Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• PPD leads to a wide range of negative consequences for the affected mother, her infant(s) and her family. For example, women with PPD may develop thoughts of self-harm or harming their child and they are at increased risk of suicide. PPD may further lead to disruptions in the interactions between mother and child, exemplified by higher rates of disengaged behaviour and lower rates of visual and vocal communication between mother and child. Evidence also suggests an association between PPD and child development, as illustrated by the fact that children of patients suffering from PPD have a greater risk of impaired cognitive development.
• SSRIs selective serotonin reuptake inhibitors
• brexanolone More recently in the U.S., brexanolone (Zulresso) received FDA approval - thus making it the first pharmacological therapy indicated specifically for PPD. Brexanolone is a positive allosteric modulator of GABAa receptors which is administered via a 60-hour infusion. The efficacy of brexanolone was displayed in two phase 3 trials - one of which showed significantly reduced Hamilton Rating Scale for Depression (HAM-D) scores 30 days after initiation of the infusion and one of which failed to show efficacy beyond 7 days. However, brexanolone requires a hospital admission for the 60-hour infusion, and significant side effects occur.
• HAM-D Hamilton Rating Scale for Depression
• Hallucinogens including psychedelics 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, like psychedelics.
• 5-methoxy-N,N-dimethyltrypta- mine 5-MeO-DMT.
• TRD treatment resistant depression
• a still further aim of the current invention is to identify specific disease aspects and specific subgroups of disease aspects which benefit from such improved psychoactive therapies.
• Still further aims of the invention are to improve maternal functioning in patients suffering from PPD. Improvement of maternal functioning in a breastfeeding mother diagnosed with a mental disorder is also an aim of the invention.
• the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating postpartum depression (PPD).
• the treatment not only improves depressive symptoms but also maternal functioning.
• the invention also allows for treating PPD in a breastfeeding mother without substantial interruption of breastfeeding.
• the present invention relates to treating a breastfeeding mother diagnosed with a mental disorder.
• the term “administration” 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.
• 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.
• dose regimen (or “dosing regimen") shall mean a defined sequence of one or more individual administrations.
• the items considered are apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item yields a score of 0 to 6.
• the overall score ranges from 0 to 60.
• One group of hallucinogens entails compounds which bind to the 5-hydroxytryptamine (5-HT) receptors, which are also referred to as serotonin receptors (described are 7 families 5-HT1 to 5-HT7 with several subtypes). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT).
• 5-HT 5-hydroxytryptamine
• serotonin receptors 7 families 5-HT1 to 5-HT7 with several subtypes. Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT).
• the compound administered in order to avoid the induction of mania or hypomania or at least reduce the risk of induction of mania or hypomania, the compound administered must be appropriately chosen and preferably is administered in a particular dosing regimen.
• K values for psilocin, DMT and 5-MeO-DMT are 37, 117 and 122 nM, respectively, at 5-HT2A receptors located in the frontal cortex of post-mortem human brain. Therefore, psilocin exhibits moderate/strong affinity and DMT and 5-MeO-DMT exhibit comparatively weak affinity for 5-HT2A receptors.
• 5-MeO-DMT displays an enhanced affinity for the 5-HT1 A receptor, where it acts as a potent agonist.
• 5-HT2A binding there is an increased contribution of 5-HT2A binding, relative to 5-MeO-DMT, with the latter displaying the largest differential affinity for 5-HT1 A over 5-HT2A of the three compounds. Therefore, 5-HT1A binding plays a much bigger role in the overall effect of 5-MeO-DMT relative to 5-HT2A binding compared to the other two compounds.
• the patient suffering from such a mental or nervous system disorder, treated according to the invention does not experience treatment-emergent mania or hypomania. It is also noted that reports of treatment-emergent mania or hypomania related to psychoactive substance use seem to indicate large quantities of the respective compounds (e.g., DMT/ayahuasca, psilocybin, LSD) were used.
• 5-MeO-DMT can induce peak experiences, i.e., experiences characterized by an emotional perspective shift, which is described as "loss of ego” which often culminates in an overwhelming sense of "oneness with the universe", more rapidly than other psychedelics and has a short duration of acute psychedelic effects (5 to 30 minutes after intravenous injection compared with several hours for e.g. oral psilocybin and oral LSD).
• These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile which can be explained by specific alterations of Resting State Network (RSN) activity under 5-MeO-DMT treatment.
• RSN Resting State Network
• 5-MeO-DMT also interacts with the 5-HT7 receptor.
• 5-MeO-DMT act as an agonist on this receptor and shows a high (nanomolar) binding affinity.
• 5-MeO-DMT offers various characteristics that renders it an attractive treatment for PPD.
• it is a rapid-acting agent (in a 5-MeO-DMT-TRD trial, 5/8 patients with TRD achieved a remission within 2h after dosing, and 8/8 patients achieved a remission on day 1 , with 7/8 patients maintaining their remission at Day 7).
• 5-MeO-DMT to treat PPD patients, not only can a rapid improvement of depressive symptoms be achieved, but also a rapid improvement of maternal functioning.
• 5-MeO-DMT is administered during a single-day treatment session, with optional infrequent redosing, thus differentiating it from SSRIs, which require a chronic daily dosing regimen associated with low compliance, and from brexanolone, requiring protracted infusions and hospital admission.
• isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof can also be used.
• isotopic variants are also contemplated.
• Deuterated forms of 5-MeO-DMT are forms having a higher deuterium content than expected based on the natural abundance of this isotope.
• Examples of deuterated forms of 5-MeO-DMT include, without limitation, 1 -deuterio-2- (5-methoxy-1 H-indol-3-yl)-N,N-dimethylethanamine, 1 ,1 -dideuterio-2-(5-methoxy-1 H-in- dol-3-yl)-N,N-dimethylethanamine, 1 ,1 ,2,2-tetradeuterio-2-(5-methoxy-1 H-indol-3-yl)- N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1 H-indol-3-yl]eth- anamine.
• mixtures of deuterated forms of 5-MeO-DMT mixtures of one or more deuterated form with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixture of such salts as well as mixtures of salts of deuterated and non-deuterated 5-MeO-DMT can also be used.
• deuterated 5-MeO-DMT and salts of deuterated 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-deuterated forms.
• prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used.
• Such prodrugs of 5-MeO-DMT can be metabol- ically converted to 5-MeO-DMT.
• this when reference is made to the use of 5-MeO- DMT or a pharmaceutically acceptable salt thereof, this can be replaced by a 5-MeO- DMT prodrug or a salt thereof.
• the T ma x value of the metabolite 5-MeO-DMT as measured in male Sprague-Dawley (SD) rats following oral dosing of the prodrug at 10 mg/kg is preferably 1 hour or less, more preferably 0.7 hours or less and in particular 0.5 hours or less.
• prodrugs of 5-MeO-DMT and salts of prodrugs of 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-prodrug forms.
• the present invention allows treating patients suffering from PPD.
• the treatment does not only lead to reductions in scores assessing the severity of depression, but also improves maternal functioning as discussed in detail below.
• a treatment according to the invention reduces or eliminates (or improves or eliminates) an aspect of the disease.
• the MADRS item "inner tension” represents feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish. It is rated according to intensity, frequency, duration and the extent of reassurance called for.
• the aggregated score for the MADRS item "inner tension" across all 8 patients was 26 at base line. After 2 hours, it was reduced to 1 1 which corresponds to an improvement of 15 points or 58%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 20 points or 77%. At day 7 after treatment, it was reduced to 12 which corresponds to an improvement of 14 points or 54%.
• An improvement in inner tension as reflected 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, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the MADRS item "lassitude” represents a difficulty getting started or slowness initiating and performing everyday activities.
• a score of 0 means that there is hardly any difficulty in getting started and no sluggishness.
• a score of 2 is assigned if the patient has difficulties in starting activities.
• a score of 4 means difficulties in starting simple routine activities which are carried out with effort.
• a score of 6 is assigned in case of complete lassitude, the patient being unable to do anything without help.
• An improvement in lassitude as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the MADRS item "inability to feel” represents the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced. A score of 0 indicates normal interest in the surroundings and in other people, a score of 2 reduced ability to enjoy usual interests. A score of 4 is assigned in case of a loss of interest in the surroundings and a loss of feelings for friends and acquaintances. A score of 6 reflects the experience of being emotionally paralysed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of inability to feel.
• An improvement in inability to feel is reflected by at least an improvement in the score of the MADRS item inability to feel about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in inability to feel as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of inability to feel by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.13
• the inventors conclude that the observed improvement in the "inability to feel" item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
• the MADRS item "concentration difficulties” represents difficulties in collecting one's thoughts mounting to incapacitating lack of concentration.
• the score is 0 if the patient has no difficulties in concentrating.
• the score is 2 in case of occasional difficulties in collecting one's thoughts.
• a score of 4 is assigned in case of difficulties in concentrating and sustaining thought which reduces ability to read or hold a conversation.
• the score is 6 if the patient is unable to read or converse without great difficulty.
• the inventors have determined that increases in the score of the MADRS item "concentration difficulties" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "concentration difficulties" impair infant care as well as management.
• the aggregated score for the MADRS item "concentration difficulties" across all 8 patients was 30 at base line. After 2 hours, it was reduced to 1 1 which corresponds to an improvement of 19 points or 63%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 29 points or 97%. At day 7 after treatment, it was reduced to 9 which corresponds to an improvement of 21 points or 70%.
• the aggregated score for the MADRS item "concentration difficulties" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 14 points or 88%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81 %.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of concentration difficulties.
• An improvement in concentration difficulties is reflected by at least an improvement in the score of the MADRS item concentration difficulties about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in concentration difficulties as reflected by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PG I- 1) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in concentration difficulties as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the MADRS item "pessimistic thoughts” represents thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and ruin.
• a score of 0 is assigned if there are no pessimistic thoughts.
• the score is 2 in case of fluctuating ideas of failure, self-reproach or self-depreciation.
• a score means persistent self-accusations, or definite but still rational ideas of guilt or sin as well as the patient being increasingly pessimistic about the future.
• a score of 6 is assigned in case of delusions of ruin, remorse or unredeemable sin and self-accusations which are unreasonable and unshakable.
• the inventors have determined that increases in the score of the MADRS item "pessimistic thoughts" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "pessimistic thoughts” impair psychological wellbeing, social support and management. Conversely, improvements regarding this MADRS item lead to improvements in maternal functioning, in particular in the BIMF functional domains psychological wellbeing, social support and/or management.
• the aggregated score for the MADRS item "pessimistic thoughts" across all 8 patients was 28 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 21 points or 75%. At day 1 after treatment, it was reduced to 4 which corresponds to an improvement of 24 points or 86%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 25 points or 89%.
• the aggregated score for the MADRS item "pessimistic thoughts" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 8 which corresponds to an improvement of 8 points or 50%. At day 1 after treatment, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 8 points or 50%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of pessimistic thoughts.
• An improvement in pessimistic thoughts is reflected by at least an improvement in the score of the MADRS item pessimistic thoughts about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in pessimistic thoughts as reflected by at least a score of "much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PG I- 1) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in pessimistic thoughts as reflected by a reduction in the CGI-S score or by at least a score of "much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of pessimistic thoughts by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof.
• pessimistic thoughts also affects other aspects of PPD, the inventors conclude that the observed improvement in the "pessimistic thoughts" item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
• the MADRS item "reduced sleep” represents the experience of reduced duration or depth of sleep compared to the subject's own normal pattern when well.
• a score of 0 is assigned when the subject sleeps as usual.
• a score of 2 reflects slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
• a score of 4 means that sleep is reduced or broken by at least two hours.
• a score of 6 means less than two or three hours sleep.
• the inventors have determined that increases in the score of the MADRS item "reduced sleep” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "reduced sleep” impair self-care, psychological well-being and management.
• the aggregated score for the MADRS item "reduced sleep" across all 8 patients was 25 at base line.
• the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
• the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
• the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 9 which corresponds to an improvement of 16 points or 64%.
• the aggregated score for the MADRS item "reduced sleep" across all 4 patients was 12 at base line. At day 1 after treatment, it was reduced to 10 which corresponds to an improvement of 2 points or 17%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 6 points or 50%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of reduced sleep.
• the reduction or elimination of reduced sleep is reflected by at least an improvement in the score of the MADRS item reduced sleep on day 1 , for instance, about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• An improvement in reduced sleep as reflected 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, preferably occurs not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in reduced sleep as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of reduced sleep by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 24 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors conclude that the observed improvement in the "reduced sleep" item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
• a further aspect of PPD which can be treated by administration of 5-MeO-DMT, is suicidal ideation.
• 5-MeO-DMT can be administered to PPD patients to reduce or eliminate suicidal ideation in said patients.
• “Suicidal thoughts” represents a feeling that life is not worth living, that a natural death would be welcome, having suicidal thoughts, and/or making the preparations for suicide. Suicidal attempts should not in themselves influence the rating for this MADRS item.
• a score of 0 means that the patient enjoys life.
• a score of 2 is assigned if the PPD patient is weary of life, and/or has only fleeting suicidal thoughts.
• a score of 4 means the patient feels they would be better off dead, suicidal thoughts are common and suicide is considered as a possible solution but the patient has no specific plans or intention.
• a score of 6 is assigned in case the patient has explicit plans for suicide and/or is making active preparations.
• This MADRS scale item is of particular relevance to suicidal ideation.
• the inventors have determined that increases in the score of the MADRS item “suicidal thoughts” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “suicidal thoughts” impair self-care, psychological well-being and management.
• the aggregated score for the MADRS item “suicidal thoughts” across all 8 patients was 11 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 8 points or 73%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 10 points or 91 %. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 8 points or 73%.
• the aggregated score for the MADRS item “suicidal thoughts” across all 4 patients was 8 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 5 points or 63%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 3 points or 38%. At day 7 after treatment, it was reduced to 7 which corresponds to an improvement of 1 point or 13%.
• the treatment of a PPD patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.
• the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score of the MADRS item suicidal thoughts about 2 hours; on day 1 , for instance, after about 24 hours, on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI-S Clinical Global Impression - Severity
• CGI-S Clinical Global Impression - Severity
• An improvement in suicidal ideation as assessed by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in suicidal ideation as assessed by a reduction of the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of suicidal thoughts by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof.
• suicidal thoughts also affects other aspects of PPD, the inventors conclude that the observed improvement in the “suicidal thoughts” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
• the BPRS item “emotional withdrawal” relates to a deficiency in the patient’s ability to relate emotionally during the interview situation. Possible scores are:
• the inventors have determined that increases in the score of the BPRS item “emotional withdrawal” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “emotional withdrawal” impair psychological well-being, mother-child interaction and social support.
• the reduction or elimination of emotional withdrawal is reflected by at least an improvement in the score of the BPRS item emotional withdrawal about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in emotional withdrawal as reflected 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, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in emotional withdrawal as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the BPRS item “blunted affect” relates to a restricted range in emotional expressiveness of face, voice, and gestures as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are:
• Emotional range is noticeably diminished, patient doesn’t show emotion, smile, or react to distressing topics except infrequently.
• Voice tone is monotonous or there is noticeable decrease in spontaneous movements. Displays of emotion or gestures are usually followed by a return to flattened affect.
• the inventors have determined that increases in the score of the BPRS item “blunted affect” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “blunted affect” impair psychological well-being and motherchild interaction.
• the aggregated score for the BPRS item “blunted affect” was 15 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 4 points or 27%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%.
• the aggregated score for the BPRS item “blunted affect” was 1 1 at base line. After 3 hours, it was reduced to 8 which corresponds to an improvement of 3 points or 27%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 5 points or 45%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 6 points or 55%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of blunted affect.
• the reduction or elimination of blunted affect is reflected by at least an improvement in the score of the BPRS item blunted affect about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in blunted affect as reflected 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, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in blunted affect as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of blunted affect by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• blunted affect also affects other aspects of PPD, the inventors conclude that the observed improvement in the “blunted affect” item on the BPRS will additionally contribute to an overall improvement in maternal functioning.
• the BPRS item “guilt feelings” relates to over concern or remorse for past behavior. Possible scores are:
• the inventors have determined that increases in the score of the BPRS item “guilt feelings” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “guilt feelings” impair self-care, mother-child interaction, psychological wellbeing and management. Conversely, improvements regarding this BPRS item lead to improvements in maternal functioning, in particular in the BIMF functional domains self-care, mother-child interaction, psychological wellbeing and/or management.
• the aggregated score for the BPRS item “guilt feelings” across all 8 patients was 34 at base line. After 3 hours, it was reduced to 14 which corresponds to an improvement of 20 points or 59%. At day 1 after treatment, it was reduced to 11 which corresponds to an improvement of 23 points or 68%. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 24 points or 71 %.
• the aggregated score for the BPRS item “guilt feelings” across all 4 patients was 18 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 9 points or 50%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of guilt feelings.
• the reduction or elimination of guilt feelings is reflected by at least an improvement in the score of the BPRS item guilt feelings about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in guilt feelings as reflected 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, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in guilt feelings as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of guilt feelings by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the BPRS item “anxiety” relates to reported apprehension, tension, fear, panic or worry. Possible scores are:
• the aggregated score for the BPRS item “anxiety” across all 8 patients was 37 at base line. After 3 hours, it was reduced to 19 which corresponds to an improvement of 18 points or 49%. At day 1 after treatment, it was reduced to 16 which corresponds to an improvement of 21 points or 57%. At day 7 after treatment, it was reduced to 17 which corresponds to an improvement of 20 points or 54%.
• the aggregated score for the BPRS item “anxiety” across all 4 patients was 25 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 14 points or 56%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of anxiety.
• the reduction or elimination of anxiety is reflected by at least an improvement in the score of the BPRS item anxiety about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI- S Clinical Global Impression - Severity
• An improvement in anxiety as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PG I- 1) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in anxiety as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of anxiety by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the BPRS item “tension” relates to observable physical and motor manifestations of tension, “nervousness,” and agitation. Possible scores are
• 5 Moderately Severe. Many and frequent signs of motor tension with one or more signs often occurring simultaneously. There are still rare times when no signs of tension are present. 6 - Severe. Same as “5,” but signs of tension are continuous.
• the inventors have determined that increases in the score of the BPRS item “tension” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “tension” impair mother-child interaction and psychological wellbeing.
• the aggregated score for the BPRS item “tension” across all 8 patients was 16 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 5 points or 31 %. At day 1 after treatment, it was reduced to 1 1 which corresponds to an improvement of 5 points or 31 %. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 6 points or 38%.
• the aggregated score for the BPRS item “tension” across all 4 patients was 14 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 5 points or 36%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%.
• 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of tension.
• the reduction or elimination of tension is reflected by at least an improvement in the score of the BPRS item tension about 2 hours; on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• a reduction in the Clinical Global Impression - Severity (CGI- S) score occurs on day 1 , for instance, about 24 hours after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
• An improvement in tension as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PG I- 1) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-I Clinical Global Impression - Improvement
• PG I- 1 Patient Global Impression - Improvement
• An improvement in tension as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the inventors furthermore conclude that a reduction or elimination of tension by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
• This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• Improvements in one or more aspects of PPD will also lead to overall improvements.
• treatment leads to a remission.
• a remission of depressive symptoms may be reflected by a MADRS score equal to or less than 10 and occurs not later than about 2 hours; occurs on day 1 , for instance, after about 24 hours; on day 7; on day 14 and/or on day 28 after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
• a remission of depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurs not later than about 2 hours; occurs on day 1 , for instance, after about 24 hours; on day 7; on day 14 and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• a HAM-D score equal to or less than 7 and occurs not later than about 2 hours; occurs on day 1 , for instance, after about 24 hours; on day 7; on day 14 and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• Improvements in maternal functioning include improvements in the functional domain of self-care. For instance, improvements in the MADRS items lassitude and/or reduced sleep lead to an increase in the BIMF scale scores reflecting self-care.
• the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10 %, more preferably at least 20 %.
• Improvements in maternal functioning include improvements in the functional domain of infant care. For instance, improvements in the MADRS items lassitude and/or concentration difficulties lead to an increase in the BIMF scale scores reflecting infant care.
• the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15 %, more preferably at least 25 %.
• Improvements in maternal functioning include improvements in the functional domain of mother-child interaction. For instance, improvements in the MADRS items inability to feel and inner tension lead to an increase in the BIMF scale scores reflecting mother-child interaction.
• the improvement of the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5 %, more preferably at least 15 %
• Improvements in maternal functioning include improvements in the functional domain of psychological well-being. For instance, improvements in the MADRS items lassitude, pessimistic thoughts, inability to feel, inner tension and/or reduced sleep lead to an increase in the BIMF scale scores reflecting psychological well-being.
• the improvement of the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25 %, more preferably at least 35 %.
• Improvements in maternal functioning include improvements in the functional domain of social support. For instance, improvements in the MADRS item pessimistic thoughts leads to an increase in the BIMF scale scores reflecting social support.
• the improvement of the cumulative score of the BIMF scale items reflecting social support is preferably at least 10 %, more preferably at least 20 % Improvements in maternal functioning include improvements in the functional domain of management. For instance, improvements in the MADRS items lassitude, pessimistic thoughts and/or concentration difficulties lead to an increase in the BIMF scale scores reflecting management.
• the improvement of the cumulative score of the BIMF scale items reflecting management is preferably at least 20 %, more preferably at least 30 %
• Improvements in maternal functioning include improvements in the functional domain of adjustment. For instance, improvements in the MADRS item lassitude leads to an increase in the BIMF scale scores reflecting adjustment.
• the improvement of the cumulative score of the BIMF scale items reflecting adjustment is preferably at least 5 %, more preferably at least 15 %
• the improvement in maternal functioning relates to one or more, in particular two or more functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
• BIMF Barkin Index of Maternal Functioning
• the BIMF total score is improved by 10 % or more, preferably by 20 % or more.
• breastfeeding PPD patients may be confronted with a situation where a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.
• the present invention also addresses the need for treating PPD in a breastfeeding mother without substantial interruption of breastfeeding.
• breastfeeding can be resumed shortly after the treatment.
• the inventors have investigated pharmacokinetic properties and metabolization of 5- MeO-DMT in an effort to determine from which point in time onwards after administration of 5-MeO-DMT or of a pharmaceutically acceptable salt breastfeeding is possible without exposing the suckling child to any relevant risk. Absorption and distribution of inhaled 5-MeO-DMT is rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing.
• Plasma protein binding is low (13-23 %).
• Metabolites as listed in the above table are formed via three different pathways.
• reaction is catalysed by monoamine oxidase A (MAO-A).
• the secondary amine, the primary amine and the aldehyde were not identified which indicates that they are not present at any time in a significant concentration.
• the aldehyde intermediate metabolite undergoes 2 separate biotransformations in human liver hepatocytes. It is either oxidised to 5-methoxyindole acetic acid or reduced to 5-methoxyindole-3-ethanol.
• Both resulting metabolites are endogenous substances and are formed in the human body, for instance, during synthesis and metabolism of melatonin and serotonin (see e.g. Biochemistry of the Pineal. Chapter 3. In Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. In Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).
• 5-MIAA is a weak acid, which will be present in plasma in ionized form, which decreases the likelihood of the compound entering into breast milk.
• 5-MIAA is considered to be a final metabolite of 5-MeO-DMT.
• 5-MIAA shows relatively low plasma binding of -50% (mean fraction unbound (Fu); see the example section). It remains in circulation subject to renal clearance. Given a standard glomerular filtration rate of 90-120ml/min, this means that all traces of 5-MIAA are removed from circulation for urinary excretion in approximately 1 -2 hours (depending on patient size and taking into account the increase in blood volume that occurs during pregnancy).
• a further metabolite identified, bufotenine, is the result of O-demethylation, which is catalysed by CYP2D6.
• the metabolized formed is then subject to glucuronidation, which is catalysed by UGT :
• Bufotenine glucuronide cannot bind to receptors and does not exert any effect. Moreover, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenine glucuronide is further converted to 5-hydroxyindole acetic acid:
• 5-hydroxyindole acetic acid is an endogenous substance, for instance, it occurs in the metabolism of melatonin and serotonin (references as above).
• the third metabolic pathway involves N-oxidation:
• 5-MeO-DMT-N-oxide was deemed to be non-genotoxic in line with the negative in vitro genotoxicity assessment of the parent molecule.
• the compound is water soluble and subject to rapid excretion, as confirmed by observations in the rat (Sitaram, B.R., Lockett, L., Blackman, G. L., McLeod, W. R., 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231 ).
• breast feeding can be resumed shortly after the treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• breastfeeding has to be interrupted for only 6 hours, more preferably, for only 3 hours, most preferably for only 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• the therapeutically effective amount of 5-MeO-DMT is administered intravenous administration, by intramuscular administration or by subcutaneous administration. Administration via these routes can assure a rapid onset of action.
• a most preferred route of administration is administration via the intravenous route, i.e. by intravenous injection.
• 5-MeO-DMT can be employed as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations being known in the art.
• the present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes) and appropriate routes of administration.
• the invention is in part based on the inventors' conclusion that the occurrence of a peak psychedelic experience during the acute phase after administration of 5-MeO-DMT is driving its therapeutic benefit in patients suffering from PPD, in particular one or more of the aspects defined above, either in a causal relationship or at least as a surrogate behavioural marker for the underlying unknown therapeutic mechanism.
• the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of relevant tolerance (i.e., the absence of diminished or no psychedelic effects after re-administration), as a basis for enabling a dosing regimen with frequent re-administrations (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 doseoptimization which reduces the risk of overdosing, which may otherwise lead to somatic side effects, such as the serotonin syndrome, negative psychic reactions, such as flashbacks of the experience at later timepoints, induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state (so- called "white-outs").
• somatic side effects such as the serotonin syndrome
• negative psychic reactions such as flashbacks of the experience at later timepoints
• induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state so- called "white-outs”
• the 5- MeO-DMT is administered as a monotherapy, i.e., the patient does not receive any other treatment for PPD or symptoms associated with PPD.
• the dosage amount of 5-MeO-DMT administered to a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation is in the range of about 1 mg to about 10 mg, or any amount of range therein, and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, which weight amount can be calculated from the stated weight amounts of the 5-MeO-DMT free base, assuming that equimolar amounts are used.
• Useful specific amounts of 5-MeO-DMT are e.g.
• the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorders and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the occurrence of a clinical response not later than about 2 hours after administration of 5-MeO-DMT.
• the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the persistence of a clinical response, including a clinical response which occurred not later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5- MeO-DMT, more preferably until at least about 28 days after the last administration of 5- MeO-DMT.
• the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the administration of more than a single dose of 5-MeO-DMT.
• this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with not less than about 1 hour and not more than about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
• this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
• this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
• the dosage amount of the 5-MeO-DMT administered to an individual patient in each of the administrations and in each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 10 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered.
• the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects.
• the dosage amount for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg to the dosage amount of the prior administration. For example, if the dosage amount of the first administration was 1 mg and the dosage amount increase is 3 mg, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be 4 mg. Preferably, the dosage amount for the third administration will be 7 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4 mg to about 6 mg for the second administration, and from about 7 mg to about 9 mg for the third administration.
• Useful specific amounts for the first, second and third administration are e.g. about 2 mg, about 5 mg, and about 8 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 1 .5 mg to about 2.5 mg for the second administration, and from about 2.5 mg to about 3.5 mg for the third administration.
• Useful specific amounts for the first, second and third administration are e.g. about 1 mg, about 2 mg, and about 3 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of the first treatment block, and then increases with each subsequent administration within that first treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects, with that highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dosage in the first treatment block was 8 mg because the patient experienced a peak psychedelic experience at that dose, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of the first treatment block, and then 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 4 mg to about 6 mg for the second administration of the first treatment block, and from about 7 mg to about 9 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
• Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 2 mg, about 5 mg, and about 8 mg.
• the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1 .5 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 1 .5 mg to about 2.5 mg for the second administration of the first treatment block, and from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
• Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 1 mg, about 2 mg, and about 3 mg.
• a pharmaceutically acceptable salt of 5-MeO-DMT can also be used used in all of the above dosing regimen, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.
• 5-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 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the SO- item revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11 ):1 182-90).
• the occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018; 8:974).
• OBN Oceanic Boundlessness
• ASC Altered States of Consciousness
• the occurrence of a "peak psychedelic experience" in a patient is preferably identified through achievement of a score of at least 75 in the Peak Experience Scale (PES) Total Score, also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ), which averages answers scored by the patient from 0 to 100 for the following three questions: 1. How intense was the experience; 2. To what extent did you lose control; 3. How profound (i.e. deep and significant) was the experience?
• PES Peak Experience Scale
• PPEQ Peak Psychedelic Experience Questionnaire
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from postpartum depression (PPD) wherein the 5-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1 wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.
• MADRS Montgomery-Asberg Depression Rating Scale
• HAM-D 17-item Hamilton Depression Rating Scale
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 2 wherein the patient has a MADRS score of 28 or more or a HAM-D score of 22 or more.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 2 wherein the patient has a MADRS score of 35 or more or by a HAM-D score of 27 or more.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of postpartum depression.
• BIMF Barkin Index of Maternal Functioning
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 8, wherein the 5-MeO-DMT or salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a peak psychedelic experience.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 9, wherein a dosage of about 1 mg to about 10 mg 5-MeO-DMT is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 9, wherein a dosage of about 2 mg; or of about 5 mg; or of about 8 mg is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 9, wherein a dosage of about 1 mg; or of about 2 mg; or of about 3 mg is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.
• OBN Oceanic Boundlessness
• ASC Altered States of Consciousness
• PES Peak Experience Scale
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 21 , wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 22, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 23, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• CGI-S Clinical Global Impression - Severity
• CGI-S Clinical Global Impression - Severity
• a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 27, wherein a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 27, wherein a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 24, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• a remission of depressive symptoms as assessed by a MADRS score equal to or less than 10
• a HAM-D score equal to or less than 7 occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 31 , wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 32, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 33, wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 34 wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 34 wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
• 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 44, wherein the treatment improves maternal functioning.
• BIMF Barkin Index of Maternal Functioning
• Step 1 A stock solution of 5-MeO-DMT free base in 100% ethanol is prepared in a volumetric flask, so that the target dosage of 5-MeO-DMT free base to be administered via inhalation to the volunteer or patient is contained in a solution volume of 200 pl.
• Typical target dosages are from 1 mg to 25 mg 5-MeO-DMT.
• a target dosage of 18 mg 5-MeO-DMT 90 mg of 5-MeO-DMT will be dissolved in 100% ethanol for a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.
• Step 2 200 pl 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 3 The dosing capsule filled with the 5-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 55°C. Then the airflow of the vaporizer is switched on for 60 seconds at the pre-set rate of about 12 l/min. The heated air will flow through the dosing capsule, allowing the ethanol to evaporate, with the target dosage of 5-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 compared to the weight of the empty capsule is about equal to the target dosage of 5-MeO-DMT.
• Step 4 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 preheated with the temperature set at 210°C and the airflow on for at least 5 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 15 seconds at the pre-set flow rate of about 12 1/min, and then turned off. This will allow the full dose of 5-MeO-DMT to aerosolize and be distributed in approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of the 5-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to about its initial weight.
• Step 5 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 6 To prepare for the administration, the patient is asked to initially perform 1 -2 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 10 ( ⁇ 2.5) seconds, followed by a normal exhalation. After completing the inhalation procedure, the patient will be instructed to lie down.
• 5-MeO-DMT HBr was prepared on a 100mg scale.
• 5-MeO-DMT free base was combined with isopropyl acetate (10 vols), and the resulting solution of 5-MeO-DMT was heated to 50°C. HBr was charged (1 M in ethanol, 1 eq) in one single aliquot. The mixture was held at temperature and equilibrated for 3 hours.
• the salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern comprising peaks at 14.5°2* ⁇ 0.2°2* ; 16.7°2* ⁇ 0.2°2* ; 17.0°2* ⁇ 0.2°2* ; 20.6°2* ⁇ 0.2°2* ; 20.7°2* ⁇ 0.2°2* ; 21 ,4°2* ⁇ 0.2°2* ; 24.2°2* ⁇ 0.2°2* ; 24.8°2* ⁇ 0.2°2* ; 25.3°2* ⁇ 0.2°2* ; 27.4°2» ⁇ 0.2°2» ; measured using Cu K* radiation.
• Hippocampus was homogenised in ice-cold 0.25 M sucrose (1 :30 w/v) using a motor driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1 ,000g for 10 minutes. The supernatant was stored on ice and the pellet re-homogenised in 0.25 M sucrose (1 :15 w/v) and centrifuged at 750g for 10 minutes. The supernatants were combined and diluted in ice-cold membrane preparation buffer, (1 :100 w/v) using a tight-fitting glass/Teflon homogeniser (12 strokes, 800 rpm) and centrifuged at 20,500 g for 10 minutes.
• the pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 minutes before being centrifuged at 20,500 g for 10 minutes.
• the pellet was resuspended and centrifuged a final time to wash the tissue (20,500 x g for 10 mins).
• the resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equivalent to 3.125 mg wet weight of tis- sue/ml. All centrifugations were carried out at 4°C.
• the membrane preparation buffer consisted of 50 mM Tris-HCI, pH 7.7, 4 mM CaCh and 0.1 % ascorbic acid.
• the assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCh, 0.1% ascorbic acid and 10 pM Pargyline.
• hippocampal membranes 400 pl; equivalent 1.25 mg wet weight tissue/tube
• 50 pl of 0.075 - 9.6 nM [ 3 H]8-OH-DPAT 50 pl of assay buffer (total binding) or 50 pl of 1 pM WAY 100635 (non-specific binding) at 25°C for 30 minutes.
• the wash buffer consisted of 50 mM Tris, pH 7.7.
• hippocampal membranes 400 pl; equivalent 1.25 mg wet weight tissue/tube
• 50 pl of 0.6 nM [ 3 H]8-OH-DPAT 50 pl of assay buffer (total binding) or 50 pl of 1 • M WAY 100635 (non-specific binding) or 50 pl of one of the test compounds in one of ten concentrations between 1 and 10000 nM at 25°C for 30 minutes.
• Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine (PEI) using a Skatron cell harvester. Filters were rapidly washed with ice-cold wash buffer (wash setting 0,9,9) and radioactivity determined by liquid scintillation counting (1 ml Packard MV Gold scintillator).
• PEI polyethylenimine
• the concentration of compound required to inhibit 50% of specific binding (IC50) and the Hill Slope were calculated by using non-linear regression. The was calculated using the one-site binding model allowing for ligand depletion.
• Frontal cortex was homogenised in ice-cold 0.25 M sucrose (1 :30 w/v) using a motor driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris was removed by centrifugation at 1 ,000g for 10 minutes. The supernatant was stored on ice and the pellet re-homogenised in 0.25 M sucrose (1 :15 w/v) and centrifuged at 750g for 10 minutes.
• the supernatants were combined and diluted in ice-cold 50 mM Tris-HCI assay buffer, pH 7.4 (1 :100 w/v), homogenised using a tight-fitting glass/Teflon homogeniser (12 strokes, 800 rpm) and centrifuged at 20,500 g for 10 minutes. The pellet was centrifuged a further two times to wash the tissue (20,500 x g for 10 mins). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCI assay buffer, pH 7.4 at a tissue concentration equivalent to 10 mg wet weight of tissue/ml. All centrifugations were carried out at 4°C.
• frontal cortical membranes 400 pl; equivalent to 4 mg wet weight of tissue/tube
• 50 pl of 0.00625 - 0.8 nM [ 3 H]MDL- 100,907 50 pl of assay buffer or 50 pl of 10 • M ketanserin (non-specific binding) at 25°C for 60 minutes.
• the assay and wash buffer consisted of 50 mM Tris-HCI buffer pH 7.4.
• frontal cortical membranes 400 pl; equivalent 4 mg wet weight tissue/tube
• 50 pl of 0.1 nM [3H]MDL-100,907 was incubated with 50 pl of 0.1 nM [3H]MDL-100,907 and either 50 pl of assay buffer (total binding) or 50 pl of 10 • M ketanserin (non-specific binding) or 50 pl of one of the test compounds in one of ten concentrations between 1 and 10000 nM at 25°C for 60 minutes.
• Membrane bound radioactivity was recovered and determined as above. Data analysis was also as above.
• the dissociation constant (K d value) of [ 3 H]8-OH-DPAT for 5-HT1A receptors in hippocampal membranes from post-mortem human brain tissue was determined for each of the three donors.
• the dissociation constants (K d values) obtained were 0.51 , 0.28 and 0.52 nM, respectively.
• the dissociation constant (K d values) of [ 3 H]MDL-100,907 for 5-HT2A receptors in frontal cortical membranes from post-mortem human brain tissue was determined for each of the three donors.
• the dissociation constants (K d values) obtained were 0.11 , 0.08 and 0.08 nM, respectively.
• the selectivity ratio of psilocin, DMT and 5-MeO-DMT for 5-HT2A over 5-HT 1 A receptors was 0.78, 3.1 and 68, respectively.
• Part B was an open-label, single-arm Phase 2 trial applying an individualized dosing regimen with intrapatient dose escalation with 5-MeO-DMT.
• the primary endpoint of Part A was to assess the safety and tolerability of single dosing of 5-MeO-DMT in patients with TRD.
• the primary endpoint of Part B was to assess the effects on the severity of depression, as assessed by the proportion of patients in remission on day seven after dosing, defined as a MADRS total score of less than or equal to 10.
• Part B 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported. The primary endpoint was met with seven of eight patients (87.5%) achieving a MADRS remission on day seven (p ⁇ 0.0001 ). The mean MADRS change from baseline at day seven was 24.4 (76%).
• Table 3-C Scores recorded against relevant MADRS and BPRS items for patients assigned to 12mg dosing regimen.
• 5-MeO-DMT concentrations were determined using LC-MS/MS.
• PK parameters were generated by algebraic analysis of the concentration versus time plots for each individual. The analysis was carried out using the software Phoenix WinNonlin 6.3.
• Table 4 below shows median percentage plasma concentrations relative to Cmax as determined for the time points indicated.
• 5-MeO-DMT did not induce mutation in four histidine-requiring bacterial strains (TA98, TA100, TA1535 and TA1537) of Salmonella typhimurium, and one tryptophan-requiring strain (WP2 uvrA pKM101 ) of Escherichia coli. These conditions included treatments at concentrations up to 5000 pg/plate (the maximum recommended concentration according to current regulatory guidelines), in the absence and in the presence of a rat liver metabolic activation system (S-9).
• 5-MeO-DMT was incubated at a nominal concentration of 1 pM and 10 pM with human hepatocytes in suspension in Leibovitz L-15 medium (1 x 106 cells/mL).
• a standard stock solution of 5-MeO-DMT was prepared in ethanol at 20 mM and was further diluted with Leibovitz L-15 medium to a concentration of 2 mM.
• the 2 mM stock solution was diluted with Leibovitz L-15 medium to a concentration of 20 pM or 2 pM.
• An aliquot (250 pL) of the 20 pM and 2 pM test substance formulations was added to each hepatocyte incubation sample (250 pL), as appropriate, so that the final test substance concentration in the incubations was 10 pM or 1 pM, respectively, and incubations contained less than 1% (v/v) solvent.
• Incubations were performed at ca. 37°C in a shaking water bath (total incubation volume 0.5 mL). For 1 pM, incubations were terminated after 0, 5, 10, 20, 30, 60 and 120 minutes, by the addition of ice-cold acetonitrile (0.5 mL). For 10 pM, incubations were terminated after 0, 10, 30, 60 and 120 minutes, by the addition of ice-cold acetonitrile containing internal standard (1 pg/mL Psilocin-d10).
• the samples were vortex mixed and centrifuged at ca 13,000 rpm for 10 minutes at room temperature. Following centrifugation, the protein-free supernatants were removed for analysis.
• Blank control incubations were carried out with Leibovitz L-15 medium in place of the test substance. No cells control samples were performed with Leibovitz L-15 medium in place of hepatocytes. Aliquots of the blank control samples were taken at 120 minutes, while no cells control samples were taken at 0, 30 and 120 for 1 pM incubations and at 0 and 120 minutes for 10 pM incubations. All 1 pM incubations were performed in duplicate, while all 10 pM incubations were performed in singlet. All samples were stored at -80°C (nominal) prior to analysis.
• Suitable chromatographic conditions were developed to retain the parent compound and give a suitable chromatographic response.
• the 0, 30 and 120-minute incubation samples generated following incubation of 5-MeO-DMT at 10 pM were analysed using reverse phase LC-MS analysis to generate high and low energy mass spectra (MSE).
• MSE mass spectra
• Prior to sample analysis a 100 pL aliquot of each sample was evaporated to near dryness under a steady stream of nitrogen at room temperature, and subsequently reconstituted in 50 pL of mobile phase A (0.1 % formic acid in water).
• Each sample (0, 30 and 120-minute, 10 pM) was analysed using accurate mass LC-MS to determine relative levels of parent compound at each time-point, and determine the profile of metabolites formed. Appropriate blank and control samples were also analysed.
• the 10 and 60-minute, 10 pM incubation samples were not analysed and were stored at -80°C (nominal).
• Results obtained are summarized in the above table 1 .
• the patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.
• the 12 mg dose was safe and well-tolerated according to the investigator, and c. Any PsE of the prior dose have subsided, and d.
• Pre-dose vital parameters and forced expiratory volume in one second (FEV1 ) are in normal range, or if outside of the normal range, are not clinically significant according to the investigator.
• the patients will be assessed for a peak psychedelic experience (based on a patient- scored visual analogue scale, the PE scale), sedation, and other endpoints after dosing.
• a peak psychedelic experience based on a patient- scored visual analogue scale, the PE scale
• sedation based on a patient- scored visual analogue scale, the PE scale
• other endpoints after dosing.
• follow-up visits are planned for Day 1 , and Day 7 after the dosing day.
• BMI body mass index
• C-SSRS Columbia-Suicide Severity Rating Scale
• MAOI monoamine oxidase inhibitor
• the primary objective of the trial is to determine the onset and 7-day durability of anti- depressive effects of a single-day individualized dosing regimen of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult, female patients with PPD.
• Secondary objectives are to determine the anti-depressive effects; the anti-anxiety effects; the effects on maternal behavior; the safety and tolerability; the intensity and duration of psychoactive effects (PsE); the impact on cognitive outcome of a single-day individualized dosing regimen of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult, female patients with PPD.
• An exploratory objective is to determine in breastmilk, blood and urine the amount of 5- MeO-DMT and metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA), measured by LC/MS/MS (metabolite identification screening may be performed, as required), following dose administration of a single-day IDR of 6 mg, 12 mg and 18 mg of 5-Meo-DMT in adult, female patients with PPD.
• 5-MIAA 5-methoxyindole-3-acetic acid
• the primary endpoint of the study is the evaluation of the anti-depressive effects of 5- MeO-DMT by the change from baseline in MADRS assessed at Day 7.
• Secondary endpoints include the anti-depressive effects of 5-MeO-DMT evaluated by
• the anti-depressive effects of 5-MeO-DMT evaluated by: o The proportion of patients in remission (MADRS* 10) at 2 hours after the final study drug dosing on Day 0, and at Day 1 and Day 7; o Change from baseline in MADRS assessed at 2 hours after the final study drug dosing on Day 0, and at Day 1 ; o The proportion of responders (• 50% reduction from baseline in MADRS total score) at 2 hours after the final study drug dosing on Day 0, and at Day 1 and Day 7; o Change from baseline in Clinical Global Impression - Severity scale (CGI-S) 2 hours after final study drug dosing on Day 0, and at Day 1 and Day 7;
• CGI-S Clinical Global Impression - Severity scale
• Diagnosis was Major Depressive Disorder without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2), with peri-partum onset that began no earlier than gestation and no later than the first 4 weeks postpartum.
• MINI Mini-International Neuropsychiatric Interview
• the patient was diagnosed with postpartum depression after giving birth to her third child.
• the patient completed all planned visit days.
• the inhalation procedure was adequately performed by the patient and was well tolerated with no inhalation-related adverse events.
• 5-MeO-DMT has a significantly improved efficacy profile compared to approved pharmacological therapies for postpartum depression and to all previously tested psychedelic agents, when used according to the present invention.
• Example 13 Clinical trial of 5-MeO-DMT administered via intravenous injection to patients with postpartum depression - prophetic example
• the clinical trial will involve adult female patients with clinically diagnosed postpartum depression (PPD).
• PPD postpartum depression
• the patients will receive a single-day individualized 5-MeO-DMT dosing regimen by intravenous injection.
• the 5-MeO-DMT will be provided in the form of its hydrobromide salt and a formulation for intravenous injection. It is understood that the dosage amounts for 5-MeO-DMT mentioned below relate to the weight amount of the free base and the dosage amounts for the hydrobromide salt of 5-MeO-DMT can be calculated assuming that equimolar amounts are used. More in particular, the patients will receive up to three doses of 5-MeO-DMT on Day 0: 2 mg, 5 mg, and 8 mg.
• the second dose (5 mg) will only be administered if: a. A peak experience (total score of * 75) has not been achieved following the 2 mg dose, and b. The 2 mg dose was safe and well-tolerated according to the investigator, c. Any psychoactive effects (PsE) of the prior dose have subsided, and d. Pre-dose vital parameters and forced expiratory volume in one second (FEV1 ) are in normal range, or if outside of the normal range, are not clinically significant according to the investigator.
• a third dose (8 mg) will only be administered if: a. A peak experience (total score of * 75) has not been achieved following the 5 mg dose, and b. The 5 mg dose was safe and well-tolerated according to the investigator, c. Any PsE of the prior dose have subsided, and d. Pre-dose vital parameters and forced expiratory volume in one second (FEV1 ) are in normal range, or if outside of the normal range, are not clinically significant according to the investigator.
• FEV1 forced expiratory volume in one second
• the patients will be assessed for a peak psychedelic experience (based on a patient- scored visual analogue scale, the PE scale), sedation, and other endpoints after dosing.
• a peak psychedelic experience based on a patient- scored visual analogue scale, the PE scale
• sedation based on a patient- scored visual analogue scale, the PE scale
• other endpoints after dosing.
• follow-up visits are planned for Day 1 , and Day 7 after the dosing day.
• BMI body mass index

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