Selective Serotonin Receptor Modulators for Use in the Treatment of Psychological Disorders

Important Compound Classes

Titles

Aerosol Comprising 5-Methoxy-N-N-Dimethyltryptamine; 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) for Treating Depression; and Crystalline 5-Methoxy-N,N-Diallyltryptamine Compounds

Patent Publication Numbers

WO 2021/170614 A1 (URL: https://patents.google.com/patent/WO2021170614A1/en?oq=WO2021170614A1); WO 2020/169850 A1 (URL: https://patents.google.com/patent/WO2020169850A1/en?oq=WO2020169850A1); and WO 2021/207137 A1 (URL: https://patents.google.com/patent/WO2021207137A1/en?oq=WO2021207137A1)

Publication Dates

September 2, 2021; August 27, 2020; and October 14, 2021

Priority Applications

EP20159161.7; EP19158774.0; and US63/006,371 and US63/132,547

Priority Dates

February 24, 2020; February 22, 2019; and April 7, 2020 and December 31, 2020.

Inventors

Terwey, T. (WO 2021/170614 A1 and WO 2020/169850 A1); Chadeayne, A. R. (WO 2021/207137 A1)

Assignee Company

GH Research Limited, Dublin, Ireland (WO 2021/170614 A1 and WO 2020/169850 A1); CaaMTech, Inc., Issaquah, WA, USA (WO 2021/207137 A1)

Disease Area

Psychological disorders

Biological Target

Serotonin receptor (SR)

Summary

Early-phase clinical trials assessing psilocybin-assisted therapy have been reported in unipolar mood disorders, anxiety, substance use disorders, and most recently major depressive and treatment-resistant disorders. The duration of action of classical psychedelics varies considerably. For oral ingestion, the subjective effect of lysergic acid diethylamide (LSD) lasts approximately 12 h, while psilocybin lasts approximately 6 h. The quest for short-acting psychedelics, if efficacious, may have therapeutic benefits of being short acting and possibly lower treatment costs.

The present Patent Highlight showcases aerosols of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, WO 2021170614 A1) and its derivatives as pharmaceutically acceptable salts which are useful for administration to a patient through an appropriate route whereby the medication is delivered to the patient systemically. 5-MeO-DMT is a short-acting serotonergic tryptamine which acts as a 5-HT_1A and 5-HT_2A receptor agonist that was first synthesized in 1936 and later isolated from Dictyoloma incanescens in 1959. Subsequently, it has been found in a large number of plants and fungi as well as the gland secretions of the Sonoran Desert toad.

The therapeutic potentials of 5-MeO-DMT have garnered renewed interest based on its pharmacological activities, which require controlled administration, exact quantity, and high purity for uses in human clinical trials. It may induce intense altered states of consciousness, including transcendence of time and space, euphoria, trance, spiritual experiences, dissolution of self-boundaries, or even near-death experiences. Due to the rapid onset of the psychedelic effects of 5-MeO-DMT, it is imperative to administer the complete or almost complete target dosage to a patient, whereas vaporization possibly lacks specificity and accuracy and in some instances may not be ideal for medical application. During vaporization, exposure of 5-MeO-DMT to undefined high temperatures over a long period of time would lead to the formation of unknown pharmacological degradants, which are also inhaled. Consequently, there is need to provide a well-controlled, standardized, and reproducible conditions for 5-MeO-DMT administration. Previously disclosed thermally generated condensation aerosols of drug molecules have shown high variability for the amount of degradation products and yields of active drug molecules.

A reproducible method is showcased for administration of 5-MeO-DMT or a pharmaceutically acceptable salt through an inhalation route with a suitable aerosol particle mass density that delivers the therapeutically effective dose of the aerosol to a patient via a single inhalation. The 5-MeO-DMT aerosol was generated by volatilization of the drug by way of the Volcano Medic Vaporization System. The device consists of a hot air generator and a detachable valve balloon from which the aerosol is inhaled mainly through the lungs and absorbs in the pulmonary alveoli of the patient. The hot (about 40–210 °C) air generator can produce adjustable temperatures with an airflow rate of about 12 L/min. Relevant doses of 5-MeO-DMT in an ethanol solution are applied via the central part of the device, which is then applied into the filling chamber of the device that is heated through the hot air. 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 patient is contained in a solution of a specific volume.

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 about 10 s, followed by a normal exhalation. After completing the inhalation procedure, the patient is instructed to lie down.

In a clinical trial performed with 5-MeO-DMT free base (purity not less than 99%), patients that met the DSM-5 diagnostic criteria for treatment-resistant major depressive disorder (TRD) were administered the drug molecule. On the day of administration, a single dose of 12 mg of 5-MeO-DMT was administered to the patients via a single inhalation as described above, and they were closely monitored for 3.5 h after administration. The patients returned for follow-up visits 1 day and 7 days after dosing. Two patients were treated with no inhalation-related adverse events. The psychedelic experience was highly intense, with both patients achieving a peak psychedelic experience as assessed by the 30-item revised Mystical Experience Questionnaire (MEQ30). The duration of the psychedelic experience, as judged by an external observer, was 16 min for patient 1 and 40 min for patient 2. Remarkably, both patients reported a formal remission of their depressive symptoms at the first assessment time point at 2 h after drug administration, and the effect further deepened at the day 1 and the day 7 follow-up visits. This data suggests that inhalation of an aerosol containing 5-MeO-DMT particles may be tolerable and the aerosol particles are rapidly and systemically absorbed via the pulmonary alveoli.

In another clinical trial performed with 5-MeO-DMT free base (WO 2020/169850 A1), different dose levels were administered via inhalation in a single day to healthy volunteers who had prior experiences with the use of synthetic or naturally occurring psychedelics. The trial consisted of two parts: In part A, 18 participants were recruited and were administered single doses of 5-MeO-DMT of 2 mg (4 participants), 6 mg (6 participants), 12 mg (4 participants), and 18 mg (4 participants). Part B had 4 participants and an initial dosage amount of 6 mg (1 participant); if no peak psychedelic experience or side effects were observed, then subsequent dosages were administered. Two participants received 6 mg and then 12 mg. In another administration, 1 participant received 6 mg, 12 mg, and then 18 mg with about 3 h between each administration. Pharmacokinetic analysis of 5-MeO-DMT and bufotenine plasma levels were performed at 1 and 3 h after drug administration in Part A, and at 3 h after drug administration in Part B. All participants completed the planned visit days, and reported adverse effects were mild, except for one moderate event, but all resolved spontaneously by the end of the study.

Finally, the disclosure in patent WO 2021/207137 A1 relates to crystalline 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT), bis(5-methoxy-N,N-diallyl-tryptammonium) fumarate (5-MeO-DALT fumarate), and crystalline bis(5-methoxy-N,N-diallyl-tryptammonium) fumarate. Crystalline forms of active pharmaceutical ingredients permit better characterization of their chemical and physical properties, which provide favorable pharmaceutical and pharmacological attributes. Furthermore, the disclosure provides a method for preventing and/or treating a psychological disorder by administering to a subject an effective therapeutic amount of the crystalline salts. The psychological disorder may be depression, bipolars I and II, major depressive disorder, dementia, schizophrenia, post-traumatic stress disorder, premenstrual syndrome, and so forth.

Definitions

The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders, such that each item is rated a score of 0–6, with 0–60 for the overall score. Diagnostic cutoff points (overall score) are 0–6 = normal/symptom-absent; 7–19 = mild depression; 20–34 = moderate depression, and >34 = severe depression.

Key Structures

Examplary 5-MeO-DMT derivatives:

Data Collection

Patients with major depressive disorder and treatment resistant depression diagnosed by a psychiatrist according to DSM-5 diagnostic criteria.

Biological Data

The table below shows plasma levels in ng/mL of 5-MeO-DMT in Part A, which were already very low at the 1-h time point. The first psychedelic symptoms occurred within a few seconds after the inhalation of the drug by the participants. Furthermore, all participants achieved a peak psychedelic experience at their maximum individual dose level.

The author declares no competing financial interest.