WO2024263859A1

WO2024263859A1 - Psilocin or psilocybin for use in the treatment of demoralisation syndrome

Info

Publication number: WO2024263859A1
Application number: PCT/US2024/034936
Authority: WO
Inventors: Susan M. LEARNED; James A. Graham; Anne Cramer ANDORN
Original assignee: Reset Pharmaceuticals, Inc.
Priority date: 2023-06-22
Filing date: 2024-06-21
Publication date: 2024-12-26

Abstract

The invention relates to a method of treating demoralisation syndrome in a patient, the method comprising administering a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, to said patient. Kits useful in the method of the invention are also described.

Description

PSILOCIN OR PSILOCYBIN FOR USE IN THE TREATMENT OF DEMORALISATION SYNDROME

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and benefit of, U.S. Provisional Application No. 63/509,548, filed on June 22, 2023, the entire contents of which are specifically incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a method of treating demoralisation syndrome in a patient.

BACKGROUND OF THE INVENTION

Demoralisation syndrome is an understandable but overwhelming and persistent psychological and behavioral response to cancer and other life-threatening or lifealtering situations and/or diseases. The International Classification of Diseases 1 1 th Revision (ICD-11 ) defines syndromal demoralisation as loss of confidence in one's ability to cope, with associated feelings of helplessness, hopelessness, and discouragement. While mild demoralisation may be ameliorated by empathic listening and supportive therapy, moderate and severe forms may require individualized psychotherapeutic intervention. Untreated demoralisation can expose individuals to chronic distress, social withdrawal including avoiding medical treatment, and a wish for hastened death leading to impulsive suicidal behavior, and requests for physician-assisted suicide.

Demoralisation syndrome has been most widely studied and appears to be best understood in cancer patients. The diagnosis of cancer is often associated with a perceived lack of control, uncertainty, and the loss of social roles and life goals that can impact successful treatment outcome. Untreated demoralisation in patients with cancer is a key contributor to poorer disease outcome, decreased quality of life, impaired psychosocial functioning, increased suicidality, and lower survival rate. For example, Watson et al (2005), “Influence of psychological response on breast cancer survival: 10-year follow-up of a population-based cohort”, European Journal of Cancer, 41 , 1710-1714, found that in breast cancer patients who were disease-free at 5 years, their baseline helplessness/hopelessness response still exerted a significant negative effect on disease-free survival beyond 5 (and up to 10) years. Since delays in engagement in treatment can worsen prognosis, and delays in death preparation and poor life planning can be devastating for patients and their survivors, addressing demoralisation in patients with cancer can be life sustaining and life affirming for themselves and their loved ones.

The symptoms of demoralisation syndrome may occur concurrently with depression and/or anxiety, thus it is important these are carefully characterized due to the differences in clinical approach to treatment and subsequent clinical outcome. Symptom and network analyses support a clear separation between symptoms of demoralisation from those of depression. These analyses demonstrate that suicidal ideation and desire for death associate with demoralisation symptoms and are distinctly remote from those observed in depression syndromes. Indeed, compared with psychological stress and depression, demoralisation has been noted to be a more significant predictor of suicidal ideation.

Psilocybin (4-phosphoryloxy-/V,/V-dimethyltryptamine) is a tryptamine serotoninergic psychedelic. The IUPAC name of psilocybin is [3-(2- dimethylaminoethyl)-1 H-indol-4-yl] dihydrogen phosphate. The structure of psilocybin is shown below.

Psilocybin is metabolised in the body to psilocin (4-hydroxy-A/,A/- dimethyltryptamine), which has effects including D2 agonism in the nucleus accumbens and 5HT2A agonism. The structure of psilocin is below.

A known intervention for the treatment of anxiety and depression in individuals with cancer is psychedelic-assisted psychotherapy with psilocybin (e.g. Ross S et al (2016), “Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial”, J Psychopharmacol, 30: 1165-1 180; Agin-Liebes et al (2020), “Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer”, J Psychopharmacol, 34: 155-166). The studies indicate that psilocybin treatment was also associated with sustained benefits in demoralisation symptoms, quality of life and improved attitudes towards death.

However, the subjects who participated in these pilot studies were identified as having mixed symptoms of demoralisation, anxiety and depression. There are no reported studies on the effect of treatment with psilocin or psilocybin in a well- defined population of individuals with demoralisation syndrome (in particular, demoralisation syndrome without depression and/or anxiety) to assess psilocybin’s impact on clinical symptoms and outcomes. The diagnosis of Demoralisation Syndrome requires that the symptoms associated with this syndrome are pervasive, persistent, and can interfere with daily functioning. It is important that patients with demoralisation syndrome are properly diagnosed given the increased risk of non-compliance with potentially effective treatment, psychological distress including increased suicidality and poorer long-term cancer outcomes. Furthermore, given there are no identified pharmacological interventions effective for demoralisation, the morbidity and mortality risks associated with demoralisation warrant identifying new effective treatments.

There remains the need for the development of an effective treatment for demoralisation syndrome in patients, particularly in patients who are not suffering from additional affective disorders or anxiety disorders and/or are suffering from life-threatening and/or life-altering diseases such as cancer.

SUMMARY OF THE INVENTION

It is a finding of the present invention that administration of a psychedelic compound such as psilocybin is effective in treating demoralisation syndrome in patients, for example patients suffering from life-threatening and/or life-altering diseases such as cancer. Advantageously, psilocybin can be used to provide a treatment for demoralisation syndrome in patients without an additional affective disorder, such as depression and/or anxiety. This means that the treatment can be tailored towards the treatment of demoralisation syndrome without having to consider the effects of the treatment on any other additional affective disorder that the patient may have.

The invention accordingly provides a method of treating demoralisation syndrome in a patient, the method comprising administering a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or cocrystal thereof, to said patient.

Also provided by the invention is a kit comprising: a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or cocrystal thereof; and instructions for use of said psychedelic compound in a method of treating demoralisation syndrome in a patient, the method comprising administering the psychedelic compound to said patient. The invention further provides a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, for use in a method of treating demoralisation syndrome in a patient.

The invention also provides a use of a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, in the preparation of a medicament for use in treating demoralisation syndrome in a patient.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “about” means any value that the skilled person would appreciate is a reasonable variation of the value that is referred to by the term “about”. Typically, “about” means ± 10% or ± 5%.

Psychedelic compound

The method comprises administering a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof. The psychedelic compound may accordingly be (i) psilocin, a pharmaceutically acceptable salt of psilocin, or a co-crystal of psilocin or (ii) a prodrug of psilocin, a pharmaceutically acceptable salt of the prodrug of psilocin, or a co-crystal of the prodrug of psilocin. In one embodiment, the psychedelic compound is a prodrug of psilocin or a pharmaceutically acceptable salt or co-crystal thereof.

A pharmaceutically acceptable salt of a compound is a salt formed with the compound and a non-toxic counter-ion which is suitable for administration to a patient. Pharmaceutically acceptable salts are well-known to the skilled person.

A co-crystal of a compound is a solid crystalline material comprising the compound and at least one additional different molecular and/or ionic co-former. The compound and the co-former are in the same crystal lattice. A co-crystal is typically neither a solvate nor a simple salt, although a co-crystal may additionally be hydrated or solvated (i.e. it may comprise the compound, the co-former and water or solvent molecules) or one of the components in the co-crystal (e.g. the co-former) may itself be a salt. A co-crystal may comprise the compound and a co-former. The compound and co-former are typically arranged in a regular repeating crystal structure. A co-crystal has a different crystal structure to that of either the compound or co-former alone. Co-crystals are well-known to the skilled person.

A prodrug of psilocin is a compound which is metabolised (or undergoes a biotransformation) to psilocin after it is administered to the patient. The prodrug of psilocin is typically an ester, carbonate ester, phosphate ester, amide or ether derivative of psilocin. Typically, the prodrug of psilocin is a phosphate ester of psilocin or a pharmaceutically acceptable salt or co-crystal thereof.

In one embodiment, the psychedelic compound is psilocybin, or a pharmaceutically acceptable salt or co-crystal thereof. The invention accordingly provides a method of treating demoralisation syndrome in a patient, the method comprising administering a psychedelic compound which is psilocybin or a pharmaceutically acceptable salt or co-crystal thereof, to said patient. In one embodiment, the psychedelic compound is psilocybin.

The psychedelic compound may be administered in any suitable form. Typically, the psychedelic compound is administered in a solid form. The psychedelic compound may be in amorphous or crystalline form. The psychedelic compound may be in the form of a solvate. The psychedelic compound may alternatively be administered as a solution.

The psychedelic compound may be administered as a compound which has been synthesised or which has been isolated from a natural source. Alternatively, the psychedelic compound may be administered as part of a natural source which comprises the psychedelic compound. In one embodiment, the method of the invention comprises administering a single dose of a natural source comprising the psychedelic compound. The natural source may be a mushroom or a fungus of one of the following genera: Psilocybe, Gymnopilus, Panaeolus, Copelandia, Hypholoma, Pluteus, Inocybe, Conocybe, Panaeolina, Gerronema, Agrocybe, Galerina or Mycena. Typically, the natural source may be a mushroom of the Psilocybe genus, for example Psilocybe cubensis, Psilocybe cyanescens, Psilocybe semilanceata or Psilocybe azurescens.

Method of treatment

The method is a method of treating or preventing demoralisation syndrome in a patient. As used herein, treating demoralisation syndrome includes reducing the symptoms of demoralisation syndrome or achieving remission of demoralisation syndrome. In one embodiment, treating demoralisation syndrome comprises reducing the symptoms of demoralisation syndrome. The patient may report a reduction of symptoms of demoralisation syndrome. Typically, symptoms of demoralisation syndrome include one or more symptoms selected from a loss of meaning, hopelessness, helplessness, sense of failure/discouragement, and subjective incompetence and inability to cope (see DCPR-SSI-Clinical Interview for Demoralization (CIDE) by Jenny Guidi and Giovanni Fava (2023)).

In one embodiment, the patient has been identified as being in need of treatment for demoralisation syndrome. Accordingly, the method of the invention may include a step of assessing the level of demoralisation syndrome in the patient prior to administering the psychedelic compound to said patient. In one embodiment, the patient has indicated that he or she is suffering from demoralisation syndrome.

Demoralisation syndrome may be diagnosed using the Diagnostic Criteria for Psychosomatic Research (DCPR) Semi-Structured Interview (Fava et al. (2017), “Current Psychosomatic Practice”, Psychother. Psychosom., 86, 13-30), a validated research diagnostic instrument used for the diagnosis of demoralisation syndrome. It has been extensively validated in both medical and psychiatric settings, and shows high inter-rater reliability and clinical utility in the psychological assessment of medical patients. The DCPR has also been successfully utilized in studies evaluating the prevalence of the demoralisation syndrome among oncology patients.

The severity of demoralisation syndrome may be measured using the Kissane Demoralisation Scale (DS), which records the severity of demoralisation symptoms (Kissane et al. (2004), “The demoralisation scale: A report of its development and preliminary validation”, J Palliat Care, 20: 269-276). The DS is a self-report questionnaire; psychometric evaluation consistently demonstrated convergent validity of the DS with established measures of psychological distress, quality of life, and desire for death, as well as strong internal reliability for the total scale. Scores above 30 are considered indicative of clinical levels of demoralisation.

Accordingly, in the method of the invention, a Kissane Demoralisation Scale score of the patient may be reduced after administration of the psychedelic compound. Typically, a Kissane Demoralisation Score of the patient is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% after administration of the psychedelic compound. In one embodiment, a Kissane Demoralisation Scale score of the patient after administration of the psychedelic compound is less than 30, less than 25, less than 20 or less than 15.

The patient to be treated may have a Kissane Demoralisation Scale score of greater than about 30 prior to administration of the psychedelic compound. The patient to be treated may have a Kissane Demoralisation Scale score of greater than about 30 in the week prior to administration of the psychedelic compound.

The severity of demoralisation syndrome may be measured using the Clinical Interview for Demoralisation (CIDE), which is a clinical global impression of severity for demoralisation (Clinical Characterization of Demoralization, Psychotherapy and Psychosomatics, v92 issue 2 pp 1 -9, May 23, 2023). In the CIDE, a clinical interviewer rates the intensity of demoralisation based on 4 key symptoms as outlined in ICD-1 1 : 1 ) Subjective incompetence and inability to cope, 2) Discouragement, 3) Helplessness, and 4) Hopelessness. There are specific anchor points on a 1 to 7 scale for each item, and the total score may range from 4 to 28. Scores above 3 on any item are considered indicative of moderate levels of demoralisation. Prior to treatment, the patient may accordingly have a total score of at least 6, at least 8, at least 10, at least 12, at least 16 or at least 20.

Accordingly, in the method of the invention a Clinical Interview for Demoralisation score of the patient may be reduced after administration of the psychedelic compound. Typically, a Clinical Interview for Demoralisation score of the patient is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% after administration of the psychedelic compound. Following treatment, the patient may for instance have a total score of 12 or less, 10 or less, 8 or less, 6 or less or 4 or less.

In one embodiment, the patient to be treated is not suffering from an additional affective disorder. The additional affective disorder may mean an affective disorder which is not demoralisation syndrome, and which is not adjustment disorder. The additional affective disorder may be any affective disorder which is not demoralisation syndrome and is not adjustment disorder, such as depression, an anxiety disorder or bipolar disorder.

In one embodiment, the patient to be treated is not suffering from an additional anxiety or affective disorder other than adjustment disorder. An anxiety disorder typically includes panic disorder, post-traumatic stress disorder, obsessive- compulsive disorder, social phobia, acute stress disorder, and generalized anxiety disorder.

In one embodiment, the patient to be treated is not suffering from an additional affective disorder which is depression or an additional affective disorder which is an anxiety disorder. In one embodiment, the patient to be treated is not suffering from an additional affective disorder which is depression or an anxiety disorder (i.e. the patient has neither depression nor an anxiety disorder). In one embodiment, the patient to be treated is not suffering from an additional affective disorder which is depression, an anxiety disorder or bipolar disorder. In one embodiment, the patient is suffering from demoralisation syndrome without depression and/or an anxiety disorder. As such, in one embodiment, the patient does not have depression, or the patient does not have an anxiety disorder, or the patient has neither depression or an anxiety disorder.

In one embodiment, the patient to be treated is not suffering from an additional mood disorder which is a depressive or bipolar disorder or an additional anxiety disorder. In one embodiment, the patient to be treated is not suffering from an additional affective disorder which is depressive disorder or an anxiety disorder (i.e. the patient has neither depression nor an anxiety disorder). In one embodiment, the patient to be treated is not suffering from an additional affective disorder which a depressive or bipolar disorder, or an anxiety disorder. In one embodiment, the patient is suffering from demoralisation syndrome without a mood and/or an anxiety disorder. As such, in one embodiment, the patient does not have depressive disorder, or the patient does not have an anxiety disorder, or the patient has neither a depressive/bipolar or an anxiety disorder.

The symptoms of depression and/or anxiety may be measured using the Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith (1983), “The hospital anxiety and depression Scale”, Acta Psychiatrica Scand, 67: 361-370). In this test, lower numbers indicate lower levels of depression and/or anxiety. Subscale scores can be calculated for depression (HADS-D) and anxiety (HADS-A). A subscale score equal to or above eight and a full scale score over 12 indicates the possible presence of a clinical disorder.

Accordingly, in the method of the invention a total Hospital Anxiety and Depression Scale score of the patient may be below about 12 prior to administration of the psychedelic compound. Typically, the total Hospital Anxiety and Depression Scale score of the patient is maintained below about 12 after administration of the psychedelic compound.

The severity of depression (or depressive symptoms) may also be measured using the Beck Depression Inventory-ll (BDI-II; Beck et al (1988), “Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation”, Clin Psych Rev, 8: 77-100). Scores above 12 indicate possible clinical depression.

Accordingly, in the method of the invention a Beck Depression Inventory-I I score of the patient may be below about 12 prior to administration of the psychedelic compound. Typically, the Beck Depression Inventory-I I score of the patient is maintained below about 12 after administration of the psychedelic compound.

The patient to be treated may be not suffering from any additional major mental health disorder. As used herein, an additional mental health disorder means a mental health or psychiatric disorder which is not demoralisation syndrome, and is not adjustment disorder. The additional mental health disorder may be any mental health or psychiatric disorder which is not demoralisation syndrome and is not adjustment disorder, such as a psychotic disorder, a drug use disorder, an eating disorder, a conduct disorder, a personality disorder or another disorder included in DSM-V.

The presence of an additional mental health disorder may be measured using the Structured Clinical Interview for DSM-5 Disorders - Clinical Trials (SCID-5-CT), (SCID-5-CT) (STRUCTURED CLINICAL INTERVIEW FOR DSM-5, CLINICAL TRIALS VERSION First et al (2015), “Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version (SCID-5-CT)”, American Psychiatric Association). Accordingly, in the method of the invention, the patient to be treated may not be suffering from any additional mental health disorder as determined using the SCID-CT.

The patient to be treated may or may not be suffering from adjustment disorder. In one embodiment, the patient is suffering from adjustment disorder. In one embodiment, the patient is not suffering from adjustment disorder. As such, in one embodiment, the patient has neither a depressive disorder (e.g. depression) or an anxiety disorder, but is suffering from adjustment disorder. Alternatively, in one embodiment, the patient has none of a depressive disorder (e.g. depression), an anxiety disorder, and adjustment disorder. The patient to be treated may be suffering from a life-threatening and/or lifealtering disease. As used herein, the term “patient suffering from a life-threatening and/or life-altering disease” describes a human patient who has been diagnosed with having a life-threatening and/or life-altering disease at the time of the administration of the psychedelic compound (e.g. psilocybin). In one embodiment, the patient suffering from a life-threatening and/or life-altering disease is a cancer patient. The patient may have an active diagnosis of the life-threatening and/or life-altering disease for as long as the demoralisation syndrome is treated. Alternatively, where the life-threatening and/or life-altering disease is one which may be cured, the patient may be cured of the disease during said treatment of demoralisation syndrome. For example, where the patient is a cancer patient, the cancer patient may enter partial or complete remission from cancer during said treatment of demoralisation syndrome.

The patient may be treated with the psychedelic compound any time after they have received a diagnosis of the life-threatening and/or life-altering disease. Typically, the psychedelic compound is administered to the patient less than twelve months, less than nine months, less than six months, less than three months, less than one month, or less than two weeks after the patient has received a diagnosis of the life-threatening and/or life-altering disease. Preferably, the psychedelic compound is administered to the patient less than twelve months, less than nine months or less than six months after the patient has received a diagnosis of the life-threatening and/or life-altering disease. In one embodiment, the psychedelic compound is administered to the patient less than twelve months after the patient has received a diagnosis of the life-threatening and/or life-altering disease. In one embodiment, the psychedelic compound is administered to the patient less than six months after the patient has received a diagnosis of the lifethreatening and/or life-altering disease. As used herein, “a diagnosis of a lifethreatening and/or life-altering disease” may be the first time that a patient has been diagnosed with a particular life-threatening and/or life-altering disease. Alternatively, the diagnosis may be a diagnosis of progression of or a change in a life-threatening and/or life-altering disease where the patient had previously received an initial diagnosis of that disease (for example, the diagnosis may be a diagnosis of late-stage cancer where the patient had previously been diagnosed with stage I or stage II cancer). Alternatively, the diagnosis may be a diagnosis of a life-threatening and/or life-altering disease from which the patient has previously suffered from, but from which the patient was in remission from (i.e. the diagnosis may be a diagnosis of a life-threatening and/or life-altering disease which has returned following remission).

Typically, the psychedelic compound is administered to the patient during a period in which the patient is receiving treatment for the life-threatening and/or lifealtering disease. However, the psychedelic compound may be administered to the patient during a period in which the patient is not receiving treatment for the lifethreatening and/or life-altering disease, for example a period before the patient begins treatment for the life disease or after treatment for the disease has concluded. The psychedelic compound may be administered to the patient both during a period in which the patient is receiving treatment for the life-threatening and/or life-altering disease and a period in which the patient is not receiving treatment for the life-threatening and/or life-altering disease.

The patient to be treated may be in remission from a life-threatening and/or lifealtering disease. As used herein, a patient who is “in remission from a lifethreatening and/or life-altering disease” describes a human patient who has previously been diagnosed with having a life-threatening and/or life-altering disease, but at the time of the administration of the psychedelic compound is no longer considered to have an active diagnosis of the disease. A patient who is in remission from a life-threatening and/or life-altering disease may be described as being cured of the life-threatening and/or life-altering disease. A patient who is in remission from a life-threatening and/or life-altering disease may still be receiving treatment for the disease. Alternatively, a patient who is in remission from a lifethreatening and/or life-altering disease may not be receiving treatment for the disease. The life-threatening and/or life-altering disease may be any chronic disease which has the potential to reduce the normal life expectancy of, or to have a significant negative impact on the quality of life of, a patient suffering from the disease. The life-threatening and/or life-altering disease may be selected from cancer, a neurological disease, an autoimmune disease, a pulmonary disease, a cardiovascular disease, an endocrinological disease, an infectious disease, a gastroenterological disease, a dermatological disease, or a traumatic condition or situation. The neurological disease may be selected from amyotrophic lateral sclerosis (ALS), Huntington’s disease, dementia, non-CNS amyloidosis, disabling spinal stenosis, motor neurone disease, Alzheimer’s disease, essential tremor, Parkinson’s disease, migraine, cluster headache, and epilepsy. The autoimmune disease may be selected from rheumatoid arthritis (RA), systemic lupus erythematosis, sarcoidosis without brain involvement, osteoarthritis, fibromyalgia, myasthenia gravis, myalgic encephalopathy, and multiple sclerosis. The pulmonary disease may be selected from pulmonary arterial hypertension (PAH), pulmonary fibromatosis, interstitial pulmonary disease, asthma, chronic obstructive pulmonary disease (COPD). The cardiovascular disease may be selected from heart disease, myocardial infarction, hypertension, and heart failure. The endocrinological disease may be diabetes. The infectious disease may be selected from prolonged postviral syndrome, acquired immune deficiency syndrome (AIDS), and recurrent malaria. The gastroenterological disease may be selected from irritable bowel syndrome and Crohn’s disease. The dermatological disease may be psoriasis. The traumatic condition or situation may be selected from a limb amputation, organ transplant, traumatic paralysis, opioid use disorder, and prisoner of war/Stockholm syndrome. Accordingly, the life-threatening and/or life-altering disease may be selected from cancer, amyotrophic lateral sclerosis (ALS), dementia, non-CNS amyloidosis, disabling spinal stenosis, motor neurone disease, Alzheimer’s, essential tremor, Parkinson’s disease, migraine, cluster headache, epilepsy, rheumatoid arthritis (RA), systemic lupus erythematosis, sarcoidosis without brain involvement, osteoarthritis, fibromyalgia, myasthenia gravis, myalgic encephalopathy, multiple sclerosis, pulmonary arterial hypertension (PAH), pulmonary fibromatosis, interstitial pulmonary disease, asthma, chronic obstructive pulmonary disease (COPD), heart disease, myocardial infarction, hypertension, heart failure diabetes, prolonged postviral syndrome, acquired immune deficiency syndrome (AIDS), recurrent malaria, irritable bowel syndrome, Crohn’s disease, psoriasis, limb amputation, organ transplant, traumatic paralysis, opioid use disorder, and prisoner of war/Stockholm syndrome. In one embodiment, the life-threatening and/or life-altering disease is cancer.

Where the life-threatening and/or life-altering disease is cancer, the cancer may be stage I, stage II, stage III or stage IV cancer. All stages, but in particular advanced stages, of cancer are associated with elevated rates of demoralisation syndrome. The cancer may be late-stage cancer. Typically, the cancer is stage III or stage IV cancer. Stage I cancer typically refers to cancer where the tumours are small and the cancer is contained with the organ it started in. Stage II cancer typically refers to cancer where the tumours are larger than in stage I, but the cancer has not yet started to spread to surrounding tissues. Stage III cancer typically refers to cancer with large tumours, where the cancer may have spread into the surrounding tissues and nearby lymph nodes. Stage IV cancer typically refers to metastatic cancer, where the cancer has spread from where it started to another organ.

The cancer may be selected from breast cancer, reproductive cancer, lymphoma, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid/rhabdoid tumor, bile duct cancer, bladder cancer, bone cancer, bowel cancer, brain cancer, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, cutaneous T-cell lymphoma, oesophageal cancer, eye cancer, intraocular melanoma, fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, germ cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, Hodgkin lymphoma, intraocular melanoma, islet cell tumor, kidney cancer, Langerhans cell histiocytosis, liver cancer, lung cancer (nonsmall cell, small cell, pleuropulmonary blastoma, and tracheobronchial tumor), melanoma, mesothelioma, metastatic cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasms, myelodysplastic syndrome, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, retinoblastoma, salivary gland cancer, sarcoma, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, throat cancer, thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, and vaginal cancer.

The method of the invention is particularly useful where a cancer patient suffering from said cancer, or who has previously been diagnosed with said cancer but is in remission from said cancer, is more likely to have demoralisation syndrome (for example because the cancer has a high mortality rate, causes a significant reduction in quality of life or has a high recurrence rate). Accordingly, the cancer may be selected from lung cancer, bowel cancer, prostate cancer, breast cancer, pancreatic cancer, oesophageal cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, vaginal cancer, cervical cancer and brain cancer.

In one embodiment, the patient to be treated has not been diagnosed with a lifethreatening and/or life-altering disease. As used herein, a patient who “has not been diagnosed with a life-threatening and/or life-altering disease” describes a patient who, at the time of administration of the psychedelic compound, has not previously been diagnosed with a life-threatening and/or life-altering disease. Typically, such a patient is not suffering from a life-threatening and/or life-altering disease. However, the patient may be suffering from a life-threatening and/or lifealtering disease, but has not been diagnosed with the disease at the time of administration of the psychedelic compound.

The patient to be treated may be suffering from demoralisation syndrome caused by non-medical factors. For example, the patient may be suffering from demoralisation syndrome caused by one or more of financial situation, employment situation, environmental concerns or housing situation. The method may further comprise providing the patient with supportive therapy, such as psychotherapy treatment or supportive workbooks/digital applications for the patient to work through. The supportive therapy may be provided before and/or after the administration of the psychedelic compound.

The supportive therapy, such as psychotherapy treatment, may be provided before the administration of the psychedelic compound, after the administration of the psychedelic compound, during the administration of the psychedelic compound, or at any combination of two or more of before, during and after the administration of the psychedelic compound. The supportive therapy such as psychotherapy treatment may be provided before, during and after the administration of the psychedelic compound. Typically, the supportive therapy such as psychotherapy treatment is provided during the administration of the psychedelic compound. As used herein, providing supportive therapy during the administration of the psychedelic compound means providing the supportive therapy at the time of administering the psychedelic compound and for at least a part of any psychedelic experience that the patient experiences following the administration of the psychedelic compound. Typically, supportive therapy that is provided during the administration of the psychedelic compound is provided for the whole duration of the psychedelic experience that the patient experiences following the administration of the psychedelic compound.

The supportive therapy, such as psychotherapy treatment, may be provided in the three months before and/or the three months after administration of the psychedelic compound. Typically the supportive therapy is provided in the two months before and/or the two months after administration of the psychedelic compound. The supportive therapy may be provided in the eight weeks before and/or the eight weeks after administration of the psychedelic compound. The supportive therapy may be provided in the two weeks before and/or the two weeks after administration of the psychedelic compound. The supportive therapy may be provided in the one week before and/or the one week after administration of the psychedelic compound. Where the supportive therapy is provided before and after the administration of the psychedelic compound, the therapy before the administration and the therapy after the administration may be provided in different timeframes. For example, the therapy may be provided in the three months before the administration and in the eight weeks after the administration. Alternatively, the therapy before the administration and the therapy after the administration may be provided in the same timeframe.

The patient may receive further supportive therapy, for example psychotherapy, in addition to the supportive therapy that may be provided as part of the method of the invention. For example, the patient may receive further supportive therapy, for example psychotherapy, at least once a year following the administration of the psychedelic compound or the end of the supportive therapy that is provided as part of the method of the invention. The patient may receive the further supportive therapy, for example psychotherapy, at least twice a year, or at least four times a year.

The supportive therapy, for example psychotherapy treatment, may comprise at least 2 hours of therapy. Typically, the supportive therapy, for example psychotherapy treatment, comprises at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours or at least 20 hours of supportive therapy. Where the therapy is provided before and after the administration of the psychedelic compound, the therapy before the administration may comprise the same number of hours as the therapy after the administration. For example, the supportive therapy such as psychotherapy treatment may comprise 6 hours of psychotherapy treatment before the administration and 6 hours of psychotherapy treatment after the administration. The supportive therapy such as psychotherapy treatment may comprise 2 hours of psychotherapy treatment before the administration and 2 hours of psychotherapy treatment after the administration. Alternatively, the supportive therapy before the administration may comprise a different number of hours to the supportive therapy after the administration. For example, the supportive therapy such as psychotherapy treatment may comprise 6 hours of psychotherapy treatment before the administration and 12 hours of psychotherapy treatment after the administration. The supportive therapy such as psychotherapy treatment may comprise 2 hours of psychotherapy treatment before the administration and 4 hours of psychotherapy treatment after the administration. Where the supportive therapy is provided during the administration of the psychedelic compound and before and/or after the administration, the therapy during the administration may comprise the same number of hours as the therapy before and/or after the administration, or the supportive therapy during the administration may comprise a different number of hours as the therapy before and/or after the administration. For example, the supportive therapy such as psychotherapy treatment may comprise 6 hours of supportive therapy before the administration, 8 hours of supportive therapy during the administration, and 6 hours of supportive therapy after the administration. The supportive therapy such as psychotherapy treatment may comprise 2 hours of supportive therapy before the administration, 4 hours of supportive therapy during the administration, and 2 hours of supportive therapy after the administration.

The supportive therapy, for example psychotherapy treatment, may be provided in sessions at least 30 minutes in duration or at least one hour in duration. Typically, the therapy is provided in sessions at least two hours in duration. The supportive therapy may comprise any number of sessions. Typically the supportive therapy comprises at least 2 sessions, for example at least 4 sessions or at least 6 sessions. Where the supportive therapy is provided before and after the administration of the psychedelic compound, the therapy before the administration may comprise the same number of sessions as the therapy after the administration. For example, the supportive therapy such as psychotherapy treatment may comprise 3 sessions before and 3 sessions after the administration. Alternatively, the supportive therapy before the administration may comprise a different number of sessions to the therapy after the administration. For example, the supportive therapy such as psychotherapy treatment may comprise 3 sessions before and 6 sessions after the administration. Any supportive therapy that is provided during the administration of the psychedelic compound is typically provided in a single session of at least 1 hour in duration, for example at least 2 hours, 4 hours or at least 6 hours in duration. Any supportive therapy that is provided during the administration of the psychedelic compound may be provided in a single session of around 2 hours, around 4 hours, around 6 hours or around 8 hours in duration.

The supportive therapy may be any suitable psychotherapy technique, such as psychotherapy treatment. The psychotherapy treatment may comprise any psychotherapy delivered by one or more therapists. Typically the psychotherapy treatment is selected from supportive psychotherapy, attachment-based psychotherapy, behavioural therapy, body psychotherapy, somatic psychotherapy, brief therapy, cognitive analytical therapy, cognitive behaviour therapy, existential psychotherapy, gestalt therapy, humanistic integrative psychotherapy, Jungian analysis, neuro-linguistic psychotherapy, object relations therapy, personcentered psychotherapy, psychodynamic psychotherapy solution-focused brief therapy, transactional analysis, transpersonal psychotherapy, emotion-focused therapy, compassion-focused therapy, mindfulness-based cognitive therapy.

The psychotherapy treatment may include elements from supportive psychotherapy; cognitive-behavioral therapy; existentially oriented therapy (i.e. psychotherapies developed specifically by psycho-oncologists to address existentially oriented issues that arise in patients with cancer and especially advanced-staged diagnoses); and psychodynamic/psychoanalytic therapy. In one embodiment, the psychotherapy may be administered by a single therapist.

Supportive therapy which is provided before and/or after the administration of the psychedelic compound may be administered to the patient remotely, or via a digital platform (such as an app).

In one embodiment, the method does not comprise providing the patient with psychotherapy treatment. In one embodiment, the method comprises providing the patient with supportive therapy which is not psychotherapy treatment. In one embodiment, the method does not comprise providing the patient with supportive therapy. The psychedelic compound may be useful in achieving rapid treatment of demoralisation syndrome in a patient. Therefore, in the method of the invention the level of demoralisation syndrome may be reduced within two weeks after administration of the psychedelic compound. Typically, the level of demoralisation syndrome is reduced within one week, within forty-eight hours, within one day (twenty-four hours), within twelve hours or within eight hours after administration of the psychedelic compound.

Advantageously, administration of a single dose of the psychedelic compound may be useful in achieving sustained, long-term treatment of demoralisation syndrome. Thus, the psychedelic compound may be administered in a single dose. Where the psychedelic compound is administered in a single dose, no further dose may be administered for at least two weeks, or at least six months, or at least one year, or at least two years, or at least three years, or at least four and a half years, after administration of the single dose. Typically, where the psychedelic compound is administered in a single dose, no further dose is administered for at least six months or at least one year after administration of the single dose. In one embodiment, where the psychedelic compound is administered in a single dose, no further dose is administered for at least six months after administration of the single dose.

In one embodiment, a single dosage form (such as a tablet) comprising the psychedelic compound is administered to the patient in order to provide the single dose. However, as this skilled person will appreciate, this does not necessarily mean that only a single dosage form comprising the psychedelic compound may be administered. The single dose of the psychedelic compound may be administered as two or more separate dosage forms, which two or more separate dosage forms are administered simultaneously or shortly after one another (for instance less than 2 hours apart or less than 10 minutes). The single dose may also be administered over a period of time, for example if being administered as a parenteral dosage form such as an intravenous infusion, or a subcutaneous or intramuscular injection. The single dose of the psychedelic compound is typically administered in a timeframe of no greater than about one hour, no greater than 30 minutes or no greater than 10 minutes.

In the method of the invention the severity of demoralisation syndrome symptoms may be reduced for a period of at least six months, at least one year, at least three years, or at least four and a half years after administration of the psychedelic compound. In one embodiment, no further dose of the psychedelic compound is administered for at least six months after administration of the single dose. Typically, the severity of demoralisation syndrome symptoms is reduced for at least six months or at least one year after administration of the single dose. In one embodiment, the severity of demoralisation syndrome symptoms is reduced for at least six months after administration of the psychedelic compound, wherein no further dose of the psychedelic compound is administered for at least six months after administration of the single dose of the psychedelic compound. For example, the severity of demoralisation syndrome symptoms may be reduced for a period of at least six months after administration of single dose. In another embodiment, the severity of demoralisation syndrome symptoms is reduced for at least one year after administration of the single dose. For example, the severity of demoralisation syndrome symptoms may be reduced for a period of at least one year after administration of the single dose.

The length of time for which no further dose of the psychedelic compound is administered after administration of the single dose may be the same as the length of time for which the severity of demoralisation syndrome symptoms is reduced. Alternatively, the length of time for which no further dose of the psychedelic compound is administered after administration of the single dose of the psychedelic compound may be different to the length of time for which the severity of demoralisation syndrome symptoms is reduced.

In one embodiment, the patient identifies as male. In one embodiment, the patient identifies as female. In one embodiment, the patient identifies as non-binary. The patient may be from 18 to 100 years old, for example from 8 to 80 years old or 21 to 80 years old. In one embodiment, the patient is from 40 to 60 years old. The patient may be from 12 to 18 years old, for example from 14 to 18 years old, 15 to 18 years old, or 16 to 18 years old. In one embodiment, the patient has not received a psychedelic compound at any point in his or her life prior to the administration of the psychedelic compound (i.e. the patient has not taken or received a psychedelic compound in his or her lifetime prior to the treatment of the invention). For instance, the patient may have never before been administered psilocybin (including self-administration). In another embodiment, the patient has received a psychedelic compound at some point in his or her life prior to the administration of the psychedelic compound in the method of the invention. For instance, the patient may have been administered psilocybin at a point in the past (e.g. prior to the diagnosis of a life-threatening and/or life-altering disease). For instance, the patient may have been administered psilocybin more than one year, or more than five years, before the treatment of the invention.

The method of the invention may further comprise assessing the patient to determine the extent to which demoralisation syndrome symptoms has been reduced. The patient may be assessed within twelve hours of administration of the psychedelic compound. The patient may be assessed at least two weeks after the administration of the psychedelic compound. In one embodiment, the patient is assessed at least six months, at least two years, at least three years or at least four and a half years after the administration of the psychedelic compound.

Treatment of demoralisation syndrome according to the methods described herein typically improves patient compliance with any treatments they are receiving for a life-threatening and/or life-altering disease. Accordingly, where the patient is undergoing treatment for a life-threatening and/or life-altering disease, the method of the invention may further comprise assessing the patient to determine the extent to which the patient’s compliance with the treatment has been increased.

The psychedelic compound is administered in an amount effective to treat demoralisation syndrome. An effective amount of the psychedelic compound may be from about 0.001 mg/kg to about 10 mg/kg, for instance from about 0.01 mg/kg to about 1 mg/kg, where mg/kg is mg per kg of the patient’s body weight at the time of the administration of the dose. Typically, an effective amount of the psychedelic compound may be a dose of from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.2 mg/kg to about 0.4 mg/kg. In one embodiment, the effective amount of the psychedelic compound is about 0.3 mg/kg.

The effective dose of the psychedelic compound may be from about 0.1 to about 100 mg. In one embodiment, the psychedelic compound is administered in a dose from about 1 mg to 60 mg or from about 5 mg to about 30 mg. Typically, the dose may be from about 10 mg to about 30 mg, or from about 15 mg to about 30 mg, or from about 20 mg to about 30 mg. In one embodiment, the dose is about 25 mg. In one embodiment, the dose may be from about 0.5 mg to about 40 mg, for example from 1 mg to about 10 mg.

Where the psychedelic compound is to be administered to the patient by subcutaneous injection, the psychedelic compound may be administered in a dose from about 1 mg to about 18 mg, for example from 1 .5 mg to about 2.5 mg, from about 2.5 mg to about 3.5 mg, from about 3.5 mg to about 4.5 mg, from about 4.5 mg to about 5.5 mg, from about 5.5 mg to about 6.5 mg, from about 6.5 mg to about 7.5 mg, from about 7.5 mg to about 8.5 mg, from about 8.5 mg to about 9.5 mg, from about 9.5 mg to about 10.5 mg, from about 10.5 mg to about 11 .5 mg, from about 1 1 .5 mg to about 12.5 mg, from about 12.5 mg to about 13.5 mg, from about 13.5 mg to about 14.5 mg, from about 14.5 mg to about 15.5 mg, from about

15.5 mg to about 16.5 mg, or from about 16.5 mg to about 17.5 mg.

Where the psychedelic compound is to be administered to the patient by intramuscular injection, the psychedelic compound may be administered in a dose from about 1 mg to about 15 mg, for example from about 1 .5 mg to about 2.5 mg, from about 2.5 mg to about 3.5 mg, from about 3.5 mg to about 4.5 mg, from about

4.5 mg to about 5.5 mg, from about 5.5 mg to about 6.5 mg, from about 6.5 mg to about 7.5 mg, from about 7.5 mg to about 8.5 mg, from about 8.5 mg to about 9.5 mg, from about 9.5 mg to about 10.5 mg, from about 10.5 mg to about 11 .5 mg, from about 1 1 .5 mg to about 12.5 mg, from about 12.5 mg to about 13.5 mg, or from about 13.5 mg to about 14.5 mg. Where the psychedelic compound is to be administered to the patient by intravenous infusion, the psychedelic compound may be administered in a dose of from about 0.5 mg to about 25 mg, from about 1 mg to about 24 mg, from about 1 .5 mg to about 23 mg, from about 2 mg to about 22 mg, from about 2.5 mg to about 21 mg, from about 3 mg to about 20 mg, from about 3.5 mg to about 19 mg, from about 4 mg to about 18 mg, from about 4.5 mg to about 17 mg, from about 5 mg to about 16 mg, from about 5.5 mg to about 15 mg, from about 6 mg to about 14 mg, from about 6.5 mg to about 13 mg, or from about 7 mg to about 12 mg.

As discussed above, the dose may be a single dose with no further dose administered for a period of time after the single dose. Alternatively, the psychedelic compound may be administered more than once. In one embodiment, the psychedelic compound is administered one, two, three or four times. The psychedelic compound may be administered one, two, three, four, five, six or greater than six times a year. Each dose of the psychedelic compound may be accompanied by supportive therapy as described herein.

In one embodiment, the psychedelic compound is psilocybin. The method of the invention may accordingly comprise administering a dose of psilocybin which is from about 0.01 mg/kg to about 1 mg/kg. The dose of psilocybin may be from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.2 mg/kg to about 0.4 mg/kg. In one embodiment, the dose of psilocybin is about 0.3 mg/kg.

Alternatively, the method of the invention may comprise administering a dose of psilocybin which is from about 5 mg to about 30 mg. The dose of psilocybin may be from about 10 mg to about 30 mg, or from about 15 mg to about 30 mg, or from about 20 mg to about 30 mg. In one embodiment, the single dose of psilocybin is about 25 mg.

In one embodiment, the psychedelic compound is psilocin. The method of the invention may accordingly comprise administering a dose of psilocin which is from about 0.01 mg/kg to about 1 mg/kg. The dose of psilocin may be from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.2 mg/kg to about 0.4 mg/kg. In one embodiment, the dose of psilocin is about 0.3 mg/kg.

Alternatively, the method of the invention may comprise administering a dose of psilocin which is from about 5 mg to about 30 mg. The dose of psilocin may be from about 10 mg to about 30 mg, or from about 15 mg to about 30 mg, or from about 20 mg to about 30 mg. In one embodiment, the single dose of psilocin is about 25 mg.

In one embodiment, the patient is not administered a separate treatment for demoralisation syndrome for the period during which the demoralisation syndrome is treated using the method of the invention.

Kits

The kit of the invention contains the psychedelic compound; and instructions for use of said psychedelic compound in the method of treating demoralisation syndrome in a patient. Said instructions may include, for example, instructions for supportive therapy such as psychotherapy treatment to be provided before, during, and/or after the administration of the psychedelic compound. The psychedelic compound is typically in the form of a pharmaceutical formulation, for instance as described below.

Formulation of the psychedelic compound

The psychedelic compound may be administered to the patient by any acceptable route of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral (including subcutaneous, intramuscular and intravenous) modes of administration. The psychedelic compound may be administered as, for example: a tablet, capsule, powder, solution or suspension for oral administration; a solution or suspension for injection (for example, a solution or suspension for subcutaneous injection, or a solution or suspension for intramuscular injection); a solution for intravenous infusion; a solution, suspension or powder for inhalation; or a dosage form or lozenge for sublingual or buccal administration. The psychedelic compound may be administered in a food stuff, for instance a food stuff comprising a natural source of the psychedelic compound such as a fungus of the genus Psilocybe. Typically, the psychedelic compound is administered to the patient by oral administration, subcutaneous injection, intramuscular injection, or intravenous infusion.

Depending on the mode of administration used, the psychedelic compound (e.g. psilocybin) may be formulated with an appropriate conventional carrier, excipient or diluent. Pharmaceutically acceptable excipients, carriers and diluents are well known to the skilled person.

The diluent may be any pharmaceutically acceptable diluent. The diluent is typically suitable for parenteral administration or for oral administration. Examples of suitable liquid diluents include water, ethanol and glycerol. The diluent may alternatively be selected from solid diluents such as lactose, dextrose, saccharose, cellulose, corn starch and potato starch. The diluent may contain buffer components to control the pH. The buffers may be derived from phosphate, citrate or acetate. The diluent may also contain sodium chloride.

The excipient may be selected from: lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose, glycerine, mannitol or sorbitol.

Suspensions or emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for subcutaneous or intramuscular injections may contain, together with the psychedelic compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. Solutions for injection or infusion, or for inhalation, may contain as carrier, for example, sterile water or they may be in the form of sterile, aqueous, isotonic saline solutions.

The invention is described in more detail by the following Example. Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

The texts of references cited in this disclosure are herein incorporated by reference in their entireties.

EXAMPLE

The present example describes a Phase I IB clinical trial to assess the efficacy of psilocybin in the treatment of demoralisation syndrome in individuals with cancer.

Inclusion criteria

• Diagnosis of Demoralisation Syndrome based on research diagnostic criteria of demoralisation as assessed by independent remote raters trained in the DCPR-Dm module

• A minimum score on the DS scale of 30 indicative of moderate to severe demoralisation symptoms

• Exclusion of other major mental health disorders, except adjustment disorder, utilizing the Structured Clinical Interview for DSM Disorders - Clinical Trial version (SCID-5-CT), an extensively validated mental health diagnostic instrument.

• Diagnosis of cancer

Method

Diagnosis at Screening, Baseline, Day 29, Day 85, and End of Study (EOS)ZEarly Termination (ET) will be performed using the Diagnostic Criteria for Psychosomatic Research (DCPR)-Dm-SSI by a trained team of raters in the SAFER program. SAFER (State vs trait, Assessability, Face and Ecological validity, Rule of 3Ps) interviews will utilise experienced clinicians associated with Massachusetts General Hospital (MGH) to independently diagnose and assess mental health conditions and to confirm that appropriate patients are enrolled.

The clinical severity of demoralization symptoms will be assessed utilizing the Clinical Interview for Demoralization (CIDE). This study will assess the utility and validity of the CIDE in the assessment of demoralization symptom response as a possibly more refined and sensitive global measure of severity for demoralization syndrome than the general Clinical Global Impression of Severity (CGI). After screening, eligible participants will then undergo a second SAFER remote interview for a confirmatory diagnostic assessment of demoralization syndrome (using the DCPR-Dm-SSI) and other major mental health disorders (using the SCID-5-CT).

Claims

1 . A method of treating demoralisation syndrome in a patient, the method comprising administering a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, to said patient.

2. The method of claim 1 , wherein the psychedelic compound is psilocybin or a pharmaceutically acceptable salt or co-crystal thereof.

3. The method of claim 1 or claim 2, wherein the patient is not suffering from an additional affective disorder which is depression or wherein the patient is not suffering from an additional affective disorder which is an anxiety disorder.

4. The method of any one of the preceding claims, wherein the patient is not suffering from an additional affective disorder which is depression or an anxiety disorder.

5. The method of any one of the preceding claims, wherein the patient is not suffering from an additional affective disorder which is depression, an anxiety disorder or bipolar disorder.

6. The method of any one of the preceding claims, wherein the patient is not suffering from any additional mental health disorder as determined using the SCID-CT.

7. The method of any one of the preceding claims, wherein the patient is suffering from adjustment disorder.

8. The method of any one of claims 1 to 6, wherein the patient is not suffering from adjustment disorder.

9. The method of any one of claims 3 to 8, wherein the anxiety disorder is selected from panic disorder, post-traumatic stress disorder, obsessive- compulsive disorder, social phobia, acute stress disorder, and generalized anxiety disorder.

10. The method of any one of the preceding claims, wherein the patient is suffering from demoralisation syndrome without depression and/or an anxiety disorder.

11 . The method of any one of the preceding claims, wherein the patient is suffering from a life-threatening and/or life-altering disease.

12. The method of any one of claims 1 to 10, wherein the patient is in remission from a life-threatening and/or life-altering disease.

13. The method of claim 11 or claim 12, wherein the psychedelic compound is administered to the patient during a period in which the patient is receiving treatment for the life-threatening and/or life-altering disease.

14. The method of any one of claims 11 to 13, wherein the life-threatening and/or life-altering disease is selected from cancer, amyotrophic lateral sclerosis (ALS), dementia, non-CNS amyloidosis, disabling spinal stenosis, motor neurone disease, Alzheimer’s disease, Huntington’s disease, essential tremor, Parkinson’s disease, migraine, cluster headache, epilepsy, rheumatoid arthritis (RA), systemic lupus erythematosis, sarcoidosis without brain involvement, osteoarthritis, fibromyalgia, myasthenia gravis, myalgic encephalopathy, multiple sclerosis, pulmonary arterial hypertension (PAH), pulmonary fibromatosis, interstitial pulmonary disease, asthma, chronic obstructive pulmonary disease (COPD), heart disease, myocardial infarction, hypertension, heart failure diabetes, prolonged postviral syndrome, acquired immune deficiency syndrome (AIDS), recurrent malaria, irritable bowel syndrome, Crohn’s disease, psoriasis, limb amputation, organ transplant, traumatic paralysis, opioid use disorder, and prisoner of war/Stockholm syndrome.

15. The method of claim 14, wherein the life-threatening and/or life-altering disease is cancer.

16. The method of claim 15, wherein the cancer is stage I or stage II cancer.

17. The method of claim 15, wherein the cancer is late-stage cancer.

18. The method of claim 15, wherein the cancer is stage III or stage IV cancer.

19. The method of any one of claims 15 to 18, wherein the cancer is selected from breast cancer, reproductive cancer, lymphoma, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid/rhabdoid tumor, bile duct cancer, bladder cancer, bone cancer, bowel cancer, brain cancer, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, cutaneous T-cell lymphoma, oesophageal cancer, eye cancer, intraocular melanoma, fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, germ cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, Hodgkin lymphoma, intraocular melanoma, islet cell tumor, kidney cancer, Langerhans cell histiocytosis, liver cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and tracheobronchial tumor), melanoma, mesothelioma, metastatic cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasms, myelodysplastic syndrome, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, retinoblastoma, salivary gland cancer, sarcoma, skin cancer, small intestine cancer, soft tissue sarcoma, testicular cancer, throat cancer, thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, and vaginal cancer.

20. The method of any one of claims 1 to 10, wherein the patient has not been diagnosed with a life-threatening and/or a life-altering disease.

21 . The method of any one of the preceding claims, wherein the patient has been identified as being in need of treatment for demoralisation syndrome.

22. The method of any one of the preceding claims, wherein the method comprises assessing the level of demoralisation syndrome in the patient; and administering a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, to said patient.

23. The method of any one of the preceding claims, wherein the method further comprises providing the patient with supportive therapy.

24. The method of any one of the preceding claims, wherein a Kissane Demoralisation Scale score of the patient prior to administration of the psychedelic compound is greater than about 30.

25. The method of any one of the preceding claims, wherein a Kissane Demoralisation Scale score of the patient is reduced after administration of the psychedelic compound.

26. The method of any one of the preceding claims, wherein a Clinical Interview for Demoralisation (CIDE) score of the patient prior to administration of the psychedelic compound is at least 6, at least 8, at least 10, at least 12, at least 16 or at least 20.

27. The method of any one of the preceding claims, wherein a Clinical Interview for Demoralisation (CIDE) score of the patient is reduced after administration of the psychedelic compound, optionally wherein the CIDE score of the patient is reduced by at least 20%.

28. The method of any one of the preceding claims, wherein the psychedelic compound is administered at a dose of from about 0.5 mg to about 40 mg.

29. The method of any one of the preceding claims, wherein the psychedelic compound is administered as a single dose, and wherein no further dose is administered for at least six months after administration of the single dose of the psychedelic compound.

30. The method of any one of the preceding claims, wherein the psychedelic compound is administered to the patient by oral administration, subcutaneous injection, intramuscular injection, or intravenous infusion.

31. A kit comprising: a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof; and instructions for use of said psychedelic compound in a method of treating demoralisation syndrome in a patient, the method comprising administering the psychedelic compound to said patient.

32. A psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, for use in a method of treating demoralisation syndrome in a patient.

3. Use of a psychedelic compound which is psilocin or a prodrug of psilocin, or a pharmaceutically acceptable salt or co-crystal thereof, in the preparation of a medicament for use in treating demoralisation syndrome in a patient.