placebo-controlled, double-blinded, and randomized study comparing oral psilocybin (25 mg) to placebo niacin (100 mg), both coupled to psychological support, for PLP. The primary outcome was to determine the safety, tolerability, and feasibility of psilocybin as a PLP treatment. The main secondary efficacy outcome was self-reported weekly phantom limb pain intensity ratings (visual analog scale (VAS)) at baseline and 2- weeks post-dosing. Given the postulated role of residual limb pain (i.e., “stump” pain at the
site of the amputation) as an ancillary peripheral driver of PLP
3, weekly residual limb VAS pain intensity ratings were assessed at these same time points alongside standardized chronic pain surveys for pain severity and its interference with daily activities and life satisfaction (Brief Pain Inventory (BPI)). Exploratory outcomes were a 4-week pain measure time point, a VAS for expectation and effectiveness of participation in the study at baseline and at 2- and 4- weeks post-dosing, respectively, the Five-Dimensional Altered States of Consciousness (5D- ASC) to assess subjective effects of psilocybin and niacin immediately following dosing, and a blinding questionnaire administered post-dosing to assess for placebo-effects. [0092] Psilocybin was found to be associated with statistically significant and sustained reductions in weekly residual limb pain intensity of 79.9% and 65.2% at 2- and 4-weeks post- dosing, respectively. The niacin group, conversely, reported increases of 4.12% and 23.3% in residual limb pain at 2- and 4-weeks, respectively. Neuroma and nerve damage at the stump characterized by localized scarring and hyperalgesia can hinder prosthetic use and/or satisfaction
52,53. This in turn may aid in reduced prosthetic embodiment, i.e., a reduction in the extent to which a prosthetic is experienced as “self”, which is correlated with higher PLP
54. Reflecting this, residual limb pain has been identified as key determinant of health-related quality of life in amputees
14. Pain interference with quality of life was also observed to have decreased by 29.9% from baseline to 4-weeks following psilocybin. At 4-weeks, the mean VAS rating for how effective the psilocybin group rated their study participation was 8.32 (SE = 1.07) out of 10. [0093] For pain severity, 2/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = -30.2%, SE = 21.7, Cohen’s d = -0.88; 95% CI, -2.41 to 0.65) compared to 1/4 of participants in the niacin group (M = 26.8%, SE = 39.2%, Cohen’s d = 0.48, 95% CI, -1.27 to 2.24). Results from the 4-week follow- up revealed that 3/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline (M = -45.3%, SE = 25.4%, Cohen’s d = -1.13, 95% CI, -2.70 to 0.44) compared to 2/4 in the niacin group (M = 12.8%, SE = 49.4%, Cohen’s d = 0.18; 95% CI, - 1.55 to 1.92). [0094] For pain interference, 1/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = -13.9%, SE = 24.0, Cohen’s d = -0.37; 95% CI, -1.84 to 1.10) compared to 1/4 participants in the niacin group (M = 4.29%, SE = 35.6%, Cohen’s d = 0.09; 95% CI, -1.65 to 1.82). Results from the 4-week
follow-up revealed that 2/5 participants in the psilocybin group (M = -29.9%, SE = 21.3%, Cohen’s d = -0.89; 95% CI, -2.41 to 0.64) demonstrated clinically meaningful reductions from baseline compared to 1/4 in the niacin group (M = 29.5%, SE = 68.1%, Cohen’s d = 0.31; 95% CI, -1.43 to 2.05). [0095] Collectively, these results suggest psilocybin may target nociceptive and centralized, neuropathic-related pain mechanisms in amputees to lead to analgesia and improvements in well-being several weeks after a single dose. This is in line with recent rodent literature showing psilocybin-induced relief of formalin-induced mechanical hypersensitivity for 28 days post-treatment
28. While psilocybin may reduce phantom and residual limb pain, antidepressants show little effectiveness for treating these pain dimensions despite comparative studies showing that antidepressants and psilocybin are similarly efficacious for depression
20. It may be that direct modulation of serotonin 2A receptors on neurons in the dorsal root ganglion
55, thalamus, and somatosensory and/or medial prefrontal cortices
56 via psilocybin agonism, rather than inhibition of serotonin reuptake in these sensory and affective pain- processing areas of the nervous system, is an important pharmacological target for relieving PLP. Such modulation may also lead to changes in synaptic grey matter, as evidenced in rodent studies on psychedelics
57,58, in populations of neurons within brain areas wherein representation of the phantom limb is maintained (e.g., SI
9), which could have functional implications relevant to pain processing. Design, Setting, and Participants [0096] This placebo-controlled, double blind, randomized pilot study comparing psilocybin to niacin for PLP was conducted between October 3, 2022, and February 14, 2024, at the Altman Clinical and Translational Research Institute and Keck Center for Functional Magnetic Resonance Imaging, at the University of California San Diego. Participants were aged 18 – 75 years, had amputation of only one extremity, phantom limb pain intensity of ≥ 3 out of 10 on the visual analog scale (VAS), and passed a physical, psychiatric, hepatic, renal, and cardiovascular screening. Exclusion criteria included current use of antidepressants, antipsychotics, opioids, and illicit substances, psychedelic use in the past 3 months, and history of psychosis or mania. Of the 159 amputees approached for the study, 9 passed screening and were randomized. Safety outcomes were assessed from baseline to the end of the study. Self- reported pain was assessed at baseline and at 2- and 4-weeks post-dosing.
Interventions [0097] Interventions were a single oral dose of either 25 mg psilocybin or 100 mg niacin in identical-appearing capsules, each coupled to psychological support. Following safety and pain assessments at a baseline session, study therapists met with participants for 3 preparatory sessions prior to dosing, supported them throughout their 8-hour dosing session, and met with them for a subsequent integration session following administration of safety assessments the day after dosing. Outcomes and Measures [0098] Primary safety outcomes were the Columbia-Suicide Severity Rating Scale (C- SSRS), and serious adverse events assessed at all study time points; changes in blood pressure (BP) and heart rate (HR) and peak adverse drug effects (anxiety, paranoia, nausea, psychological and physical discomfort) via the Monitor Rating Questionnaire (0 = none, 1 = slight, 2 = moderate, 3 = strong, 4 = extreme) assessed during the dosing session; and headache assessed the day after dosing. Secondary efficacy outcomes were changes in phantom and residual (i.e., “stump”) limb pain experienced in the past week (VAS; “0” = “no pain intensity at all” to “10” = “most intense pain imaginable”), and pain severity and interference (Brief Pain Inventory (BPI)) at baseline and at 2- and 4-weeks post-dosing. Linear mixed models and one- way analysis of variance were employed to analyze data. Study research assistants collecting and analyzing data, physicians, therapists, and sponsors were blinded to group assignment. Study Design Overview and Oversight [0099] This placebo-controlled, double-blinded, and randomized study tested the safety, feasibility, and efficacy of oral psilocybin (25 mg) compared to placebo (niacin, 100 mg) for amputees with PLP. Both groups received concurrent psychological support. Enrollment began on October 3, 2022, and concluded on February 14, 2024. The study was pre-registered on ClinicalTrials.gov and approved by the United States Food and Drug Administration, the California Research Advisory Panel, and the University of California, San Diego (UCSD) Institutional Review Board. Psilocybin and niacin were provided by the Usona Institute (Madison, WI), as single opaque capsules
22. [00100] Study inclusion criteria were an age range of 18 – 75 years, amputation of only one extremity, phantom limb pain intensity of ≥ 3 out of 10 on the VAS, and fluency with English.
Participants were excluded for concurrent use of antidepressants and antipsychotics for an axis I diagnosis, opioids, and/or illicit substances, use of psychedelics in the past three months, presence of a chronic pain type indistinguishable from phantom limb pain, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria for bipolar disorder, schizophrenia, or other psychotic disorders or having a first-degree relative with a history of these disorders, suicidal ideation, history of seizure or migraine, active substance use disorder, neurological conditions resulting in altered cognition, uncontrolled cardiovascular disease or hypertension (SBP > 140 mmHg or DBP > 90 mmHg), QTc prolongation (QTc > 0.045 for man, QTc > 0.047 for women), history of stroke or angina, clinically significant electrocardiogram abnormality, artificial heart valve, severe renal impairment (GFR < 30 mL/min/1.73 m2 ), myocardial infarction within the last 12 months, Child-Pugh class B or higher, and evidence of severely compromised hepatic function. Female participants of child-bearing age had to pass a pregnancy exam and practice a viable form of birth control throughout study participation. All participants were compensated $600 upon completing the study. [00101] In total, 159 individuals expressing study interest were telephone screened. Of these individuals, 16 were scheduled for a clinic screening visit, two of which missed their appointments and did not reschedule, and one of which reported contraindicative drug use (methamphetamine). Thus, 13 subjects signed consent. However, six of these subjects failed screening due to MRI contraindications (n = 3), concomitant medication contraindications (n = 2), and psilocybin use during the screening period (n = 1). Of the six subjects that failed screening, one was re-screened to complete the behavioral-only study arm, and one was re- screened following tapering off an antidepressant medication. Thus, 9 subjects (7 White) completed the study (see FIG. 1). Mean age (SD) of participants was 37 (13) years. Chronic PLP (≥ 3 out of 10 on the VAS) diagnosis was confirmed via medical records (mean duration (SD) = 4.40 (4.42) years). Overall, 5 participants received psilocybin (4 lower limb, 1 index finger amputation; 2 female) while 4 received niacin (3 lower limb, 1 index finger amputation; 2 female) in a non-crossover design, and 1/5 psilocybin and 1/4 niacin group participants, respectively, reported no prior use of psychedelics.
Table 1. Study Demographics. ID Age Gender Race Amputation Cause Amputation Phantom Height Weight Employment Income Prior Date Limb Status Psychedelic Pain Use
Study Procedures [00102] The study procedures are summarized as follows (see FIG. 2). Participants were enrolled in the study after being evaluated by study physicians via a physical examination, blood work, urinalysis, electrocardiogram, and psychiatric assessment during a screening visit at the ACTRI. Participants then reported to the UCSD Center for fMRI for baseline assessments. At baseline, safety and pain assessments and a 10-minute BOLD resting state fMRI scan (fMRI data not shown) were acquired. Nine participants were then randomized to
either a 25 mg psilocybin or 100 mg niacin group by a study coordinator who did not collect any data. All volunteers participated in 3 intensive preparatory sessions where two trained monitors prepared them for the dosing session, established rapport and trust, and discussed their treatment expectations and intentions. Participants arrived at the ACTRI (9:00 AM) for the dosing session. After heart rate (HR), blood pressure (BP), suicidality, and urinalysis were assessed, participants orally ingested a capsule containing 25 mg of psilocybin or 100 mg of niacin at ~10:00 AM and were supervised by their two monitors for the duration of the session. Adverse drug effects, HR, and BP were continuously assessed. The session was completed by 5:00 PM. One day after dosing, volunteers reported back to the Keck Center for fMRI and performed the same procedures as described in the baseline session (Session 1) and headache was assessed. Participants met with monitors to discuss their experience during the dosing session. Pain assessments were completed via the Research Electronic Data Capture (REDCap)
35 at 2- and 4-weeks post-dosing. [00103] The research methods are described in greater detail below. [00104] Recruiting methods. Recruitment methods included (1) University of California, San Diego (UCSD) physician referrals; (2) the ResearchMatch website; (3) a website maintained by the study investigators; (4) social media and amputee-based publications; (5) flyers placed throughout Southern California, and (6) pre-screening electronic medical records of UCSD Health clinics. All methods were approved by UCSD’s Institutional Review Board. [00105] Phone and in-person screening. Participants first passed an initial phone screen interview conducted by a trained study research assistant before reporting to the ACTRI for an in-person screening. Here, they first provided informed consent and were then trained to rate their phantom and residual limb pain using a digital VAS. A medication questionnaire and the Customary Drinking and Drug Use Record
67 were administered via Research Electronic Data Capture (REDCap)
68, followed by a urine screen for illicit drug, opioids, and pregnancy (if applicable). Participants then met with a study physician or nurse practitioner for a physical and a psychiatric evaluation wherein the Mini-International Neuropsychiatric Interview 7.0.2 (MINI)
69 and Columbia-Suicide Severity Rating Scale (C-SSRS)
70 were administered. Heart rate (HR) and blood pressure (BP) readings were acquired, and a nurse collected an ECG as well as ≤ 5 mL blood sample for basic metabolic and liver panels, hemogram/platelet count, and prothrombin time. Finally, participants underwent an MRI safety screening and psychophysical training wherein they rated the pain intensity and unpleasantness of heat stimuli
(ranging from 35°C to 48°C) delivered to their forearm via an MRI-compatible thermal sensory testing device (QST.Lab, Strasbourg, France) fitted with a 45mm surface area probe. Results from the in-person screening were reviewed by study physicians to determine eligibility. [00106] Baseline (Session 1): Eligible participants next reported to the UCSD Keck Center for fMRI for baseline assessments. Volunteers completed a battery of pain and safety assessments. While only these data were analyzed in the current manuscript, participants also completed a battery of additional behavioral surveys, underwent pain tolerance testing, a 10- minute blood-oxygen-level dependent (BOLD) resting state fMRI scan, and were administered two fixed-order heat series delivered via an MRI-compatible thermal probe placed on the back of their calf during acquisition of BOLD fMRI: 1) “heat 1” = eight, 10 second 46°C heat stimuli interspersed with 30 second 35°C neutral stimuli followed by; 2) “heat 2” = eight, 10 second 48°C heat stimuli interspersed with 30 second 35°C neutral stimuli. Participants provided ratings for pain intensity and unpleasantness corresponding to the heat by controlling a digital VAS presented on a projector screen following each heat series with a “button box”. Nine participants were next randomized to their respective group by a study coordinator who did not collect any data. The participant that failed the prior MRI safety screening participated in the behavioral-only arm and did not undergo acquisition of fMRI data at this or the post-dosing MRI session. [00107] Preparatory Sessions (Session 2 - 4): Participants next met with 2 study therapists (monitors) for 3 intensive preparatory sessions (i.e., psychological support), which collectively lasted no more than 8 hours total, at the UCSD La Jolla Medical Campus (Sessions 2 & 4) and via a secure online Zoom link (Session 3). Primary monitors were licensed physicians or mental health providers with a doctoral degree (M.D., Ph.D., Psy.D., D.O.) and had at least one year of clinical experience in a mental health setting, attended a training program for psychedelic therapists, and/or had direct experience working in United States Food and Drug Administration-sponsored trials on psychedelic therapy. The secondary monitors, supervised by the primary monitor, had at least a bachelor’s degree in a mental health-related discipline and a year of experience working in a mental health setting. One primary monitor was always present for study sessions where they provided support, and female participants were matched with at least one female primary monitor. The goal of these preparatory sessions was to establish rapport and trust between the participants and monitors. During the preparatory sessions, monitors explained what will happen during the dosing session, including the range
of experiences produced by psilocybin and niacin. The participant's life history and current life situation were reviewed, including the events leading up to and following the amputation. Expectations and intentions for the dosing session were also discussed alongside the participant's values and goals. The participants were instructed to notify the monitors if they experienced anxiety, fear, or confusion during the dosing session, and to have a light breakfast the morning of the dosing session. At Session 4, participants met with monitors in the ACTRI hospital room where the dosing sessions occur, to acclimate with the setting wherein they would orally ingest psilocybin or niacin. This room was comfortably furnished and decorated in the same fashion as on the day of the dosing session. It was free from extraneous medical or research equipment and did not contain any potentially dangerous objects. Collectively, these approaches reduce the incidence of psychedelic-induced adverse reactions and have been used successfully in multiple psilocybin clinical research trials
71. [00108] Dosing Session (Session 5): Participants arrived at the ACTRI (9:00 AM) and were greeted by their 2 monitors who escorted them to the dosing session room and remained with them until discharge. After HR, BP, suicidality, urinalysis, pregnancy, behavioral assessments (data not shown), and a VAS for expectation of study participation were assessed, participants orally ingested (with a glass of water) an identical-appearing capsule containing 25 mg of psilocybin or 100 mg of niacin delivered by study pharmacists at ~10:00 AM. Niacin was chosen as an active placebo due to its inclusion is several clinical trials on psilocybin and its ability to induce similar physiological effects (e.g., flushing). Next, participants were instructed to lie down on the bed, wear eyeshades, and listen a standardized music playlist through headphones while focusing their attention inward. Monitors were non-directive in their interactions with participants, only providing gentle reassurance in the event of psychologically difficult experiences. Participants were free to sit up, take off the eyeshades, and/or talk to the monitors as needed. A medical station adjacent to the ACTRI dosing session room housed all study rescue medications (benzodiazepines, antipsychotics, labetalol, nitroglycerin, Zofran). Adverse drug effects (anxiety, paranoia, nausea, and psychological and physical discomfort) and vitals were continuously assessed throughout the session. A study physician was always within 5-minutes walking distance of the dosing session room. Approximately six hours after dosing, study team members contacted a predetermined chaperone to escort the participant home. Prior to leaving the clinic at approximately 5:00 PM, participants filled out additional behavioral assessments (data not shown) and the Five-Dimensional Altered States of Consciousness (5D-ASC)
72 questionnaire. Once the study team established that the participant
was back to their psychological and physiological baseline, they were discharged from the ACTRI in the care of their chaperone. [00109] Post-dosing Session (Session 6): One day after the dosing session, participants reported back to the Keck Center for fMRI and performed all the same procedures as described in the baseline session (Session 1). Additional safety metrics were also assessed, including headache, and a blinding questionnaire was administered to determine if participants could correctly identify group assignment. [00110] Integration (Session 7): After the post-dosing Session 6, participants met with their monitors to discuss their experience during the dosing session and receive psychological support in integrating said experience into the ongoing context of their life situation. [00111] Follow-up: A battery of pain assessments and a VAS for effectiveness of participation in the study were completed online via REDCap at 2- and 4-week post-dosing. Additional behavioral data matched to baseline were collected at both time points but likewise were not analyzed. Safety Assessments [00112] Vitals (HR, BP) and adverse events were assessed throughout the study alongside the C-SSRS
36, which was administered at every study visit to monitor for suicidal ideation. During the dosing session, study monitors recorded HR, BP and peak adverse drug effects (anxiety, paranoia, nausea, and psychological and physical discomfort; 0 = none, 1 = slight, 2 = moderate, 3 = strong, 4 = extreme) via the Monitor Rating Form at 0, 30, 60, 90, 120, 180, 240, 300, and 360 min relative to ingestion of psilocybin or niacin. To obtain peak drug effect scores, the mean of the two monitors’ ratings at each time point was calculated, and the maximum rating for each participant subscale at each time point was utilized to report mean of all max scores per subscale. Results thus represent the most aversive reports
37. Headache incidence was assessed the day after dosing, given reports of transient headache following psilocybin use
38. [00113] A summary of all safety and efficacy assessments administered at each time point from baseline to follow-up is shown in FIG.3. Efficacy Assessments
[00114] Phantom limb and residual limb pain intensity: Phantom limb pain intensity was the main efficacy outcome assessed at baseline and 2-weeks post-dosing. Participants rated the intensity of their phantom limb pain experiences in the past week using a digital VAS
39 (0 = “no pain intensity at all” to 10 = “most intense pain imaginable”). Using the same scale, participants also rated the intensity of their residual limb (stump) pain (emanating from the site of their amputation), a distinct dimension of pain experienced in amputees
40, at the same time points. All participants enrolled verified they could distinguish between these two pain dimensions. Participants were asked to provide ratings for pain experienced in the past week as opposed to acutely (i.e., “right now”) to fully capture the intermittent and variable nature of phantom limb pain given reports that only ~10% of individuals with PLP experience it constantly
41. [00115] Brief pain inventory: Phantom pain can interfere with physical functioning and daily activities. Hence, measures of physical functioning at baseline and at a 2-week online follow-up were similarly assessed by employing the Brief Pain Inventory (BPI)
42, a standardized chronic pain survey that in addition to a metric for pain severity contains 7 items that assess pain interference with general activity, mood, walking ability, work, relationships with others, sleep, and enjoyment of life. Exploratory Outcomes [00116] Four-week pain assessments: To assess the longitudinal analgesic outcomes, VAS phantom and residual limb pain and BPI pain severity and interference were also collected at 4-weeks post-dosing. [00117] Expectation/effectiveness: Participants were asked to “provide a rating for how effective you feel the experience of participating in this study will be/was” (VAS; 0 = “not effective at all” to 10 = “as effective as possible”). Expectation was measured the morning of Session 5 prior to dosing with psilocybin or niacin. Effectiveness was measured at 2- and 4- week online follow-ups. [00118] Five-dimensional altered States of consciousness: The 5D-ASC questionnaire assesses the major dimensions of altered states of consciousness in an etiology-independent manner and has been used in numerous studies to assess the subjective response induced by psychedelics
43. The 5D-ASC was administered to both groups following dosing, just prior to discharge from the clinic.
[00119] Blinding questionnaire: In line with psychedelic unblinding guidelines, participants were asked at the beginning of Session 6 (post-dosing), “which treatment do you think you received?”. Their choices were A) psilocybin, B) niacin, or C) “don’t know”
44. Successful blinding was characterized as responding “don’t know” and incorrect guesses, while correct guesses were characterized as unblinded. Statistical Analysis [00120] Analyses were carried out in R statistical software (version 4.3.1). A linear mixed- effects model was fit to predict all outcome measures that included multiple data collection time points by group, time point, and the group*time point interaction (LME4 package). Group and time point were dummy coded and mean centered. Participant was included in the model as a random effect. Significant main effects and interactions were assessed with nested model comparisons. Post-hoc pairwise comparisons of estimated marginal means were performed using the emmeans package with the Tukey method for adjustment. One-way analysis of variance (ANOVA) tested for group differences in peak adverse drug effects, expectation for and effectiveness of study participation, and 5D-ASC subscales. For all analyses, p < .05 was considered statistically significant. Of note, one participant in the niacin group did not provide VAS ratings for weekly phantom and residual limb pain at baseline. A power analysis was not performed given that the purpose of this study was to provide an initial impression of safety, tolerability, and efficacy of psilocybin for PLP to inform future fully powered clinical trials. Safety and Feasibility [00121] There were no increases in suicidal ideation at any time point, or clinically significant changes in HR or BP (i.e, exceeding 140/90 mmHg for >20 min) during the dosing session (see FIG. 3; Table 2). Moreover, there was no significant interaction between group and time point ( ^
2(1) = 1.27, p = .23, ^
2 = 0.02; 95% CI, 0 to 0.12) on systolic BP, or significant main effects of group ( ^
2(1) = 0.82, p = .37, ^
2 = 0.09; 95% CI, 0 to 0.52) or time point ( ^
2(1) = 0.003, p = .96, ^
2 = 0.0005; 95% CI, 0 to 0.02). Similarly, there was no significant interaction between group and time point on diastolic BP ( ^
2(1) = 2.52, p = .11, ^
2 = 0.04; 95% CI, 0 to 0.16), or significant main effects of group ( ^
2(1) = 0.25, p = .62, ^
2 = 0.0395%; CI, 0 to 0.44) or time point ( ^
2(1) = 0.44, p = .51, ^
2 = 0.006; 95% CI, 0 to 0.09). For HR, there was no significant interaction between group and time point ( ^
2(1) = 0.49, p = .48, ^
2 = 0.007; 95% CI, 0 to 0.09), significant main effect of group ( ^
2(1) = 1.70, p = .19, ^
2 = 0.17; 95% CI, 0 to
0.60), or significant main effect of time point ( ^
2(1) = 2.70, p = 0.10, ^
2 = 0.04; 95% CI, 0 to 0.16). [00122] There were no significant differences between groups on any peak adverse drug effect subscale (Table 2). The highest rating observed was anxiety in the psilocybin group (mean (SD) = 1.60 (0.40)) and no participants required concomitant treatment with anxiolytic medications. One participant experienced nausea that persisted after the acute effects of psilocybin subsided and was successfully treated with Zofran and discharged. This participant reported feeling no nausea at the post-dosing session (Session 6) the next day. In the psilocybin group, 3/5 participants reported headache at Session 6 that was transient and thereafter subsided, compared to 0/4 participants in the niacin group. Overall, adverse events were expected, mild, and/or transient, and no serious adverse events occurred. Table 2. Safety and Tolerability of Psilocybin and Niacin. Psilocybin Niacin
Adverse Events oups on
any physiological measures or peak effects as assessed via Monitor Ratings. Shown is mean (SD) for Physiological Measures and Monitor Ratings and number of participants (%) for Adverse Events. Chronic Phantom Limb Pain [00124] Linear mixed models revealed no significant interaction between group and time point ( ^
2(1) = 0.14, p = 0.70, ^
2 = 0.007; 95% CI, 0 to 0.24) on phantom limb pain intensity in the past week (FIG. 4, Panel A). There was a significant main effect of group ( ^
2(1) = 8.40, p = .0038, ^
2 = 0.59; 95% CI, 0.05, to 0.82), driven by between-group differences at baseline. Post-hoc analyses revealed that participants in the psilocybin group (m = 3.75, SE = 0.80) had significantly lower scores (t(7) = 3.24, p = .014, Cohen’s d = 1.38; 95% CI, 0.42 to 2.35) than those in the niacin group (m = 7.71, SE = 0.93). There was no significant main effect of time point ( ^
2(1) = 1.33, p = .25, ^
2 = 0.07; 95% CI, 0 to 0.37). [00125] Of note, 4/5 participants in the psilocybin group demonstrated clinically meaningful decreases (≥ 30%)
45 in weekly phantom limb pain intensity from baseline to 2-weeks post- dosing (M = -58.9%, SE = 26.6%, Cohen’s d = -1.40; 95% CI, -3.03 to 0.23) compared to 0/3 participants in the niacin group (M = -2.77%, SE = 3.38%, Cohen’s d = -0.67; 95% CI, -3.00 to 1.66). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin
group (M = -14.8%, SE = 40.8%, Cohen’s d = -0.23; 95% CI, -1.69 to 1.23) and 1/3 participants in the placebo group (M = -17.4%, SE = 21.9%, Cohen’s d = -0.65; 95% CI, -2.98 to 1.68) demonstrated clinically meaningful decreases. Residual Limb Pain [00126] Linear mixed models revealed a significant interaction between group and time point ( ^
2(1) = 9.31, p = .002, ^
2 = 0.41; 95% CI, 0.06 to 0.66) on residual limb pain intensity in the past week (FIG.4, Panel B). Post-hoc analyses revealed that, for participants in the niacin group, there were no differences in pain intensity scores across time points. However, for participants in the psilocybin group, their scores were significantly lower versus baseline at the 2-week (t(13) = 8.23, p < 0.001, Cohen’s d = 3.21; 95% CI, 1.00 to 5.41) and 4-week (t(13) = 6.60, p < .001, Cohen’s d = 1.73; 95% CI, 0.02 to 3.44) follow-ups. Scores did not differ significantly between 2- and 4-weeks (t(13) = -1.63, p = .27). There was no significant main effect of group ( ^
2(1) = 0.47, p = .49, ^
2 = 0.05; 95% CI, 0 to 0.48) or time point ( ^
2(1) = 2.35, p = .13, ^
2 = 0.13; 95% CI, 0 to 0.45). [00127] Additionally, 5/5 of participants in the psilocybin group demonstrated clinically meaningful reductions in residual limb pain from baseline to 2-weeks post-dosing (M = -79.7%, SE = 7.11%, Cohen’s d = -7.10; 95% CI, -11.04 to -3.16) compared to 0/3 participants in the niacin group (M = 4.12%, SE = 7.14%, Cohen’s d = 0.47; 95% CI, -1.83 to 2.77). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin group (M = -65.2%, SE = 16.4%, Cohen’s d = -2.52; 95% CI, -4.47 to -0.57) demonstrated clinically meaningful reductions from baseline compared to 0/3 in the niacin group (M = 23.3%, SE = 14.3%, Cohen’s d = 1.34; 95% CI, -1.17 to 3.84). Brief Pain Inventory [00128] Linear mixed models revealed no significant interaction between group and time point ( ^
2(1) = 2.18, p = .14, ^
2 = 0.11; 95% CI, 0 to 0.42) or main effects of group ( ^
2(1) = 0.47, p = .49, ^
2 = 0.05; 95% CI, 0 to 0.48) or time point ( ^
2(1) = 2.73, p = .10, ^
2 = 0.14; 95% CI, 0 to 0.45) on pain severity (FIG. 4, Panel C). A similar pattern was found for pain interference (FIG.4D), i.e., no interaction between group and time point ( ^
2(1) = 1.74, p = .19, ^
2 = 0.09; 95% CI, 0 to 0.4), or significant main effects of group ( ^
2(1) = 1.32, p = .25, ^
2 = 0.14; 95% CI, 0 to 0.57) or time point ( ^
2(1) = 0.005, p = .95, ^
2 = 0.0003; 95% CI, 0 to 0.08).
[00129] For pain severity (FIG. 4, Panel C), 2/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = - 30.2%, SE = 21.7, Cohen’s d = -0.88; 95% CI, -2.41 to 0.65) compared to 1/4 of participants in the niacin group (M = 26.8%, SE = 39.2%, Cohen’s d = 0.48, 95% CI, -1.27 to 2.24). Results from the 4-week follow-up revealed that 3/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline (M = -45.3%, SE = 25.4%, Cohen’s d = -1.13, 95% CI, -2.70 to 0.44) compared to 2/4 in the niacin group (M = 12.8%, SE = 49.4%, Cohen’s d = 0.18; 95% CI, -1.55 to 1.92). [00130] For pain interference (FIG. 4, Panel D), 1/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = - 13.9%, SE = 24.0, Cohen’s d = -0.37; 95% CI, -1.84 to 1.10) compared to 1/4 participants in the niacin group (M = 4.29%, SE = 35.6%, Cohen’s d = 0.09; 95% CI, -1.65 to 1.82). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin group (M = -29.9%, SE = 21.3%, Cohen’s d = -0.89; 95% CI, -2.41 to 0.64) demonstrated clinically meaningful reductions from baseline compared to 1/4 in the niacin group (M = 29.5%, SE = 68.1%, Cohen’s d = 0.31; 95% CI, -1.43 to 2.05). Table 3. Mean Scores for Pain Outcomes. VAS = Visual analog scale; PLP = phantom limb pain; BPI = Brief Pain Inventory; mean (SD) is shown for all groups and time points. Expectation and Effectiveness
[00131] A One-way ANOVA revealed no significant main effect of group (F(1,7) = 0.95, p = .36, Cohen’s d = -0.65; 95% CI, -2.28 to 0.97) on expectation effects. Participants in the niacin group (m = 7.35, SE = 1.56) and psilocybin group (m = 8.74 , SE = 0.36) had similar expectations for the effectiveness of their experiences. Similarly, linear mixed models revealed no significant interaction between group and time point ( ^
2(1) = 0.26, p = .61, ^
2 = 0.03; 95% CI, 0 to 0.44), main effect of group ( ^
2(1) = 3.05, p = .081, ^
2 = 0.29; 95% CI, 0 to 0.67), or main effect of time point ( ^
2(1) = 0.56, p = .46, ^
2 = 0.06; 95% CI, 0 to 0.5), on effectiveness of study participation. At 2-weeks participants in the psilocybin group (m = 8.56, SE = 1.07) and niacin group (m = 6.6, SE = 0.78) rated their experience in the study as similarly effective. Likewise, at 4-weeks participants in the psilocybin group (m = 8.32, SE = 1.07) and niacin group (m = 5.38, SE = 2.04) rated their experience in the study as similarly effective (FIG.5). Five-Dimensional Altered States of Consciousness [00132] Participants in the psilocybin group exhibited significantly higher scores on the spiritual experience (F(1, 7) = 10.8, p = .013, Cohen’s d = 2.20; 95% CI, 0.20 to 4.21), elemental imagery (F(1, 7) = 83.5, p < .001, Cohen’s d = 6.13; 95% CI, 2.36 to 9.90), and audiovisual synesthesia (F(1, 7) = 29.2, p = .001, Cohen’s d = 3.62; 95% CI, 1.06 to 6.20) sub- scales of the 5D-ASC. There were no significant between group differences on any other subscales (FIG.6). Blinding Questionnaire [00133] All 9 participants correctly identified their group via the blinding questionnaire administered at Session 6. Results [00134] Of the 9 participants who completed the study (mean (SD) age = 37 (13) years; PLP duration = 4.40 (4.42) years, 5 received psilocybin (4 lower limb, 1 finger amputation; 2 female) and 4 received niacin (3 lower limb, 1 finger amputation; 2 female). There were no reports of suicidal ideation or serious adverse events, and no clinically significant changes in HR or BP (> 140/90 mmHg for > 20 min) in either group during dosing. Anxiety in the psilocybin group (mean (SD) = 1.60 (0.40)) was the peak adverse drug effect during dosing. No anxiolytic medications were required and there were no significant between group differences in any peak adverse drug effects. Transient headache the day after dosing was noted
in 3/5 psilocybin and 0/4 niacin group participants. There were no significant between group differences in phantom limb pain ( ^
2(1) = 0.14, p = .70, ^
2 = 0.007; 95% CI, 0 to 0.24), BPI pain severity ( ^
2(1) = 2.18, p = .14, ^
2 = 0.11; 95% CI, 0 to 0.42) or interference scores ( ^
2(1) = 1.74, p = .19, ^
2 = 0.09; 95% CI, 0 to 0.4) from baseline to 2- and 4-weeks post-dosing, but clinically meaningful (≥ 30%) reductions in phantom limb pain were observed in 4/5 psilocybin group participants 2-weeks post-dosing. Additionally, psilocybin was associated with significant decreases in residual limb pain from baseline to 2-weeks (t(13) = 8.23, p <. 001, Cohen’s d = 3.21; 95% CI, 1.00 to 5.41) and 4-weeks (t(13) = 6.60, p < .001, Cohen’s d = 1.73; 95% CI, 0.02 to 3.44) post-dosing, compared to the niacin group (p > .05). Residual limb pain scores in the psilocybin group did not differ between 2- and 4-weeks post-dosing [t(13) = - 1.63, p = .27]. [00135] The findings of this study demonstrate that the administration of psilocybin in combination with psychological support is a potentially safe, well-tolerated, and feasible treatment approach to elicit clinically meaningful and sustained reductions in phantom and residual limb pain.
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Adverse Events oups on
any physiological measures or peak effects as assessed via Monitor Ratings. Shown is mean (SD) for Physiological Measures and Monitor Ratings and number of participants (%) for Adverse Events. Chronic Phantom Limb Pain [00124] Linear mixed models revealed no significant interaction between group and time point ( ^2(1) = 0.14, p = 0.70, ^2 = 0.007; 95% CI, 0 to 0.24) on phantom limb pain intensity in the past week (FIG. 4, Panel A). There was a significant main effect of group ( ^2(1) = 8.40, p = .0038, ^2 = 0.59; 95% CI, 0.05, to 0.82), driven by between-group differences at baseline. Post-hoc analyses revealed that participants in the psilocybin group (m = 3.75, SE = 0.80) had significantly lower scores (t(7) = 3.24, p = .014, Cohen’s d = 1.38; 95% CI, 0.42 to 2.35) than those in the niacin group (m = 7.71, SE = 0.93). There was no significant main effect of time point ( ^2(1) = 1.33, p = .25, ^2 = 0.07; 95% CI, 0 to 0.37). [00125] Of note, 4/5 participants in the psilocybin group demonstrated clinically meaningful decreases (≥ 30%)45 in weekly phantom limb pain intensity from baseline to 2-weeks post- dosing (M = -58.9%, SE = 26.6%, Cohen’s d = -1.40; 95% CI, -3.03 to 0.23) compared to 0/3 participants in the niacin group (M = -2.77%, SE = 3.38%, Cohen’s d = -0.67; 95% CI, -3.00 to 1.66). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin
group (M = -14.8%, SE = 40.8%, Cohen’s d = -0.23; 95% CI, -1.69 to 1.23) and 1/3 participants in the placebo group (M = -17.4%, SE = 21.9%, Cohen’s d = -0.65; 95% CI, -2.98 to 1.68) demonstrated clinically meaningful decreases. Residual Limb Pain [00126] Linear mixed models revealed a significant interaction between group and time point ( ^2(1) = 9.31, p = .002, ^2 = 0.41; 95% CI, 0.06 to 0.66) on residual limb pain intensity in the past week (FIG.4, Panel B). Post-hoc analyses revealed that, for participants in the niacin group, there were no differences in pain intensity scores across time points. However, for participants in the psilocybin group, their scores were significantly lower versus baseline at the 2-week (t(13) = 8.23, p < 0.001, Cohen’s d = 3.21; 95% CI, 1.00 to 5.41) and 4-week (t(13) = 6.60, p < .001, Cohen’s d = 1.73; 95% CI, 0.02 to 3.44) follow-ups. Scores did not differ significantly between 2- and 4-weeks (t(13) = -1.63, p = .27). There was no significant main effect of group ( ^2(1) = 0.47, p = .49, ^2 = 0.05; 95% CI, 0 to 0.48) or time point ( ^2(1) = 2.35, p = .13, ^2 = 0.13; 95% CI, 0 to 0.45). [00127] Additionally, 5/5 of participants in the psilocybin group demonstrated clinically meaningful reductions in residual limb pain from baseline to 2-weeks post-dosing (M = -79.7%, SE = 7.11%, Cohen’s d = -7.10; 95% CI, -11.04 to -3.16) compared to 0/3 participants in the niacin group (M = 4.12%, SE = 7.14%, Cohen’s d = 0.47; 95% CI, -1.83 to 2.77). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin group (M = -65.2%, SE = 16.4%, Cohen’s d = -2.52; 95% CI, -4.47 to -0.57) demonstrated clinically meaningful reductions from baseline compared to 0/3 in the niacin group (M = 23.3%, SE = 14.3%, Cohen’s d = 1.34; 95% CI, -1.17 to 3.84). Brief Pain Inventory [00128] Linear mixed models revealed no significant interaction between group and time point ( ^2(1) = 2.18, p = .14, ^2 = 0.11; 95% CI, 0 to 0.42) or main effects of group ( ^2(1) = 0.47, p = .49, ^2 = 0.05; 95% CI, 0 to 0.48) or time point ( ^2(1) = 2.73, p = .10, ^2 = 0.14; 95% CI, 0 to 0.45) on pain severity (FIG. 4, Panel C). A similar pattern was found for pain interference (FIG.4D), i.e., no interaction between group and time point ( ^2(1) = 1.74, p = .19, ^2 = 0.09; 95% CI, 0 to 0.4), or significant main effects of group ( ^2(1) = 1.32, p = .25, ^2 = 0.14; 95% CI, 0 to 0.57) or time point ( ^2(1) = 0.005, p = .95, ^2 = 0.0003; 95% CI, 0 to 0.08).
[00129] For pain severity (FIG. 4, Panel C), 2/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = - 30.2%, SE = 21.7, Cohen’s d = -0.88; 95% CI, -2.41 to 0.65) compared to 1/4 of participants in the niacin group (M = 26.8%, SE = 39.2%, Cohen’s d = 0.48, 95% CI, -1.27 to 2.24). Results from the 4-week follow-up revealed that 3/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline (M = -45.3%, SE = 25.4%, Cohen’s d = -1.13, 95% CI, -2.70 to 0.44) compared to 2/4 in the niacin group (M = 12.8%, SE = 49.4%, Cohen’s d = 0.18; 95% CI, -1.55 to 1.92). [00130] For pain interference (FIG. 4, Panel D), 1/5 participants in the psilocybin group demonstrated clinically meaningful reductions from baseline to the 2-week follow-up (M = - 13.9%, SE = 24.0, Cohen’s d = -0.37; 95% CI, -1.84 to 1.10) compared to 1/4 participants in the niacin group (M = 4.29%, SE = 35.6%, Cohen’s d = 0.09; 95% CI, -1.65 to 1.82). Results from the 4-week follow-up revealed that 2/5 participants in the psilocybin group (M = -29.9%, SE = 21.3%, Cohen’s d = -0.89; 95% CI, -2.41 to 0.64) demonstrated clinically meaningful reductions from baseline compared to 1/4 in the niacin group (M = 29.5%, SE = 68.1%, Cohen’s d = 0.31; 95% CI, -1.43 to 2.05). Table 3. Mean Scores for Pain Outcomes. VAS = Visual analog scale; PLP = phantom limb pain; BPI = Brief Pain Inventory; mean (SD) is shown for all groups and time points. Expectation and Effectiveness
[00131] A One-way ANOVA revealed no significant main effect of group (F(1,7) = 0.95, p = .36, Cohen’s d = -0.65; 95% CI, -2.28 to 0.97) on expectation effects. Participants in the niacin group (m = 7.35, SE = 1.56) and psilocybin group (m = 8.74 , SE = 0.36) had similar expectations for the effectiveness of their experiences. Similarly, linear mixed models revealed no significant interaction between group and time point ( ^2(1) = 0.26, p = .61, ^2 = 0.03; 95% CI, 0 to 0.44), main effect of group ( ^2(1) = 3.05, p = .081, ^2 = 0.29; 95% CI, 0 to 0.67), or main effect of time point ( ^2(1) = 0.56, p = .46, ^2 = 0.06; 95% CI, 0 to 0.5), on effectiveness of study participation. At 2-weeks participants in the psilocybin group (m = 8.56, SE = 1.07) and niacin group (m = 6.6, SE = 0.78) rated their experience in the study as similarly effective. Likewise, at 4-weeks participants in the psilocybin group (m = 8.32, SE = 1.07) and niacin group (m = 5.38, SE = 2.04) rated their experience in the study as similarly effective (FIG.5). Five-Dimensional Altered States of Consciousness [00132] Participants in the psilocybin group exhibited significantly higher scores on the spiritual experience (F(1, 7) = 10.8, p = .013, Cohen’s d = 2.20; 95% CI, 0.20 to 4.21), elemental imagery (F(1, 7) = 83.5, p < .001, Cohen’s d = 6.13; 95% CI, 2.36 to 9.90), and audiovisual synesthesia (F(1, 7) = 29.2, p = .001, Cohen’s d = 3.62; 95% CI, 1.06 to 6.20) sub- scales of the 5D-ASC. There were no significant between group differences on any other subscales (FIG.6). Blinding Questionnaire [00133] All 9 participants correctly identified their group via the blinding questionnaire administered at Session 6. Results [00134] Of the 9 participants who completed the study (mean (SD) age = 37 (13) years; PLP duration = 4.40 (4.42) years, 5 received psilocybin (4 lower limb, 1 finger amputation; 2 female) and 4 received niacin (3 lower limb, 1 finger amputation; 2 female). There were no reports of suicidal ideation or serious adverse events, and no clinically significant changes in HR or BP (> 140/90 mmHg for > 20 min) in either group during dosing. Anxiety in the psilocybin group (mean (SD) = 1.60 (0.40)) was the peak adverse drug effect during dosing. No anxiolytic medications were required and there were no significant between group differences in any peak adverse drug effects. Transient headache the day after dosing was noted
in 3/5 psilocybin and 0/4 niacin group participants. There were no significant between group differences in phantom limb pain ( ^2(1) = 0.14, p = .70, ^2 = 0.007; 95% CI, 0 to 0.24), BPI pain severity ( ^2(1) = 2.18, p = .14, ^2 = 0.11; 95% CI, 0 to 0.42) or interference scores ( ^2(1) = 1.74, p = .19, ^2 = 0.09; 95% CI, 0 to 0.4) from baseline to 2- and 4-weeks post-dosing, but clinically meaningful (≥ 30%) reductions in phantom limb pain were observed in 4/5 psilocybin group participants 2-weeks post-dosing. Additionally, psilocybin was associated with significant decreases in residual limb pain from baseline to 2-weeks (t(13) = 8.23, p <. 001, Cohen’s d = 3.21; 95% CI, 1.00 to 5.41) and 4-weeks (t(13) = 6.60, p < .001, Cohen’s d = 1.73; 95% CI, 0.02 to 3.44) post-dosing, compared to the niacin group (p > .05). Residual limb pain scores in the psilocybin group did not differ between 2- and 4-weeks post-dosing [t(13) = - 1.63, p = .27]. [00135] The findings of this study demonstrate that the administration of psilocybin in combination with psychological support is a potentially safe, well-tolerated, and feasible treatment approach to elicit clinically meaningful and sustained reductions in phantom and residual limb pain.