Combinations of 5-meo-DMT with antidepressants for treating depression

Abstract

The present invention relates to 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in treating a patient who has been diagnosed with a mental disorder or a nervous system disorder by administration of a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course involves administration of one or more doses of 5-MeO-DMT or a pharmaceutically acceptable salt thereof on a single day to remove or alleviate one or more symptoms of the mental disorder or the nervous system disorder. The patient is also treated with one or more antidepressant(s).

Description

[0001] Combination Pharmaceuticals

[0002] Technical Field

[0003] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in a combination treatment of a patient who has been diagnosed with a mental disorder or a nervous system disorder, such as a disorder involving depressive episodes and / or episodes of anxiety.

[0004] Background of the Invention

[0005] Various treatments of mental disorders and nervous system disorders, such as disorders involving depressive episodes and / or episodes of anxiety, are established or have been suggested which rely on the administration of psychotropic drugs.

[0006] For instance, various classes of antidepressants are in use, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, serotonin modulators, tricyclic antidepressants (TCAs), NMDA antagonists and monoamine oxidase inhibitors (MAOI).

[0007] Antidepressants are often used in combination with other psychotropic drugs, such as in combination with non-antidepressants like antipsychotics (APs).

[0008] Despite the widespread use, treatment with antidepressants and combinations of antidepressants with other psychotropic drugs has only limited success. Long-term administration is usually required. A course of antidepressant treatment will usually last for at least 6 months, and patients may be advised to take antidepressants indefinitely.

[0009] Remission is nevertheless often not achieved. A significant proportion of patients suffers from treatment-resistant disease which does not respond to currently available antidepressant therapies. Even in those patients who respond to the therapy, improvements are not achieved in all aspects of the disease.

[0010] Recently, psychedelic compounds have been used in clinical trials, often in combination with psychotherapy. 5-MeO-DMT has demonstrated therapeutic efficacy on its own, i.e. , when administered without any other concurrent therapy, in the treatment of mental disorders and nervous system disorders, such as disorders involving depressive episodes and / or episodes of anxiety. For instance, administration of 5-MeO-DMT led to rapid clinical responses in patients suffering from MDD, and remission was achieved even in patients that did not respond to previous therapies (treatment-resistant patients). In many cases, rapid remission can be achieved after a single treatment course.

[0011] The therapeutic use of 5-MeO-DMT and pharmaceutically acceptable salts thereof is described, for instance, in WO 2020 / 169850, WO 2020 / 169851 , WO2023 / 186823,

[0012] WO2023 / 186816, WO2023 / 186797, WO2023 / 186829, WO2023 / 186830,

[0013] WO2023 / 186824, WO2023 / 186828, WO2023 / 186798, WO2023 / 186832,

[0014] WO2023 / 186831 , WO2023 / 186820, WO2023 / 186821 , WO2023 / 186808,

[0015] WO2023 / 186835, WO2023 / 186806, WO2023 / 186837, WO2023 / 186826, and

[0016] WO2023 / 186827.

[0017] While discontinuation of psychotropic medications, including a wash-out period of several weeks, is well possible in the context of clinical studies, it may be less practical in actual clinical use, in particular since many severely ill patients who deserve treatment with 5-MeO-DMT will take one or more psychotropic medications, in particular one or more antidepressants.

[0018] Further, while treatment with 5-MeO-DMT leads to clinical effects which last much longer than the duration of the actual treatment course, such that a patient may still be in remission 4 weeks after having received a 5-MeO-DMT / salt treatment course, there are patients in whom the duration of treatment effects is limited.

[0019] Thus, there is a need for further and in particular for improved methods of treatment.

[0020] Summary of the Invention

[0021] The present invention relates to 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in treating a patient who has been diagnosed with a mental disorder or a nervous system disorder by administration of a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course involves administration of one or more doses of 5- MeO-DMT or a pharmaceutically acceptable salt thereof on a single day to remove or alleviate one or more symptoms of the mental disorder or the nervous system disorder. The patient is also treated with one or more antidepressant(s).

[0022] The antidepressant may be a selective serotonin reuptake inhibitor (SSRI) selected from fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram; a serotonin and norepinephrine reuptake inhibitor (SNRI) selected from duloxetine, venlafaxine, desvenlafaxine, milnacipran and levomilnacipran; a serotonin modulator selected from nefazodone, trazodone, vilazodone and vortioxetine; a tricyclic antidepressant (TCA) selected from amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline and trimipramine; a tetracyclic antidepressant (TeCA) selected from mirtazapine, maprotiline and mianserin; NMDA receptor antagonists such as ketamine, esketamine and dextromethorphan alone or in combination with bupropion; an atypical antidepressant selected from bupropion, agomelatine and gepirone.

[0023] The antidepressant does not comprise a monoamine oxidase inhibitor (MAOI), such as selegiline, moclobemide, tranylcypromine, isocarboxazid, or phenelzine.

[0024] The patient may also be treated with one or more augmentation medicine(s), selected from mood stabilisers and thyroid agents. Mood stabilisers are antipsychotics, such as quetiapine (immediate-release or extended-release), olanzapine, aripiprazole, risperidone and brexpiprazole; anticonvulsants, such as lamotrigine; or lithium. Thyroid agents include liothyronine and levothyroxine.

[0025] The patient suffers from a mental disorder or a nervous system disorder, such as Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder (SAD) and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Anxiety Disorder, for example Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobias, and Substance / Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post- Traumatic Stress Disorder (PTSD); Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Eating Disorders for example bulimia nervosa or anorexia nervosa; Attention Deficit Hyperactivity Disorder (ADHD); Sleep Disturbances, for example insomnia; Cognitive Dysfunction; Social / Emotional Withdrawal or Detachment; Negative Thinking; Psychomotor Retardation; or Suicidal Ideation.

[0026] An aim of the invention is in particular the provision of therapies which are more effective (i.e., a) a larger percentage of patients experiencing a clinical response, b) a larger average clinical response, c) an earlier onset of the clinical response, and / or d) a more durable clinical response) than previously described therapies.

[0027] A further aim of the current invention is to provide a compound for improved psychoactive therapies and dosing regimens for said therapies which have a better safety profile and / or are better tolerated than previously described therapies. Another aim of the current invention is to provide a compound for improved psychoactive therapies and dosing regimens for said therapies which are more convenient than previously described therapies. Another aim of the current invention is to provide a compound for improved psychoactive therapies and dosing regimens for said therapies which are associated with higher rates of patient compliance (including higher rates of treatment initiation) than previously described therapies. A still further aim of the current invention is to identify specific disease aspects and specific subgroups of disease aspects which benefit from such improved psychoactive therapies.

[0028] Detailed Description of the Invention

[0029] Definitions

[0030] As used herein, a "depressive episode" is a period of depressed mood and / or loss of pleasure in most activities. A depressive episode is in particular a major depressive episode. A "major depressive episode", in line with the definition according to DSM-V, is characterized by five or more symptoms that have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms being either (1) depressed mood or (2) loss of interest or pleasure.

[0031] An "episode of anxiety", also referred to as an anxiety attack, involves feelings of overwhelming fear and worry of some specific occurrence or problem that could happen. An episode of anxiety may be accompanied by physical symptoms like shortness of breath, nausea, dizziness, and a racing heartbeat.

[0032] As used in the context of the present invention, unless otherwise noted, the term "5- MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are in particular acid addition salts, wherein the acid may be selected from, for instance, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and triflic acid. For instance, the pharmaceutically acceptable salt of 5-MeO-DMT is the benzoate salt or the hydrobromide salt. An especially preferred example is the hydrobromide salt. The appropriate weight amount of a salt to be administered can be calculated from the weight amount of the free base, assuming that equimolar amounts are used.

[0033] As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety, by a licensed professional in accordance with accepted medical practice or who is diagnosed by a licensed professional in accordance with accepted medical practice with a mental disorder or a nervous system disorder.

[0034] Diagnosis of a mental disorder or a nervous system disorder can, for instance, be in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. In some instances, as is apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or patient groups particularly benefiting from a treatment according to the invention. The diagnosis will be by a physician or a psychologist. It is not sufficient that the human subject himself / herself considers that he / she is suffering from the disorder. As used in the context of the present invention, unless otherwise noted, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or eliminate the disease, condition, or disorder.

[0035] The patient may suffer from an anxiety disorder or a disorder associated with anxiety. Anxiety may be associated with sleep disturbance.

[0036] The patient may suffer from treatment resistant disease. Treatment resistance means that the patient had no adequate improvement after at least two adequate courses of therapy. The patient in particular had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy; for instance, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy. The at least two prior courses of treatment were in particular administered in the current episode of the disease, for instance, if the patient suffers from a disorder involving depressive episodes, in the current episode of depression.

[0037] A "relapse" is the return of a disease or the signs and symptoms of a disease after a period of improvement.

[0038] As used in the context of the present invention, "suicidal ideation" refers to thinking about, considering, or planning for suicide. The presence of suicidal ideation in a patient will be diagnosed by a physician or a psychologist, using established protocols and methods for diagnosing suicidality. It is generally not sufficient that the patient himself considers that he / she is suffering from suicidal ideation. In some situations, a patient experiencing suicidal ideation will be at imminent risk of committing suicide, or will be considered to have 'intent to act.'

[0039] As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" shall mean the amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0040] "Clinical response" includes, but is not limited to, improvements on rating scales such as the Clinical Global Impression - Severity scale (CGI-S), the Patient Global Impression - Severity scale (PGI-S), the Clinical Global Impression - Improvement scale (CGI-I) or the Patient Global Impression - Improvement scale (PGI-I) and further includes, but is not limited to, endpoints such as the Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) for major depressive disorder and persistent depressive disorder, anxiety symptoms e.g. as measured by the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Scale (HAM-A) or the State- Trait Anxiety Inventory (STAI) for anxiety disorder, the Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS) for posttraumatic stress disorder, the Yale- Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder (BDD- YBOCS) for body dysmorphic disorder, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for obsessive-compulsive disorder, weight gain for anorexia nervosa, frequency of binge- purge episodes for bulimia nervosa, frequency of binge episodes for binge eating disorder, duration of abstinence or reduced substance use in psychoactive substance abuse and suicidality rating scales such as the Columbia-Suicide Severity Rating Scale (C- SSRS) or the suicidal thoughts item of the MADRS for suicidal ideation or the Clinical Global Impression - Severity of Suicidality - Revised (CGI-SS-R) scale (the CGI-SS-R is derived from the CGI-S, and is scored 0 = Normal, Not At All Suicidal; 1 = Questionably Suicidal; 2= Mildly Suicidal; 3 = Moderately Suicidal; 4 = Markedly Suicidal;

[0041] 5 = Severely Suicidal; 6 = Extremely Suicidal).

[0042] The Barkin Index of Maternal Functioning (BIMF) was designed to measure functioning in the year after childbirth and can be applied to postpartum depression. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score between 0 and

[0043] 6 so that the maximum total score is 120. The higher the score, the better maternal functioning is rated. The BIMF identifies the key functional domains of a mother during the postnatal period as: self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.

[0044] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and / or mixed symptoms expressed by patients currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms. The scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.

[0045] The Hamilton Anxiety Rating Scale (HAM-A) is used to measure the severity of anxiety symptoms in a variety of anxiety disorders (panic, phobia, and generalized). The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Item 5 is ‘Intellectual’, defined as ‘difficulty in concentration, poor memory’. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

[0046] The severity of anxiety disorders can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0047] Subthreshold anxiety as the term is used herein in particular means that the patient has a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 but of less than 18 and / or a Beck Anxiety Inventory (BAI) score of at least 11 but of less than 16.

[0048] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptom

[0049] - Adult measure. This measure comprises 15 somatic symptoms. Respondents are asked to rate the severity of the individual’s somatic symptoms during the past 7 days. Scoring ranges from "0" ("Not bothered at all"), "1" ("Bothered a little") to "2" ("Bothered a lot"). The total score can range from 0 to 30, with higher scores indicating greater severity of somatic symptoms. A cut-off value of 5, 10 and 15 indicates low, medium, high somatic symptom severity, respectively. Also, the Somatic Symptom Disorder-B Criteria Scale (SSD-12) can be used. Cognitive, affective, and behavioural criteria are measured by 12 items with all item scores ranging between 0 and 4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = very often). Ratings are summed up to make a simple sum score, which can vary between 0 and 48 points. Shift in attention is considered by the item "Due to my physical complaints, I have poor concentration on other things" or "My physical complaints occupy me for most of the day".

[0050] Improvements in sleep disturbance may be assessed by any scale reflecting changes in sleep quality or quantity, for instance the Pittsburgh Sleep Quality Index (PSQI). The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction. Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Detailed Scoring Instructions for the Pittsburgh Sleep Quality Index can be found in the Appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0051] The seven component scores are then summed to yield one global score, with a range of 0-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas. A global score cut-off of 5 distinguishes poor from good sleepers. A global score > 5 indicates that a patient is having severe difficulties in at least two areas, or moderate difficulties in more than three areas.

[0052] Common tests that assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screen for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

[0053] Symptoms of social / emotional withdrawal or detachment can be assessed by the Snaith- Hamilton Pleasure Scale (SHAPS), which is a 14-item scale that measures anhedonia, i.e., the inability to experience pleasure; by the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort and consummatory pleasure across four domains: hobbies, food / drink, social activities and sensory experience; or by the Personality Inventory for DSM-5 (PID-5) - Adult, which is a 220 item self-rated personality trait assessment scale for adults age 18 and older, which assesses 25 personality trait facets including Anhedonia, Anxiousness, Attention Seeking, Callousness, Deceitfulness, Depressivity, Distractibility, Eccentricity, Emotional Lability, Grandiosity, Hostility, Impulsivity, Intimacy Avoidance, Irresponsibility, Manipulativeness, Perceptual Dysregulation, Perseveration, Restricted Affectivity, Rigid Perfectionism, Risk Taking, Separation Insecurity, Submissiveness, Suspiciousness, Unusual Beliefs and Experiences, and Withdrawal.

[0054] Instruments evaluating relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule - Expanded Form (PANAS-X) or the State Hope Scale (SHS).

[0055] Psychomotor retardation can be assessed by measuring various aspects. These may include for instance various types of drawing tasks and tests, such as the trail making test (TMT), the digit symbol substitution test (DSST), or the Gibson Spiral Maze Test (GSM) and others which are known in the art.

[0056] When assessing a clinical response, for instance, using one of the scales to assess severity of a mental disorder or a nervous system disorder, at an early timepoint after drug administration {e.g. at 2 hours) based on endpoints which have been developed for a longer recall period (e.g. normally 7 days for the MADRS), a rational modification of such endpoint (e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied. The same applies with respect to any other scale applied herein, unless a recall period is specifically indicated.

[0057] The considerations outlined apply for early timepoints because, on the one hand, in order to assess a clinical response, the influence of the patient's status before the treatment on any score recorded after treatment should be kept as low as possible, whereas on the other hand the sleep item cannot be assessed 2 hours after drug administration.

[0058] At later timepoints, for instance, on day 1 or later, typically all items of the relevant scales to assess a clinical response can be assessed, using, if necessary, an adapted recall period, so that it is not necessary to carry forward any pre-treatment score.

[0059] The severity of a condition as well as changes of the severity can be assessed by the Clinical Global Impression (CGI) rating scales which are measures of symptom severity, treatment response and the efficacy of treatments.

[0060] The CGI rating scales were developed to provide a brief, stand-alone assessment of the clinician’s view of the patient’s global functioning prior to and after a treatment (Busner, J. and Tagrum, S. D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0061] The CGI-Severity (CGI-S) is based on one question the clinician has to answer: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" This is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.

[0062] The CGI-S can be used to assess treatment success by comparing scores before and after treatment. Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which is similarly simple in its format. After the treatment, the clinician compares the patient's overall clinical condition to the one prior to the treatment (the so-called baseline value). Again, only one query is rated on a seven-point scale: "Compared to the patient's condition at admission to the project [prior to medication initiation], this patient's condition is: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment."

[0063] The Patient Global Impression scale (PGI), also known as Subject Global Impression (SGI), is the counterpart to the Clinical Global Impressions scale (CGI). It consists of one item based on the CGI and adapted to the patient. It can measure disease severity (PGI- S) or disease improvement (PGI-I).

[0064] Individual items of scales as described herein as well as sub-combinations of individual items may be used to assess specific disease aspects.

[0065] As used in the context of the present invention, unless otherwise noted, the term "administration" (or "application") shall mean the introduction of an amount, which may be a predetermined amount, of active compound or pharmaceutical ingredient into a patient via any route.

[0066] A "5-MeO-DMT / salt treatment course" as the term is used herein, involves administration of one or more doses of 5-MeO-DMT or a pharmaceutically acceptable salt thereof on a single day, / .e., within 24 hours.

[0067] 5-MeO-DMT is preferably administered by inhalation, nasally, by buccal administration or by sublingual administration. The most preferred route for administration of 5-MeO- DMT is by inhalation. Alternatively, 5-MeO-DMT is administered by intravenous administration, by intramuscular administration or by subcutaneous administration, in particular by intravenous administration.

[0068] Compounds administered in the context of the combination therapy of the present invention, which are not 5-MeO-DMT or a pharmaceutically acceptable salt thereof, are ad- ministered preferably orally.

[0069] As used in the context of the present invention, unless otherwise noted, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient which is administered to a patient in an individual administration. '1

[0070] The term "dosage regimen" (or "dosing regimen") shall mean a defined sequence of one or more individual administrations.

[0071] As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and miniscule suspended solid and / or liquid particles. The term "degradation product" refers to a compound resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation. Such reaction includes, without limitation, oxidation. When a percentage of a "degradation product" is described in the context of the present invention, then this refers to the quantity of 5-MeO-DMT degradation products present in a sample divided by the quantity of 5-MeO-DMT plus 5-MeO-DMT degradation products present in the sample multiplied by 100%, i.e., (Sum of quantities of all 5-MeO-DMT degradation products present in the sample) I ((Quantity of 5-MeO-DMT present in the sample) + (Sum of quantities of all 5-MeO-DMT degradation products present in the sample)) x 100%. As used herein, the term "impurity" refers to unwanted compounds contaminating a sample of 5-MeO-DMT (or of a pharmaceutically acceptable salt thereof). Impurities may be contained in the starting material before aerosol formation or may be degradation products.

[0072] The term "purity" refers to 100% minus the percent of all 5-MeO-DMT degradation products and all other impurities present, i.e., 100% - (Sum of quantities of all 5-MeO- DMT degradation products present + Sum of quantities of all other impurities present) I (Quantity of 5-MeO-DMT present + Sum of quantities of all 5-MeO-DMT degradation products present + Sum of quantities of all other impurities present) x 100%.

[0073] The term "mass median aerodynamic diameter" (MMAD), is the diameter at which 50% of the particles present in an aerosol are larger than this calculated diameter, and 50% are smaller. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the aerosolized mass of 5-MeO-DMT per unit of aerosolization time.

[0074] A "combination treatment" is a treatment involving the concurrent administration of two or more active agent wherein a patient receives two or more active agents within a period of time. Unless specified otherwise, the time period contemplated herein is 24 hours.

[0075] A combination treatment does not require administration of combination products. A combination treatment involving administration of one or more antidepressants and of a 5-MeO-DMT / salt treatment course does not require that the one or more antidepressants are still administered after completion of the 5-MeO-DMT / salt treatment course. An "antidepressant" as the term is used herein is a drug that can be used to alleviate depressive symptoms. The term does not include 5-MeO- DMT and pharmaceutically acceptable salts thereof.

[0076] A "psychedelic compound" as the term is used herein is a hallucinogen which binds to 5-hydroxytryptamine (5-HT) receptors and has the ability to induce qualitatively altered states of consciousness such as euphoria, trance, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences.

[0077] An "augmentation medicine" as the term is used herein is a compound which can be added to an antidepressant with the aim of increasing the antidepressant effect.

[0078] Doses of antidepressants are often varied during treatment, depending on the presence or absence of treatment progress and the patient’s needs.

[0079] At initiation of an antidepressant therapy, a patient will typically receive low doses of antidepressants. For instance, a starting dose is administered for some time, such as one to several weeks, which may then be adjusted, depending on the patient’s reaction to the drug.

[0080] A "stable dose" of an antidepressant or of another psychotropic drug is a dose which has been administered to a patient for a certain time period, such as 1 week or more, without adjustment of dose amount or dosing regimen. In the context of the combination treatment according to the present invention, a stable dose of one or more antidepressants may be administered before administration of a 5-MeO-DMT / salt treatment course, meaning that there is no change of dose for the indicated time before the 5-MeO- DMT / salt treatment course.

[0081] A "maintenance dose" of an antidepressant is an adequate dose of an antidepressant for long term therapy. It is the dose the patient receives after adjustments during the phase of treatment initiation.

[0082] A "low dose" of an antidepressant is a dose which is lower than the maintenance dose.

[0083] A "sub-therapeutic" dose of an antidepressant is a dose which does not lead to a significant clinical response when administered as a monotherapy. Combination Treatments of Mental or Nervous System Disorders

[0084] The present invention is in part based on the inventors' consideration that processes involving adaptive structural and functional changes to the brain, which processes are often referred to as neuroplasticity, can be used to restore normal functioning in patients diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety and that such processes can be stimulated by administration of combinations of certain psychotropic drugs with 5- MeO-DMT or a pharmaceutically acceptable salt thereof.

[0085] Combination treatments as further discussed herein in particular have beneficial longterm effects.

[0086] Mental disorders and nervous system disorders, such as disorders involving depressive episodes and / or episodes of anxiety, involve neuroanatomical changes. Such changes in brain structure parallel pathological alterations in neural networks, which are brain regions consisting of groups of functionally associated neurons with coordinated activity.

[0087] Neurons (or nerve cells) are excitable cells that communicate with other cells using a combination of electrical and chemical signals. Signals can be transferred via synapses.

[0088] Each neuron has between a few to hundreds of thousands of synaptic connections, for instance, with neighbouring neurons or neurons in other regions of the brain

[0089] At presynaptic terminals or axon terminals, electrical signals (action potentials) coming via the axon, a long, thin structure of a neuron, are converted into chemical signals through the release of a neurotransmitter. The neurotransmitter released from the presynaptic terminal is one of the factors determining the quality and intensity of information transmitted by neurons.

[0090] The released neurotransmitter rapidly (in microseconds) diffuses across the synaptic cleft and binds to specific receptors on the postsynaptic neuron. Type (such as excitatory or inhibitory) and number of postsynaptic receptors are another factor determining the quality and intensity of information transmitted.

[0091] The postsynaptic neuron integrates the signals it receives via the postsynaptic terminals. A response is initiated based on the integrated signals. Postsynaptic terminals can be found on the cell body and in particular on dendrites, small projections from the cell body that receive incoming signals from other neurons and relay them to the cell body.

[0092] On the dendrites of most principal neurons in the brain, dendritic spines are found. Dendritic spines are tiny membranous protrusions from the dendritic shaft and are, for many synapses, the postsynaptic terminals. As signals are typically received via dendritic spines, they are cellular substrates of brain connectivity and the major sites of information processing in the brain.

[0093] The dendritic spines consist of a spine head and a spine neck. Spines can be classified into various types. The variable spine shape and volume is thought to be correlated with the strength and maturity of each spine-synapse.

[0094] Large mushroom spines represent strong synaptic contacts. Thin and stubby spines, as well as dendritic filopodia, are prevalent during development. Thin and stubby spines are considered to be immature, plastic spines. Dendritic filopodia are precursors of dendritic spines.

[0095] Formation, growth, and elimination of the dendritic spines are important processes contributing to synaptic plasticity, the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity.

[0096] Changes in the number, location, and properties of postsynaptic receptors, to which neurotransmitters bind, are other important processes contributing to plasticity.

[0097] A number of human disease states are associated with alterations of receptor expression and / or with alterations in number, location, and properties of postsynaptic receptors and with alterations in spine morphology and / or spine density.

[0098] Formation, growth, and elimination of the dendritic spines are commonly dysregulated or disrupted in mental disorders or nervous system disorders, such as disorders involving depressive episodes. For instance, disorders involving depressive episodes and / or episodes of anxiety are associated with structural changes, altered cellular resilience, and neuronal atrophy. Changes can involve changes in receptor expression as well as structural and molecular remodelling of dendritic spines in specific brain regions.

[0099] While there are different classes of antidepressants which interact with different pharmacological drug targets, there is emerging evidence that antidepressants share a common mechanism of action downstream of their particular targets which involves reversal of some of the structural changes associated with mental disorders or nervous system disorders, such as disorders involving depressive episodes and / or episodes of anxiety, at the cellular level, so that synaptic connections in neural circuits can be restored to improve mood regulation and other functions. Therapeutic effects are visible in particular after administration for a prolonged time, for instance, for several weeks or several months.

[0100] The reversal of pathologic structural changes induced by antidepressant therapy is, however, not necessarily lasting and discontinuation of the antidepressant medication may lead to worsening of a patient's clinical situation. The patient may suffer from a relapse of the disease.

[0101] Treatment with 5-MeO-DMT has been successfully used in clinical trials involving patients suffering from a mental disorder or a nervous system disorder, in particular a disorder characterized by depressive symptoms.

[0102] The tested monotherapy led to rapid clinical effects, for instance, remission within hours after administration of the last dose of a 5-MeO-DMT / salt treatment course, even in patients resistant to treatment courses involving the administration of antidepressants.

[0103] Simultaneous improvements in various aspects of the disease were observed, in particular in the areas of cognitive dysfunction, sleep disturbance, psychomotor retardation, negative thinking and social / emotional withdrawal.

[0104] The inventors consider that binding of 5-MeO-DMT to particular receptors, such as the 5-HT7 receptor as well as the 5-HT1A receptor, leads to specific alterations of Resting State Network (RSN) activity, in particular functional connectivity "resets" of networks, and promotes plasticity via the activation of signal transduction cascades.

[0105] In the trials carried out so far, patients were advised to discontinue any psychotropic medications including antidepressant medications. In fact, such medications were not only discontinued before the 5-MeO-DMT / salt treatment course, but a wash out period of typically several weeks was even applied.

[0106] However, discontinuation of psychotropic medications, including a wash-out period of several weeks, is considered disadvantageous in actual clinical use. Many severely ill patients who deserve treatment with 5-MeO-DMT will take one or more psychotropic medications, in particular one or more antidepressants. Discontinuation and wash-out of such medications may leave patients without adequate treatment for some time and may lead to a discontinuation syndrome. Patients will in any event have to wait for some time until treatment with 5-MeO-DMT can be started, which is a disadvantage.

[0107] The requirement of a wash-out would be particularly troublesome in patients experiencing a worsening of their condition, for instance, an acute deterioration of their condition, while being treated with one or more antidepressant.

[0108] These disadvantages are addressed by the present invention.

[0109] The present invention further addresses the duration of the treatment.

[0110] Treatments with 5-MeO-DMT so far described led to clinical effects lasting much longer than the duration of the actual treatment course. For instance, there are patients still in remission weeks after having received a 5-MeO-DMT / salt treatment course. Nevertheless, the duration of treatment effects may be limited. There are patients suffering from a worsening of disease symptoms after an initially successful treatment, and these patients may need treatment for their disease.

[0111] Longer duration of treatment effects would be beneficial.

[0112] According to the present invention, patients diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety, can advantageously be treated by the concurrent administration of 5-MeO-DMT and one or more antidepressants, optionally together with one or more other psychotropic drugs, to remove or alleviate symptoms of the mental disorder or the nervous system disorder, such as depressive symptoms and / or symptoms of anxiety.

[0113] The combination according to the present invention is suitable to address symptoms not adequately treated by antidepressants. The combination leads to beneficial effects also in patients suffering from symptoms or conditions such as sleep disturbance, cognitive dysfunction, psychomotor retardation, negative thinking and / or social / emotional withdrawal.

[0114] Antidepressants, alone or together with other psychotropic drugs, and 5-MeO-DMT have so far not been administered in combination for treating patient diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety. It has now been found that patients who have been diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety and who receive a concurrent treatment with one or more antidepressants, can be treated with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0115] The inventors have determined that antidepressants and 5-MeO-DMT can be safely administered in combination. In particular when all components of the combination are used at their therapeutic doses or at sub-therapeutic doses, no serotonin-related adverse reactions of concern are observed.

[0116] To the extent that serotonin-related adverse reactions are observed at all, they are transient and rapidly disappear after administration of the last dose of 5-MeO-DMT.

[0117] The inventors believe that this is related to the short duration of the 5-MeO-DMT / salt treatment course; to the short duration of acute effects of 5-MeO-DMT; and to the low affinity 5-MeO-DMT has for 5-HT2A receptor, compared to other psychedelic compounds.

[0118] It is noted that monoamine oxidase inhibitors (MAOIs), such as the antidepressants selegiline, moclobemide, tranylcypromine, isocarboxazid, or phenelzine, require particular care when choosing doses since MAOIs inhibit metabolization of 5-MeO-DMT and thus lead to increased levels of 5-MeO-DMT for prolonged periods of time.

[0119] According to the invention, MAOIs and 5-MeO-DMT are preferably not used in combination. Combination treatments according to the invention preferably do not involve selegiline, moclobemide, tranylcypromine, isocarboxazid, or phenelzine.

[0120] Combination treatments as disclosed herein are not only safe but also lead to advantageous therapeutic effects.

[0121] The inventors consider that an antidepressant therapy leads to improvements in relation to plasticity, albeit the effect may be limited and may last only for a limited time if treatment is discontinued; that a 5-MeO-DMT / salt treatment course also has an effect on plasticity; and that a combination treatment leads to combined effects on plasticity.

[0122] The administration of a 5-MeO-DMT / salt treatment course and the concurrent treatment with one or more antidepressants lead to beneficial long-term effects, in particular longterm effects related to plasticity. Antidepressants and 5-MeO-DMT work through specific and distinct mechanisms to foster neuroplasticity. When administered in combination, they will each have a therapeutic effect.

[0123] Given the different mechanisms through which the antidepressants and 5-MeO-DMT act, combination treatments will have additive effects and even synergistic effects.

[0124] If a patient has received one or more antidepressants for some time, this will lead to improvements in plasticity and consequential improvements in neuronal connectivity. Such improvements will occur even if the patient is not in remission and even if the patient shows an inadequate response to the one or more antidepressants such as a partial response insufficient to be considered a clinical response. Improvements in plasticity and consequential improvements in neuronal connectivity will occur even patients considered treatment resistant.

[0125] Improvements in plasticity and consequential improvements in neuronal connectivity in turn make the patient more amenable to treatment with 5-MeO-DMT or a salt thereof.

[0126] Given the significant impact of 5-MeO-DMT on neuroplasticity and depressive symptoms, the inventors have moreover determined that there is a bidirectional relationship between the action of 5-MeO-DMT and antidepressants. If one or more antidepressants are used in combination with 5-MeO-DMT or a salt thereof, the 5-MeO- DMT enhances the patients’ ability to respond to the antidepressants. The combined effects on plasticity, in particular the augmentation of synaptic plasticity, support various treatment regimen.

[0127] Patients diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety and who receive a treatment with one or more antidepressants may receive a 5-MeO-DMT / salt treatment course without the necessity to discontinue the one or more antidepressants and in particular without the necessity to observe a wash-out period after discontinuation of the one or more antidepressants.

[0128] Thus, patients who are treated with one or more antidepressants and preferably have been so treated for some time, in particular receiving a stable dose of the one or more antidepressants for some time, receive in addition a 5-MeO-DMT / salt treatment course.?Q

[0129] For instance, patients who are treated with one or more antidepressants and preferably have been so treated for some time, in particular receiving a stable dose of the one or more antidepressants for some time, may receive a 5-MeO treatment course upon acute deterioration of the disease.

[0130] Patients diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety may be treated by

[0131] (i) administering one or more antidepressants

[0132] (ii) administering a 5-MeO-DMT / salt treatment course wherein 5-MeO-DMT / salt treatment course is preferably administered after the patients received the one or more antidepressants for some time.

[0133] Patients may also be treated with one or more antidepressants and one or more other psychotropic drugs and preferably have been treated with that combination for some time, in particular at stable doses of the drugs of the combination, and in addition receive a 5-MeO-DMT / salt treatment course.

[0134] Patients diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety may be treated by

[0135] (i) administering one or more antidepressants;

[0136] (ii) administering one or more other psychotropic drugs in combination with the one or more antidepressants;

[0137] (iii) administering a 5-MeO-DMT / salt treatment course; wherein 5-MeO-DMT / salt treatment course is preferably administered after the patients received the one or more antidepressants for some time.

[0138] According to one aspect of the present invention, continued antidepressant management after administration of a 5-MeO-DMT / salt treatment course prolongs the improved clinical state which is rapidly achieved after the 5-MeO-DMT / salt treatment course. According to the invention, a combination treatment provides benefits in patients considered treatment-resistant before the administration of a 5-MeO-DMT / salt treatment course. For instance, a previously treatment-resistant patient achieves remission after administration of a 5-MeO-DMT / salt treatment course.

[0139] Examples of Specific Conditions to Be Treated

[0140] Conditions that can be treated are mental disorders and nervous system disorders, such as disorders involving depressive episodes and / or episodes of anxiety.

[0141] Major Depressive Disorder

[0142] An example of a disorder involving depressive episodes and / or episodes of anxiety is Major Depressive Disorder (MDD). MDD is a mood disorder that causes a persistent feeling of sadness and loss of interest. It affects how a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0143] Moreover, patients suffering from MDD, including treatment-resistant forms of the disorder, have an increased incidence of suicidal ideation, with intent to act, and he may be considered at imminent risk for suicide.

[0144] The invention in particular relates to combination treatments for patients who are diagnosed with MDD by a licensed professional in accordance with accepted medical practice. The disorder may be diagnosed in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. For instance, the patient may suffer from moderate or severe major de- pressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 17 or more. It is further considered that the patient may suffer from severe major de- pressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 25 or more. The patient may be diagnosed with a treatment-resistant form of major depressive disorder.

[0145] Suicidal ideation may be assessed using the MADRS item "suicidal thoughts".

[0146] A patient suffering from MDD will often be treated with one or more antidepressants.

[0147] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from MDD may suffer from a treatment resistant form of the disorder (TRD). According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission isnot achieved by a treatment with one or more antidepressants or a patient suffering from TRD, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0148] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0149] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0150] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0151] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0152] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0153] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0154] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0155] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0156] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0157] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0158] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0159] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0160] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a remission of 94 depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0161] The remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0162] Treating a patient suffering from MDD, including a treatment resistant form of the disorder, with the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0163] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the MADRS item "suicidal thoughts", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0164] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0165] Postpartum Depression (PPD)

[0166] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Postpartum Depression (PPD). PPD is a complex mix of physical, emotional, and behavioral changes that happen in some women after giving birth. PPD is also known as major depressive disorder with peripartum onset. According to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when major depressive disorder (MDD) symptoms begin during pregnancy or within four weeks of delivery.

[0167] A patient treated according to the present invention is preferably a woman diagnosed with PPD and > 4 weeks postpartum. Further, the patient will preferably be <9 months postpartum. Moreover, patients suffering from PPD, including treatment-resistant forms of the disorder, have an increased incidence of suicidal ideation, with intent to act, and he may be considered at imminent risk for suicide.

[0168] Depressive aspects of PPD may be assessed by the HAM-D or the MADRS score. The Edinburgh Postnatal Depression Scale (EPDS) can also be used.

[0169] The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p.382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which would be more sensitive to the changes brought on by antidepressants and other forms of treatment. Higher MADRS score indicates more severe depression. The items considered are apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.

[0170] A patient may suffer from moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 16 or more. It is further considered that the patient may suffer from severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or more or by a Hamilton Depression Rating Scale (HAM- D) score of 27 or more. The patient may be diagnosed with a treatment-resistant form of PPD.

[0171] A patient treated according to the invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.

[0172] Further, a patient treated according to the invention may have a MADRS score of 28 or more or a HAM-D score of 22 or more.

[0173] Still further, a patient treated according to the invention may have a MADRS score of 35 or more or a HAM-D score of 25 or more.

[0174] Suicidal ideation may be assessed using the MADRS item "suicidal thoughts".

[0175] In addition to the above, the inventors consider that PPD compromises maternal functioning. In particular the first year after childbirth marks a critical window for both mother and child. In most cases, mothers are the primary caregivers and are, therefore, responsible for the majority of the work related to infant care tasks. Maternal functioning includes aspects of maternal competence relating to interactions with the infant(s) as well as maternal self-care.

[0176] Maternal functioning, including the emotional aspect of mothering, is also important for the child’s development. In fact, the quality of mother-child interaction in the year after birth affects infant development. High levels of maternal functioning are likely to correlate with positive infant development outcomes. Likewise, impaired functioning in the postpartum period might impede optimal infant development.

[0177] The Barkin Index of Maternal Functioning (BIMF) was designed to measure functioning in the year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score between 0 and 6 so that the maximum total score is 120. The higher the score, the better maternal functioning is rated.

[0178] The Bl MF identifies the key functional domains of a mother during the postnatal period as: self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.

[0179] A BIMF score of 95 or below is considered herein as representing slightly compromised maternal functioning, score of 80 or below is considered herein as representing compromised maternal functioning, a score of 65 or below is considered herein as representing severely compromised maternal functioning. The invention in particular allows improving maternal functioning in patients having a score of 80 or below before treatment and in patients having a score of even 65 or below.

[0180] A patient suffering from PPD will often be treated with one or more antidepressants.

[0181] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from PPD may suffer from a treatment resistant form of PPD.

[0182] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering froma treatment resistant form of PPD, may be treated by administering a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0183] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0184] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0185] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0186] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0187] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0188] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0189] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0190] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0191] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0192] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0193] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0194] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a remission of Q depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0195] The remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0196] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by an improvement of the Bl MF score by at least 10 points, preferably by at least 20 points, in particular by at least 30 points, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0197] The clinical response, as assessed by an improvement of the BIMF score by at least 10 points, preferably by at least 20 points, in particular by at least 30 points, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0198] The clinical response, as assessed by an improvement of the BIMF score by at least 10 points, preferably by at least 20 points, in particular by at least 30 points can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0199] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to an improvement in maternal functioning, as assessed by 10% or more, preferably 20% or more improvement in the BIMF score, compared to the respective score prior to administration of the 5-MeO- DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.

[0200] An improvement in maternal functioning, as assessed by 10% or more, preferably 20% or more improvement in the BIMF score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0201] An improvement in maternal functioning, as assessed by 10% or more, preferably 20% or more improvement in the BIMF score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0202] Treating a patient suffering from PPD, including a treatment resistant form of the disorder, with the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0203] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the MADRS item "suicidal thoughts", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0204] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0205] Persistent Depressive Disorder

[0206] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Persistent Depressive Disorder. Persistent Depressive Disorder, also referred to as dysthymia, is a chronic form of depression. It is diagnosed if depression is present for most of the day for the majority of days over at least a two years period. Any symptom- free period is less than 2 months.

[0207] While depressed, two or more of the following must be present: 1. Hopelessness; 2. Energy low or fatigue; 3. Self-esteem is low; 4. Sleep decreased (insomnia) or increased (hypersomnia): 5. Appetite poor, or overeating; 6. Difficulty making decisions or poor concentration. Moreover, patients suffering from Persistent Depressive Disorder, including treatmentresistant forms of the disorder, have an increased incidence of suicidal ideation, with intent to act, and he may be considered at imminent risk for suicide.

[0208] Depressive aspects of Persistent Depressive Disorder may be assessed by the HAM-D or the MADRS score. Suicidal ideation may be assessed using the MADRS item "suicidal thoughts".

[0209] The patient suffering from Persistent Depressive Disorder may suffer from a treatment resistant form of the disorder.

[0210] A patient suffering from Persistent Depressive Disorder will often be treated with one or more antidepressants.

[0211] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Persistent Depressive Disorder may suffer from a treatment resistant form of Persistent Depressive Disorder.

[0212] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Persistent Depressive Disorder, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0213] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0214] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0215] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0216] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0217] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0218] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0219] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0220] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0221] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0222] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0223] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0224] Treating a patient suffering from Persistent Depressive Disorder, including a treatment resistant form of the disorder, with the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0225] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the MADRS item "suicidal thoughts", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0226] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0227] Seasonal Affective Disorder A further example of a disorder involving depressive episodes and / or episodes of anxiety is Seasonal Affective Disorder (SAD). SAD is a mood disorder with seasonal pattern, with symptoms often beginning in autumn and remitting in spring. Many people experience sadness, hopelessness, a loss of interest in activities, fatigue, and social withdrawal.

[0228] The patient suffering from Seasonal Affective Disorder may suffer from a treatment resistant form of the disorder.

[0229] Moreover, patients suffering from SAD, including treatment-resistant forms of the disorder, have an increased incidence of suicidal ideation, with intent to act, and he may be considered at imminent risk for suicide.

[0230] Depressive aspects of SAD may be assessed by the HAM-D or the MADRS score. Suicidal ideation may be assessed using the MADRS item "suicidal thoughts".

[0231] A patient suffering from Seasonal Affective Disorder will often be treated with one or more antidepressants.

[0232] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Seasonal Affective Disorder may suffer from a treatment resistant form of Seasonal Affective Disorder.

[0233] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Seasonal Affective Disorder, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0234] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0235] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0236] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0237] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0238] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0239] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0240] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 50% improvement of the HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0241] The clinical response, as assessed by at least 50% improvement of the HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0242] The clinical response, as assessed by at least 50% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0243] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0244] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0245] The clinical response, as assessed by at least 75% improvement of the MADRS or HAM- D score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO- DMT / salt treatment course.

[0246] Treating a patient suffering from SAD, including a treatment resistant form of the disorder, with the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0247] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the MADRS item "suicidal thoughts", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0248] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Bipolar Disorder

[0249] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder. BD is a mental health condition characterized by extreme mood swings that include emotional lows (major depressive episodes) and highs (manic or hypomanic episodes). Bipolar disorder is a recurrent chronic disorder that affects more than 1 % of the world’s population irrespective of ethnic origin or socioeconomic status.

[0250] BD is classified as Bipolar I Disorder if there has been at least one manic episode, with or without depressive episodes. It is classified as Bipolar II Disorder if there has been at least one hypomanic episode (but no full manic episodes) and one major depressive episode. If these symptoms are due to drugs or medical problems, they are not diagnosed as bipolar disorder.

[0251] The patient suffering from BD including Bipolar I Disorder and Bipolar II Disorder may suffer from a treatment resistant form of the disorder. Moreover, patients suffering from BD, including treatment-resistant forms of the disorder, have an increased incidence of suicidal ideation, with intent to act, and may be considered at imminent risk for suicide.

[0252] Various other scales are also useful to assess the severity of disease as well as the clinical outcome of treatments.

[0253] The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p.382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which would be more sensitive to the changes brought on by antidepressants and other forms of treatment. Higher MADRS score indicates more severe depression The items considered are apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Score ranges used herein for assessing the severity of depressive episodes in patients with bipolar disorder are 13-18 for "mildly ill", 19-23 for "moderately ill", 24-36 for "markedly ill", 37-39 for "severely ill", and >40 for "extremely ill" (Thase, 2021).

[0254] Suicidal ideation may be assessed using the MADRS item "suicidal thoughts". The Hamilton Depression Rating Scale (Ham-D) is a clinician-administered depression assessment scale. The original version contains 17 items (HDRS 17) pertaining to symptoms of depression (Hamilton, M., 1960. A Rating Scale for Depression, J Neurol Neurosurg Psychiatry 23:56-62; Hamilton, M., 1967. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6(4):278-96). Although the scale was designed for completion after an unstructured clinical interview, there are now semistructured interview guides available (Williams, J. B., 1988. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 45(8): 742-7). A later 21- item version includes 4 items intended to subtype the depression.

[0255] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and / or mixed symptoms expressed by patients currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms. The scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.

[0256] The questions address depressed mood; sleep disturbance; appetite disturbance; reduced social engagement; reduced energy and activity; reduced motivation; impaired concentration and memory; anxiety; anhedonia; affective flattening; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation.

[0257] Each of these aspects is assessed and assigned a score of 0, 1 , 2 or 3.

[0258] Depressed mood is scored as 0 if there is no self-reported and / or observed depression as evidenced by gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) in case of brief or transient periods of depression, or mildly depressed mood; 2 (moderate) in case a depressed mood is clearly but not consistently present and other emotions are expressed, or depression is of moderate intensity; 3 (severe) in case of pervasive or continuous depressed mood of marked intensity.

[0259] Suicidal ideation may be assessed using the BDRS item "suicidal ideation".

[0260] A patient treated according to the invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37. A patient treated according to the invention may have a Hamilton Depression Rating Scale (HAM-D) score of 17 or more. It is further considered that the patient may suffer from severe major depressive disorder as indicated by a Hamilton Depression Rating Scale (HAM-D) score of 25 or more.

[0261] A patient treated according to the invention may have a Bipolar Depression Rating Scale (BDRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

[0262] A patient suffering from Bipolar Disorder, such as Bipolar I Disorder and Bipolar II Disorder, will often be treated with one or more antidepressants.

[0263] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Bipolar Disorder, such as Bipolar I Disorder and Bipolar II Disorder, may suffer from a treatment resistant form of Bipolar Disorder, such as Bipolar I Disorder and Bipolar II Disorder.

[0264] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Bipolar Disorder, such as Bipolar I Disorder and Bipolar II Disorder, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0265] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0266] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0267] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0268] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0269] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0270] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0271] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 50% improvement of the MADRS, HAM-D or BDRS score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0272] The clinical response, as assessed by at least 50% improvement of the MADRS, HAM- D or BDRS score, compared to the respective score prior to administration of the 5-MeO- DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0273] The clinical response, as assessed by at least 50% improvement of the MADRS, HAM- D or BDRS score, compared to the respective score prior to administration of the 5-MeO- DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least 75% improvement of the MADRS, HAM-D or BDRS score, compared to the respective score prior to administration of the 5-MeO-DMT / salt treatment course, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0274] The clinical response, as assessed by at least 75% improvement of the MADRS, HAM- D or BDRS score, compared to the respective score prior to administration of the 5-MeO- DMT / salt treatment course, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0275] The clinical response, as assessed by at least 75% improvement of the MADRS, HAM- D or BDRS score, compared to the respective score prior to administration of the 5-MeO- DMT / salt treatment course can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0276] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, a HAM-D score equal to or less than 7, or a BDRS score of equal to or less than 10, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0277] The remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0278] The remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Treating a patient suffering from BD, including a treatment resistant form of the disorder, with the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0279] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the MADRS item "suicidal thoughts", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0280] In a further embodiment, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation, as reflected by a decrease of the score of the BDRS item "suicidal ideation", not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0281] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0282] Anxiety Disorders

[0283] A further example of a disorder involving depressive episodes and / or episodes of anxiety is an Anxiety Disorder. An Anxiety Disorder is a type of mental health condition. Symptoms include feelings of nervousness, panic and fear as well as sweating and a rapid heartbeat. Anxiety involves a complex cognitive, affective, physiological, and behavioural response system associated with preparation for anticipated events or circumstances perceived as threatening.

[0284] The patient suffering from an Anxiety Disorder may suffer from a treatment resistant form of the disorder.

[0285] The Hamilton Anxiety Rating Scale (HAM-A) is used to measure the severity of anxiety symptoms in a variety of anxiety disorders (panic, phobia, and generalized). The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Item 5 is ‘Intellectual’, defined as ‘difficulty in concentration, poor memory’. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

[0286] A patient suffering from an Anxiety Disorder will often be treated with one or more antidepressants.

[0287] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from an Anxiety Disorder may suffer from a treatment resistant form of an Anxiety Disorder.

[0288] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of an Anxiety Disorder, may be treated by administering a 5- MeO- DMT / salt treatment course.

[0289] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0290] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0291] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0292] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0293] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0294] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0295] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0296] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0297] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0298] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0299] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0300] Separation Anxiety Disorder

[0301] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Separation Anxiety Disorder. Separation Anxiety Disorder is characterized by an excessive anxiety regarding separation from home and / or from someone to whom the patient has a strong emotional attachment.

[0302] Situations of separation cause the patient significant distress, and they may have difficulty going to school or work due to the separation. Patients suffering from Separation Anxiety Disorder may also have excessive anxiety about unwelcome events happening to important people in their lives, such as family members.

[0303] A patient suffering from Separation Anxiety Disorder may suffer from a treatment resistant form of the disorder.

[0304] The severity of Separation Anxiety Disorder can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0305] A patient suffering from Separation Anxiety Disorder will often be treated with one or more antidepressants.

[0306] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Separation Anxiety Disorder may suffer from a treatment resistant form of Separation Anxiety Disorder.

[0307] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Separation Anxiety Disorder, may be treated by administering a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0308] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0309] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0310] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0311] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0312] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0313] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0314] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0315] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0316] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0317] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0318] Agoraphobia

[0319] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Agoraphobia. Agoraphobia is a fear of situations or places that may cause feelings of panic, entrapment, helplessness, or embarrassment.

[0320] A patient suffering from agoraphobia may have difficulty leaving the house. The thought of leaving the house may cause considerable anxiety to the point of avoidance. Fears of crowds, traveling, elevators, movie theatres, malls, etc., might cause significant challenges.

[0321] Patients with agoraphobia may also have recurrent panic attacks.

[0322] The severity of Agoraphobia can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety". A patient suffering from Agoraphobia will often be treated with one or more antidepressants.

[0323] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Agoraphobia may suffer from a treatment resistant form of Agoraphobia.

[0324] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Agoraphobia, may be treated by administering a 5-MeO- DMT / salt treatment course.

[0325] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0326] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0327] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0328] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0329] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0330] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0331] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0332] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0333] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0334] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0335] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. Generalized Anxiety Disorder

[0336] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Generalized Anxiety Disorder (GAD). GAD is characterized by persistent and excessive, difficult to control worry about a wide range of situations and issues. Patients suffering from GAD may anticipate disaster and may be overly concerned about money, health, family, work, or other issues.

[0337] Generalized anxiety disorder is diagnosed when an individual experiences persistent worry about everyday challenges out of proportion to the perceived threat. Patients with GAD usually experience excessive fear that can last months to years.

[0338] GAD interferes with social, occupational, or other important areas of functioning.

[0339] The patient suffering from GAD may suffer from a treatment resistant form of the disorder.

[0340] The severity of GAD can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0341] A patient suffering from GAD will often be treated with one or more antidepressants.

[0342] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from GAD may suffer from a treatment resistant form of GAD.

[0343] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of GAD, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0344] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0346] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0347] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0349] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0350] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0351] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. 5*^

[0352] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0353] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0354] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0355] Social Anxiety Disorder

[0356] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Social Anxiety Disorder (SAD), also called social phobia, is one of the most common types of anxiety.

[0357] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in a social or performance situation. This often leads to avoidance of the social situation and can cause impairments in school, work, or relationships.

[0358] The patient suffering from SAD may suffer from a treatment resistant form of the disorder.

[0359] The severity of SAD can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0360] A patient suffering from SAD will often be treated with one or more antidepressants.

[0361] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from SAD may suffer from a treatment resistant form of SAD. According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of SAD, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0362] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0363] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0364] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0365] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0367] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0368] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0369] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0370] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0371] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0373] Panic Disorder

[0374] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Panic Disorder. Patients suffering from Panic Disorder experience spontaneous panic attacks with an abrupt onset of intense fear or discomfort that reaches a peak within minutes.

[0375] The panic attacks feature many somaticized symptoms of anxiety including sweating, trembling, shaking, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea. Furthermore, the disorder can often feature anxiety of future panic attacks. Patients may be very preoccupied with the fear of a recurring attack.

[0376] The patient suffering from Panic Disorder may suffer from a treatment resistant form of the disorder.

[0377] The severity of Panic Disorder can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0378] A patient suffering from Panic Disorder will often be treated with one or more antidepressants.

[0379] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Panic Disorder may suffer from a treatment resistant form of Panic Disorder.

[0380] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Panic Disorder, may be treated by administering a 5-MeO- DMT / salt treatment course.

[0381] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0382] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0383] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0384] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0385] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0386] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0388] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0389] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0390] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0391] Phobia

[0392] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Phobia. A Phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation.

[0393] A patient suffering from phobia experiences extreme anxiety when anticipating exposure or being exposed to a feared stimulus. There are animal type (spiders, snakes, dogs) phobias, natural environment type (tornadoes, heights, water, fire) phobias, blood injection type (needles, medical procedures) phobias, situational type (flying on an airplane, enclosed spaces) phobias and other type phobias (phobias that do not fit into one the previous categories).

[0394] Phobias typically result in a rapid onset of fear and are usually present for more than six months. Patients make great efforts to avoid the feared stimulus. Fear and avoidance cause significant distress and / or impairment in occupational, academic, or social functioning.

[0395] The patient suffering from Phobia may suffer from a treatment resistant form of the disorder.

[0396] The severity of Phobia can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0397] A patient suffering from Phobia will often be treated with one or more antidepressants. This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Phobia may suffer from a treatment resistant form of Phobia.

[0398] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Phobia, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0399] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0400] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0401] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0402] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0403] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0404] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0405] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0406] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0407] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0408] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0409] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0410] Substance / Medication Induced Anxiety Disorder

[0411] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Substance / Medication Induced Anxiety Disorder. Substance / Medication Induced Anxiety Disorder is an anxiety disorder in which anxiety or panic occurs after using alcohol, a drug of abuse, or a medication or after a toxin exposure. Substance / medication- induced anxiety disorder leads to prominent symptoms of panic or anxiety and can occur during the intoxication or withdrawal phases of using a substance or medication. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0412] While taking substances or medication or within a short time thereafter, individuals suffering from Substance / Medication Induced Anxiety Disorder may feel nervous and worried, experience symptoms of negative thinking, may have trouble concentrating or remembering things, may have fear of losing control or insanity or death, may lose weight due to gastrointestinal problems, may have chills, hot flashes, sweating, shaking, numbness, or a pounding heartbeat, trouble breathing, trouble swallowing, or chest pain.

[0413] The patient suffering from Substance / Medication Induced Anxiety Disorder may suffer from a treatment resistant form of the disorder.

[0414] The severity of Substance / Medication-lnduced Anxiety Disorder can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

[0415] A patient suffering from Substance / Medication Induced Anxiety Disorder will often be treated with one or more antidepressants.

[0416] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from Substance / Medication Induced Anxiety Disorder may suffer from a treatment resistant form of Substance / Medication Induced Anxiety Disorder.

[0417] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of Substance / Medication Induced Anxiety Disorder, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0418] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0419] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0420] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0421] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0422] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0423] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0424] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0425] The clinical response, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0426] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a HAM-A score of 7 or less, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0427] The clinical response, as reflected by a HAM-A score of 7 or less, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0428] The clinical response, as reflected by a HAM-A score of 7 or less, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0429] Somatic Symptom Disorder

[0430] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Somatic Symptom Disorder. Somatic Symptom Disorder is a mental disorder diagnosed when a person has a significant focus on physical symptoms, such as pain, weakness, or shortness of breath to a level that results in major distress and / or problems functioning and / or cause disruption in daily life. Feelings and behaviours related to the illness are excessive or out of proportion.

[0431] Health-related quality of life is often impaired, both physically and mentally. In severe Somatic Symptom Disorder, the impairment is marked, and when persistent, the disorder can lead to invalidism.

[0432] In somatic symptom disorder (SSD), cognitive dysfunction is related to a perceptive distortion that excessively amplifies bodily sensations. Attention is focused on somatic symptoms, normal bodily sensations are attributed to physical illness (possibly with catastrophic interpretations), leads to worry about illness, and fear that any physical activity may damage the body. The relevant associated behavioural features may include repeated bodily checking for abnormalities, repeated seeking of medical help and reassurance, and avoidance of physical activity.

[0433] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptom

[0434] - Adult measure. This measure comprises 15 somatic symptoms. Respondents are asked to rate the severity of the individual’s somatic symptoms during the past 7 days. Scoring ranges from "0" ("Not bothered at all"), "1" ("Bothered a little") to "2" ("Bothered a lot"). The total score can range from 0 to 30, with higher scores indicating greater severity of somatic symptoms. A cut-off value of 5, 10 and 15 indicates low, medium, high somatic symptom severity, respectively. Also, the Somatic Symptom Disorder-B Criteria Scale (SSD-12) can be used. Cognitive, affective, and behavioural criteria are measured by 12 items with all item scores ranging between 0 and 4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = very often). Ratings are summed up to make a simple sum score, which can vary between 0 and 48 points. Shift in attention is considered by the item "Due to my physical complaints, I have poor concentration on other things" or "My physical complaints occupy me for most of the day".

[0435] A patient suffering from Somatic Symptom Disorder will often be treated with one or more antidepressants.

[0436] This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0437] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0438] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0439] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0440] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0441] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0442] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0443] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] Obsessive Compulsive and Related Disorders

[0445] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Obsessive Compulsive Disorder (OCD). OCD is a mental illness that causes repeated unwanted thoughts or sensations (obsessions) or the urge to do something over and over again (compulsions). Patients may suffer from both obsessions and compulsions.

[0446] The patient suffering from OCD may suffer from a treatment resistant form of the disorder.

[0447] A patient suffering from OCD will often be treated with one or more antidepressants.

[0448] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from OCD may suffer from a treatment resistant form of OCD.

[0449] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of OCD, may be treated by administering a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0451] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0452] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0455] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0456] Body Dysmorphic Disorder A further example of a disorder involving depressive episodes and / or episodes of anxiety is Body Dysmorphic Disorder (BDD). Patients suffering from Body Dysmorphic Disorder (BDD). misperceive defects in their appearance, disrupting their ability to function in their daily lives, with disturbing preoccupations, ritualistic behaviours, and emotional dis- tress.

[0457] A patient suffering from BDD will often be treated with one or more antidepressants.

[0458] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from BDD may suffer from a treatment resistant form of BDD.

[0459] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of BDD, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0460] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0461] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0462] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0463] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0464] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0465] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0466] Post-Traumatic Stress Disorder

[0467] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Post-Traumatic Stress Disorder (PTSD). PTSD is a mental health condition that can develop based on a terrifying event - either experienced or witnessed by the patient. Symptoms may include flashbacks, nightmares and severe anxiety, as well as uncontrollable thoughts about the event.

[0468] A patient suffering from PTSD may suffer from a treatment resistant form of the disorder.

[0469] A patient suffering from PTSD will often be treated with one or more antidepressants.

[0470] This treatment may not lead to an adequate improvement. It may in particular not lead to remission. The patient suffering from PTSD may suffer from a treatment resistant form of PTSD.

[0471] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of PTSD, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0472] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0473] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0474] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0476] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0477] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0478] Mental and Behavioural Disorders due to Psychoactive Substance Use

[0479] Substance Use Disorder

[0480] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Substance Use Disorder (SUD). SUD is a mental disorder that affects a person's behaviour, leading to a person’s inability to control their use of substances such as legal or illegal drugs, alcohol, or medications. Symptoms can range from moderate to severe, with addiction being the most severe form of SUD.

[0481] A patient suffering from a Substance Use Disorder will often be treated with one or more antidepressants. This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0482] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0483] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0486] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] Eating Disorders

[0490] A further example of a disorder involving depressive episodes and / or episodes of anxiety is an Eating Disorder, in particular bulimia nervosa and anorexia nervosa, which is a mental disorder characterised by abnormal eating behaviours that negatively affect a person's physical or mental health.

[0491] A patient suffering from an Eating Disorder, in particular bulimia nervosa and anorexia nervosa, will often be treated with one or more antidepressants. The patient suffering from an Eating Disorder may suffer from a treatment resistant form of an Eating Disorder.

[0492] This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0493] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants or a patient suffering from a treatment resistant form of an Eating Disorder, may be treated by administering a 5- MeO-DMT / salt treatment course.

[0494] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0495] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0496] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course. In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0497] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0499] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0500] Attention Deficit Hyperactivity Disorder (ADHD)

[0501] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a condition that affects a patient's behaviour. ADHD is characterised by age-inappropriate symptoms of inattention, hyperactivity and impulsivity. A patient suffering from ADHD can seem restless, may have trouble concentrating and may act on impulse.

[0502] Patients with ADHD may also have additional problems, such as sleep and anxiety disorders.

[0503] A patient suffering from an ADHD will often be treated with one or more antidepressants.

[0504] This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0505] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0506] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0508] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0509] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0510] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0511] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0512] Sleep Disturbances A further example of a disorder involving depressive episodes and / or episodes of anxiety is Sleep disturbance. Sleep disturbance refers to conditions, whether idiopathic or occurring in the context of a medical condition such as for example a mental disorder or a nervous system disorder, or a medical health condition leading to an associated mental or nervous system condition, that affect sleep quality, timing, or duration. It impacts a person’s ability to properly function while the person is awake and in particular compromises cognitive function and also gives rise to anxiety.

[0513] There are two fundamental types of sleep: rapid eye movement (REM) sleep and non- REM sleep. Non-REM sleep can be divided into four stages (l-IV). These non-REM stages correspond to an increasing depth of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. During the earlier proportion of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, particularly within the first cycle of sleep. As the night progresses, non- REM sleep becomes shallow and more of each cycle is allocated to REM sleep.

[0514] Normal healthy sleep consists of different phases as outlined above that proceed in successive, tightly regulated order through the night.

[0515] Disruption of this tight regulation results in sleep disturbances.

[0516] Common forms of sleep disturbances encompass disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleepwake schedule (circadian rhythm disorders), dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia), disorders characterized by respiratory disturbance during sleep (sleep-related breathing disorders) and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0517] Insomnia is a sleep disturbance where people have difficulty falling or staying asleep. People with insomnia have difficulty falling asleep; wake up often during the night and have trouble going back to sleep; wake up too early in the morning; have unrefreshing sleep; and / or have at least one daytime problem such as fatigue, sleepiness, problems with mood, concentration, accidents at work or while driving, etc. due to poor sleep.

[0518] Hypersomnia is characterized by excessive daytime sleepiness, and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomnia patients. It is a difficulty transitioning from sleep to wake. Individuals experiencing sleep drunkenness report waking with confusion, disorientation, slowness and repeated returns to sleep. Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances due to alterations of the individual’s internal circadian rhythm or due to misalignments between their circadian rhythm and their desired or required work or social schedule. This desynchrony may be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during the desired waking state is impaired, and temporary opportunities to revert to a regular sleep schedule are unsuccessful.

[0519] Parasomnia designates various forms of sleep disturbance characterized by abnormal behavioural or physiological activity (such as sleepwalking or nightmares) that people experience prior to falling asleep, while asleep, or during the arousal period between sleep and wakefulness. There are considerable variations in terms of characteristics, severity, and frequency. Parasomnia may compromise the quality of sleep.

[0520] Sleep-related breathing disorders are characterized by abnormal and difficult respiration during sleep. Respiration is a complex process that relies heavily on the coordinated action of the muscles of respiration and the (control center in the) brain. One form of a sleep-related breathing disorder is central sleep apnoea. It occurs when the brain stops sending signals that control breathing, for instance, based on an underlying health condition. Central sleep apnoea has a potentially serious impact on sleep and the balance of oxygen and carbon dioxide in the blood. The reduction of airflow leads to intermittent hypoxia which in leads to sleep fragmentation due to microarousals or awakenings. A consequence can be excessive daytime sleepiness.

[0521] In sleep-related movement disorders repetitive, relatively simple, usually stereotyped, movements interfere with sleep or its onset. The most common of these are restless leg syndrome (RLS) and periodic limb movement disorder (PLMD).

[0522] Not getting the proper amount or quality of sleep may lead to personality changes and may not only exacerbate existing mental illness, but also be a trigger for the development of mental illness.

[0523] Improvements in sleep disturbance may be assessed by any scale reflecting changes in sleep quality or quantity, for instance the Pittsburgh Sleep Quality Index (PSQI).

[0524] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction.

[0525] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Detailed Scoring Instructions for the Pittsburgh Sleep Quality Index can be found in the Appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193- 213.

[0526] The seven component scores are then summed to yield one global score, with a range of 0-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas. A global score cut-off of 5 distinguishes poor from good sleepers. A global score > 5 indicates that a patient is having severe difficulties in at least two areas, or moderate difficulties in more than three areas.

[0527] If treatment outcome is assessed using the PSQI, treatment success is indicated (i) by a decrease of the score, preferably (ii) by a decrease to 5 or below. The recall period applied does not start earlier than the time point when acute psychedelic experiences have subsided after the last administration.

[0528] A patient suffering from a Sleep Disturbance will often be treated with one or more antidepressants.

[0529] This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0530] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0531] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0532] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0533] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0534] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0536] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an improvement in the PSQI global score, in particular by a decrease to 5 or below, not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] The clinical response, as reflected by an improvement in the PSQI global score, in particular by a decrease to 5 or below, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof.

[0538] The clinical response, as reflected by an improvement in the PSQI global score, in particular by a decrease to 5 or below, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0540] Cognitive Dysfunction

[0541] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Cognitive Dysfunction, which is a deficit in or is an impairment of one or more cognitive domains such as complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. The cognitive dysfunction may affect one or more subdomains of the cognitive domain complex attention selected from sustained attention, divided attention, selective attention, and processing speed.

[0542] Cognitive dysfunction is associated with several mental or nervous system disorders. It also occurs in patients suffering from certain medical health conditions leading to associated mental or nervous system conditions.

[0543] Cognitive dysfunction can take the form of neurocognitive disorder, where cognitive dysfunction is the defining characteristic of the disorder.

[0544] Further, cognitive dysfunction is associated with sleep disturbance, for instance, insomnia.

[0545] Cognitive complaints are related to relatively lower quality of daily life, greater depression, more anxiety, higher perceived stress, and lower general mental wellbeing.

[0546] For cognitive dysfunction, a detailed assessment and management is required.

[0547] Cognitive dysfunction is treated by non-pharmacologic approaches with cognitive, physical, and social activities, and by pharmacologic approaches. Some interventions focus mainly on the improvement of quality of life and the limitation of residual defects.

[0548] Physical activity, cognitive training and exercises, proper sleep, and relaxation techniques can help cognitive health. Environmental approaches, such as reducing noise around the patient, help the patient focus on tasks, and reduce distraction, confusion, and frustration. In patients suffering from cognitive dysfunction in association with a mental or nervous system disorder known treatments of the mental or nervous system disorder do not necessarily improve the cognitive dysfunction.

[0549] Common tests that assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screen for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

[0550] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses different cognitive domains: short-term memory; visuospatial abilities; executive functions; attention, concentration and working memory; language; orientation to time and space. The total possible score is 30 points; a score of 26 or above is considered normal; a score of 18-25 is considered mild cognitive impairment, a score of 10-17 is considered moderate cognitive impairment and a score less than 10 is considered severe cognitive impairment.

[0551] The Mini-Mental State Examination (MMSE) is an 11-question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. The raw score may also need to be corrected for educational attainment and age.

[0552] Four cut-off levels are employed herein to classify the severity of cognitive impairment: 24-30 means no cognitive impairment; 19-23 means mild cognitive impairment; 10-18 means moderate cognitive impairment; and <9 means severe cognitive impairment.

[0553] Used repeatedly, the MMSE is suitable to measure changes in cognitive status.

[0554] The Mini-Cog™ is a short cognitive impairment screening questionnaire. It combines a 3-word recall with a clock drawing test. The clock drawing test assesses many cognitive areas that can be affected, such as executive function, visuospatial abilities, motor programming, and attention. One point is given for each of the three words correctly recalled after performing the clock drawing test; a correctly drawn clock is worth two points. A score of <4 indicates cognitive impairment.

[0555] The Screen for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening instrument for the examination of cognitive performance in psychiatric patients. The SCIP consists of five subscales: verbal learning test - immediate (VLT-I), working memory test (WMT), verbal fluency test (VFT), verbal learning test - delayed (VLT-D) and processing speed test (PST). There are three different test forms to facilitate test repetition and therefore reducing learning effect. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score of less than 70 indicates cognitive dysfunction.

[0556] Cognitive dysfunction can also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of the various subtests. The subtests are: Trail Making Test, Part A (testing speed of processing); Brief Assessment of Cognition in Schizophrenia, symbol coding subtest (speed of processing); Hopkins Verbal Learning Test-Re- vised, immediate recall, three learning trials only (verbal learning); Wechsler Memory Scale, 3rd ed., spatial span subtest (working memory (nonverbal)); Letter- Number Span test (working memory (verbal)); Neuropsychological Assessment Battery, mazes subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category fluency test, animal naming (speed of processing); Mayer- Salovey-Caruso Emotional Intelligence Test, managing emotions branch (social cognition); and Continuous Performance Test, Identical Pairs version (attention / vigilance).

[0557] The test battery is appropriate to measure cognitive change.

[0558] Further tests are the Verbal Recognition Memory (VRM) test, the Rapid Visual information Processing (RVP) test, the Spatial Working Memory (SWM) test and the Digit Symbol Substitution Test (DSST).

[0559] A patient suffering from a Cognitive Dysfunction will often be treated with one or more antidepressants.

[0560] This treatment may not lead to an adequate improvement. It may in particular not lead to remission.

[0561] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course. The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0563] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0564] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0565] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0567] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score, in particular by a decrease to 5 or below, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score, in particular by a decrease to 5 or below, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0568] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0569] The clinical response, as reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score, in particular by a decrease to 5 or below, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0570] Social / Emotional Withdrawal or Detachment

[0571] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Social / Emotional Withdrawal or Detachment, which refers to symptoms such as anhedonia, emotional withdrawal and affective flattening. Anhedonia is the inability to experience pleasure. A patient suffers from anhedonia if there is subjectively a reduced ability to experience pleasure in usual activities. Anhedonia comprises consummatory (or liking) and anticipatory (or wanting) components. Consummatory pleasure refers to the "in the moment" pleasure experienced by the subject directly engaged in an enjoyable activity, whereas anticipatory pleasure refers to the experience of pleasure related to future activities. Emotional withdrawal or detachment is an inability or unwillingness to connect with other people on an emotional level. Affective flattening characterises the subjective sense of reduced intensity or range of feelings or emotions.

[0572] Reduced social engagement is a further aspect associated with Social / Emotional Withdrawal or Detachment. Reduced social engagement characterises subjective reports of reduced social and interpersonal engagement or interactions.

[0573] Social / Emotional Withdrawal or Detachment is associated with several mental or nervous system disorders. It also occurs in patients suffering from certain medical health conditions leading to associated mental or nervous system conditions.

[0574] Social / Emotional Withdrawal or Detachment or individual aspects thereof, such as anhedonia, emotional withdrawal and affective flattening, can be evaluated by different instruments, such as questionnaires or scales. Questionnaires assess the mental status of a patient based on observations made by the patient himself / herself, caregivers or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a particular mental or nervous system disorder may comprise items related to social / emotional withdrawal or detachment.

[0575] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, i.e., the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest / pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Either of the "disagree" responses score one point, and either of the "agree" responses score 0 points. Thus, the final score ranges from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used for measuring anhedonia in depression, but it is also frequently used to assess anhedonia in other patient groups.

[0576] In principle, the SHAPS measures hedonic tone during the last few days with 14 hypothetically formulated items. However, due to the hypothetical nature of the items an appropriate shorter recall period can also be applied for an earlier assessment time point.

[0577] Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS) measuring interest, motivation, effort and consummatory pleasure across four domains: hobbies, food / drink, social activities and sensory experience can be used for the assessment of anhedonia. It comprises 17 items assessing state anhedonia right now. The DARS is rated on a five-point Likert scale from 0 (not at all) to 4 (very much), higher values indicating less anhedonia. All items are summed up to a total score in the range of 0 to 68. For each of the four hedonic domains, hobbies (four items, sum score 0-16), food / drink (four items, sum score 0-16), social activities (four items, sum score 0-16) and sensory experiences (5 items, sum score 0-20), participants are asked to provide two or three of their own favourite examples.

[0578] The Personality Inventory for DSM-5 (PID-5) - Adult is a 220 item self-rated personality trait assessment scale for adults age 18 and older. It assesses 25 personality trait facets including Anhedonia, Anxiousness, Attention Seeking, Callousness, Deceitfulness, Depressivity, Distractibility, Eccentricity, Emotional Lability, Grandiosity, Hostility, Impulsivity, Intimacy Avoidance, Irresponsibility, Manipulativeness, Perceptual Dysregulation, Perseveration, Restricted Affectivity, Rigid Perfectionism, Risk Taking, Separation Insecurity, Submissiveness, Suspiciousness, Unusual Beliefs and Experiences, and Withdrawal, with each trait facet consisting of 4 to 14 items. The trait facet Anhedonia contains the items 1 , 23, 26, 30R, 124, 155R, 157, 189 (reverse scored items are marked with the letter "R"), the trait facet Withdrawal contains the items 10, 20, 75, 82, 136, 146, 147, 161 , 182, 186 and the trait facet Intimacy Avoidance contains the items 89, 97R, 108, 120, 145, 203. These three trait facets can be combined to yield the broader trait domain designated Detachment.

[0579] The measure is completed by the individual prior to a visit with the clinician. Each item asks the individual to rate how well the item describes him or her generally.

[0580] Each item on the measure is rated on a 4-point scale. The response categories for the items are 0=very false or often false; 1=sometimes or somewhat false; 2=sometimes or somewhat true; 3=very true or often true. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131 , 142, 155, 164, 177, 210, and 215, the items are reverse-coded prior to entering into scale score computations.

[0581] The scores on the items within each trait facet should be summed and entered in the appropriate raw facet score box. In addition, the clinician is asked to calculate and use average scores for each facet and domain. The average scores reduce the overall score as well as the scores for each domain to a 4-point scale, which allows the clinician to think of the individual’s personality dysfunction relative to observed norms. The average facet score is calculated by dividing the raw facet score by the number of items in the facet (e.g., if all the items within the "Anhedonia" facet are rated as being "sometimes or somewhat true," then the average facet score would be 16 / 8 = 2, indicating moderate anhedonia). An average domain score is calculated by summing and then averaging the 3 facet scores contributing primarily to the specific domain. For example, if the average facet scores on Anhedonia, Intimacy Avoidance and Withdrawal (scales primarily indexing Detachment) are all 2, then the sum of these scores would be 6, and the average domain score would be 6 / 3 = 2. Higher average scores indicate greater dysfunction in a specific personality trait facet or domain.

[0582] High scores on a facet or domain may indicate significant and problematic areas for the individual receiving care that might warrant further assessment, treatment, and followup.

[0583] A patient suffering from symptom of Social / Emotional Withdrawal or Detachment will often be treated with one or more antidepressants.

[0584] This treatment may not lead to an adequate improvement in the symptoms of Social / Emotional Withdrawal or Detachment. It may in particular not lead to remission. According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0585] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0586] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0587] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0588] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0589] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course. The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0591] Negative Thinking

[0592] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Negative Thinking, which refers to symptoms such as pessimism, feelings of worthlessness, feelings of helplessness and hopelessness, and feelings of pathological, excessive or inappropriate guilt.

[0593] Feelings of helplessness and hopelessness (also simply referred to as helplessness and hopelessness) characterize the subjective sense of pessimism or gloom regarding the future, inability to cope, or sense of loss of control.

[0594] Feelings of worthlessness (also simply referred to as worthlessness) characterize the subjective sense or thoughts of decreased self-value or self-worth.

[0595] Feelings of guilt (also simply referred to as guilt) characterise the subjective sense of self blame, failure, or remorse for real or imagined past errors.

[0596] Negative Thinking is associated with several mental or nervous system disorders. It also occurs in patients suffering from certain medical health conditions leading to associated mental or nervous system conditions.

[0597] Negative thinking or individual aspects thereof, such as worthlessness, helplessness and hopelessness, and guilt, can be evaluated by different instruments, such as questionnaires or scales.

[0598] Questionnaires assess the mental status of a patient based on observations made by the patient himself / herself, caregivers or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a particular mental or nervous system disorder may comprise items related to negative thinking.

[0599] Instruments evaluating relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule - Expanded Form (PANAS-X) or the State Hope Scale (SHS).

[0600] The State Shame and Guilt Scale (SSGS) is a self-rating scale of in-the-moment (state) feelings of shame, and guilt experiences. It comprises two subscales, a shame and a guilt subscale. The shame subscale comprises items 1 , 3, 5, 7, 9. The guilt subscale comprises items 2, 4, 6, 8, 10. All items are scored in a positive direction and are rated on a 5-point Likert scale. It contains some statements which may or may not describe how the patient is feeling right now. A higher score indicates a more intense feeling of shame or guilt.

[0601] The Positive and Negative Affect Schedule - Expanded Form (PANAS-X) is a 60-item, expanded version of the PANAS. The PANAS-X measures 11 specific affects: Fear, Sadness, Guilt, Hostility, Shyness, Fatigue, Surprise, Joviality, Self-Assurance, Attentiveness, and Serenity. The PANAS-X thus provides for mood measurement at two different levels. The basic negative emotion scales are fear, hostility, guilt and sadness, while the scale guilt encompasses six items: guilty, ashamed, blameworthy, angry at self, disgusted with self, dissatisfied with self. Each answer should be scored as 1= very slightly or not at all; 2= a little; 3= moderately; 4= quite a bit; or 5= extremely. However, investigators facing more severe time constraints can select and assess only those scales that are most relevant to their research.

[0602] More intense feelings of guilt are reflected by a higher score on the guilt scale.

[0603] The PANAS-X is simple and easy to administer. Most subjects complete the entire 60- item schedule in 10 minutes or less. This scale consists of a number of words and phrases that describe different feelings and emotions. While it should be indicated to what extent the patient has felt this way during the past few weeks, it has been found that the trait scores on the PANAS-X scales are stable over time, including "at the present moment", "today" and during "the past few days", indicating that an appropriate shorter recall period can be applied.

[0604] The State Hope Scale (SHS) has three agency and three pathways items to which respondents describe themselves in terms of how they are "right now." The agency subscale score is derived by summing items 2, 4 and 6, relating to the perceived capacity to use one's pathways to reach desired goals; the pathways subscale score is derived by adding the items 1 , 3 and 5, relating to thinking that is used to identify possible ways to achieve a goal. The total State Hope Scale score is derived by summing the three agency and the three pathways items. Scores can range from a low of 6 to a high of 48, wherein higher hope is reflected by a higher score on this scale. Negative thinking or aspects thereof are also reflected in other scales such as HAM-D, the MADRS, the BPRS or the BDRS, wherein relevant items thereof may be commonly applicable for assessing negative thinking or aspects thereof.

[0605] A patient suffering from symptom of Negative Thinking will often be treated with one or more antidepressants.

[0606] This treatment may not lead to an adequate improvement in the symptoms of Negative Thinking. It may in particular not lead to remission.

[0607] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0608] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0609] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0611] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0612] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0613] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0614] Psychomotor Retardation

[0615] A further example of a disorder involving depressive episodes and / or episodes of anxiety is Psychomotor Retardation, which is characterized by reduced energy and activity and reduced motivation. Psychomotor Retardation involves a slowing down of thought and a reduction of physical movements in an individual. Psychomotor impairment can cause a visible slowing of physical and emotional reactions.

[0616] Psychomotor Retardation is associated with several mental or nervous system disorders. It also occurs in patients suffering from certain medical health conditions leading to associated mental or nervous system conditions.

[0617] Psychomotor retardation can be assessed by measuring various aspects. These may include for instance various types of drawing tasks and tests, such as the trail making test (TMT), the digit symbol substitution test (DSST), or the Gibson Spiral Maze Test (GSM) and others which are known in the art.

[0618] In the trail making test (TMT), for instance, subjects must connect 25 circles that contain either numbers (TMT A) or a combination of numbers and letters (TMT B) in ascending order. Task requirements are similar for TMT-B, except that the subject must alternate between numbers and letters (1 , A, 2, B, 3, C and so on). The test thus evaluates processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the amount of time required to complete the task.

[0619] Another test that involves graphomotor ability is the Gibson Spiral Maze (GSM) assessing psychomotor speed only, is not influenced by cognitive abilities. Subjects who complete the GSM must correctly trace through a spiral maze from a starting point to an end point without touching bordering lines.

[0620] The digit symbol substitution test (DSST) measures also psychomotor speed and consists of digit-symbol pairs followed by a list of digits. Under each digit, the subject should write down the corresponding symbol as fast as possible. The score consists in the number of symbols correctly reported in 90 s. A further example for a motor test is the finger tapping test.

[0621] Thus, certain tests combine measurements of both motor and cognitive aspects of psychomotor retardation, while further others assess only motor aspects.

[0622] Analysis of speech can be a further indicator of psychomotor retardation.

[0623] Major scales available to assess and measure include the severity of psychomotor retardation, the Salpetriere Retardation Rating Scale (SRRS) and the Motor Agitation and Retardation Scale (MARS).

[0624] The Salpetriere Retardation Rating Scale (SRRS), developed by Widlbcher assesses cognitive and motor aspects by fifteen items. The first three measure movement, specifically the quality of stride and slowness of limb, trunk, head, and neck movement. The next three items focus on speech including verbal flow, tone of voice, and length of response. Two items are designed to objectively measure cognitive function. These questions are based on the interview conversation and measure the patient’s ability to approach and expand on topics. The further items are subjective and assess rumination, fatigue, level of interest, perception of time, memory, and concentration. The last item of the scale relates to an overall assessment of the patient’s psychomotor retardation. The items are scaled from 0 (symptom absence) to 4 (severe) based on the severity of the presenting symptom, for a total score range of 0 to 60.

[0625] The Motor Agitation and Retardation Scale (MARS) assesses motor aspects only. It was designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five major body categories including eyes, face, voice, limbs, and trunk with a total of 19 items on the scale. Items of the eyes category include direction of gaze, amount of blinking, staring, and eye movement. Items associated with the face category include facial expression and facial expressivity. The category of voice has items that include volume, slurring, tone and time for onset. Items under the limbs category include hand, foot, and leg movement, stride, motor slowness, and tension in hands. The trunk category items include posture, immobility, and axial movement. The severity of each item ranges from a 1 to a 4, with 4 being the most severe. Of the 19 items 9 relate to motor agitation and 10 items assess motor retardation. The retardation items include abnormal gait, immobility of trunk I proximal limbs, postural collapse, motor slowness (i.e. the limb and trunk category); lack of facial expressivity, downcast gaze (i.e. the eyes and face category); and reduced voice volume, slurring of speech, delayed speech onset, monotone speech (i.e. the voice category). The MARS scale offers a rapid clinical assessment of motor signs.

[0626] A patient suffering from symptom of Psychomotor Retardation will often be treated with one or more antidepressants.

[0627] This treatment may not lead to an adequate improvement in the symptoms of Psychomotor Retardation. It may in particular not lead to remission.

[0628] According to the present invention, a patient not achieving an adequate improvement by a treatment with one or more antidepressants, such as a patient in whom remission is not achieved by a treatment with one or more antidepressants, may be treated by administering a 5-MeO-DMT / salt treatment course.

[0629] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI- I) score or the Patient Global Impression - Improvement (PGI-I) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0630] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0631] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0632] In a further aspect, the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, leads to a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] The clinical response, as reflected by a reduction in the CGI-S score, persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0634] The clinical response, as reflected by a reduction in the CGI-S score, can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0635] The patient is still in remission after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0636] Suicidal Ideation

[0637] The presence of suicidal ideation in a patient will be diagnosed by a physician or a psychologist, using established protocols and methods for diagnosing suicidality. It is generally not sufficient that the patient himself considers that he / she is suffering from suicidal ideation. In some situations, a patient experiencing suicidal ideation will be at imminent risk of committing suicide, or will be considered to have 'intent to act.'

[0638] Suicidal ideation may be assessed using the Columbia Suicide Severity Rating Scale (C- SSRS) or by another appropriate scale, subscale or item of a scale.

[0639] Suicidal ideation can be comorbid with any one of the above specified diseases or conditions.

[0640] A patient suffering from suicidal ideation comorbid with any one of the above specified diseases or conditions may be treated with one or more antidepressants, however, this treatment may not lead to an adequate improvement in the suicidal ideation.

[0641] In particular, psychotropic medications are known to increase the suicidal ideation.

[0642] Treating a patient suffering from suicidal ideation comorbid with any one of the above specified diseases or conditions, including a treatment resistant form of the disorder, with Q the 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation.

[0643] The 5-MeO-DMT / salt treatment course, administered in combination with one or more antidepressants as discussed herein, reduces or eliminates suicidal ideation not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0644] The reduction or elimination of suicidal ideation is still observed after more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] The reduction or elimination of suicidal ideation can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

[0646] Antidepressants and Augmentation Medicines for Use in Co-Therapy

[0647] Antidepressants are drugs that can be used to alleviate depressive symptoms. They are used to treat disorders characterized by depressive episodes to relieve symptoms and / or prevent recurring of symptoms

[0648] Antidepressants are also used for the treatment of several other disorders which may involve depressive episodes but may also be characterized by other symptoms, in particular episodes of anxiety.

[0649] Antidepressants are usually administered to the patient continuously over a longer period of time, for instance, for several weeks and typically for several months or even years. The clinical response can normally only be observed after a longer period of continuous treatment with the antidepressant.

[0650] Antidepressants are typically subdivided into several classes.

[0651] Selective serotonin reuptake inhibitors (SSRIs) are a class of medication that is widely used to treat depression. This class of medication is usually the first choice medicine for depression because they generally have fewer side effects than most other types of antidepressant. However, SSRIs can be used to treat a number of other mental health conditions, including generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic disorder, severe phobias, such as agoraphobia and social phobia, eating disorders such as bulimia and post-traumatic stress disorder (PTSD). SSRIs can sometimes be used to treat other conditions, such as premenstrual syndrome (PMS), fibromyalgia and irritable bowel syndrome (IBS). Occasionally, they may also be prescribed to treat pain.

[0652] As the name suggests, SSRIs inhibit the reuptake of serotonin. They in particular inhibit the serotonin transporter (SERT) at the presynaptic axon terminal. This results in increased availability of serotonin at postsynaptic receptors.

[0653] A therapeutic effect, which evolves over several weeks to months of treatment, results from presynaptic and postsynaptic adaptive mechanisms secondary to the inhibition of serotonin reuptake.

[0654] For instance, increased serotonin availability promotes the expression of the cellular transcription factor CREB (cAMP response element-binding protein) and also increases the expression of the growth factor BDNF (Brain-derived neurotrophic factor) and of the corresponding tyrosine receptor kinase TrkB (Tropomyosin receptor kinase B). These processes contribute to plasticity.

[0655] SSRIs are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0656] This class of medication includes the following compounds, which are in clinical use: fluoxetine, fluoxetine in combination with the antipsychotic olanzapine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram.

[0657] Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a further class of medications that are effective in treating depression. SNRIs are also sometimes used to treat other conditions, such as anxiety disorders and long-term (chronic) pain, especially nerve pain. SNRIs may be helpful if you have chronic pain in addition to depression.

[0658] Serotonin norepinephrine reuptake inhibitors (SNRIs) differ from selective serotonin reuptake inhibitors (SSRIs) in that they also inhibit the reuptake of norepinephrine, as the class name indicates, but their potency with regard to serotonin reuptake inhibition is comparable to that of the SSRIs.

[0659] Blockade of serotonin and norepinephrine transporters, increasing bioavailability of serotonin and norepinephrine at the synapse. This results in an increase in the extracellular concentration of serotonin and noradrenaline in the synaptic cleft. The antidepressant effect of SNRIs is explained by the increase in this neurotransmitter activity in the central nervous system.

[0660] Increased serotonin availability promotes CREB and neurotrophic signalling. Expression of BDNF (Brain-derived neurotrophic factor) and of the corresponding tyrosine receptor kinase receptor TrkB (Tropomyosin receptor kinase B) are increased. A key role for BDNF has been suggested in the mediation of antidepressant-induced neuroplasticity. BDNF is a member of neurotrophic factor family found mostly in the central nervous system. BDNF is considered to be important for neuroplasticity, such as synaptic remodeling, neuronal differentiation, axonal growth, and neuronal survival.

[0661] SNRIs are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0662] This class of medication includes the following compounds, which are in clinical use: duloxetine, venlafaxine (immediate-release or extended-release), desvenlafaxine (extended-release), milnacipran, levomilnacipran (extended-release).

[0663] Serotonin modulator antidepressants act by altering the activity of various post-syn- aptic serotonin (5-HT) receptors, in addition to inhibiting the reuptake of serotonin via the same mechanism as selective serotonin reuptake inhibitors (SSRIs).

[0664] Serotonin modulator antidepressants are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months. This class of medication includes the following compounds, which are in clinical use: nefazodone, trazodone (immediate-release or extended-release), vilazodone and vortioxetine.

[0665] Tricyclic antidepressants (TCAs) are also called cyclic antidepressants. Tricyclic Antidepressants are a class of antidepressants that have a very broad mechanism of action compared to the SSRI medications. These medications were developed in an effort to deal with the potential serious side effects of monoamine oxidase inhibitors. These medications block the reuptake mechanism for the neurotransmitters serotonin, norepinephrine, and partially for the neurotransmitter dopamine. Inhibiting serotonin and norepinephrine reuptake within the presynaptic terminals results in elevated concentrations of these neurotransmitters within the synaptic cleft. The increased levels of norepinephrine and serotonin in the synapse can contribute to the antidepressant effect.

[0666] This class of medication is used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia also known as social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), neurological disorders such as attention-deficit hyperactivity disorder (ADHD), Parkinson's disease as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, migraine, insomnia, and as an adjunct in schizophrenia.

[0667] TCAs are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0668] This class of medication includes the following compounds, which are used in the clinic: amitriptyline (immediate-release or prolonged-release), amoxapine, clomipramine (immediate-release or prolonged-release), desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine. Tetracyclic antidepressants is a class of medication first introduced in the 1970s. The agents of this class of medication have a tetracyclic chemical structure, containing four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

[0669] Tetracyclic antidepressants (TeCAs) are one class of medication that works by modifying hormones such as serotonin, norepinephrine, and dopamine. TeCAs, such as mianserin, maprotiline, and mirtazapine, are compounds that assist in preventing the brain from reabsorbing the neurotransmitters norepinephrine and serotonin. Each of these medications interacts with adrenergic (alphai and alpha2) and serotonin (5HTi and 5HT2) receptors independently.

[0670] This class of medication is used primarily in the clinical treatment of depression, including MDD, bipolar disorder, and anxiety. Agents of this class may be used off-label for treating insomnia, panic disorder, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) and migraine.

[0671] TeCAs are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0672] This class of medication includes the following compounds, which are clinically used: mirtazapine, maprotiline, mianserin.

[0673] The antidepressant effects of N-Methyl D-Aspartate (NMDA) Receptor Antagonists, a further class of medication, such as esketamine, are also multi-mechanistic, one of which is through blocking NMDA receptors on gamma-aminobutyric acid (GABA) interneurons and activating alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AM PA) receptor, which increases with BNDF levels, a neurotrophic signal that restores synaptic function. Another important pathway mediating the antidepressant effects of esketamine is the activation of monoaminergic receptors and increased release of monoamine transmitters such as 5-hydroxytryptamine (5-HT) and dopamine.

[0674] NMDA receptor antagonists are usually administered to the patient continuously over a longer period of time, for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0675] This class of medication includes the following compounds, which are clinically used: ketamine, esketamine and dextromethorphan. Dextromethorphan can be combined with bupropion.

[0676] Atypical antidepressants have various mechanisms of action. Bupropion, for example, works by inhibiting the reuptake of dopamine and norepinephrine at the presynaptic cleft. Agomelatine works as an agonist at melatonin receptors MT1 and MT2. It also antagonizes serotonergic 5-HT2C receptors, promoting dopamine and norepinephrine release. In contrast, gepirone is a 5-HT1A receptor agonist.

[0677] Atypical antidepressants are usually administered to the patient continuously over a longer period of time, in particular for several weeks and typically for several months or even years. A patient suffering from severe or recurring mental or nervous system disorders may need to take psychotropic medications, such as antidepressants, for more than 6 or even more than 12 months.

[0678] This class of medication includes the following compounds, which are clinically used: bupropion (immediate-release or sustained-release), agomelatine and gepirone.

[0679] An augmentation medicine is a class of medication which can be added to an antidepressant with the aim of increasing the antidepressant effect.

[0680] Augmentation medicines are usually administered to the patient continuously over a longer period of time, in particular of two or more months.

[0681] Augmentation medicines can be divided into at least two classes: mood stabiliser and thyroid agents.

[0682] Mood stabiliser are e.g. antipsychotics, such as quetiapine (immediate-release or extended-release), olanzapine, aripiprazole, risperidone and brexpiprazole; anticonvulsants, such as lamotrigine; and lithium.

[0683] Thyroid agents include liothyronine and levothyroxine.

[0684] When it is intended to treat a patient with a 5-MeO-DMT / salt treatment course in combination with an antipsychotic, the 5-MeO-DMT / salt treatment course should preferably be administered to the patient after the expiry of three, preferably five blood plasma half times of the antipsychotic after the last administration of the medication with the antipsychotic.

[0685] Monoamine Oxidase Inhibitors

[0686] Monoamine Oxidase Inhibitors (MAOIs) MAOIs are the oldest of the major classes of antidepressant medications. MAOIs interrupt the chemical breakdown of neurotransmitters in the brain, and this is believed to be their action of efficacy regarding the treatment of depression. These medications are no longer the frontline treatment for depression, and they are used sparingly.

[0687] MAOIs are usually administered to the patient continuously over a longer period of time, in particular of two or more months.

[0688] 5-MeO-DMT

[0689] The inventors identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for use in therapy. 5-MeO-DMT has a distinct pharmacological profile which differs from that of other psychedelic compounds.

[0690] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist, acting at both the 5-HT1 A and the 5-HT2A receptor, with higher affinity for the 5-HT1 A receptor subtype compared to other classical psychedelics.

[0691] Inhibition constants (Kj values) as further detailed on the example section below for psilocin (the dephosphorylated from of psilocybin which is formed after uptake of psilocybin), DMT and 5-MeO-DMT are 48, 38 and 1.80 nM, respectively, at 5-HT1A receptors located in the hippocampus of post-mortem human brain. Thus, 5-MeO-DMT exhibits high affinity and psilocin and DMT exhibit moderate affinity for 5-HT 1 A receptors. Inhibition constants (Kj values) for psilocin, DMT and 5-MeO-DMT are 37, 117 and 122 nM, respectively, at 5-HT2A receptors located in the frontal cortex of post-mortem human brain. Therefore, psilocin exhibits moderate / strong affinity and DMT and 5-MeO-DMT exhibit comparatively weak affinity for 5-HT2A receptors.

[0692] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT displays an enhanced affinity for the 5-HT1 A receptor, where it acts as a potent agonist. In the case of psilocin and DMT, there is an increased contribution of 5-HT2A binding, relative to 5-MeO-DMT, with the latter displaying the largest differential affinity for 5- HT1A over 5-HT2A of the three compounds. Therefore, 5-HT1A binding plays a much bigger role in the overall effect of 5-MeO-DMT relative to 5-HT2A binding compared to the other two compounds.

[0693] It has been reported that 5-HT1A agonism reduces impulsivity and aggression, whereas 5-HT2A agonism can result in short-term increases in these same traits. Furthermore, the dopamine system has been implicated in contributing to mania, with increased dopamine drive being linked to mania. LSD, psilocybin and DMT all display increased affinity for a variety of dopamine receptors relative to 5-MeO-DMT

[0694] Compared to other psychedelics, like LSD, psylocibin or DMT, 5-MeO-DMT can be administered to patients, preferably using dosing schemes as described herein, without a significant risk of inducing mania or hypomania in a patient suffering from a mental or nervous system disorder, including a disorder which involves depressive episodes and / or episodes of anxiety. The patient suffering from such a mental or nervous system disorder, treated according to the invention, does not experience treatment-emergent mania or hypomania.

[0695] It is also noted that reports of treatment-emergent mania or hypomania related to psychoactive substance use seem to indicate large quantities of the respective compounds (e.g., DMT / ayahuasca, psilocybin, LSD) were used.

[0696] The inventors’ approach of sequential up-titration of 5-MeO-DMT significantly reduces the risk of excessive dose administration with its potential for attendant adverse events.

[0697] 5-MeO-DMT can induce peak experiences, i.e., experiences characterized by an emotional perspective shift, which is described as "loss of ego" which often culminates in an overwhelming sense of "oneness with the universe", more rapidly than other psychedelics and has a short duration of acute psychedelic effects (5 to 30 minutes after inhalation compared with several hours for e.g. oral psilocybin and oral LSD). These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile which can be explained by specific alterations of Resting State Network (RSN) activity under 5-MeO- DMT treatment.

[0698] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist showing high affinity towards the receptor. The inventors determined, using recombinant human 5-HT7 receptor, [3H]LSD as a radio ligand and serotonin to estimate non-specific binding, a Kj of 2.3 nM. Thus, besides the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT act as an agonist on this receptor and shows a high (nanomolar) binding affinity.

[0699] The 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation. It is, among other things, associated with central processes such as learning and memory, with sleep regulation and circadian rhythm and with nociception.

[0700] The 5-HT7 receptor is in particular expressed in the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the cerebellum.

[0701] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination will result in disease states, in particular disease states involving sleep disturbance. In patients suffering from sleep disturbance resting state functional connectivity analysis reveals alterations in functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0702] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of the receptor in regulation of sleep / wake cycles. The inventors consider that this allows treatment of patients suffering from sleep disturbance by 5-MeO-DMT which acts on the receptor.

[0703] The inventors consider that binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT, which involve functional connectivity "resets" of networks and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disturbance and / or cognitive dysfunction.

[0704] The inventors further consider that binding of 5-MeO-DMT to the 5-HT7 receptor as well as to the 5-HT1A receptor as two mediators of effects exerted by 5-MeO-DMT, which include functional connectivity "resets" of networks and neuroplasticity effects, allows achieving beneficial effects also in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social / emotional withdrawal. This is supported by the clinical results demonstrated in studies referred to herein.

[0705] Another feature of 5-MeO-DMT is its short half-life. 5-MeO-DMT is mainly inactivated through a deamination pathway mediated by monoamine oxidase A, and it is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzyme.

[0706] The inventors investigated pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0707] An analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline of the plasma concentration. Already 10 minutes after administration, the concentration drops to 10 % of Cmax or below; after 2 hours, it is 1 % of Cmax or below; after 3 hours, 5-MeO-DMT is no longer detectable in the plasma. This applies over the whole dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed upon repeated administration within a time frame of 1 to 4 hours. Uptitration as disclosed herein will not lead to accumulation and thus not to higher plasma concentrations, for instance, 10 minutes, 2 hours, or 3 hours after administration.

[0708] The properties of 5-MeO-DMT make the compound especially suitable for the treatment of cognitive dysfunction, in particular for patients suffering from a mental disorder or a nervous system disorder, or a medical health condition leading to an associated mental or nervous system condition; in a patient suffering from sleep disturbance, for instance, insomnia; in a patient suffering from an unspecified neurocognitive disorder.

[0709] The properties of 5-MeO-DMT also allow specific dosage regimens, as discussed in more detail below.

[0710] According to the invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof can also be used. When reference is made to the use of 5-MeO- DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0711] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0712] Deuterated forms of 5-MeO-DMT are forms having a higher deuterium content than expected based on the natural abundance of this isotope.

[0713] Deuterated forms of 5-MeO-DMT are in particular forms wherein deuterium has been introduced at one or more defined hydrogen positions. 10*^

[0714] Examples of deuterated forms of 5-MeO-DMT include, without limitation, 1-deuterio-2- (5-methoxy-1 H-indol-3-yl)-N,N-dimethylethanamine, 1 ,1-dideuterio-2-(5-methoxy-1 H- indol-3-yl)-N,N-dimethylethanamine, 1 ,1 ,2,2-tetradeuterio-2-(5-methoxy-1 H-indol-3-yl)- N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1 H-indol-3- yl]ethanamine.

[0715] Further examples include forms of 5-MeO-DMT wherein deuterium has been introduced at one or more hydrogen positions of the N-bound methyl groups. Still further examples include forms of 5-MeO-DMT wherein one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is moreover noted that combinations of the above substitution patterns are also contemplated.

[0716] Preparation methods for these compounds are known in the art.

[0717] According to the invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated form with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixture of such salts as well as mixtures of salts of deuterated and non-deuterated 5-MeO-DMT can also be used.

[0718] Further according to the invention, deuterated 5-MeO-DMT and salts of deuterated 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-deuterated forms.

[0719] According to the invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used. Such prodrugs of 5-MeO-DMT can be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5- MeO- DMT or a pharmaceutically acceptable salt thereof, this can be replaced by a 5- MeO- DMT prodrug or a salt thereof.

[0720] In suitable prodrugs, the hydrogen in position 1 of the indole moiety is substituted by an organic moiety which can be split off after administration.

[0721] Examples of suitable organic moieties are -C(O)OR1, -C(O)R2, -CH(R3)OR4, - C(O)OCH(R3)OC(O)R4, -C(O)OCH(R3)OC(O)OR4, -CH(R3)C(O)R4, -CH(R3)OC(O)R4, - CH(R3)OC(O)OR4, wherein each of R1, R2, R3, and R4is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted. Preferred examples of organic moieties are -CH(R3)OC(O)R4and -C(O)OR1, wherein R1, R3, and R4are defined as above.

[0722] Prodrugs, especially those of the above structure, can also be used on the form of pharmaceutically acceptable salts.

[0723] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropyl valinate, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2- methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1 H-indole-1 -carboxylate di-trifluoro- acetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-rnethoxy-1 H- indol-1-yl)methyl pivalate).

[0724] Preparation methods for prodrugs as discussed herein are known in the art.

[0725] According to the invention, the Tmax value of the metabolite 5-MeO-DMT as measured in male Sprague-Dawley (SD) rats following oral dosing of the prodrug at 10 mg / kg is preferably 1 hour or less, more preferably 0.7 hours or less and in particular 0.5 hours or less.

[0726] Further according to the invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-prodrug forms.

[0727] Salts are known in the art, for instance, from WO 2023 / 186834.

[0728] Modes of Administration

[0729] Administration By Inhalation or By Nasal, Buccal, Sublingual Administration

[0730] According to one aspect of the invention, the therapeutically effective amount of 5-MeO- DMT is administered by inhalation, by nasal administration, by buccal administration or by sublingual administration. Administration via these routes can assure a rapid onset of action. A most preferred route of administration is administration by inhalation. Preferably, the inhalation of the therapeutically effective amount of 5-MeO-DMT occurs within a single breath.

[0731] For nasal administration, 5-MeO-DMT can be employed as a neat substance or in the form of a formulation for nasal administration, examples of which are known in the art. For nasal administration, 5-MeO-DMT can be employed as a pharmaceutically acceptable salt, such as the benzoate salt or the hydrobromide salt, or in the form of a formulation of a pharmaceutically acceptable salt, preferable the hydrobromide salt. Examples of appropriate devices are known in the art.

[0732] Buccal administration or sublingual administration can also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the benzoate salt or the hydrobromide salt, as such or in the form of formulations, for instance, tablets, films, sprays, creams, as generally known in the art.

[0733] Administration is in particular by inhalation of an aerosol. Such an aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as about

[0734] 0.5 mg / l to about 12.5 mg / l, preferably of about 1.3 mg / l to about 10 mg / l, in particular of about 2 mg / l to about 9 mg / l. The pharmaceutically acceptable gas is preferably air.

[0735] The aerosol particles preferably contain less than 1 wt% impurities, in particular less than 0.5 wt% impurities. They furthermore preferably contain less than 0.5 wt% 5-MeO-DMT degradation products, in particular less than 0.2 wt% 5-MeO-DMT degradation products resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation.

[0736] In a further preferred aspect, the aerosol essentially consists of (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0737] The aerosol particles preferably contain 5-MeO-DMT in the form of the free base.

[0738] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 pm and more than 0.1 pm, in particular by a mass median aerodynamic diameter of less than 2 pm and more than 0.1 pm.

[0739] The aerosol may be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to produce aerosol particles. The thin layer may have a thickness of less than about 10 pm, in particular less than about 7.5 pm. It may have a thickness in the range of about 0.1 pm to about 10 pm, in particular in the range of about 0.3 pm to about 7.5 pm. The thin layer of 5-MeO-DMT, configured on a solid support, may be exposed to thermal energy via the air passing over the thin layer. Alternatively, the thin layer of 5-MeO-DMT, configured on a solid support, may be exposed to thermal energy via the solid support.

[0740] The air passing over the thin layer may have a temperature in the range of about 180°C to about 260°C. The air passing over the thin layer may in particular have a temperature of about 210°C and pass over the thin layer at a rate of about 12 l / min for a duration of about 15 seconds.

[0741] The aerosol particles may be contained in a volume of equal or less than about 3 liters, in particular in a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. It is preferably delivered to a patient via a single inhalation.

[0742] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical context. 5-MeO-DMT and pharmaceutically acceptable salts thereof are provided in the form of aerosols. These aerosols have a suitable aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

[0743] Aerosols useful in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is very difficult to predict which conditions are suitable for safe, efficient and predictable aerosolization, in particular if the aerosol is to be used for systemic delivery of that compound to a patient via the lungs. Relevant variables in this context include a) the dose of the compound, b) the morphological state in which that compound is made available for aerosolization (e.g. in crystal form, or in form as a thin layer), c) the amount of thermal energy to which the compound is exposed (defined by temperature and duration of exposure), and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of air flow).

[0744] The compositions and methods described herein are for safe, efficient and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient through inhalation. "Safe" means that the aerosol particles should contain only a very small amount of impurities and 5-MeO-DMT degradation products, "efficient" means that the dosage is aerosolized to a defined extent and preferably almost completely or completely, that the aerosol has desirable physical properties for delivery of the 5-MeO- DMT or a pharmaceutically acceptable salt thereof systemically via the lungs mainly via absorption in the pulmonary alveoli, and that the aerosol can be inhaled by the patient in a single inhalation (i.e., within one deep breath), and "predictable" means that there should be almost no or no variability in the amount of degradation products, in the extent of aerosolization, and in the physical properties of the aerosol.

[0745] A suitable aerosol can be achieved by a) providing the therapeutically effective amounts of 5-MeO-DMT as a thin layer, on a solid support, b) exposing the thin 5-MeO-DMT layer to elevated controlled temperatures for a short duration of time, and c) providing a controlled amount of air so that an aerosol is formed.

[0746] A composition for delivery of a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by a) exposing a thin layer of 5-MeO- DMT, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT; wherein said aerosol has one or more of the following features: 1) it contains aerosol particles which are characterized by a mass median aerodynamic diameter of less than 3 micron, 2) it contains aerosol particles which are characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, 3) it can be delivered to a patient via a single inhalation.

[0747] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, with less than 1% wt impurities and less than 0.5% wt 5-MeO-DMT drug degradation products, in an aerosol volume which can be delivered to a patient via a single inhalation, is achieved by defining a) the dosage amount of 5-MeO- DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of the 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of the air which passes over the thin layer of 5-MeO-DMT (defined by airflow rate and duration of airflow).

[0748] Preferably the thin layer of 5-MeO-DMT is exposed to thermal energy via the air passing over the thin layer, in which case that air is heated. The heated air passing over the thin layer may have a temperature in the range of about 180°C to about 260°C. The air passing over the thin layer may in particular have a temperature of about 210°C.

[0749] Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy via the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The heated solid support may have a temperature in the range of about 180°C to about 420°C.

[0750] Preferably the 5-MeO-DMT used for formation of the thin layer, on the solid support, is highly pure, with a purity of at least 99%, preferably at least 99.5%. Preferably the dosage amount of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, configured on the solid support, is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg. Useful specific amounts are, e.g., about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are e.g. about 6 mg, about 12 mg, and about 18 mg.

[0751] Solid supports, on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided, can have a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1 .0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm2per gram).

[0752] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).

[0753] A number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.

[0754] Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m2 / g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Carbon yams and felts are available from American Kynol, Inc., New York, N.Y.

[0755] Preferably the thickness of the thin layer of the 5-MeO-DMT, configured on the solid support, is less than about 10 pm, in particular less than about 7.5 pm. It may have a thickness in the range of about 0.1 pm to about 10 pm, in particular in the range of 0.3 pm to 7.5 pm. Preferably the total amount of the air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of between about 6 liters per minute and about 40 liters per minute, preferable between about 8 liters per minute and about 16 liters per minute and the duration of airflow is chosen so that the total volume of aerosol does not exceed about 3 liters, preferably is between about 1 liter and 3 liters, such as between 2 liters and 3 liters. E.g., at an airflow rate of about 6 liters per minute, the duration of airflow should be less than about 30 seconds. A useful specific airflow rate and duration is about 12 liters per minute and about 15 seconds, leading to an aerosol volume of about 3 liters. Another useful specific airflow rate and duration is 10 liters per minute and about 15 seconds, leading to leading to an aerosol volume of about 2.5 liters. Another useful specific airflow rate and duration is 8 liters per minute and about 15 seconds, leading to leading to an aerosol volume of about 2 liters. Another useful specific airflow rate and duration is 10 liters per minute and about 12 seconds, leading to leading to an aerosol volume of about 2 liters.

[0756] The aerosol formation rate is greater than 0.1 mg / sec.

[0757] The aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as of about 0.5 mg / l to about 12.5 mg / l, preferably of about 1.3 mg / l to about 10 mg / l, in particular of about 2 mg / l to about 9 mg / l.

[0758] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 micron and more than 0.1 micron, preferably of less than 2.5 micron and more than 0.1 micron, most preferably of less than 2 micron and more than 0.1 micron. The 5-MeO-DMT aerosol particles are characterized by less than 1 % wt impurities, preferably by less than 0.5% wt impurities.

[0759] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt 5-MeO-DMT degradation products, preferably by less than 0.2% wt 5-MeO-DMT degradation products.

[0760] A composition for delivery of a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by a) exposing a dosage amount of 12 mg 5-MeO-DMT, configured as a thin layer of less than 5 micron thickness on a solid support, to a temperature of 210° C via passing heated air over the thin layerfor a duration of 15 seconds; wherein said aerosol has one or more of the following features: 1) it contains aerosol particles which are characterized by a mass median aerodynamic diameter of less than 3 micron, 2) it contains aerosol particles which are characterized by less than 1 % impurities and less than 0.5% wt 5-MeO-DMT degradation products, 3) it can be delivered to a patient via a single inhalation.

[0761] A skilled person, knowing the aerosol characteristics and the aerosolization conditions defined in the present invention, can identify suitable vaporization devices or systems, which lead to the required aerosol characteristics. Examples of such suitable vaporization devices or systems include e.g. the Volcano Medic Vaporization System with the associated dosing capsules with drip pad (Storz & Bickel, Germany; as disclosed in e.g. EP 0 933 093 B1, and EP 1 884 254 B1 and Registered Community Design 003387299- 0001) and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA; as dis- closed e.g. in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The aerosol generated may be collected in a balloon and inhaled by the patient from the balloon.

[0762] Intravenous, Intramuscular and Subcutaneous Administration

[0763] Alternatively, the therapeutically effective amount of 5-MeO-DMT is administered by intravenous administration, by intramuscular administration or by subcutaneous administration. Administration via these routes can assure a rapid onset of action. Among these routes of administration, the preferred route of administration is the administration via the intravenous route, i.e. by intravenous injection.

[0764] 5-MeO-DMT can be employed as a pharmaceutically acceptable salt, such as the benzoate salt or the hydrobromide salt, or in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations being known in the art.

[0765] Dosing Regimen

[0766] Dosing Regimen Comprising the Administration of 5-MeO-DMT by Inhalation, by Nasal, Buccal or Sublingual Administration

[0767] The present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes) for the administration of 5-MeO-DMT as part of a combination treatment.

[0768] Dosing regimen suggested are in part based on the inventors' conclusion that the occurrence of a peak psychedelic experience during the acute phase after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is driving its therapeutic benefit, either in a causal relationship or at least as a surrogate behavioural marker for the underlying unknown therapeutic mechanism.

[0769] Consequently, achieving peak experiences more rapidly, in a larger proportion of patients and with better reproducibility in an individual patient, compared with previously tested psychedelic agents and dosing regimens, will lead to a better therapeutic profile.

[0770] Further, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of relevant tolerance (i.e., the absence of diminished or no psychedelic effects after re-administration), as a basis for enabling a dosing regimen with frequent re-administrations, in particular within a 5-MeO-DMT / salt treatment course so that the rate of occurrence of peak experiences can be increased, thereby increasing the therapeutic benefit.

[0771] Repeat administrations within short time also allow an intraindividual dose-optimization which reduces the risk of overdosing, which may otherwise lead to somatic side effects, such as the serotonin syndrome, negative psychic reactions, such as flashbacks of the experience at later timepoints, induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state (so-called "white- outs").

[0772] Further, starting with a low dose allows familiarization of the patient with the psychedelic experience in general, and allows preparation for the more intense symptoms to occur at the higher doses, which will positively influence the experience at those higher doses. Also, the prospect of being able to initiate treatment with a low dose will increase patient acceptance of the therapeutic approach and improve overall compliance rates on the patient population level.

[0773] Frequent re-administrations of a serotonergic psychedelic with the aim to increase the rate and tailor the reproducibility of peak experiences and to improve the therapeutic effect, reduce the side effects and improve the compliance rates may not be possible with other psychedelics, due to the late onset and long duration of psychedelic effects and due to the rapid development of tolerance (i.e. diminished or no psychedelic effects after re-administration) which can last for several days.

[0774] A patient who has been diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety and who receives a treatment with one or more antidepressants, is treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The dosage amount of 5-MeO-DMT administered to a patient, as defined herein, in particular by inhalation, by nasal administration, by buccal administration or by sublingual administration, is in the range of about 1 mg to about 25 mg, or any amount of range therein, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg. Useful specific amounts are e.g. about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the benzoate salt or the hydrobromide salt. Note that in this specification, when ranges are set forth, such as "about 1 mg to about 25 mg," the inventor contemplates all discrete values within that range, some of which are specifically mentioned, but all of which are not - simply for the purpose of brevity.

[0775] In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a therapeutically effective amount of 5-MeO-DMT or a salt thereof, comprise the occurrence of a clinical response not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0776] In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a therapeutically effective amount of 5-MeO-DMT, comprise the persistence of a clinical response, including a clinical response which occurred not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after administration of 5-MeO-DMT. The clinical response persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0777] The clinical response can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course.

[0778] In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a therapeutically effective amount of 5-MeO-DMT comprise the administration of more than a single dose of 5-MeO-DMT.

[0779] In a preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with not less than about 1 hour and not more than about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0780] In an even more preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0781] In a most preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0782] In an embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient in each of the administrations and in each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg. Useful specific amounts are e.g. about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0783] In a preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered.

[0784] In an even more preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects.

[0785] For embodiments where the dosage amount increases for subsequent administrations, the dosage amount for the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, most preferably about 6 mg, to the dosage amount of the prior administration. For example, if the dosage amount of the first administration was 6 mg and the dosage amount increase is 6 mg, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be 12 mg. Preferably, the dosage amount for the third administration will be 18 mg.

[0786] In a preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 8 mg to about 14 mg for the second administration, and from about 14 mg to about 20 mg for the third administration. Useful specific amounts for the first, second and third administration are e.g. about 6 mg, about 12 mg, and about 18 mg.

[0787] In a further preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, and then increases with each subsequent administration within that first treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects, with that highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dosage in the first treatment block was 18 mg because the patient experienced a peak psychedelic experience at that dose, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 18 mg.

[0788] In a most preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block, and from about 14 mg to about 20 mg for the third ad- ministration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 6 mg, about 12 mg, and about 18 mg.

[0789] It is understood that a pharmaceutically acceptable salt of 5-MeO-DMT can also be used in all of the above dosing regimen, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.

[0790] Dosing Regimen Comprising the Administration of 5-MeO-DMT by Intravenous, Intramuscular or Subcutaneous Administration

[0791] The present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes) as part of a combination treatment.

[0792] Dosing regimen suggested are in part based on the inventors' conclusion that the occurrence of a peak psychedelic experience during the acute phase after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is driving its therapeutic benefit, either in a causal relationship or at least as a surrogate behavioural marker for the underlying unknown therapeutic mechanism.

[0793] Consequently, achieving peak experiences more rapidly, in a larger proportion of patients and with better reproducibility in an individual patient, compared with previously tested psychedelic agents, dosing regimens, will lead to a better therapeutic profile.

[0794] Further, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of relevant tolerance (i.e., the absence of diminished or no psychedelic effects after re-administration), as a basis for enabling a dosing regimen with frequent re-administrations, in particular within a 5-MeO-DMT / salt treatment course so that the rate of occurrence of peak experiences can be increased, thereby increasing the therapeutic benefit.

[0795] Repeat administrations within short time also allow an intraindividual dose-optimization which reduces the risk of overdosing, which may otherwise lead to somatic side effects, such as the serotonin syndrome, negative psychic reactions, such as flashbacks of the experience at later timepoints, induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state (so-called "white- outs"). Further, starting with a low dose allows familiarization of the patient with the psychedelic experience in general, and allows preparation for the more intense symptoms to occur at the higher doses, which will positively influence the experience at those higher doses. Also, the prospect of being able to initiate treatment with a low dose will increase patient acceptance of the therapeutic approach and improve overall compliance rates on the patient population level.

[0796] Frequent re-administrations of a serotonergic psychedelic with the aim to increase the rate and tailor the reproducibility of peak experiences and to improve the therapeutic effect, reduce the side effects and improve the compliance rates may not be possible with other psychedelics, due to the late onset and long duration of psychedelic effects and due to the rapid development of tolerance (i.e. diminished or no psychedelic effects after re-administration) which can last for several days.

[0797] A patient who has been diagnosed with a mental disorder or a nervous system disorder, such as a disorder which involves depressive episodes and / or episodes of anxiety and who receives a treatment with one or more antidepressants is treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0798] The dosage amount of 5-MeO-DMT administered to a patient, as defined herein, in particular by intravenous administration, by intramuscular administration, or by subcutaneous administration, is in the range of about 1 mg to about 10 mg, or any amount of range therein and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the benzoate salt or the hydrobromide salt, which weight amount can be calculated from the stated weight amounts of the 5-MeO-DMT free base, assuming that equimolar amounts are used. Useful specific amounts of 5-MeO-DMT are e.g. about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Note that in this specification, when ranges are set forth, such as "about 1 mg to about 10 mg," the inventor contemplates all discrete values within that range, some of which are specifically mentioned, but all of which are not - simply for the purpose of brevity.

[0799] In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a therapeutically effective amount of 5-MeO-DMT, comprise the occurrence of a clinical response not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof. In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a therapeutically effective amount of 5-MeO-DMT, comprise the persistence of a clinical response, including a clinical response which occurred not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after administration of 5-MeO-DMT. The clinical response persists until more than 28 days, preferably more than 56 days, and in particular more than 84 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0800] The clinical response can still be observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5- MeO-DMT / salt treatment course

[0801] In preferred embodiments the improved methods for the treatment of a patient, as defined herein with a therapeutically effective amount of 5-MeO-DMT comprise the administration of more than a single dose of 5-MeO-DMT.

[0802] In a preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with not less than about 1 hour and not more than about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0803] In an even more preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0804] In a most preferred embodiment this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0805] In an embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient in each of the administrations and in each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 10 mg. Useful specific amounts are e.g. about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, preferably about 2 mg, about

[0806] 4 mg, and about 6 mg.

[0807] In a preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered.

[0808] In an even more preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects.

[0809] For embodiments where the dosage amount increases for subsequent administrations, the dosage amount for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg to the dosage amount of the prior administration. For example, if the dosage amount of the first administration was 2 mg and the dosage amount increase is 2 mg, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be 4 mg. Preferably, the dosage amount for the third administration will be 6 mg.

[0810] In an also preferred embodiment, the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1.5 mg to about 2.5 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 3.5 mg to about 4.5 mg for the second administration, and from about 5.5 mg to about 6.5 mg for the third administration. Useful specific amounts for the first, second and third administration are e.g. about 2 mg, about 4 mg, and about 6 mg.

[0811] In a further preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of the first treatment block, and then increases with each subsequent administration within that first treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects, with that highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dosage in the first treatment block was 6 mg because the patient experienced a peak psychedelic experience at that dose, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 6 mg.

[0812] In a particularly preferred embodiment the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 3 mg to about 5 mg for the second administration of the first treatment block, and from about 5 mg to about 7 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 2 mg, about 4 mg, and about 6 mg.

[0813] It is understood that a pharmaceutically acceptable salt of 5-MeO-DMT can also be used in all of the above dosing regimen, such as the benzoate salt or the hydrobromide salt, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.

[0814] According to the invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0815] The occurrence of a "peak psychedelic experience" in a patient can be identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30- item revised Mystical Experience Questionnaire (M EQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0816] The occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018; 8:974).

[0817] In accordance with the invention, the occurrence of a "peak psychedelic experience" in a patient is preferably identified through achievement of a score of at least 75 in the Peak Experience Scale (PES) Total Score, also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ), which averages answers scored by the patient from 0 to 100 for the following three questions: 1. How intense was the experience; 2. To what extent did you lose control; 3. How profound (i.e. deep and significant) was the experience?

[0818] Dosing Regimen of the Antidepressant or Augmentation Medicine

[0819] The present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes) as part of a combination treatment.

[0820] Dosage regimens usually applied to the antidepressants and / or the augmentation medicines, such as mood stabilisers or thyroid agents, used in the combination treatment of the present invention are described herein.

[0821] It is understood that a pharmaceutically acceptable salt of the antidepressants or the augmentation medicines, such as mood stabilisers and thyroid agents, can also be used in all of the below dosing regimen, such as the hydrochloride salt, the oxalate salt or the hydrobromide salt, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.

[0822] Note that in this specification, when ranges are set forth, such as "10 mg / day to 80 mg / day," the inventor contemplates all discrete values within that range, some of which are specifically mentioned, but all of which are not - simply for the purpose of brevity.

[0823] Dosing is typically initiated with a low dose of the agent (initial dose) and may be increased after some time if the patient's response is inadequate. If an adequate response is achieved or if a maximum dose considered acceptable for the particular agent is reached, the patient is typically treated with that dose (maintenance dose) for a longer period of time, in particular for several weeks and typically for several months, for instance for more than 6 or even more than 12 months, or even years.

[0824] The patient may also receive a stable dose of one or more antidepressants and / or of an augmentation medicine, such as mood stabilisers or thyroid agents. The stable dose is administered before administration of a 5-MeO-DMT / salt treatment course, meaning that there is no change of dose for the indicated time before the 5-MeO-DMT / salt treatment course.

[0825] As far as reference is made to formulations characterised by a particular release-profile, such as delayed-release, extended-release, prolonged-release or sustained-release formulations, it is understood that formulations having the specified release-profile are commercially available.

[0826] Selective serotonin reuptake inhibitors (SSRIs)

[0827] Dosing regimens for typical SSRIs which can be applied to treat a patient in a method according to the present invention in combination with 5-MeO-DMT are described in the following.

[0828] Fluoxetine

[0829] Fluoxetine is administered to the patient orally. The dosage amount of fluoxetine administered to the patient is in the range of 10 mg / day to 80 mg / day, preferably in the range of 20 mg / day to 80 mg / day. Fluoxetine may be administered in form of an immediate- release formulation.

[0830] Alternatively, the dosage amount of fluoxetine administered to the patient is about 90 mg fluoxetine per week. Fluoxetine may be administered in form of a delayed-release formulation.

[0831] The treatment may encompass a maintenance period and a prior adjustment period. In the maintenance period a maintenance dosage amount is administered to the patient. This maintenance dosage amount is reached in the prior adjustment period starting with the administration of an initial dosage amount.

[0832] The maintenance dosage amount of fluoxetine administered to the patient is in the range of 10 mg / day to 80 mg / day, preferably in the range of 20 mg / day to 80 mg / day. '1

[0833] The adjustment period prior comprises the administration of an initial dosage amount of 10 mg fluoxetine once daily, preferable an initial dosage amount of 20 mg fluoxetine once daily. The dosage amount administered to the patient is optionally increased and / or decreased one or more times in daily increment(s) after the administration of the initial dosage amount and before said maintenance dosage amount is reached. The dosage amount administered to the patient during the adjustment period is within the ranges specified for the maintenance dosage amount.

[0834] Fluoxetine in Combination with the Antipsychotic Olanzapine

[0835] Fluoxetine and olanzapine are administered orally in one composition or in form of separate compositions to the patient. The dosage amount of olanzapine administered to the patient is within a range of 2.5 mg to 20 mg once per day, preferably within a range of 6 mg to 18 mg once a day, and the dosage amount of fluoxetine administered to the patient is within a range of 20 mg to 50 mg once per day, preferably withing a range of 25 mg to 50 mg once per day.

[0836] The treatment may encompass a maintenance period and a prior adjustment period. In the maintenance period a maintenance dosage amount is administered to the patient. This maintenance dosage amount is reached in the prior adjustment period starting with the administration of an initial dosage amount.

[0837] The maintenance dosage amount of olanzapine administered to the patient is within a range of 2.5 mg to 20 mg once per day, preferably within a range of 6 mg to 18 mg once a day, and the maintenance dosage amount of fluoxetine administered to the patient is within a range of 20 mg to 50 mg once per day, preferably withing a range of 25 mg to 50 mg once per day.

[0838] The adjustment period comprises the administration of an initial dosage amount of olanzapine in the range of 2.5 mg to 6 mg once per day and the administration of an initial dosage amount of fluoxetine in the range of 20 mg to 25 mg once per day in one composition or in separate compositions to the patient. The dosage amount of olanzapine and fluoxetine administered to the patient is optionally increased and / or decreased one or more times in daily increment(s) after the administration of the initial dosage amount and before said maintenance dosage amount is reached. The dosage amount of olanzapine administered to the patient during the adjustment period is within the ranges specified for the maintenance dosage amount of olanzapine. The dosage amount of fluoxetine administered to the patient during the adjustment period is within the ranges specified for the maintenance dosage amount of fluoxetine.

[0839] Fluvoxamine

[0840] Fluvoxamine is administered orally to the patient. The dosage amount of fluvoxamine administered to the patient is in the range of 25 mg to 300 mg per day, preferably in the range of 50 mg to 300 mg per day.

[0841] The treatment may encompass a maintenance period and a prior adjustment period. In the maintenance period a maintenance dosage amount is administered to the patient. This maintenance dosage amount is reached in the prior adjustment period starting with the administration of an initial dosage amount.

[0842] The maintenance dosage amount of fluvoxamine administered to the patient is in the range of 25 mg to 300 mg per day, preferably in the range of 50 mg to 300 mg per day.

[0843] The adjustment period prior comprises the administration of an initial dosage amount of 25 mg per day, preferably 50 mg fluvoxamine per day, in one dose. The dosage amount administered to the patient is optionally increased and / or decreased one or more times in daily increment(s), for instance of 25 mg to 50 mg per day, after the administration of the initial dosage amount and before said maintenance dosage amount is reached. Each change is made at an interval of 4 to 7 days. The dosage amount administered to the patient during the adjustment period is within the ranges specified for the maintenance dosage amount.

[0844] Paroxetine

[0845] Paroxetine is administered orally to the patient. The dosage amount of paroxetine administered to the patient is preferably in the range of 10 mg to 60 mg per day, preferably in the range of 20 mg to 50 mg per day.

[0846] The treatment may encompass a maintenance period and a prior adjustment period. In the maintenance period a maintenance dosage amount is administered to the patient. This maintenance dosage amount is reached in the prior adjustment period starting with the administration of an initial dosage amount.

[0847] The maintenance dosage amount of paroxetine administered to the patient is in the range of 10 mg to 60 mg per day, preferably the maintenance dosage amount of paroxetine is 20 mg to 50 mg per day. The adjustment period comprises the administration of an initial dosage amount in the range of 10 mg to 40 mg per day, preferably 20 mg paroxetine per day. The dosage amount administered to the patient is optionally increased and / or decreased one or more times in daily increment(s), for instance of 10 mg per day, after the administration of the initial dosage amount and before said maintenance dosage amount is reached. Each change is made at an interval of no less than one week. T...

Claims

Claims1. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in treating a patient who has been diagnosed with a mental disorder or a nervous system disorder by administration of a 5-MeO-DMT / salt treatment course, wherein the 5-MeO-DMT / salt treatment course involves administration of one or more doses of 5-MeO-DMT or a pharmaceutically acceptable salt thereof on a single day to remove or alleviate one or more symptoms of the mental disorder or the nervous system disorder, wherein the patient is also treated with one or more antidepressant(s).

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 1 , wherein the patient has taken the one or more antidepressant(s) for at least 2 weeks, preferably for at least 4 weeks, in particular for at least 6 weeks prior to receiving the 5-MeO-DMT / salt treatment course.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 2, wherein the patient has been on a stable dose of the one or more antidepressant(s) for the indicated period.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 2, wherein the patient has been on a maintenance dose of the one or more antidepressant(s) for the indicated period.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 4, wherein the last dose of the one or more antidepressant(s) has been administered to the patient not more than 24 hours, such as not more than 12 hours, in particular not more than 6 hours before the start of the 5-MeO-DMT / salt treatment course.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 5, wherein the patient has not been treated with a psychedelic during at least 6 weeks.3?67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 6, wherein the patient is treated with one or more antidepressant(s) after the 5- MeO-DMT / salt treatment course.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 7, wherein the antidepressant comprises an antidepressant selected from selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin modulators, tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), NMDA receptor antagonists, and atypical antidepressants.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 8, wherein the selective serotonin reuptake inhibitor (SSRI) is selected from fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 9, wherein the one or more antidepressant(s) is / are discontinued after administration of the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof of the 5-MeO-DMT / salt treatment course.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 10, wherein the patient takes no dose of the one or more antidepressant(s) after the 5-MeO-DMT / salt treatment course.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 10, wherein the one or more antidepressant(s) is / are tapered after administration of the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof of the 5-MeO-DMT / salt treatment course.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 12, wherein the 5-MeO-DMT or salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a peak psychedelic experience.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 12 wherein the 5-MeO-DMT or salt thereof is administered in a first dosage amount for a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 12, wherein the 5-MeO-DMT or salt thereof is administered in a first dosage amount for a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations wherein each subsequent administration uses a dosage amount higher than the previous administration.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 12 wherein the 5-MeO-DMT or salt thereof is administered in a first dosage amount for a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations wherein each subsequent administration uses a dosage amount higher than the previous administration unless the patient experiences a peak psychedelic experience.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 16, wherein the 5-MeO-DMT or pharmaceutically acceptable salt thereof is administered by inhalation, nasally, by buccal administration or by sublingual administration, preferably by inhalation.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 17, wherein a dosage of about 1 mg to about 25 mg 5-MeO-DMT, preferably in the range of about 4 mg to about 20 mg 5-MeO-DMT, is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 18, wherein a dosage of about 6 mg 5-MeO-DMT ; or of about 12 mg 5-MeO-DMT ; or of about 18 mg 5-MeO-DMT is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 19, wherein the 5-MeO-DMT or pharmaceutically acceptable salt thereof is administered via the intravenous, intramuscular or subcutaneous route, preferably via the intravenous route.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 20, wherein a dosage of about 1 mg to about 10 mg 5-MeO-DMT is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 21 , wherein a dosage of about 2 mg 5-MeO-DMT ; or of about 4 mg 5-MeO-DMT ; or of about 6 mg 5-MeO-DMT is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 22, wherein the patient is diagnosed with major depressive disorder.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 23, wherein the patient suffers from a treatment-resistant form of the disorder.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 23 or 24, wherein the patient suffers from a moderate or severe form of the disorder.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 23 to 25, wherein the severity of the disease corresponds to a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 17 or more.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 26, wherein the severity of the disease corresponds to a MADRS score of 35 or more or by a HAM-D score of 25 or more.3^928. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 27, wherein a clinical response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after administration of the 5-MeO-DMT / salt treatment course.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 28, wherein the clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, is still observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 1 to 29, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after administration of the 5-MeO-DMT / salt treatment course.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 30, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, is still observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 23 to 27, wherein a clinical response, as assessed by at least 50%, preferably at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 32, wherein the clinical response, as assessed by at least 50%, preferably at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, is still observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claims 23 to 27, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs not later than about 2 hours, or not later than 1 day, for instance about 24 hours, or not later than 1 week after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 34, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, is still observed after at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 24 weeks after the 5-MeO-DMT / salt treatment course.