WO2024079647A1

WO2024079647A1 - Composition comprising tryptamines and maois compounds selected from β-carboline inhibitors, and pharmaceutical uses thereof

Info

Publication number: WO2024079647A1
Application number: PCT/IB2023/060210
Authority: WO
Inventors: Luca Santi; Luigi Mondello; Anna NOTTI; Ilaria CACCIOTTI; Salvatore Cuzzocrea
Original assignee: Sintalica Srl
Current assignee: Sintalica Srl
Priority date: 2022-10-11
Filing date: 2023-10-11
Publication date: 2024-04-18
Anticipated expiration: 2025-04-11
Also published as: EP4601665A1

Abstract

The present invention relates to a composition comprising at least one psychedelic tryptamine, preferably derived from psychedelic psilocybin mushrooms, more preferably from psychedelic psilocybin mushrooms belonging to the Psilocybe genus, and at least a MAOIs compound 5 selected from β-carboline inhibitors. The invention relates also to the pharmaceutical uses of the composition of the invention.

Description

DESCRIPTION TITLE Composition comprising tryptamines and MAOIs compounds selected from p-carboline inhibitors, and pharmaceutical uses thereof FIELD OF INVENTION

The present invention relates to a composition comprising at least one psychedelic tryptamine and at least a MAOIs compound selected from [3- carboline inhibitors.

The invention relates also to the pharmaceutical uses of the composition of the invention.

BACKGROUND OF THE INVENTION

In recent years, the scientific interest towards the potential use of psilocybin and other psychedelics for medical applications, such as the psychiatric disorders treatment, including mood disorders, depression, anxiety and alcoholism and nicotine addiction is increasing (Rucker, J.J.H et al., “Psychiatry & psychedelic drugs. Past, present & future”, Neuropharmacology (2018), v.142, p. 200-218).

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a substituted indolealkylamine and belongs to the group of hallucinogenic tryptamines (tryptamine alkaloid). Psilocybin is isolated from various genera of fungi including the genus Psilocybe, which is known to have hallucinogenic, anxiolytic, and psychoactive activities.

As well known, psilocybin is a prodrug: in fact, when it is orally administered, while passing through the liver it undergoes dephosphorylation to psilocin active drug, which can cross the blood-brain barrier and produce its psychoactive effects.

Psilocin binds serotonin 2A (5-HT2A) receptors in the central nervous system (CNS), mimicking the effects of serotonin. The serotonin 2A receptors (5-HT2A) are implicated in mental disorders with complex etiologies and in physiological processes such as learning and memory and in neurogenesis. The activation of these receptors by psychedelic compounds, such as psilocybin and psilocin has been shown to provide benefit in therapies that address mental health disorders. However, due to rapid metabolism and clearance of psilocin in the body by both monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) to 4- hydroxy-indole-3-acetaldehyde, further metabolized to 4-hydroxyindole-3- acetic acid, only a small amount can act on a serotonin receptor. As a result, there is a need to provide improved methods and compositions to inhibit the metabolic breakdown and clearance of a psychedelic compound, such as psilocin, by the monoamine oxidase (MAO) as well as to improve the tryptamine compositions to synergistically modulate the activity of the physiological response to the psychedelic compounds because of the activation of a serotonin receptor.

Monoamine oxidases (MAOs) are metabolic enzymes attached to cytosolic side of the outer membrane of mitochondria of neuronal, glial and several cell types. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines into the corresponding aldehyde and ammonia, both in the central nervous system and peripheral tissues. Several monoamine oxidase inhibitors (MAOIs) have been extensive employed as antidepressants and neuroprotective agents in Parkinson’s disease, as well as in the treatment of anxiety. There are two main isoforms, MAO-A and MAO-B. Monoamine oxidase A is predominantly responsible for the metabolism of psilocin (Reniers et al., “Synthesis and evaluation of [3-carboline derivatives as potential monoamine oxidase inhibitors”, Bioorg. Med. Chem. (2011 ) v. 19(1 ), p. 134-44).

Thus, the use of monoamine oxidases inhibitors (MAOIs) could allow to inhibit the metabolic breakdown and clearance of psychedelic compounds (Ostadkarampour, M. et al., “Monoamine oxidase inhibitors: a review of their anti-inflammatory therapeutic potential and mechanisms of action”, Frontiers in Pharmacology, (2021 ), v. 12, p. 676239).

Psilocybe mushrooms and several plant species have been reported to contain monoamine oxidase inhibitors (MAOIs), in particular [3-carbolines, capable of increasing/enhancing the pharmacological effects of psilocybin (e.g., harmane, harmine, norharmane, perlolyrine, harmol, cordysinins, tetrahydroharmane) (Blei F. et al., “Simultaneous Production of Psilocybin and a Cocktail of [3-Carboline Monoamine Oxidase Inhibitors in "Magic" Mushrooms”, Chem. Eur. J. (2020). V. 26, p. 729-734). In addition, the [3- carbolines seem to have antidepressant and neuroprotective effects. Similarly, in the case of Psilocybe mushrooms, endogenous MAOIs compounds could increase the bioavailability of psychoactive compounds and have their own therapeutic effects.

In this respect, some solutions have been proposed.

US20180021326A1 discloses compositions and methods for enhancing neuroregeneration and cognition by combining mushroom extracts containing active ingredients psilocin or psilocybin with erinacines or hericenones enhanced with niacin.

W02022072808A1 describes psychedelic compositions comprising MAOIs, delivery systems and therapeutic uses thereof.

Despite the above solutions, it remains the need for compositions useful for the treatment of pain.

DEFINITIONS

Unless otherwise defined, all the terms of the art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those who are experts in the technique to which this description belongs. In some cases, terms with commonly understood meanings are defined here for clarity and I or for ready reference; the inclusion of these definitions in this description should therefore not be interpreted as representing a substantial difference with respect to what is generally understood in the art.

The terms "comprise", "have", "include", "contain", "comprising", "having", "including" and "containing" are to be understood as open terms (ie the meaning "comprising, but not limited to") and are to be considered as a support also for terms such as "essentially consist of”, “consisting essentially of”, “consist of” or “consisting of”.

For all the ranges indicated in the text and in the claims of the present patent application, it is understood that the extremes of these ranges are included.

The terms “psychedelic drugs” or “psychedelic compounds” or “psychedelics” are synonymous, and they mean classes including tryptamines (“psychedelic tryptamines”), phenethylamines, and lysergamides. Some of the psychedelic drugs being researched for therapy include psilocybin, psilocin LSD (lysergic acid diethylamide), DMT (dimethyltryptamine), ibogaine, mescaline, and MDMA (3,4- methylenedioxymethamphetamine). Tryptamines are known to be a broad class of classical or serotonergic hallucinogens.

The “psychedelic compounds”, in particular the psychedelic tryptamines used in the invention, are preferably derived from psychedelic psilocybin mushrooms, more preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus.

The psychedelic psilocybin mushrooms include a polyphyletic, informal group of fungi that contain psilocybin, psilocin or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject

Preferred psychedelic tryptamines used in the invention comprise psilocybin and/or psilocin and/or their derivatives, such as baeocystin, norpsilocin, norbaeocystin and/or aeruginascin, and combinations thereof. Also comprised in the definition of said psychoactive compounds are the extracts from psychedelic psilocybin mushrooms, preferably belonging to the Psilocybe genus.

The pharmaceutically acceptable salts, derivatives, hydrate, or solvate of the above cited psychedelic compounds are comprised in the definition too.

The term “Psilocybe genus” may refer to the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.

The term “pharmaceutically acceptable salts or derivatives” herein refers to those salts or derivatives which possess the biological effectiveness and properties of the salified or derivatized compound and which and which do not produce adverse reactions when administered to a mammal, preferably a human. The pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH, 127-133, (2008), herein incorporated by reference. The pharmaceutically acceptable derivatives include the esters, the ethers and the N-oxides.

“Psilocybin” is the common name of 4-phosphoryloxy-N,N- dimethyltryptamine.

“Psilocin” is the common name of 4-hydroxy-N,N-dimethyltryptamine.

“Baeocystin” is the common name of 4-phosphoryloxy-N- methyltryptamine.

“Norpsilocin” is the common name of 4-hydroxy-N-methyltryptamine. “Norbaeocystin” is the common name of 4-Hydroxytryptamine 4- phosphate.

“Aeruginascin” is the common name of N,N,N-trimethyl-4- phosphoryloxytryptamine.

The term “MAOIs” means monoamine oxidases inhibitors. The MAOIs used in the present invention belong to the p-carboline class of inhibitors and are selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8- hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A , ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

SUMMARY OF INVENTION The present invention relates to a composition of at least one psychedelic tryptamine and at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro- P-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 - trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6- methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A , ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

A further object of the invention relates to the composition comprising at least one psychedelic tryptamine, and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and at least one MAOIs compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8- hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.

According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.

DETAILED DESCRIPTION

The present invention relates to a composition comprising at least one psychedelic tryptamine and at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6- methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-[3-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

The at least one psychedelic tryptamine is a compound of the class of tryptamines and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof, and preferably it is selected from baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof The at least one psychedelic tryptamine can be derived from psychedelic psilocybin mushrooms, which term includes a polyphyletic, informal group of fungi that contain psilocybin, psilocin, or both within their biomass, typically within their fruiting bodies, resulting in their activation of a psychedelic reaction in a subject.

The at least one psychedelic tryptamine of the composition of the invention can be preferably derived from psychedelic psilocybin mushrooms belonging to the Psilocybe genus and more preferably it can be baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof. According to a more preferred embodiment, the at least one psychedelic tryptamine of the composition of the invention is a combination of at least one of baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin, and psilocybin and/or psilocin.

According to a further preferred embodiment, the at least one psychedelic tryptamine of the composition of the invention is a combination of baeocystin and psilocybin and/or psilocin or it is a combination of baeocystin and norpsilocin and psilocybin and/or psilocin

In a preferred embodiment, the psilocybin-containing mushrooms are of the genus Psilocybe. Non limiting examples of suitable psilocybin- containing mushrooms that are in the genus Psilocybe include Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and combinations thereof.

The at least one psychedelic tryptamine of the composition of the invention can be an extract of psychedelic psilocybin mushrooms, preferably an extract of psychedelic psilocybin mushrooms belonging to the Psilocybe genus.

The at least one MAOI compound of the composition of the invention belongs to the p-carboline class of inhibitors and it is selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6- methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p- carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6- deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8- methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

Optionally, the composition of the invention can further comprise at least one antioxidant together with the at least one psychedelic tryptamine and at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-p-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl-tetrahydro-p-carboline MTHpC, pinoline, 1 -trichloromethyl- 1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl p-carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymanzamine A, 6- hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8- hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

According to a preferred embodiment, the at least one antioxidant is selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

The preferred molar ratio between the at least one psychoactive tryptamine and the at least one MAOI compound used in the composition of the invention is comprised between about 10 : 1 to about 1 : 10.

In one embodiment, the composition disclosed herein comprise a molar ratio between about 100 : 1 to about 1 : 100 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.

In another embodiment, the compositions disclosed herein comprise a molar ratio between about 1 ,000 : 1 to about 1 : 1 ,000 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.

In one embodiment, the compositions disclosed herein comprise a molar ratio of about 10,000: 1 to about 1 : 10,000 of the at least one psychoactive tryptamine and of the at least one MAOI compound used in the composition of invention.

A further object of the invention relates to the composition comprising at least one psychedelic tryptamine, and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and at least one MAOIs compound selected from norharmane, perillartine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DHpC), tetrahydro-p-carboline (THpC), methyl- tetrahydro-[3-carboline MTHpC, pinoline, 1 -trichloromethyl-1 ,2,3,4- tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3- carboline-3-carboxylate (PCCE), p-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8- hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease. According to a preferred embodiment, the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.

Claims

1. A composition comprising at least one psychedelic tryptamine and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro-[3-carboline (TH[3C), methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl- 1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3-carboline-3-carboxylate ([3CCE), [3-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymanzamine A, 6- hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8- hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

2. The composition according to claim 1 , wherein the at least one psychedelic tryptamine is selected from baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

3. The composition according to claim 2, wherein the at least one psychedelic tryptamine is a combination of at least one of baeocystin, norpsilocin, norbaeocystin, and/or aeruginascin, and psilocybin and/or psilocin.

4. The composition according to claim 3, wherein the at least one psychedelic tryptamine is a combination of baeocystin and psilocybin and/or psilocin or it is a combination of baeocystin and norpsilocin and psilocybin and/or psilocin.

5 The composition according to any one of claims 1 to 4, wherein the at least one psychedelic tryptamine is derived from psychedelic psilocybin mushrooms, preferably psychedelic psilocybin mushrooms belonging to the Psilocybe genus.

6. The composition according to claim 1 , wherein the at least one psychedelic tryptamine is an extract of psychedelic psilocybin mushrooms, preferably an extract of psychedelic psilocybin mushrooms belonging to the Psilocybe genus.

7. The composition according to claim 1 , wherein the at least one MAOI is selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

8. The composition according to any one of claims 1 to 7, wherein the molar ratio between the at least one psychedelic tryptamine and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof and the at least one MAOI compound selected from norharmane, perlolyrine, harmol, cordysinins tetrahydroharmine, 6-methoxyharmalan, harmalan, harmaline, harmalol, dihydro-[3-carbolines (DH[3C), tetrahydro-[3-carboline (TH[3C), methyl-tetrahydro-[3-carboline MTH[3C, pinoline, 1 -trichloromethyl- 1 ,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl [3-carboline-3-carboxylate ([3CCE), [3-carboline-3-carboxylate (PCCM), manzamine A, manzamine X, 6-deoxymanzamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymanzamine A, 6- hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8- hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, hyrtioerectines A, gesashidine A, plakortamines A, plakortamines B, lucartamides D, plakortamines C, eudistomidins, threctandramine, fascaplysin and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof is comprised between about 10 : 1 to about 1 : 10, preferably comprised between about 100 : 1 to about 1 : 100, more preferably comprised between about 1 ,000 : 1 to about 1 : 1 ,000 and further more preferably comprised between 10,000: 1 to about 1 : 10,000.

9. The composition according to any one of claims 1 to 8, further comprising at least one antioxidant, preferably selected from ascorbic acid, tannic acid, carotenoids, melatonin, curcumin, retinol, silver derivatives, zinc derivatives and/or salts, derivatives, hydrate, or solvate thereof and/or combinations thereof.

10. A composition according to any one of claims 1 to 9, for use in the treatment of fibromyalgia, spinal cord injury-induced chronic neuropathic pain, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-a- induced inflammatory disease.

11. The composition according to claim 10, wherein the TNF-a-induced inflammatory disease is selected between rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.