Patent Description:
Hallucinogens are chemical compounds, some naturally occurring, some synthetic, which are defined by their ability to induce in humans after consumption sensory distortions, such as changes in auditory and visual perception, as well as distortions of mood and cognition. The term hallucinogen encompasses a rather broad group of psychoactive molecules with different modes of action. Some mental disorders have been suggested as in principle being amenable for treatment with psychoactive molecules.

Document <NPL>, presents the case of a <NUM>-year-old male military veteran with moderate alcohol use disorder who sought treatment that utilized a sequential protocol with ibogaine hydrochloride (<NUM>, <NUM>/kg) on day <NUM>, followed by vaporized <NUM>-MeO-DMT (bufotoxin source <NUM>, estimated <NUM>-MeO-DMT content, <NUM>-mg) on day <NUM>.

Document<NPL>, discloses the use of psilocybin, a phosphate derivative of DMT, for treating treatment resistant depression in patients, at two oral doses of psilocybin (<NUM> and <NUM>), <NUM> days apart, together with psychological support.

Any subject-matter falling outside the scope of the claims is provided for information purposes only. The references to methods of treatment in the detailed description of the invention in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy.

The present invention relates to <NUM>-Methoxy-N,N-dimethyltryptamine (<NUM>-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a patient who is diagnosed with major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein the <NUM>-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.

The disorder may be diagnosed in accordance with the <NPL>. For instance, the patient may suffer from moderate or severe major depressive disorder as indicated by a Montgomery-Åsberg Depression Rating Scale (MADRS) score of <NUM> or more or by a Hamilton Depression Rating Scale (HAM-D) score of <NUM> or more. It is further considered that the patient may suffers from severe major depressive disorder as indicated by a Montgomery-Åsberg Depression Rating Scale (MADRS) score of <NUM> or more or by a Hamilton Depression Rating Scale (HAM-D) score of <NUM> or more. The patient may be diagnosed with a treatment-resistant form of major depressive disorder.

Further, the patient may suffer from suicidal ideation, in particular from suicidal ideation with intent to act. The patient may even be at imminent risk for suicide.

In the context of the present invention, <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous administration.

<NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof may be administered at a dose or in a dosage regimen that causes the patient to experience a peak psychedelic experience. A dosage of about <NUM> to about <NUM> <NUM>-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt may be administered.

<NUM>-MeO-DMT or a pharmaceutically acceptable salt may be administered in a first dosage amount for a first administration; and then be 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.

The interval between two administrations may not be less than <NUM> hour and not more than <NUM> hours and may preferably be about <NUM> to <NUM> hours.

The occurrence of a peak psychedelic experience can be identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) or is identified through achievement of at least <NUM>% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire or preferably is identified through achievement of a Peak Psychedelic Experience Questionnaire (PPEQ) Total Score of at least <NUM>.

Treatment as indicated above with <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof leads to a clinical response. The response may be 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, which improvement preferably occurs not later than about <NUM> hours after the last administration of <NUM>-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, preferably persists until at least <NUM> days, more preferably at least <NUM> days and in particular at least <NUM> days, after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response may also be assessed by at least <NUM>% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of <NUM>-MeO-DMT. This response preferably occurs not later than about <NUM> hours after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof. Further, a remission of depressive symptoms, as assessed by a MADRS score equal to or less than <NUM>, or a HAM-D score equal to or less than <NUM>, preferably occurs not later than about <NUM> hours after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response, as assessed by at least <NUM>% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, preferably persists until at least <NUM> days, more preferably until at least <NUM> days, in particular until at least <NUM> days, after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof.

Preferably, there is a clinical response, as assessed by at least <NUM>% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day <NUM>, more preferably also on day <NUM> and in particular also on day <NUM>, after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof. Further preferably, the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than <NUM>, or a HAM-D score equal to or less than <NUM>, on day <NUM> preferably also on day <NUM>, in particular also on day <NUM>, after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof.

Hallucinogens include, e.g., the cannabinoid tetrahydrocannabinol (THC) which acts on cannabinoid receptors, the entactogen <NUM>,<NUM>-methylenedioxymethamphetamine (MDMA, "Ecstasy") which acts on trace amine-associated receptor <NUM> (TAAR1) and vesicular monoamine transporter <NUM> (VMAT2), and the dissociative anesthetic ketamine which acts as a N-methyl-D-aspartate (NMDA) receptor antagonist.

A further group of hallucinogens entails the compounds which bind to the <NUM>-hydroxytryptamine (<NUM>-HT) receptors, or serotonin receptors (described are <NUM> families <NUM>-HT1 to <NUM>-HT7 with <NUM> subtypes), such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). This latter group of serotonergic agents is often referred to as "classical hallucinogens" or "psychedelics", which emphasizes their predominant 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, while other effects such as sedation, narcosis, or excessive stimulation are only minimal.

Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamine class being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine having the following formula:
<CHM>.

The various serotonergic psychedelics have different binding affinity and activation potency for various serotonin receptors, particularly <NUM>-HT1A, <NUM>-HT2A, and <NUM>-HT2C, and their activity may also be modulated by interaction with other targets such as monoamine transporters and trace amine-associated receptors.

Naturally occurring psychedelics, such as the tryptamine DMT, which is contained in the South American shrub Psychotria viridis, or the tryptamine psilocybin, which is contained in over <NUM> mushroom species, or the phenylalkylamine mescaline, which is contained in the Peyote cactus of the American Southwest and Northern Mexico, have been used for centuries by indigenous cultures in ritual or sociocultural contexts and in the context of religious sacraments. While an unspecific "healing" potential had been ascribed to the use of naturally occurring psychedelics in those settings, more scientific investigations into their potential therapeutic application for defined disease entities had not been pursued until after the discovery of the synthetic ergoline LSD in <NUM>.

Those early clinical experiences of the <NUM> and <NUM> were methodologically still relatively weak, but encouraging data was e.g. reported from a treatment program of alcoholism, where patients who received LSD together with psychotherapy had higher rates of abstinence or improvement than patients who received psychotherapy alone (<NPL>), or from observations in patients with personality trait disturbance or anxiety where administration of LSD as an aid to psychotherapy yielded an outcome of "much improved" or "improved" in over <NUM>% of patients (<NPL>), or from treatment of patients suffering from terminal state of cancer, where about two-thirds of patients who received LSD treatment improved in varying degrees (<NPL>).

With the emerging knowledge about the serotonin system and its role in brain function, researchers more and more specified the molecular activity of the psychedelic drugs. However, how that activity translated into their observed therapeutic effects in mental disorders was less clear. Two main concepts were proposed: The first concept was coined "psycholytic therapy" and it emphasized the ability of psychedelics given at low doses to facilitate the loosening of psychological defensive mechanisms, which in combination with psychotherapy allows a deep introspective insight and the revival of traumata and their subsequent catharsis. The basic mechanism considered in the psycholytic approach was therefore the activation and deepening of the concomitant psychotherapeutic process, and it required multiple drug and therapy sessions. The second concept was coined as "psychedelic therapy" and it emphasized the ability of psychedelics given at high single doses to induce so called "peak psychedelic experiences". Peak experiences are predominantly characterized by the loss of judgment to time and space and the dissolution of ego boundaries, which often culminates in the experience of a blissful state and feelings of being a whole and harmonious existence in the cosmic unity. The basic mechanism considered in the psychedelic approach was therefore to produce a unique, overwhelming experience with an intuitive perception of psychological integration and harmony and subsequent self-improvements and enhanced joy in living and a sense of inner peace.

While scientific research around the use of psychedelics for the treatment of mental disorders blossomed in the <NUM>, there was also a rapidly growing recreational use of these substances, and soon psychedelics were depicted in the media as highly dangerous drugs of abuse. A perceived danger to the social order led to the passage of the United States Controlled Substances Act of <NUM>, under which LSD and other psychedelics were placed into the most restrictive category Schedule <NUM>, which contains drugs deemed to have no medical use and a high potential for abuse. Very little progress was made regarding possible therapeutic uses of psychedelic drugs for the next <NUM> years.

Only recently has the interest in the field of psychedelic therapy resurged. For example, in a randomized, double-blind, cross-over trial comparing a very low placebo-like single dose of psilocybin with a high single dose in <NUM> cancer patients with anxiety and/or mood symptoms, the high dose produced large decreases in clinician- and self-rated measures of depression, anxiety or mood disturbances and increases in measures of quality of life at five weeks after treatment, and these effects were sustained at <NUM>-months (<NPL>). In another randomized, double-blind, cross-over trial of a single dose of psilocybin with niacin as comparator in <NUM> cancer patients with anxiety and depression psilocybin produced immediate and substantial improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness and increased quality of life, with enduring effects at the <NUM>-month follow-up (<NPL>). Further positive experiences with psilocybin were generated in an open-label, single arm feasibility study where <NUM> patients with treatment-resistant depression (as specifically defined in the study) received a low dose and a high dose of psilocybin seven days apart, and in this trial depressive symptoms were significantly reduced from baseline at one and five weeks after treatment (<NPL>; <NPL>). Psilocybin has also shown promise in the treatment of obsessive-compulsive disorder (<NPL>) and alcohol (<NPL>) and tobacco dependency (<NPL>; <NPL>). Further, for the serotonergic psychedelic LSD, a double-blind, randomized, active placebo-controlled pilot study in <NUM> patients with anxiety associated with life-threatening diseases reported significant effects on anxiety measures at two months follow-up (<NPL>). Also, for the shamanic brew Ayahuasca, which contains the psychoactive agent DMT together with the monoamine oxidase (MAO) inhibitors harmine, harmaline and tetrahydroharmine, a randomized, double-blind, placebo-controlled trial of a single dosing session in <NUM> patients with treatment-resistant major depression (as specifically defined in the trial) showed a rapid antidepressant effect compared to placebo (<NPL>).

The inventor considers that those results show that administration of certain serotonergic psychedelics may be a promising approach for the treatment of various mental disorders. However, at this point efficacy and safety studies complying with regulatory standards have yet to be conducted and no psychedelic drug has been approved by any regulatory agency. Further, it is evident from the currently available data that none of the tested drugs will achieve remissions in all patients, that some patients may lose response after achieving a remission, and that the tested drugs still suffer from relevant side effects. Also, the acute psychedelic effects after oral dosing of psychedelics currently proposed for therapeutic use have a duration of several hours, which is inconvenient for the patient and the provider and which poses significant limitations in their practical use. For example, in the study of psilocybin in treatment-resistant depression (as specifically defined in the study) published by Carhart-Harris et al. <NUM> of <NUM> patients had a response at week <NUM>, but <NUM> relapsed again until month <NUM>, with frequently reported side effects of anxiety, headache and nausea, and monitoring requirements for at least <NUM> hours after drug administration, based on a duration of the acute psychedelic effects of psilocybin of approximately <NUM> to <NUM> hours (<NPL>;<NPL>). Additionally, not only a shorter duration of psychedelic effects, but also a more rapid onset of clinical response compared with currently available treatments and currently studied psychedelics would be beneficial. Further, while some mental disorders have been suggested as in principle being amenable for treatment with psychedelics, specific disease entities and specific subgroups of disease entities remain to be identified. Therefore, an aim of the current invention is to provide a compound for improved psychoactive therapies as well as dosing regimens and administration routes for such therapies which are more effective (i.e., (a) larger percentage of patients experiencing a clinical response, b) a larger average clinical response, c) an earlier onset of the clinical response, d) a more durable clinical response) than previously described therapies. A further aim of the current invention is to provide a compound for improved psychoactive therapies as well as dosing regimens and administration routes for such 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 as well as dosing regimens and administration routes for such therapies which are more convenient. Another aim of the current invention is to provide a compound for improved psychoactive therapies as well as dosing regimens and administration routes for such 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 entities and specific subgroups of disease entities which benefit from such improved psychoactive therapies.

The currently available treatments for mental disorders, in particular for major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse are unsatisfactory because of the often limited or not durable treatment response, the late onset of response, side effects which limit the long-term drug administration, and inconvenient dosing regimens which often limit compliance of the patient.

Recently published clinical studies which have used serotonergic psychedelic drugs such as LSD, psilocybin and DMT (using the shamanic brew Ayahuasca) in some of those mental disorders suggest that those compounds could provide an alternative to the currently available treatments. However, even for those drugs still not all patients will respond, some patients will lose response over time, and specific side effects will occur. Further, the acute psychoactive effects of the so far tested compounds based on current dosing regimens and administration routes persist for several hours after administration, which is a significant implementation and convenience problem. Also, the onset of clinical response with those compounds is not rapid enough, e.g. for treatment of very symptomatic patients or for patients with active suicidal ideation with intent to act, including such patients who are at imminent risk for suicide. Finally, while some indications have been shown to be in principle amenable for treatment with those serotonergic psychedelic agents, specific disease entities and specific subgroups of disease entities remain to be identified.

The technical problem to be solved by the present invention is therefore in a broad sense to provide an improved psychoactive therapy based on the application of a serotonergic psychedelic in a patient with a mental disorder. The technical problem further encompasses the identification of specific mental disorders and subgroups of mental disorders amenable for treatment with such improved therapy.

Although it is believed that most serotonergic psychedelics mediate their psychoactive effects primarily via <NUM>-HT2A receptors, other receptors also play a role and the complete pharmacology is rather complex. Because there is furthermore no clear correlation between the various mental conditions and specific <NUM>-HT receptor systems, it is not easily predictable which specific receptor affinity profile of a psychedelic will provide the optimal therapeutic effects.

The inventor has recognized that the occurrence of a peak psychedelic experience during the acute phase after administration of a specific psychedelic is driving its therapeutic benefit, either in a causal relationship or at least as a surrogate behavioral marker for the underlying unknown therapeutic mechanism.

The inventor considers that the relevance of the type and intensity of psychedelic experiences is e.g. supported by the study on depression and anxiety in patients with life-threatening cancer where Griffiths et al. reported that the immediate post-session mystical experience score after administration of psilocybin showed a significant association with various therapeutic outcome measures <NUM> weeks later (<NPL>). Also, in the comparable study in cancer patients with anxiety and depression reported by Ross et al. it was found that intensity of the subjective mystical experience during the drug exposure significantly mediated (e.g. suggestive of causality) the clinical benefit (<NPL>). In the study of psilocybin in treatment-resistant depression (as specifically defined in the study), it was found that Oceanic Boundlessness (OBN) (sharing features with mystical-type experiences, e.g. experiences of unity and blissful state) was significantly more predictive of reduced depressive symptoms than psilocybin's more generic visual and auditory perceptual effects (<NPL>). Further, in the study of psilocybin in alcohol dependence by Bogenschutz et al. it was found that the intensity of effects in the first psilocybin session strongly predicted change in drinking during weeks <NUM>-<NUM> (<NPL>). Also, in the study on tobacco dependence by Johnson et al. it was found that those who were smoke-free at six months scored significantly higher on a measure of psilocybin-occasioned mystical experience compared to those who had relapsed (<NPL>; <NPL>). Similar observations had already been made in the early days of psychedelic research, where e.g. in patients with alcohol dependence who had received therapy with LSD it was reported that "<NUM> per cent of these people are changed [that is, they stop drinking or are much improved]. As a general rule. those who have not had the transcendental experience are not changed; they continue to drink. However, the large proportion of those who have had it are changed" (cited in<NPL>). In fact, those early experiences had spurred the previously discussed concept of "psychedelic therapy".

The inventor believes that the prominent role of the type and intensity of the acute psychedelic experience for long-term clinical improvement in such a broad range of mental conditions can be explained by recent observations regarding human brain functional connectivity (FC) via so called resting-state networks (RSNs). Those RSNs have been shown to be responsible for various aspects of complex cognitive function, and it has been found that these connectivity networks can be disturbed in mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, and also in patients with suicidal ideation which can be comorbid with those diseases.

The inventor believes that disruption of the normal hierarchical architecture of RSNs is a final common pathway of those diseases, which may also explain why many of the involved diseases can occur in the same patient at the same time. The inventor considers that the further showings that a) administration of psychedelics such as psilocybin, LSD and DMT can lead to decreased connectivity within specific RSNs (<NPL>; <NPL>;<NPL>), that b) this decreased connectivity correlates with ratings of peak experiences (<NPL>;<NPL>), and that c) after the peak experience an increased reorganization (or normalization) of specific RSN activity can be observed (<NPL>), which d) correlates with treatment response (<NPL>), explains the observations that the type and intensity of the acute psychedelic experience is correlated with therapeutic outcome.

The inventor has recognized that the occurrence of a peak experience is an important mechanism or at the least a surrogate behavioral marker for the underlying mechanism for the therapeutic efficacy of a psychedelic drug. Therefore, the inventor has recognized that 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 their dosing regimens and administration routes, will lead to a better therapeutic profile.

The inventor has identified <NUM>-MeO-DMT (see formula below) as a serotonergic psychedelic with larger propensity to induce peak experiences than the serotonergic psychedelics previously studied for the treatment of mental disorders, and the inventor has also recognized that peak experiences under <NUM>-MeO-DMT more often involve the dissolution of ego boundaries and experiences of a blissful state and/or unity. The inventor has also recognized that <NUM>-MeO-DMT can induce peak experiences more rapidly than the serotonergic psychedelics previously studied for the treatment of mental disorders, and that the duration of the psychedelic experience is shorter. The inventor considers that those characteristics of <NUM>-MeO-DMT are associated with an improved therapeutic profile and can be explained by specific alterations of RSN activity under <NUM>-MeO-DMT treatment.

The invention relates to <NUM>-methoxy-N,N-dimethyltryptamine (<NUM>-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a patient who is diagnosed with major depressive disorder (MDD) by a licensed professional in accordance with accepted medical practice, wherein the <NUM>-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.

In one aspect, the disclosure relates to the use of therapeutically effective amounts of <NUM>-MeO-DMT in the treatment of mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse. The use of therapeutically effective amounts of <NUM>-MeO-DMT in the treatment of such disorders includes the use of therapeutically effective amounts of <NUM>-MeO-DMT in patients with such a disorder and suicidal ideation. It in particular includes the use of therapeutically effective amounts of <NUM>-MeO-DMT in patients with a treatment-resistant form of such a disorder, including the use in patients with suicidal ideation. All those conditions are known to be associated with disturbed activity of RSNs, and the inventor has recognized that this makes them amenable for treatment with <NUM>-MeO-DMT.

In another aspect, the disclosure relates to the use of therapeutically effective amounts of <NUM>-MeO-DMT in the treatment of mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, whereby a clinical response is achieved rapidly after administration of <NUM>-MeO-DMT.

In another aspect, the disclosure relates to the use of therapeutically effective amounts of <NUM>-MeO-DMT in the treatment of mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, whereby a clinical response persists for extended periods of time after administration of <NUM>-MeO-DMT.

In another aspect, the disclosure relates to novel dosing regimens and administration routes of <NUM>-MeO-DMT for use in the treatment of mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, which novel dosing regimen and administration routes allow achievement of peak experiences in a large proportion of patients and with good reproducibility within the same patient. Besides allowing for a high rate of peak experiences and consequently improved therapeutic effects those novel dosing regimens and administration routes at the same time reduce the risk of overdosing which improves the safety profile. Such improved dosing regimens rely on the application of increasing dosages of <NUM>-MeO-DMT to the same patient on subsequent administrations on the same day or on directly subsequent days. Such improved administration routes rely on the intravenous, intramuscular or subcutaneous administration of <NUM>-MeO-DMT.

Via each of those aspects and in particular by a combination of those aspects the invention solves the problems of <NUM>) providing an improved psychoactive therapy based on the application of a psychedelic in a patient with a mental disorder and <NUM>) identifying specific mental disorders and specific subgroups of mental disorders amenable for treatment with such improved therapy.

The fact that <NUM>-MeO-DMT has improved therapeutic effects despite its short duration of acute psychedelic effects (<NUM> to <NUM> minutes after intravenous injection compared with several hours for e.g. oral psilocybin and oral LSD) is surprising, but in fact this short duration of action, and the absence of relevant tolerance (i.e. the absence of diminished or no psychedelic effects after re-administration), is a basis for enabling the novel dosing regimen with frequent re-administrations (such as more than once daily, or daily), which are designed to increase the rate of occurrence of peak experiences, thereby increasing the therapeutic benefit. Such 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, 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.

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 have not been contemplated in the prior art, and in fact they may not be possible with the currently tested administration regimens for other psychedelics, due to the late onset and long duration of psychedelic effects observed with their current dosing regimens and administration routes and due to the rapid development of tolerance (i.e. diminished or no psychedelic effects after re-administration) which can last for several days. The hitherto described dosing regimens for psychedelic drugs used in the therapeutic context either contemplated only a single administration or repeat administrations only after several days, and they only contemplated oral administration. Hence, those currently applied dosing regimens and administration routes do not allow peak experiences to be reliably achieved and they do not offer the additional benefits as described above.

The intravenous, intramuscular or subcutaneous administration of <NUM>-MeO-DMT allows for high bioavailability and low variability in bioavailability between patients and between re-administrations in the same patient, and it therefore allows for a high rate and a high reproducibility of peak experiences. Also, intravenous, intramuscular or subcutaneous administration will be considered at least by some patients as more convenient and better tolerable as compared to administration via inhalation or intranasal insufflation, and intravenous, intramuscular or subcutaneous administration will be preferred by at least some physicians for ease of use. Further, intravenous, intramuscular or subcutaneous administration avoids exposure of the physician or caregiver to <NUM>-MeO-DMT, which could occur when applied via the inhalation route.

<NUM>-MeO-DMT is a naturally occurring serotonergic psychedelic tryptamine which acts as a <NUM>-HT1A and <NUM>-HT2A receptor agonist. <NUM>-MeO-DMT was first isolated from the bark of Dictyoloma incanescens, but it is also contained in other plants, and it has been identified as the major active ingredient in the venom of Bufo alvarius toads. In addition, <NUM>-MeO-DMT is synthesized in human pineal and retina, and it has been found in human body fluids including urine, blood, and cerebrospinal fluid. <NUM>-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 to produce an active metabolite, bufotenine. Bufotenine binds to the <NUM>-HT2A receptor with much higher affinity than <NUM>-MeO-DMT itself.

<NUM>-MeO-DMT and compositions comprising <NUM>-MeO-DMT besides other active components have hitherto only been used in the ritual or recreational context (erowid. org/chemicals/5meo_dmt/ 5meo_dmt_dose. shtml and erowid. org/chemicals/5meo_dmt/5meo_dmt_effects. shtml, accessed March <NUM>, <NUM>). A recent internet survey which aimed to examine patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with the use of <NUM>-MeO-DMT and compositions comprising <NUM>-MeO-DMT besides other active ingredients, described that the majority of respondents with self-reported psychiatric conditions, including anxiety, depression, substance use problems, and post-traumatic stress disorder, perceived improvements in symptoms related to those disorders (<NPL>). However, as noted by the authors, "this study is cross-sectional, lacked a validated measure of psychiatric symptoms and assessment of prior psychiatric treatment, included many polysubstance users, which limits any causal inferences in the relation between the use of <NUM>-MeO-DMT and an improvement in symptoms, and thus the associations of psychiatric benefits remain observational".

Application of <NUM>-MeO-DMT together with a MAO inhibitor leads to an enhanced and prolonged drug effect but can also lead to more toxicity. Most commonly described routes of administration for <NUM>-MeO-DMT in the ritual or recreational context are inhalation of smoke or vapor or intranasal insufflation, but other routes such as intravenous, rectal or oral application have also been described, with absorption via the latter route being limited by a substantial first-pass effect, probably through the rapid action of MAO enzymes in the gut and liver.

The advantageous effects of the invention, as compared to the current standard of care in the respective indication include, but are not limited to: a) a larger percentage of patients experiencing a clinical response, b) a larger average clinical response, c) an earlier onset of the clinical response, d) a more durable clinical response, e) a similar or better clinical response with fewer or different side effects and therefore improved compliance, and f) a similar or better clinical response with a more convenient therapeutic regimen with fewer drug administrations and therefore improved compliance. As compared to the previously studied psychedelics the invention can additionally provide, for example, for g) a similar or better clinical response with a shorter duration of the acute psychoactive effects after dosing and therefore improved convenience and compliance, h) an improved dosing regimen and administration route with higher propensity for and better reproducibility of achievement of peak psychedelic experiences, while avoiding unnecessary high doses and associated side effects, and with better tolerability, and therefore improved compliance. It is further noted that the advantageous effects are in particular achieved in treatment-resistant patients as defined herein.

As used in the context of the present invention, unless otherwise noted, the term "<NUM>-MeO-DMT" refers to the free base <NUM>-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of <NUM>-MeO-DMT will typically be used. An example for such a salt is the hydrochloride. 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.

As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed with major depressive disorder by a licensed professional in accordance with accepted medical practice. Diagnosis can, for instance, be in accordance with the <NPL> as suffering from a mental disorder, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder, or psychoactive substance abuse. The diagnosis will be by a physician or a psychologist. It is not sufficient that the human subject himself considers that he is suffering from one of the disorders.

As used 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 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.

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 present invention to alleviate the signs and/or symptoms or eliminate the disease, condition, or disorder.

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.

"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 <NUM>-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 <NUM> = Normal, Not At All Suicidal; <NUM> = Questionably Suicidal; <NUM>= Mildly Suicidal; <NUM> = Moderately Suicidal; <NUM> = Markedly Suicidal; <NUM> = Severely Suicidal; <NUM> = Extremely Suicidal). When assessing a clinical response at an early timepoint after drug administration (e.g. at <NUM> hours) based on endpoints which have been developed for a longer recall period (e.g. normally <NUM> days for the MADRS), a rational modification of such endpoint (e.g. changing the MADRS recall period to <NUM> hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied.

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. The active compound is administered by intravenous administration, by intramuscular administration or by subcutaneous administration.

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

The present invention is directed to improved methods for the treatment of major depressive disorder, as defined in the claims. The present disclosure also relates to improved methods for the treatment of mental disorders, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse comprising administering to a patient as defined herein a therapeutically effective amount of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof. Treatment of these disorders includes, but is not limited to, the use of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof in patients as defined herein with such a disorder and suicidal ideation. Treatment of these disorders specifically includes the use of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof in patients as defined herein with a treatment-resistant form of a mentioned disorder. As used in the context of the present invention, "treatment-resistant" is defined for major depressive disorder and persistent depressive disorder as no adequate improvement to at least two adequate courses of pharmacological therapy in the current episode of depression, for anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder and obsessive-compulsive disorder as no adequate improvement to at least one adequate course of pharmacological therapy and at least one adequate course of psychotherapy, and for eating disorder and psychoactive substance abuse as no adequate improvement after at least one adequate course of psychotherapy with or without pharmacological therapy. Whether an improvement is adequate is assessed in terms of clinical response and whether a therapy course is adequate is assessed in terms of regimen, dose, duration, and compliance. Adequateness is assessed and documented by a physician or psychologist using a defined set of criteria and it is not sufficient that the patient himself considers that a prior therapy course was not adequate or that he not adequately responded. Adequateness can be assessed retrospectively and prospectively.

The treatment of patients with anxiety disorder includes, but is not limited to, patients with panic disorder, phobic anxiety disorders, social anxiety disorder and generalized anxiety disorder. The treatment of patients with eating disorder includes but is not limited to anorexia nervosa, bulimia nervosa and binge eating disorder. The treatment of patients with substance abuse includes, but is not limited to, patients with alcohol related disorders, opioid related disorders, sedative, hypnotic, or anxiolytic related disorders, cocaine related disorders, other stimulant related disorders and nicotine dependence.

Disorders preferably treated according to the disclosure are major depressive disorder, generalized anxiety disorder, obsessive compulsive-disorder and anorexia nervosa including their treatment-resistant forms. The disorder treated according to the invention is major depressive disorder including its treatment-resistant form, and including patients with major depressive disorder having suicidal ideation. In an embodiment the dosage amount of <NUM>-MeO-DMT administered to a patient, as defined herein, with a mental disorder, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, including a treatment-resistant form of these disorders, and including these disorders associated with suicidal ideation, is in the range of about <NUM> to about <NUM>, or any amount of range therein. Useful specific amounts are e.g. about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> and about <NUM>. It is understood that a pharmaceutically acceptable salt of <NUM>-MeO-DMT is preferably used in this embodiment, and that the appropriate weight amounts of the salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.

Note that in this specification, when ranges are set forth, such as "about <NUM> to about <NUM>," 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.

In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a mental disorder, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, including a treatment-resistant form of these disorders, and including these disorders associated with suicidal ideation, with a therapeutically effective amount of <NUM>-MeO-DMT, comprise the occurrence of a clinical response not later than about <NUM> hours after administration of <NUM>-MeO-DMT.

In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a mental disorder, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, including a treatment-resistant form of these disorders, and including these disorders associated with suicidal ideation, with a therapeutically effective amount of <NUM>-MeO-DMT, comprise the persistence of a clinical response, including a clinical response which occurred not later than about <NUM> hours after administration of <NUM>-MeO-DMT, until at least about <NUM> days after the last administration of <NUM>-MeO-DMT, preferably until at least about <NUM> days after the last administration of <NUM>-MeO-DMT, more preferably until at least about <NUM> days after the last administration of <NUM>-MeO-DMT.

In preferred embodiments the improved methods for the treatment of a patient, as defined herein, with a mental disorder, in particular major depressive disorder, persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, including a treatment-resistant form of these disorders, and including these disorders associated with suicidal ideation, with a therapeutically effective amount of <NUM>-MeO-DMT comprise the administration of more than a single dose of <NUM>-MeO-DMT.

In a preferred embodiment this more than a single dose of <NUM>-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of <NUM> to <NUM> administrations, with not less than about <NUM> hour and not more than about <NUM> hours between each administration within each treatment block, and not less than about <NUM> days between the end of one treatment block and the start of the next treatment block.

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

In a most preferred embodiment this more than a single dose of <NUM>-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of <NUM> to <NUM> administrations, with about <NUM> to <NUM> hours between each administration within each treatment block, and not less than about <NUM> days between the end of one treatment block and the start of the next treatment block.

In an embodiment the dosage amount of the <NUM>-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 <NUM> to about <NUM>.

In a preferred embodiment the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of <NUM> being reached or all administrations within that treatment block being administered.

In an even more preferred embodiment the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of <NUM> 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.

For embodiments where the dosage amount increases for subsequent administrations, the dosage amount for the next administration is determined by adding about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, to the dosage amount of the prior administration. For example, if the dosage amount of the first administration was <NUM> and the dosage amount increase is <NUM>, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be <NUM>. Preferably, the dosage amount for the third administration will be <NUM>.

In a preferred embodiment the dosage amount of the <NUM>-MeO-DMT administered to an individual patient in each treatment block is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration, and from about <NUM> to about <NUM> for the third administration. Useful specific amounts for the first, second and third administration are e.g. about <NUM>, about <NUM>, and about <NUM>.

In a further preferred embodiment the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> 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 <NUM> 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 <NUM> 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 <NUM>.

In a most preferred embodiment the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration of the first treatment block, and from about <NUM> to about <NUM> 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 <NUM>, about <NUM>, and about <NUM>.

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

According to the invention, <NUM>-MeO-DMT is preferably not administered together with a MAO inhibitor.

The occurrence of a "peak psychedelic experience" in a patient can be identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) (as described in<NPL>; Score items shown in Example <NUM>).

The occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of at least <NUM>% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in <NPL>).

The occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of a score of at least <NUM> in the Peak Psychedelic Experience Questionnaire (PPEQ) Total Score, which averages answers scored by the patient from <NUM> to <NUM> for the following three questions: <NUM>. How intense was the experience; <NUM>. To what extent did you lose control; <NUM>. How profound (i.e. deep and significant) was the experience?.

The therapeutically effective amount of <NUM>-MeO-DMT is administered by intravenous administration, by intramuscular administration or by subcutaneous. Administration via these routes can assure a rapid onset of action. A most preferred route of administration is administration via the intramuscular route, i.e. by intramuscular injection.

<NUM>-MeO-DMT can preferably be employed as a pharmaceutically acceptable salt in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations being known in the art.

The patient may also receive psychotherapeutic interventions.

According to the invention, the disease to be treated is major depressive disorder. In this same specific embodiment the patient may suffer from a treatment-resistant form of major depressive disorder. In this same specific embodiment the patient may also suffer from suicidal ideation with intent to act, and he may be considered at imminent risk for suicide. In this same specific embodiment the dosage amount of <NUM>-MeO-DMT administered to a patient, as defined herein, with a major depressive disorder, is in the range from about <NUM> to about <NUM>, and is administered via intramuscular administration in the form of a formulation for administration based on a pharmaceutically acceptable salt of <NUM>-MeO-DMT, which weight amount can be calculated from the stated weight amounts of the <NUM>-MeO-DMT free base, assuming that equimolar amounts are used. Useful specific amounts of <NUM>-MeO-DMT in this specific embodiment are, e.g., about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, and about <NUM>.

In this same specific embodiment, a clinical response, as assessed by at least <NUM>% improvement of the MADRS or HAM-D score, compared to the respective score prior to administration of <NUM>-MeO-DMT, or a clinical response as assessed as at least a score of "much improved" in CGI-I or PGI-I scores, occurs not later than about <NUM> hours after administration of <NUM>-MeO-DMT.

In this same specific embodiment, a remission of depressive symptoms as assessed by a MADRS score equal or less than <NUM>, or a HAM-D score equal or less than <NUM>, occurs not later than about <NUM> hours after administration of <NUM>-MeO-DMT.

In this same specific embodiment, a clinical response as assessed by at least <NUM>% improvement of the MADRS or HAM-D score compared to the respective score prior to administration of <NUM>-MeO-DMT, or a clinical response as assessed as at least a score of "much improved" in CGI-I or PGI-I scores, including a clinical response which occurred not later than about <NUM> hours after administration of <NUM>-MeO-DMT, persists until at least about <NUM> days after the last administration of <NUM>-MeO-DMT, preferably until at least about <NUM> days after the last administration of <NUM>-MeO-DMT, more preferably until at least about <NUM> days after the last administration of <NUM>-MeO-DMT.

According to the invention, the disease to be treated is major depressive disorder. In this same specific embodiment, the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration of the first treatment block, and from about <NUM> to about <NUM> 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 <NUM>, about <NUM>, and about <NUM>. In this same specific embodiment, the interval between each administration within the first treatment block is about <NUM> hours. In this same specific embodiment, the <NUM>-MeO-DMT is administered via intramuscular administration in the form of a formulation for administration based on a pharmaceutically acceptable salt of <NUM>-MeO-DMT, which weight amount can be calculated from the stated weight amounts of the <NUM>-MeO-DMT free base, assuming that equimolar amounts are used. In this same specific embodiment, the occurrence of a peak psychedelic experience is identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) (as described in <NPL>) or by achievement of a Peak Psychedelic Experience Questionnaire (PPEQ) Total Score of at least <NUM>.

According to the invention, the disease to be treated is major depressive disorder. In this same specific embodiment, the dosage amount of the <NUM>-MeO-DMT administered to an individual patient in each treatment block is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration, and from about <NUM> to about <NUM> for the third administration. Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about <NUM>, about <NUM>, and about <NUM>. In this same specific embodiment, the interval between each administration within each treatment block is about <NUM> hours and the interval between the end of one treatment block and the start of the next treatment block is about <NUM> days. In this same specific embodiment, the <NUM>-MeO-DMT is administered via intramuscular administration in the form of a formulation for administration based on a pharmaceutically acceptable salt of <NUM>-MeO-DMT, which weight amount can be calculated from the stated weight amounts of the <NUM>-MeO-DMT free base, assuming that equimolar amounts are used. In this same specific embodiment, the occurrence of a peak psychedelic experience is identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) (as described in <NPL>) or by achievement of a Peak Psychedelic Experience Questionnaire (PPEQ) Total Score of at least <NUM>.

In a specific embodiment the disease to be treated is treatment-resistant major depressive disorder. In this same specific embodiment the patient may suffer from suicidal ideation with intent to act, and he may be considered at imminent risk for suicide. In this same specific embodiment, the dosage amount of the <NUM>-MeO-DMT administered to an individual patient is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration of the first treatment block, and from about <NUM> to about <NUM> 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 <NUM>, about <NUM>, and about <NUM>. In this same specific embodiment, the interval between each administration within the first treatment block is about <NUM> hours. In this same specific embodiment, the <NUM>-MeO-DMT is administered via intramuscular administration in the form of a formulation for administration based on a pharmaceutically acceptable salt of <NUM>-MeO-DMT, which weight amount can be calculated from the stated weight amounts of the <NUM>-MeO-DMT free base, assuming that equimolar amounts are used. In this same specific embodiment, the occurrence of a peak psychedelic experience is identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) (as described in <NPL>) or by achievement of a Peak Psychedelic Experience Questionnaire (PPEQ) Total Score of at least <NUM>.

In a further specific embodiment the disease to be treated is treatment-resistant major depressive disorder. In this same specific embodiment, the dosage amount of the <NUM>-MeO-DMT administered to an individual patient in each treatment block is selected from about <NUM> to about <NUM> 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 <NUM> to about <NUM> for the second administration, and from about <NUM> to about <NUM> for the third administration. Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about <NUM>, about <NUM>, and about <NUM>. In this same specific embodiment, the interval between each administration within each treatment block is about <NUM> hours and the interval between the end of one treatment block and the start of the next treatment block is about <NUM> days. In this same specific embodiment, the <NUM>-MeO-DMT is administered via intramuscular administration in the form of a formulation for administration based on a pharmaceutically acceptable salt of <NUM>-MeO-DMT, which weight amount can be calculated from the stated weight amounts of the <NUM>-MeO-DMT free base, assuming that equimolar amounts are used. In this same specific embodiment, the occurrence of a peak psychedelic experience is identified through achievement of at least <NUM>% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) (as described in <NPL>) or by achievement of a Peak Psychedelic Experience Questionnaire (PPEQ) Total Score of at least <NUM>.

Specific embodiments of the present invention are listed below.

It is emphasized that embodiments and claims which describe that a clinical response a) occurs not later than a specified timepoint, b) persists until at least a specified timepoint, or c) is present at a specified timepoint "after the last administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof", include, through dependencies from other embodiments and claims, such as embodiments and claims where a) the "last administration" is actually the first administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof, and b) the "last administration" is actually the administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof, where the patient experienced a peak psychedelic experience, which can be the first administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof, but can also be a later administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof at a higher dose than the first administration of <NUM>-MeO-DMT or a pharmaceutically acceptable salt thereof.

The following Examples are listed to aid understanding of the invention.

A <NUM>-MeO-DMT aerosol was generated by volatilization of the drug by way of the Volcano Medic Vaporization System (Storz & Bickel, Germany). The device consists of a hot air generator and a detachable valve balloon from which the aerosol is inhaled by the patient. The hot air generator can generate temperatures adjustable between about <NUM> to about <NUM>, with an airflow rate of about <NUM> liters per minute. The central part of the device is the dosing capsule to which relevant doses of <NUM>-MeO-DMT in an ethanol solution are applied and which is then applied into the filling chamber of the device, where it is heated via the hot air. The dosing capsules contain a small disc made of tightly packed stainless-steel wire mesh (called the drip pad or liquid pad). The bottom and the lid of the dosing capsules have holes, allowing airflow through the dosing capsules. The dosing capsules and drip pad have the following characteristics, based on measurements of <NUM> sample capsules:.

All measurements show the mean and standard deviation for measurements of <NUM> capsules, except for the diameter of holes in lid and base, which is based on <NUM> measurements across <NUM> capsules and for diameter of the stainless steel wire in drip pad, which is based on <NUM> measurements in different locations.

Step <NUM>: A stock solution of <NUM>-MeO-DMT free base in <NUM>% ethanol is prepared in a volumetric flask, so that the target dosage of <NUM>-MeO-DMT free base to be administered via inhalation to the volunteer or patient is contained in a solution volume of <NUM>µl. Typical target dosages are from <NUM> to <NUM> <NUM>-MeO-DMT. for a target dosage of <NUM> <NUM>-MeO-DMT, <NUM> of <NUM>-MeO-DMT will be dissolved in <NUM>% ethanol for a final solution volume of <NUM>. Aliquots of the stock solution can then be stored in vials until further use.

Step <NUM>: <NUM>µl of the solution is transferred to a dosing capsule containing the drip pad (Storz & Bickel, Germany), and then the dosing capsule is closed with its lid.

Step <NUM>: The dosing capsule filled with the <NUM>-MeO-DMT ethanol solution is transferred to the filling chamber of a first Volcano Medic Vaporizer, which has been pre-heated with the temperature set at <NUM>. Then the airflow of the vaporizer is switched on for <NUM> seconds at the pre-set rate of about <NUM>/min. The heated air will flow through the dosing capsule, allowing the ethanol to evaporate, with the target dosage of <NUM>-MeO DMT being left in the capsule, as a thin layer covering the stainless-steel wire mesh. Accurate preparation of the dosing capsule can be confirmed by demonstrating that the final weight increase of the capsule compare to the weight of the empty capsule is about equal to the target dosage of <NUM>-MeO-DMT.

Step <NUM>: The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which has been pre-heated with the temperature set at <NUM> and the airflow on for at least <NUM> minutes and then turned off immediately prior to transfer. An inhalation balloon with a valve (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is closed tightly and immediately afterwards the airflow is switched on for exactly <NUM> seconds at the pre-set flow rate of about <NUM>/min, and then turned off. This will allow the full dose of <NUM>-MeO-DMT to aerosolize and be distributed in approximately <NUM> liters of air in the inhalation balloon. Accurate aerosolization of the <NUM>-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to about its initial weight.

Step <NUM>: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After attachment of the mouthpiece to the balloon, the aerosol is ready for immediate administration to the volunteer or patient.

Step <NUM>: To prepare for the administration, the patient is asked to initially perform <NUM>-<NUM> deep inhalations with full exhalations, ending this sequence with a deep exhalation. Then, with the mouthpiece firmly held against the lips, the full and complete volume of the inhalation balloon is inhaled in one inhalation, holding the breath for <NUM> (±<NUM>) seconds, followed by a normal exhalation. After completing the inhalation procedure, the patient will be instructed to lie down.

<NUM>-MeO-DMT (<NUM>) was dissolved in MTBE (<NUM>, <NUM> volumes) at <NUM> to <NUM> before being cooled to room temperature over <NUM> minutes. After stirring at room temperature for <NUM> minutes no crystallisation was observed, therefore, the batch temperature was decreased to <NUM> to <NUM> over <NUM> minutes. After stirring at <NUM> to <NUM> for <NUM> minutes crystallisation occurred. The batch was subsequently filtered following a <NUM> hour stir out at <NUM> to <NUM>. After washing with MTBE (<NUM>, <NUM> volumes), at <NUM> to <NUM>, the batch was pulled dry under vacuum for <NUM> hours to yield a pale orange solid in <NUM> (<NUM>% recovery). The isolated solid was analysed for purity by HPLC. The purity was found to be <NUM> %area.

The table below displays the impurity profile of isolated material.

The results from the analysis indicated that the overall purity of the material was increased and the impurities at RRT <NUM> and at RRT <NUM> were purged to below <NUM>%. The impurity at RRT <NUM> was also reduced to below the target of NMT <NUM>%.

Solvent analysis of sample indicated an MTBE level of <NUM> ppm against an expected limit of NMT <NUM> ppm.

A clinical trial was performed in which <NUM>-MeO-DMT free base (purity not less than <NUM>%) was administered to patients with treatment-resistant major depressive disorder (TRD). The objectives of the study were to assess the safety and tolerability, the dose-related psychedelic effects and the effects on various measures of depression of single-day dosing of <NUM>-MeO-DMT. The trial was reviewed and approved by the relevant national competent authority and local medical ethics committee. Patients recruited into the trial had to meet the<NPL>on (DSM-<NUM>) diagnostic criteria for single-episode or recurrent major depressive disorder and had to be treatment-resistant, both aspects as evaluated by a psychiatrist or registered psychologist. Patients who were using any psychoactive medication or substance (such as anti-depressive medication) had to discontinue such medication or substance and had to observe a wash-out period before the <NUM>-MeO-DMT administration. On the administration day, a single dose of <NUM> <NUM>-MeO-DMT was administered to the patients via a single inhalation as described in Example 1A. Patients were closely monitored for <NUM> hours after administration, with additional follow-up visits <NUM> day and <NUM> days after dosing. Various safety related measures (e.g., adverse event reporting, safety laboratory analyses, vital signs, electrocardiogram (ECG), Clinician Administered Dissociative States Scale (CADSS), Psychomotor Vigilance Test (PVT), Digit Symbol Substitution Test (DSST)), measures of the intensity of the psychedelic effects (e.g., Peak Pyschedelic Experience Questionnaire (PPEQ), Altered States of Consciousness (ASC) Questionnaire, Mystical Experience Questionnaire (MEQ30), subjective description of the psychedelic experience), measures of depression severity (Montgomery-Åsberg Depression Rating Scale (MADRS), Patient's Global Impression of Severity scale (PGI-S), Patient's Global Impression of Improvement scale (PGI-I)), and additional psychological measures (e.g., Columbia-Suicide Severity Rating Scale (C-SSRS), Brief Psychiatric Rating Scale (BPRS)) were recorded at different time points. Psychological support via a psychologist and/or psychiatrist was available to the patients throughout the study, but no specific psychotherapy was applied, and no additional psychoactive medication was provided.

Two patients with major depressive disorder diagnosed by a psychiatrist according to DSM-<NUM> diagnostic criteria were recruited into the study (Example <NUM>, Table <NUM>). The patients were considered treatment-resistant because they had not shown adequate improvement to at least two adequate courses of pharmacological therapy in the current episode of depression.

The patients completed all planned visit days. The inhalation procedure was adequately performed by the patients and was well tolerated with no inhalation-related adverse events. The first psychedelic symptoms occurred within a few seconds after the inhalation. The duration of the psychedelic experience as judged by an external observer was <NUM> for patient <NUM> and <NUM> minutes for patient <NUM>.

Except for a temporary, not clinically relevant increase in heart rate and blood pressure shortly after administration of <NUM>-MeO-DMT, no other noteworthy changes in vital parameters occurred. Assessments of ECG (at <NUM> hours after administration), safety laboratory analyses (at <NUM> hours and <NUM> days), CADSS (at <NUM> hours, <NUM> day and <NUM> days) and cognitive tests (PVT, DSST; at <NUM> day and <NUM> days) were unremarkable. The few reported adverse events were mild, short-lasting and resolved spontaneously by the end of the study (Example <NUM>, Table <NUM>).

All reported adverse events were mild and resolved spontaneously by the end of the study.

With regard to the intensity of the psychedelic experience, patient <NUM> fulfilled the criteria for a peak psychedelic experience based on all three assessed scores, while patient <NUM> fulfilled the criteria for the MEQ30 and PPEQ, but not for the ASC (Example <NUM>, Table <NUM>).

Astonishingly, the patients reported a major improvement of their depressive symptoms as assessed by the MADRS, PGI-S and PGI-I already at the first assessment time point at <NUM> hours after drug administration, with the effect further deepening over time (Example <NUM>, Table <NUM>). The patients also fulfilled standard criteria for MADRS response (at least <NUM>% improvement from baseline) and MADRS remission (MADRS total score equal or less than <NUM>), rated "Normal, not at all ill" on the PGI-S and reported that their depressive symptoms had "very much improved" or "much improved" on the PGI-I at all assessment time points after drug administration, which is a highly surprising result.

The patients also improved on their ratings for suicidality after drug administration, as assessed using the suicidal thoughts item of the MADRS and the C-SSRS Suicidal ideation items. Other general psychiatric symptoms as assessed by the BPRS, e.g., somatic concern, anxiety, guilt and tension, also improved after the drug administration.

Importantly, patient <NUM> and patient <NUM> had a very similar intensity of psychedelic effects, which correlated with very similar anti-depressive clinical response. This observation supports that the occurrence of a peak experience is an important mechanism or at the least a surrogate behavioral marker for the underlying mechanism for the therapeutic efficacy of <NUM>-MEO-DMT.

Each of the aforementioned aspects A) to G) is unexpected, and is medically highly relevant. Aspects A) to G) show that <NUM>-MeO-DMT has a significantly improved efficacy profile compared to approved pharmacological therapies for major depressive disorder and to all previously tested psychedelic agents, when used according to the present invention. Together with the short duration of the acute psychedelic effects and the favorable safety profile, these data show that the technical problem to provide an improved psychoactive therapy in a patient with a major depressive disorder is solved by the present invention. The technical problem is also plausibly solved for persistent depressive disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder and psychoactive substance abuse, based on the effects of <NUM>-MeO-DMT on specific psychiatric symptoms observed in this study.

A clinical trial was performed in which <NUM>-MeO-DMT free base (purity not less than <NUM>%) at different dose levels was administered via inhalation (as described in Example <NUM>) in a single day to healthy volunteers who had prior experiences with the use of synthetic or naturally-occurring psychedelics. The trial was reviewed and approved by the relevant national competent authority and local medical ethics committee. The trial consisted of two parts: Part A, where single doses of <NUM>-MeO-DMT dosage amounts of <NUM>, <NUM>, <NUM> and <NUM> were administered; and Part B, where an initial <NUM>-MeO-DMT dosage amount of <NUM> was administered, and then, unless the participant had already experienced a peak psychedelic experience based on the PPEQ or the supervising physician had decided that further dose increases were inappropriate based on observed side effects, further subsequent dosage amounts of <NUM> and <NUM> were administered with about <NUM> hours in between each administration. Participants in Part A only received one dose and were not allowed to receive higher doses in later parts of Part A and were not allowed to participate in Part B. Participants were closely monitored for <NUM> hours after the last dose, with additional follow-up visits <NUM> day and <NUM> days after dosing. Various safety related measures (e.g., adverse event reporting, safety laboratory analyses, vital signs, ECG, CADSS, PVT, DSST, Prospective Memory Task (PMT)) as well as measures of the intensity of the psychedelic effects (MEQ30, ASC, PPEQ, subjective description of the psychedelic experience) were recorded. Pharmacokinetic analysis of <NUM>-MeO-DMT and bufotenine plasma levels was performed at <NUM> hour and <NUM> hours after drug administration in Part A, and at <NUM> hours after drug administration in Part B.

<NUM> participants were recruited into Part A of the study and <NUM> participants were recruited into Part B. <NUM> Participants were female and <NUM> participants were male. Median age was <NUM> years (range: <NUM> to <NUM> years). In Part A, <NUM> participants received <NUM>, <NUM> participants received <NUM>, <NUM> participants received <NUM> and <NUM> participants received <NUM> of <NUM>-MeO-DMT. In Part B, <NUM> participant received <NUM>, <NUM> participants received <NUM> and then <NUM> and one participant received <NUM>, <NUM> and then <NUM> of <NUM>-MeO-DMT.

All participants completed all planned visit days. In Part A, the inhalation procedure was adequately performed by <NUM> of the <NUM> participants, while <NUM> participants performed <NUM> inhalation sequences to inhale the total inhalation volume, and <NUM> participants inhaled only about % of the total inhalation volume. In Part B, the inhalation procedure was adequately performed by <NUM> of the <NUM> participants, while <NUM> participant performed an adequate inhalation at the first dose level but inhaled only about % of the total inhalation at the second dose level. No inhalation-related adverse events were reported.

The first psychedelic symptoms occurred within a few seconds after the inhalation in all participants. The duration of the psychedelic experience as judged by an external observer was between <NUM> minutes and <NUM> minutes, apparently with no dose-related trends.

Except for a temporary, not clinically relevant increase in heart rate and blood pressure shortly after administration of <NUM>-MeO-DMT, no noteworthy changes in vital parameters occurred. The evaluation of ECG, safety laboratory analyses, CADSS and cognitive tests (PVT, DSST, PMT) was unremarkable.

The reported adverse events were all mild (except for one moderate event) and all resolved spontaneously by the end of the study (Example <NUM>, Table <NUM> for Part A; Example <NUM>, Table <NUM> for Part B). While the overall tolerability profile of <NUM>-MeO-DMT was very good, it was observed that the <NUM> dose group in Part A had the highest number of adverse events, and that this was the only dose group where hallucinations and flashbacks of the experience were reported at the day <NUM> and day <NUM> timepoints, respectively. In Part B, only few adverse events were reported despite the up to three administrations of <NUM>-MeO-DMT in a single day, and in fact no adverse events were reported for the <NUM> dose (that followed a <NUM> and a <NUM> dose).

Shown are possibly related and probably related adverse events. <NUM>This event was moderate, all other events were mild in severity.

Shown are possibly related and probably related adverse events. All events were mild in severity.

With regard to the intensity of the psychedelic experience as measured by the PPEQ in Part A, a dose-related trend for the individual PPEQ questions, for the PPEQ Total Score, and for the fraction of patients who achieved a peak psychedelic experience was observed for the <NUM>, <NUM> and <NUM> dose levels. For the <NUM> dose level, however, this dose-related trend only continued for the Loss of Control question (Example <NUM>, Table <NUM>). Based on the subjective descriptions by the participants, it was found that the psychedelic experience for the <NUM> dose level was associated with a very quick onset but only few memories of the altered state of consciousness in some participants, which may explain this observation (in line with the so-called "white-out" phenomenon). In Part B, where participants started with a <NUM> dosage amount and received further subsequent dosage amounts of <NUM> and <NUM>, if they had not achieved a peak psychedelic experience at the lower dose, it was observed that the intensity of the psychedelic experience increased with the increasing dosage amounts in all participants. Further, all participants were able to achieve a peak psychedelic experience at their maximum individual dose level, which was <NUM> for <NUM> participant, <NUM> for <NUM> participants and <NUM> for <NUM> participant. At this maximum individual dose level, the scores for the individual PPEQ questions and for the PPEQ Total Score were higher than in all dose groups of Part A (Example <NUM>, Table <NUM>). No predictors for the maximum individual dose level that was required to achieve a peak psychedelic experience could be identified.

Shown are average results for all participants in the respective group. In Part A, participants received only <NUM> dose. In Part B, one participant received <NUM> and then had a PPE, two participants received <NUM> and then <NUM> and then had a PPE and one participant received <NUM>, then <NUM> and then <NUM> and then had a PPE. PPEQ, Peak Psychedelic Experience Questionnaire; PPE, Peak Psychedelic experience. <NUM>Shown are data for the highest dose for each participant. <NUM>Shown is the fraction of participants who achieved a PPEQ Total Score of at least <NUM>.

With regard to plasma levels of <NUM>-MeO-DMT, it was found that for any dose in Part A, plasma levels were already very low at the <NUM>-hour timepoint, and that plasma levels in Part A and Part B reached the lower level of quantification (LLOQ) of the <NUM>-MeO-DMT assay (<NUM> ng/ml) at the <NUM>-hour time point (Example <NUM>, Table <NUM>). With regard to the plasma levels of the <NUM>-MeO-DMT metabolite bufotenine, minimal amounts below the LLOQ of the bufotenine assay (<NUM> ng/ml) were seen in three participants at the <NUM>-hour time point, but bufotenine was undetectable in all other samples.

Shown is the group median (range minimum to maximum) of <NUM>-MeO-DMT plasma levels in ng/ml.

In conclusion, the studied dosage amounts between <NUM> and <NUM> administered via inhalation were able to induce psychedelic experiences, and dosage amounts of <NUM>, <NUM> and <NUM> of <NUM>-MeO-DMT administered via inhalation were able to induce peak psychedelic experiences in healthy participants. Because Example <NUM> makes it plausible that peak psychedelic experiences are associated with a therapeutic benefit in patients diagnosed with major depressive disorder and other mental diseases, it can be predicted that dosage amounts between <NUM> and <NUM>, in particular between <NUM> and <NUM>, of <NUM>-MeO-DMT administered via inhalation are therapeutically effective amounts. An individualized up-titration regimen, as applied in Part B, provides a higher chance to achieve peak psychedelic experiences along with superior tolerability, and therefore provides a superior therapeutic profile compared with administration of a single fixed dose.

The following questionnaire is applied in situations where the acute psychedelic experience after treatment with <NUM>-MeO-DMT needs to be quantified. At the end of relevant treatment sessions, the patient is handed a paper form and asked to rate the degree to which at any time during that session he experienced any of the phenomena listed below using the scale listed below. The MEQ30 is then computed and the occurrence of a peak psychedelic experience is then evaluated as described under scoring instructions.

The score for each individual subscale is computed by calculating the average score (from the scale of <NUM> to <NUM>) for the phenomena belonging to the subscale as listed below.

The MEQ30-total score is computed by taking the average response to all phenomena. Patients or probands with a score ≥<NUM>% of the maximum possible score on each of the four subscales of the MEQ30 are considered to have experienced a "peak psychedelic experience".

The Peak Psychedelic Experience Questionnaire (PPEQ) has been developed by the inventor as an improved alternative to the oceanic boundlessness dimension of the ASC and the MEQ30 to allow a simpler and quicker assessment of the intensity of a psychedelic experience. The PPEQ is comprised of three questions, all to be scored from <NUM> to <NUM> by marking a Visual Analogue Scale between <NUM> and <NUM>:.

The PPEQTotal Score is the average of the scores of the three questions. A "peak psychedelic experience" is identified through achievement of a PPEQTotal Score of at least <NUM>. A statistically significant correlation between the PPEQ Total Score and the oceanic boundlessness dimension of the ASC, respectively the MEQ30 Total Score, has been observed in the data set described in Example <NUM>.

The purpose of this study is to assess the efficacy of <NUM>-MeO-DMT compared with placebo in improving symptoms of major depressive disorder. This first study will be performed in patients with treatment-resistant major depressive disorder, but this is not to be understood that <NUM>-MeO-DMT does not have efficacy and cannot be used in untreated patients with major depressive disorder. The study consists of a screening phase, a randomized, double-blind, placebo-controlled treatment phase, an evaluation phase, and a follow-up phase with optional open-label re-treatment.

Screening Phase: Patients will be screened by a psychiatrist for eligibility for the study based on a comprehensive set of inclusion and exclusion criteria. Patients will also be informed in detail about the study procedures, and effects and potential side effects of the medication and other potential risks.

Patients will confirm their willingness to participate in the study by signing a consent form. Key inclusion criteria for the study are participant <NUM>) must meet <NPL>on (DSM-<NUM>) diagnostic criteria for Major Depressive Disorder, without psychotic features, and <NUM>) must have had an inadequate response to at least <NUM> antidepressants, at least one of which is in the current episode of depression. Key exclusion criteria are <NUM>) patient or immediate family member with current or prior DSM-<NUM> diagnosis of a psychotic disorder, <NUM>) patients with a history of substance abuse within the prior one year, <NUM>) any previous (recreational) use of <NUM>-MeO-DMT, <NUM>) prior participation in any clinical study with any other hallucinogen, <NUM>) known allergies or hypersensitivity or any other contraindication to <NUM>-MeO-DMT or any of the excipients used in the study drug formulation, <NUM>) current treatment with a monoamine oxidase inhibitor such as isocarboxazid, phenelzine, selegiline or tranylcypromine, and <NUM>) positive pregnancy test, lack of appropriate contraception.

Treatment Phase: The study is a double-blind, randomized, placebo-controlled study comparing the administration of <NUM>-MeO-DMT with the administration of placebo. Both compounds are to be provided by intramuscular injection. The <NUM>-MeO-DMT will be provided in the form of its hydrochloride salt and a formulation for intramuscular injection. It is understood that the dosage amounts for <NUM>-MeO-DMT mentioned below relate to the weight amount of the free base and the dosage amounts for the hydrochloride salt of <NUM>-MeO-DMT can be calculated assuming that equimolar amounts are used. Patients will be admitted to the study site in the morning. First, the patient's eligibility to the study will be re-confirmed by the responsible study physician, who is blinded for the assigned treatment group. Second, baseline assessments for the primary endpoint (Montgomery Asberg Depression Rating Scale (MADRS) total score) and all relevant secondary endpoints will be performed by a trained rater who is blinded for the assigned treatment group. Third, the patient will be informed about the application via intramuscular injection. Fourth, the first dose of the study drug (<NUM>-MeO-DMT or placebo) will be administered through intramuscular injection. The initial dose to be applied in this study is <NUM> of <NUM>-MeO-DMT or placebo. After the injection, the patient will lie down in a comfortable position and safe environment (e.g. on a mattress on the floor) and will be supervised by the study physician and a second trained observer. The onset of psychedelic symptoms is expected to occur within a few minutes after intramuscular administration. The normal duration of acute psychedelic symptoms after intramuscular administration of the <NUM>-MeO-DMT is about <NUM> to <NUM> minutes. After the subjective symptoms have subsided, the intensity of the subjective experience will be assessed by evaluating responses to the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) and the Peak Psychedelic Experience Questionnaire (PPEQ). In case a peak psychedelic experience (defined as at least <NUM>% of the maximum possible score in each of the <NUM> subscales of the MEQ30 or at least a PPEQ Total Score of <NUM>) occurred, the patient can be discharged, but at the earliest two hours after the last dose. If no peak psychedelic experience occurred, a higher dose of <NUM>-MeO-DMT or placebo, now <NUM>, will be administered at <NUM> hours after the first dose according to the same procedure as for the first dose. A third dose, now <NUM>, can be given after another <NUM>-hour interval, if no peak psychedelic experience has been achieved and no intolerable side effects have occurred with any of the prior doses.

Evaluation Phase: The patient will have follow-up visits at days <NUM>, <NUM>, and <NUM> after the last dose of study medication. Efficacy and safety evaluations will be performed at each of those visits. The primary endpoint of the study will be the change from baseline to day <NUM> in the MADRS total score. Key secondary endpoints will be the sustained response in the MADRS total score (<NUM>% reduction from baseline in MADRS total score) at day <NUM> and the change from baseline in the <NUM>-item Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16) at day <NUM> and <NUM>. Further efficacy assessments include achievement of remission, defined as a MADRS total score <=<NUM>, the Hamilton Depression Rating scale (HAM-D), the Clinical Global Impression - Severity (CGI-S) and the Patient Global Impression - Severity (PGI-S), and Generalized Anxiety Disorder <NUM>-item Scale (GAD-<NUM>). All endpoints will be assessed at each time point by a trained rater who is blinded for the assigned treatment group.

Follow-up phase, and optional open-label retreatment: Patients and physicians will be unblinded regarding the treatment group association after the <NUM>-day visit, but further monthly follow-up visits with efficacy and safety evaluations similar to the evaluations during the blinded phase will be performed. Patients who had achieved at least a <NUM>% reduction from baseline in MADRS total score at the primary endpoint will be eligible for three-monthly re-treatment with <NUM>-MeO-DMT using the highest dose given in the blinded phase, with the first re-treatment on day <NUM>.

Analysis: The treatment will be deemed effective if a significant difference can be detected for the change from baseline to day <NUM> in the MADRS total score for the active <NUM>-MeO-DMT arm compared with the placebo arm, as defined in the statistical analysis plan of the study. The analysis of secondary endpoints can provide further evidence of clinical efficacy.

The purpose of this study is to assess the efficacy of <NUM>-MeO-DMT compared with active control in improving symptoms of anxiety disorders. This first study will be performed in patients with treatment-resistant anxiety disorders, but this is not to be understood that <NUM>-MeO-DMT does not have efficacy and cannot be used in untreated patients with anxiety disorders. The study consists of a screening phase, a randomized, active-controlled, treatment phase, an evaluation phase, cross-over of participants into the other study arm and then another active-controlled treatment phase and evaluation phase, and a follow-up phase with optional open-label re-treatment.

Screening Phase: Patients will be screened by a psychiatrist for eligibility for the study based on a comprehensive set of inclusion and exclusion criteria. Patients will also be informed in detail about the study procedures, and effects and potential side effects of the medication and other potential risks. Patients will confirm their willingness to participate in the study by signing a consent form. Key inclusion criteria for the study are participant <NUM>) must meet DSM-<NUM> diagnostic criteria for social anxiety disorder, generalized anxiety disorder, and/or panic disorder and <NUM>) must have failed to achieve remission with at least one adequate prior anxiolytic medication (e.g. selective serotonin reuptake inhibitors) meaning at least <NUM> weeks at therapeutic dosing, including at least <NUM> weeks of stable dosing and must have failed to achieve remission with previous cognitive behavioral therapy or must have declined current cognitive behavioral therapy. Key exclusion criteria are <NUM>) patient or immediate family member with current or prior DSM-<NUM> diagnosis of a psychotic disorder, <NUM>) patients with a history of substance abuse within the prior one year, <NUM>) any previous (recreational) use of <NUM>-MeO-DMT, <NUM>) prior participation in any clinical study with any other hallucinogen, <NUM>) known allergies or hypersensitivity or any other contraindication to <NUM>-MeO-DMT or midazolam or any of the excipients used in the study drug formulations, <NUM>) current treatment with a monoamine oxidase inhibitor such as isocarboxazid, phenelzine, selegiline or tranylcypromine, and <NUM>) positive pregnancy test, lack of appropriate contraception.

Treatment Phase: The study is a randomized, active-controlled study comparing the administration of <NUM>-MeO-DMT with the administration of midazolam. <NUM>-MeO-DMT is to be provided via intravenous injection. The <NUM>-MeO-DMT will be provided in the form of its hydrochloride salt and a formulation for intravenous injection. It is understood that the dosage amounts for <NUM>-MeO-DMT mentioned below relate to the weight amount of the free base and the dosage amounts for the hydrochloride salt of <NUM>-MeO-DMT can be calculated assuming that equimolar amounts are used. Midazolam is to be provided via intravenous infusion. Patients will be admitted to the study site in the morning. First, the patient's eligibility to the study will be re-confirmed by the responsible study physician, who is blinded for the assigned treatment group. Second, baseline assessments for the primary endpoint (the Hamilton Anxiety Scale (HAM-A)) and all relevant secondary endpoints will be performed by a trained rater who is blinded for the assigned treatment group. Third, the study drug will be administered, as intravenous injection, at an initial dose of <NUM>, and Midazolam via intravenous infusion over <NUM> minutes at a dose of <NUM>/kg of Midazolam. After study drug administration, the patient will lie down in a comfortable position and safe environment (e.g. on a mattress on the floor) and will be supervised by the study physician and a second trained observer.

The onset of psychedelic symptoms in the <NUM>-MeO-DMT group is expected to occur within a few seconds after administration injection of the <NUM>-MeO-DMT. The normal duration of acute psychedelic symptoms after administration of the <NUM>-MeO-DMT is <NUM> to <NUM> minutes. After the subjective symptoms have subsided in both groups, the intensity of the subjective experience will be assessed by evaluating responses to the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) and the Peak Psychedelic Experience Questionnaire (PPEQ). The midazolam group can now be discharged, but at the earliest two hours after the last dose. The <NUM>-MeO-DMT group can also be discharged in case a peak psychedelic experience (defined as at least <NUM>% of the maximum possible score in each of the <NUM> subscales of the MEQ30 or at least a PPEQ Total Score of <NUM>) has occurred, but at the earliest two hours after the last dose. If no peak psychedelic experience occurred, a higher dose of <NUM>-MeO-DMT, now <NUM>, will be administered at <NUM> hours after the first dose according to the same procedure as for the first dose. A third dose, now <NUM>, can be given after another <NUM>-hour interval, if no peak psychedelic experience has been achieved and no intolerable side effects have occurred with any of the prior doses.

Evaluation Phase: The patient will have follow-up visits at days <NUM>, <NUM>, <NUM>, and <NUM> after the last dose of study medication. Efficacy and safety evaluations will be performed at each of those visits. The primary endpoint of the study will be the change from baseline to day <NUM> in the HAM-A total score. Key secondary endpoints will be the change from baseline to day <NUM>, <NUM>, <NUM> and <NUM> in Clinical Global Impression - Improvement (CGI-I) and Patient Global Impression - Improvement (PGI-I). All endpoints will be assessed at each time point by a trained rater who is blinded for the assigned treatment group.

Cross-over and second evaluation phase: Patients will cross over to the other study arm on day <NUM>, and patients will receive treatment of the other study group and evaluation as described above.

Follow-up phase, and optional open-label retreatment: Patients and physicians will be unblinded with regard to the treatment group association after the <NUM>-day visit, but further monthly follow-up visits with efficacy and safety evaluations similar to the evaluations during the initial phase will be performed. Patients who had achieved at least a <NUM>% reduction from baseline in HAM-A total score at the primary endpoint (or after cross-over at day <NUM>) will be eligible for three-monthly re-treatment with <NUM>-MeO-DMT using the highest dose given in the blinded phase.

Analysis: The treatment will be deemed effective if a significant difference can be detected for the change from baseline to day <NUM> in the HAM-A total score for the active <NUM>-MeO-DMT arm compared with the midazolam arm, as defined in the statistical analysis plan of the study. The analysis of secondary endpoints can provide further evidence of clinical efficacy.

The purpose of this study is to assess the efficacy of <NUM>-MeO-DMT in improving symptoms of anorexia nervosa. The study consists of a screening phase, a treatment phase, an evaluation phase, and a follow-up phase with optional re-treatment.

Screening Phase: Patients will be screened by a psychiatrist for eligibility for the study based on a comprehensive set of inclusion and exclusion criteria. Patients will also be informed in detail about the study procedures, and effects and potential side effects of the medication and other potential risks. Patients will confirm their willingness to participate in the study by signing a consent form. Key inclusion criteria for the study are participant <NUM>) must meet DSM-<NUM> diagnostic criteria for anorexia nervosa, <NUM>) must have a body mass index less than <NUM>/m2 and greater than <NUM>/m2 and <NUM>) must have had a duration of disease of at least <NUM> years. Key exclusion criteria are <NUM>) patient or immediate family member with current or prior DSM-<NUM> diagnosis of a psychotic disorder, <NUM>) patients with a history of substance abuse within the prior one year, <NUM>) any previous (recreational) use of <NUM>-MeO-DMT, <NUM>) prior participation in any clinical study with any other hallucinogen, <NUM>) known allergies or hypersensitivity or any other contraindication to <NUM>-MeO-DMT or any of the excipients used in the study drug formulation, <NUM>) current treatment with a monoamine oxidase inhibitor such as isocarboxazid, phenelzine, selegiline or tranylcypromine, and <NUM>) positive pregnancy test, lack of appropriate contraception.

Treatment Phase: The study is a single arm study. <NUM>-MeO-DMT is to be provided via intramuscular injection. The <NUM>-MeO-DMT will be provided in the form of its hydrochloride salt and a formulation for intramuscular injection. It is understood that the dosage amounts for <NUM>-MeO-DMT mentioned below relate to the weight amount of the free base and the dosage amounts for the hydrochloride salt of <NUM>-MeO-DMT can be calculated assuming that equimolar amounts are used. Patients will be admitted to the study site in the morning of the first treatment day. First, the patient's eligibility to the study will be re-confirmed by the responsible study physician. Second, baseline assessments for the primary endpoint and all relevant secondary endpoints will be performed by a trained rater. Third, the patient will be informed about the application of the study drug via intramuscular injection. Fourth, the first dose of the study drug will be administered under the supervision of the responsible study physician. The initial dose to be applied in this study is <NUM> of <NUM>-MeO-DMT. After the administration, the patient will lie down in a comfortable position and safe environment (e.g. on a mattress on the floor) and will be supervised by the study physician and a second trained observer. The onset of psychedelic symptoms is expected to occur within a few minutes after intramuscular administration. The normal duration of acute psychedelic symptoms after intramuscular administration of the <NUM>-MeO-DMT is about <NUM> to <NUM> minutes. After the subjective symptoms have subsided, the intensity of the subjective experience will be assessed by evaluating responses to the <NUM>-item revised Mystical Experience Questionnaire (MEQ30) and the Peak Psychedelic Experience Questionnaire (PPEQ. In case a peak psychedelic experience (defined as at least <NUM>% of the maximum possible score in each of the <NUM> subscales of the MEQ30 or at least a PPEQ Total Score of <NUM>) occurred, the patient can be discharged, but at the earliest three hours after the last dose. If no peak psychedelic experience occurred, a higher dose of <NUM>-MeO-DMT, now <NUM>, will be administered at <NUM> hours after the first dose according to the same procedure as for the first dose. A third dose, now <NUM>, can be given after another <NUM>-hour interval, if no peak psychedelic experience has been achieved and no intolerable side effects have occurred with any of the prior doses.

Evaluation Phase: The patient will have follow-up visits at days <NUM>, <NUM>, <NUM> and <NUM> after the last dose of study medication. Efficacy and safety evaluations will be performed at each of those visits. The primary endpoint of the study will be the change from baseline to day <NUM> in BMI of the patient. Key secondary endpoints will be change from baseline to day <NUM> in Eating Disorder Inventory (EDI) scale and change from baseline to day <NUM> in the MADRS total score. Further efficacy assessments include the Clinical Global Impression - Severity (CGI-S) and the Patient Global Impression - Severity (PGI-S). All endpoints will be assessed at each time point by a trained rater.

Follow-up phase, and optional retreatment: After the <NUM>-day visit further monthly follow-up visits with efficacy and safety evaluations similar to the evaluations during the initial phase will be performed. Patients who had achieved at least a <NUM>-point increase in their BMI from baseline at the primary endpoint will be eligible for three-monthly re-treatment with <NUM>-MeO-DMT using the same uptitration schedule as for the first treatment, with the first re-treatment on day <NUM>.

Claim 1:
<NUM>-Methoxy-N,N-dimethyltryptamine (<NUM>-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a patient who is diagnosed with major depressive disorder by a licensec professional in accordance with accepted medical practice, wherein the <NUM>-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.