WO2023053090A1

WO2023053090A1 - Extraction technique

Info

Publication number: WO2023053090A1
Application number: PCT/IB2022/059357
Authority: WO
Inventors: Justin KIRKLAND
Original assignee: Optimi Health Corp.
Priority date: 2021-10-01
Filing date: 2022-09-30
Publication date: 2023-04-06

Abstract

Disclosed herein is as an improved process for the extraction of valuable active chemicals found in fungal and biomass with a simultaneous protection of degradation of active compounds which may be subject to oxidative degradation among other quality reducing processes.

Description

EXTRACTION TECHNIQUE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of United States Provisional Patent Application No. 63/251 ,292 filed on October 1 , 2021 ; and claims the benefit of the filing date of United States Provisional Patent Application No. 63/301,140 filed on January 20, 2022, the disclosures of which are each hereby incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention is directed to techniques for extracting natural products from a biomass, such as extracting compounds naturally produced by the mycelium of psilocybin mushrooms.

BACKGROUND OF THE DISCLOSURE

[0001] Mushrooms containing psilocybin (so-called magic mushrooms) are a group of psychoactive mushrooms, also known as magic mushrooms or hallucinogenic mushrooms. Mushrooms belonging to this group, such as Psilocybe cyanescens, also known as blue bald head, contain the psychedelic (mind-expanding, hallucinogenic) substances psilocybin and psilocin, which are being researched as active ingredients. Psilocybin itself is not psychoactive - rather it is the dephosphorylated derivative psilocin that causes the hallucinogenic effect. Psilocybin is rapidly dephosphorylated to psilocin following ingestion in the mucosa by alkaline phosphatases and nonspecific esterases. Psilocin is structurally similar to human signaling molecules such as serotonin and has been shown to bind to over 15 human serotonin-related receptors.

[0002] Scientific interest in classic psychedelics, such as psilocybin, has returned and grown because of several promising studies, validating earlier research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. A small, open-label study in patients with treatmentresistant depression showed reductions in depression and anxiety symptoms three months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions (Source: Johnson & Griffiths, 2017). Based on a recent report by Data Bridge Market Research, Market Analysis Study, 2020, the psychedelic drug market is growing with a compound annual growth rate of 16.3% and is expected to reach USD 6,859.95 million by 2027.

[0003] Clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. Preliminary results suggest that psilocybin assisted treatment may be a good candidate for managing substance addiction (Bogenschutz et al. , 2015; Riaz et al., 2016), anxiety in terminally ill patients (Grab et al., 2011), cluster headaches (Tyls et al., 2014), and treatment- resistant depression (Carhart-Harris et al., 2018). Psilocybin seems to be a particularly interesting candidate for "treatment resistant depression" - a term applied to the 13% of patients with Major Depressive Disorder (MDD) who relapse, in spite of four rounds of traditional treatment (Rush et al., 2006). Approximately 16 million Americans carried the MDD diagnosis in 2016, indicating a large number of people with untreated mental illness (Tice, 2017). Unfortunately, the content of psilocybin and psilocin in hallucinogenic mushrooms is too low (0.2%-l% dry weight) to make extraction a commercially viable option (Tyls et al., 2014), and chemical synthesis is complicated and expensive (Nichols and Frescas, 1999). Although the chemical synthesis of psilocybin has been improved since its discovery by Hoffman et al. in 1959, who achieved final yields of 20% of semi pure psilocybin, it continues to challenge chemists primarily due to the difficulty of the last synthetic step; the phosphorylation of psilocin (Nichols and Frescas, 1999).

BRIEF SUMMARY OF THE DISCLOSURE

[0004] Described herein is as an improved process for the extraction of valuable active chemicals found in fungal and biomass with a simultaneous protection of degradation of active compounds which may be subject to oxidative degradation among other quality reducing processes.

[0005] Detailed below is an improved extraction of heterocyclic compounds found in mushrooms, e.g., compounds naturally produced by the mycelium of psilocybin mushrooms. Examples of such compounds include baeocystin, norbaeocystin, N,N-dimethyl tryptamine, 5- hydroxytryptamine (serotonin), 5 -hydroxy tryptophan, psilocybin and psilocin.

[0006] It is believed that the process described herein shows an increased yield in overall compound volume by way of treatment of the fungal biomass by cell wall degrading enzymes. Without wishing to be bound by any particular theory, it is believed that the addition of cyclodextrins to the extraction solution creates a cyclodextrin-natural compound complex (e.g., cyclodextrin-psilocybin complex) that protects the natural compound from degradation including oxidation. The cyclodextrin further provides solid support for further processing into a dried powder by way of spray drying, pulse atomization spray drying, rotary evaporation, or other methods of removal of the liquid phase. The resulting solid preparation can be directly used in solid oral dosage formats, such as tablets, capsules, and rapid dissolving tablets (RDT).

[0007] It is believed that the complexation of the cyclodextrin and the natural compound provides improved solubility and transfer across biological membranes. Cyclodextrins have been shown to increase permeability through intranasal delivery across the sinuses. Cyclodextrin complexation has shown increased permeability across human dermal surfaces. Cyclodextrins include 3 primary sizes described as alpha, beta, and gamma with 6, 7, and 8 glucose subunits respectively. Derivatives included randomly methylated, hydroxypropylated, acetylated, tosylated, and sulphonylbutylated ethers and other substitutions across each size of cyclodextrin. [0008] Psilocybin containing mushrooms have been known to bruise in the color blue. This is believed to be due to a chemically complex mixture of linked psilocybin oxidation products. Without wishing to be bound by any particular theory, it is believed that the cyclodextrin complexation will prevent this side product degradation.

[0009] In a first aspect of the present disclosure is a particle comprising one or more natural product - cyclodextrin complexes, wherein the natural product of the one or more natural product - cyclodextrin complexes is derived from psilocybin mushrooms. In some embodiments, the natural product derived from the psilocybin mushrooms are selected form the group consisting of include baeocystin, norbaeocystin, N,N-dimethyltryptamine, 5 -hydroxy tryptamine (serotonin), 5- hydroxy tryptophan, psilocybin and psilocin. In some embodiments, the particle further includes one or more antioxidants. In some embodiments, the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, Alpha lipoic acid, cysteine and its salts.

[0010] In some embodiments, the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of a-cyclodextrins, P-cyclodextrins, y-cyclodex trins, and 5-cyclodextrins, and combinations thereof.

[0011] In some embodiments, the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of hydroxypropylated a- cyclodextrin, hydroxypropylated P-cyclodextrin, hydroxypropylated y-cyclodextrin, hydroxyethylated a-cyclodextrin, hydroxyethylated P-cyclodextrin, hydroxyethylated y- cyclodextrin, hydroxyisopropylated a-cyclodextrin, hydroxyisopropylated P-cyclodextrin, hydroxyisopropylated y-cyclodextrin, carboxymethylated a-cyclodextrin, carboxymethylated P- cyclodextrin, carboxymethylated y-cyclodextrin, carboxyethylated a-cyclodextrin, carboxyethylated P-cyclodextrin, carboxyethylated y-cyclodextrin, octyl succinated-a- cyclodextrin, octyl succinated-P-cyclodextrin, octyl succinated-y-cyclodextrin, acetylated-a- cyclodextrin, acetylated- P-cyclodextrin, acetylated-y-cyclodextrin, sulfated-a-cyclodextrin, sulfated-P-cyclodextrin, and sulfated-y-cyclodextrin.

[0012] In some embodiments, the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of 2,3-dimethyl-6-aminomethyl-a- cyclodextrin, 6-azido- a-cyclodextrin, 6-bromo-P-cyclodextrin, 6A,6B-dibromo-P-cyclodextrin, 6A,6B-diiodo-P-cyclodextrin, 6-O-maltosyl-P-cyclodextrin, 6-iodo-a-cyclodextrin, 6-tosyl-P- cyclodextrin, peracetyl-maltosyl-P-cyclodextrin, 6-t-butyldimethylsilyl-P-cyclodextrin, 2,3- diacetyl-6-butyldimethylsilyl-P-cyclodextrin, 2,6-dibutyl-3-acetyl-P-cyclodextrin, 2,6-dibutyl-P- cyclodextrin, 2,6-t-butyl-dimethylsilyl-P-cyclodextrin, and 2,6-di-O-methyl-3-allyl-P- cyclodextrin.

[0013] In some embodiments, the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of hydroxypropyl -beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta cyclodextrin, Cl-24-alkyl- gamma-cyclodextrin, and Cl-24-hydroxyalkyl-gamma-cyclodextrin.

[0014] A second aspect of the present disclosure is a spray-dried particle comprising a psilocybin - cyclodextrin complex. In some embodiments, the spray-dried particle further comprises at least one natural product - cyclodextrin complex other than the psilocybin - cyclodextrin complex. In some embodiments, the spray-dried particle further includes one or more antioxidants. In some embodiments, the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, Alpha lipoic acid, cysteine and its salts.

[0015] A third aspect of the present disclosure is a method of preparing a spray-dried particle comprising a psilocybin-cyclodextrin complex, comprising: (i) processing psilocybin mushrooms; (ii) transferring the processed psilocybin mushrooms to a solution comprising (a) one or more solvents; (b) one or more enzymes; and (c) one or more cyclodextrins; and (d) converting the solution including the processed psilocybin mushrooms to a dry material. In some embodiments, the solution further includes one or more antioxidants. In some embodiments, the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, Alpha lipoic acid, cysteine and its salts.

[0016] In some embodiments, the processing of the psilocybin mushrooms comprises homogenizing the psilocybin mushrooms. In some embodiments, the homogenization comprises at least one of grinding, chopping, and mechanical shearing.

[0017] In some embodiments, the one or more solvents are selected from the group consisting of water, methanol, ethanol, and combinations thereof.

[0018] In some embodiments, the solution further comprises a buffer.

[0019] In some embodiments, the buffer has a pH ranging from between about 4 and about

5.5. In some embodiments, the buffer is selected from the group consisting of acetate, carbonate, phosphate, Tris-HCl, acetic acid, tris buffer, and phosphate buffer.

[0020] In some embodiments, the one or more enzymes are selected from the group consisting of chitinase, 1,6-glucanase, 1,3-glucanase, and combinations thereof.

[0021] In some embodiments, the one or more cyclodextrins are selected from the group consisting of a-cyclodex trins, P-cyclodextrins, y-cyclodextrins, and 5-cyclodextrins, and combinations thereof. In some embodiments, the one or more cyclodextrins are selected from the group consisting of hydroxypropylated a-cyclodextrin, hydroxypropylated P-cyclodextrin, hydroxypropylated y-cyclodextrin, hydroxyethylated a-cyclodextrin, hydroxyethylated P- cyclodextrin, hydroxyethylated y-cyclodextrin, hydroxyisopropylated a-cyclodextrin, hydroxyisopropylated P-cyclodextrin, hydroxyisopropylated y-cyclodextrin, carboxymethylated a-cyclodextrin, carboxymethylated P-cyclodextrin, carboxymethylated y-cyclodextrin, carboxyethylated a-cyclodextrin, carboxyethylated P-cyclodextrin, carboxyethylated y- cyclodextrin, octyl succinated-a-cyclodextrin, octyl succinated-P-cyclodextrin, octyl succinated- y-cyclodextrin, acetylated-a-cyclodextrin, acetylated- P-cyclodextrin, acetylated- y-cyclodextrin, sulfated-a-cyclodextrin, sulfated-P-cyclodextrin, and sulfated-y-cyclodextrin. In some embodiments, the one or more cyclodextrins are selected from the group consisting of 2,3- dimethyl-6-aminomethyl-a-cyclodextrin, 6-azido-a-cyclodextrin, 6-bromo- P-cyclodextrin, 6A,6B-dibromo-P-cyclodextrin, 6A,6B-diiodo-P-cyclodextrin, 6-O-maltosyl- P-cyclodextrin, 6- iodo-a-cyclodextrin, 6-tosyl-P-cyclodextrin, peracetyl-maltosyl-P-cyclodextrin, 6-t- butyldimethylsilyl-P-cyclodextrin, 2,3-diacetyl-6-butyldimethylsilyl-P-cyclodextrin, 2,6-dibutyl- 3-acetyl-P-cyclodextrin, 2,6-dibutyl-P-cyclodextrin, 2,6-t-butyl-dimethylsilyl-P-cyclodextrin, and 2,6-di-O-methyl-3-allyl-P-cyclodextrin. In some embodiments, the one or more cyclodextrins are selected from the group consisting of hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta- cyclodextrin, heptakis(2,6-di-O-methyl)-beta cyclodextrin, Cl-24-alkyl-gamma-cyclodextrin, and C 1 -24-hydroxy alkyl-gamma-cyclodextrin.

[0022] In some embodiments, the converting of the solution including the processed psilocybin mushrooms to the dry material comprises one or more of spray drying, pulse atomization spray drying, or rotary evaporation.

[0023] A fourth aspect of the present disclosure is a particle comprising one or more natural product - cyclodextrin complexes, wherein the natural product of the one or more natural product - cyclodextrin complexes are derived from psilocybin mushrooms and wherein the natural product - cyclodextrin complexes comprise a mixture of two different cyclodextrins. In some embodiments, the two different cyclodextrins are provided in a 1:1 ratio. In some embodiments, the two different cyclodextrins are provided in a 2: 1 ratio. In some embodiments, the two different cyclodextrins are provided in a 1:2 ratio.

BRIEF DESCRIPTION OF THE FIGURES

[0024] For a general understanding of the features of the disclosure, reference is made to the drawings. In the drawings, like reference numerals have been used throughout to identify identical elements.

[0025] FIG. 1 provides a flowchart illustrating an overview of the methods of the present disclosure.

[0026] FIG. 2 sets forth a flowchart illustrating a method of extracting one or more heterocyclic compounds from one or more mushrooms in accordance with one embodiment of the present disclosure.

[0027] FIG. 3 sets forth a flowchart illustrating a method of extracting one or more heterocyclic compounds from one or more mushrooms in accordance with one embodiment of the present disclosure. [0028] FIG. 4 sets forth a flowchart illustrating a method of extracting one or more heterocyclic compounds from one or more mushrooms in accordance with one embodiment of the present disclosure.

DETAILED DESCRIPTION

[0029] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. [0030] As used herein, the singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "includes" is defined inclusively, such that "includes A or B" means including A, B, or A and B.

[0031] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of" or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0032] The terms "comprising," "including," "having," and the like are used interchangeably and have the same meaning. Similarly, "comprises," "includes," "has," and the like are used interchangeably and have the same meaning. Specifically, each of the terms is defined consistent with the common United States patent law definition of "comprising" and is therefore interpreted to be an open term meaning "at least the following," and is also interpreted not to exclude additional features, limitations, aspects, etc. Thus, for example, "a device having components a, b, and c" means that the device includes at least components a, b, and c. Similarly, the phrase: "a method involving steps a, b, and c" means that the method includes at least steps a, b, and c. Moreover, while the steps and processes may be outlined herein in a particular order, the skilled artisan will recognize that the ordering steps and processes may vary.

[0033] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0034] The concentration of active psilocybin mushroom compounds varies not only from species to species, but also from mushroom to mushroom inside a given species, subspecies, or variety. The same holds true even for different parts of the same mushroom. In the species Psilocybe samuiensis, the dried cap of the mushroom contains the most psilocybin at about 0.23 wt. %-0.90 wt. %. The mycelium contains about 0.24 wt. %-0.32 wt. %.

[0035] The term "psilocybin" refers to a naturally occurring psychedelic prodrug compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms. The most potent are members of the genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. As a prodrug, psilocybin is quickly converted by the body to psilocin, which has mindaltering effects similar, in some aspects, to those of LSD, mescaline, and DMT. In general, the effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and can also include possible adverse reactions such as nausea and panic attacks. [0036] The term "psilocin" (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) refers to a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin.

[0037] The term "baeocystin" refers to a psilocybin mushroom alkaloid and analog of psilocybin. It is found as a minor compound in most psilocybin mushrooms together with psilocybin, norbaeocystin, and psilocin. Baeocystin is an N-demethylated derivative of psilocybin, and a phosphorylated derivative of 4-HO-NMT (4-hydroxy-N-methyltryptamine).

[0038] In some embodiments, and with reference to FIGS. 1 - 4, one or more mushrooms are harvested (step 10). In some embodiments, the one or more mushrooms are psilocybin mushrooms. Next, the one or more harvested mushrooms are processed (step 20). In some embodiments, processing includes at least one of drying to dehydrate (step 21), treatment with liquid nitrogen and/or lyophilization (step 22), or homogenization (step 23).

[0039] In some embodiments, the harvested one or more mushrooms are processed by homogenizing the one or more mushrooms to provide a homogenate (step 23). In some embodiments, the homogenizing of the one or more mushrooms may be performed "neat" or may be performed in the presence of a water, an aqueous solution, or a water miscible polar organic solvent. In the methods of the present disclosure, the mushroom homogenate may be prepared by homogenizing the one or more mushrooms at temperature from about 10°C to about 100°C for a period of time of about 0.5 minutes to about 30 minutes.

[0040] As will be described herein, the homogenization can be done by any means, notably manual or mechanical. For example, the tissue homogenate may be obtained by shearing using a blender, or by crushing using a pestle. By way of other examples, homogenization may be obtained using a blender homogenizing tool, an ultrasound homogenizing method, a pressure homogenizing method or the like. An example of a homogenization apparatus and method is described in United States Patent No. 9,556,410, the disclosure of which is hereby incorporated by reference herein in its entirety.

[0041] In the homogenizing step 23, the one or more mushrooms may be fragmented so as to form a more or less fine homogenate, notably liquid, semi-liquid, pasty, etc. The homogenate may not be homogeneous and may for example include mushroom fragments of different sizes. It is possible, if necessary, to add a homogenizing solution to the homogenate obtained, and notably an aqueous solution, so as to dilute the homogenate and render it less compact. The homogenizing solution can be added upstream, downstream or during the homogenization step.

[0042] Mechanical/physical methods for disrupting samples include grinding, shearing, beating, and shocking. Grinding, which is done with such tools as a mortar and pestle, involves applying force downward on a sample in conjunction with a separate tangential (i.e., rotating) force. Shearing is like that of a blender where a force is tangentially applied to a sample. Directly impacting a sample with a ball or hammer is beating. Shock is similar to beating, but there is no physical implement contacting the sample, just shockwaves. At times it is difficult to discern between the different forces that relate to each method. For instance, grinding is a combination of shearing and beating, but for the sake of simplicity we will segregate the different tools into these categories.

[0043] Disrupting cells and tissues by applying a force not inherent to the sample is considered a mechanical disruption method. Mechanical homogenization procedures generate lysates with characteristics different than those produced by chemical lysis. By avoiding detergents and chaotropes, many cytosolic molecules remain intact following liberation from the cell. Regardless of the mechanical approach, whether it is to beat, grind, shear, or explode cells, they are tools that can be applied in many different ways to sample preparation.

[0044] Grinding relies on creating friction by sandwiching the sample between two hard surfaces that slide against each other. Forces on the sample are two-fold, namely downward pressure accompanied by a tangential shearing force. Grinding causes tearing and ripping of samples, much like shearing, but differs in that there is direct contact between sample and homogenizer. Mortar and pestle is the best known tool for grinding, but others are grain mills and certain types of glass homogenizers. With adequate patience, solids can be reduced to very fine particles by grinding, part of which is dependent upon the topology of the grinding surfaces. In its various forms grinding can be used on wet, dry, and frozen samples, however it is most efficient on solid samples. One key characteristic of grinding is that friction generates heat and at times can be significant. Consequently, the heat tolerance of the analyte should be considered when selecting a grinding method. Frequently samples are frozen prior to grinding, commonly with liquid nitrogen, which can be used for chilling both sample and homogenizer. This cryogenic grinding makes the sample brittle and fracture easily, but it also preserves analytes that are heat labile or which may rapidly degrade upon liberation. [0045] Homogenizers such as blenders work by shearing, which is created by a tangential force being applied to the sample. There are several tools that disrupt by shearing, including blenders, rotor- stators, and some of the glass homogenizers.

[0046] Next, the processed one or more mushrooms are transferred to a solvent (step 30). As used herein, the term "solvent" refers to a compound or composition that dissolves another (solute), thereby creating a solution. In some embodiments, the solvent is water. In some embodiments, the solvent is alcohol. In some embodiments, the solvent may be selected from a range of different solvents, including lower aliphatic alcohols (C=l, 2, 3 or 4), water, alcohol- water mixtures, strong alkaline buffers, and strong acidic buffers. A wide range of solvent to solid ratios can be used. Typically, a 1 to 50: 1 solvent-solid ratio (L:kg) may be used for the extraction. In some embodiments, the amount of solvent used generally varies according to the weight of the raw psilocybin fungus. In some embodiments, the solvent and/or the mixture of solvent and processed mushrooms are maintained at a temperature ranging from 10°C to about 50°C for a time period ranging from between about 1 minute to about 240 minutes.

[0047] In some embodiments, the extraction is performed with an extraction solvent comprising one or more organic solvents, and optionally comprising water. Examples of organic solvents that can be used according to the disclosure are, without being limited to, methanol, ethanol, acetonitrile, ethyl acetate, chloroform, hexane, cyclohexane, isooctane, and dichloromethane .

[0048] In some embodiments, the extraction solvent is a sole organic solvent used alone, e.g., dichloromethane (DCM), methanol or ethanol, or together with water, methanol, or ethanol (e.g., 70% ethanol). In some embodiments, the solvent is a mixture of two organic solvents, optionally with water, such as methanol and ethyl acetate.

[0049] Yet other extraction suitable solvents include: water, methanol, ethanol, propanol, butanol, amyl alcohol, pentanol, fusel oil, hexanol, heptanol, octanol, cyclohexanol, benzyl alcohol, furfuryl alcohol, tetrahydrofurfuryl alcohol, hexane, heptane, octane, decane, petroleum ether, petroleum benzine, ligroin, gasoline, kerosene, cyclohexane, benzene, toluene, xylene, tetralin, decalin, terpene oil, chloroform, carbon tetrachloride, ethylene chloride, ethylidene chloride, trichloroethane, tetrachloroethane, trichloroethylene, tetrachloroethylene, trichloropropane, isopropyl chloride, dichloropropane, butyl chloride, amyl chloride, hexyl chloride, ethylene bromide, tetrabromoethane, chlorobenzene, dichlorobenzene, trichlorobenzene, bromobenzene, chlorotoluene, isopropylether, dibutyl ether, diisoamyl ether, hexyl ether, methylphenyl ether, ethylphenyl ether, butylphenyl ether, ethylbenzyl ether, dioxane, 2- methylfuran, tetrahydrofuran, tetrahydropyran, cineole, acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl amyl ketone, methyl hexyl ketone, diethyl ketone, ethyl butyl ketone, dipropyl ketone, diisobutyl ketone, diacetone alcohol, phorone, isophorone, cyclohexanone, methyl cyclohexanone, acetophenone, ethyl formate, propyl formate, butyl formate, amyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, amyl acetate, methyl isoamyl acetate, methoxybutyl acetate, hexyl acetate, cyclohexyl acetate, benzyl acetate, methyl propionate, ethyl propionate, butyl propionate, amyl propionate, methyl butyrate, ethyl butyrate, butyl butyrate, amyl butyrate, methyl acetoacetate, ethyl acetoacetate, isoamyl isovalerate, methyl lactate, ethyl lactate, butyl lactate, amyl lactate, methyl benzoate, diethyl oxalate, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monoethyl ether acetate, ethylene glycol isopropyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, ethylene glycol monobutyl ether acetate, ethylene glycol monophenyl ether, methoxymethoxyethanol, ethylene glycol monoacetate, ethylene glycol diacetate, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monoethyl ether acetate, diethylene glycol monobutyl ether, diethylene glycol monobutyl ether acetate, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol acetate, propylene glycol, propylene glycol monoethyl ether, propylene glycol propyl ether, propylene glycol monobutyl ether, dipropylene glycol, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, trimethylene glycol, butanediol, hexylene glycol, formic acid, acetic acid, acetic anhydride, propionic acid, propionic anhydride, butyric acid, valeric acid, lactic acid, pyridine, picoline, quinoline, isoquinoline, dimethyl sulfoxide, triethyl phosphate, dimethylformamide, y-butyrolactone, y-valerolactone, 6-hexanolactone, methyl salicylate, ethyl salicylate, butyl salicylate, diethyl adipate, ethyl carbonate, butyl sulfide, and diacetone alcohol. Any of these solvents may be used either alone or in admixture.

[0050] In some embodiments, a buffer may optionally be introduced, such as to the extraction solvent or the mixture comprising the processed mushrooms and the extraction solvent. Suitable buffers include, but are not limited to, citrate buffers, lithium lactate, sodium lactate, potassium lactate, calcium lactate, lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, lithium maleate, sodium maleate, potassium maleate, calcium maleate, lithium tartarate, sodium tartarate, potassium tartarate, calcium tartarate, lithium succinate, sodium succinate, potassium succinate, calcium succinate, lithium acetate, sodium acetate, potassium acetate, calcium acetate, or mixtures thereof. Further non-limiting examples of suitable citrate buffers include lithium citrate monohydrate, sodium citrate monohydrate, potassium citrate monohydrate, calcium citrate monohydrate, lithium citrate dihydrate, sodium citrate dihydrate, potassium citrate dihydrate, calcium citrate dihydrate, lithium citrate trihydrate, sodium citrate trihydrate, potassium citrate trihydrate, calcium citrate trihydrate, lithium citrate tetrahydrate, sodium citrate tetrahydrate, potassium citrate tetrahydrate, calcium citrate tetrahydrate, lithium citrate pentahydrate, sodium citrate pentahydrate, potassium citrate pentahydrate, calcium citrate pentahydrate, lithium citrate hexahydrate, sodium citrate hexahydrate, potassium citrate hexahydrate, calcium citrate hexahydrate, lithium citrate heptahydrate, sodium citrate heptahydrate, potassium citrate heptahydrate, or calcium citrate heptahydrate.

[0051] In some embodiments, one or more antioxidants may optionally be introduced, such as to the extraction solvent or the mixture comprising the processed mushrooms and the extraction solvent. In some embodiments, a single antioxidant is added to the extraction solvent or the mixture comprising the processed mushrooms and the extraction solvent. In other embodiments, at least two antioxidants are added to the extraction solvent or the mixture comprising the processed mushrooms and the extraction solvent. In yet other embodiments, at least three antioxidants are added to the extraction solvent or the mixture comprising the processed mushrooms and the extraction solvent.

[0052] The term "antioxidant" is used herein includes any compound or combination of compounds that prevent or slow down oxidation of components caused by the damaging reactive oxygen species (ROS). Any of the known antioxidants may be used, including but not limited to tocopherols, phospholipids (PL), phytosterols, phycocyanin, vitamins E, A and C, betacarotene, coenzyme Q10, fatty acids omega-3, omega-6 and w-9, phytoantioxidants such as polyphenols, terpenes as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, lecithin, sesamin, sesamol, sesamolin, Alpha lipoic acid, a-tocopherol, y-tocopherol, salicylic acid, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate and sodium metabisulphite, as well as chelating agents such as disodium EDTA. Pharmaceutically acceptable nutraceutical dietary supplements may also be employed as antioxidants including plants, alga, and lichen and may include one or more extracts of honeybee propolis, red clover, soybean, caper, almond, milk thistle, green tea, pomegranate, orange red, grape seed, bilberry, fo-ti root, ginseng, English ivy, red algae, brown algae, green algae, and lichens.

[0053] In some embodiments, the antioxidant is selected from the group consisting of ascorbic acid and its salts, tocopherols, sulfite salts such as sodium metabisulfite or sodium sulfite, sodium sulfide, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propyl gallate.

[0054] In other embodiments, the antioxidant is selected from the group consisting of sodium sulfite, sodium bisulfite, sodium metabisulphite, sodium metabisulfite, ascorbic acid, thioglycerol, thiosorbitol, thiocarbamide, sodium thiosulphate, thioacetic acid, cysteine, methionine, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, hydroquinone, propyl gallate, nordihyroguaiaretic acid, Vitamin E (alpha-tocopherol) and lecithin. The preferred antioxidants are micronized propyl gallate, micronized BHA, micronized BHT, Vitamin E, ascorbic acid, sodium thiosulphate, and cysteine.

[0055] In yet other embodiments, the antioxidant is selected from the group consisting of hydroquinones; n-alkyl gallates (such as n-propyl, n-octyl, and n-dodecyl gallates); reducible sugars such as sorbitol and mannitol; benzoates and hydroxy benzoates; sulfites and metabisulfites; certain acids such as citric acid, tartaric acid, lactic acid, erythorbic acid ascorbic acid, uric acid, tannic acid, and salts of such acids (such as Mg2+, NH4+, Na+, K+and Ca2+ salts); chelators such as EDTA that remove metals that function as oxidants.

[0056] In even further embodiments, the antioxidant is a water-based antioxidant selected from the group consisting of sodium sulphite; sodium metabisulphite; ascorbic acid; and sodium formaldehyde sulphoxylate.

[0057] In yet even further embodiments, the antioxidant is an oil based antioxidant which selected from the group consisting of ascorbyl palmitate, butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); propyl gallate; and alpha-tocopherol.

[0058] In a preferred embodiment, the antioxidant is ascorbic acid.

[0059] In some embodiments, an extraction solution may include up to about 1% of one or more antioxidants; up to about 5% of one or more antioxidants; up to about 6% of one or more antioxidants; up to about 7% of one or more antioxidants; up to about 8% of one or more antioxidants; up to about 9% of one or more antioxidants; up to about 10% of one or more antioxidants; ; up to about 11% of one or more antioxidants; up to about 12% of one or more antioxidants; up to about 13% of one or more antioxidants; up to about 13% of one or more antioxidants; or up to about 15% or more of one or more antioxidants.

[0060] Following the transfer of the processed one or more mushrooms to the solvent, the one or more cell wall degrading or digesting enzymes are introduced to the mixture (step 40). In some embodiments, non-limiting examples of cell wall digesting enzymes include expansin, swollenin, xyloglucan endotransglycosylase (XET), esterases, ferulic esterases, lysozyme, amylases, cellulases, maltase, saccharase, a- and P-glycosidase, chitinase, 1,6-glucanases, and 1,3- glucanases.

[0061] Next, one or more cyclodextrins are introduced to the mixture (step 50). As used herein, the term "cyclodextrin" refers to a cyclic oligosaccharide comprising glucose monomers arranged in a toroidal shape or a derivative thereof.

[0062] Naturally occurring cyclodextrins are cyclic polymers of glucose units that are formed by the enzymatic action of specific cyclodextrin glycosyltransferases (CGT) on partially hydrolyzed corn starch. Depending on the CGT used, cyclic polymers of six, seven, or eight glucose units are produced, which are respectively named a-cyclodextrin, P-cyclodextrin, and y- cyclodextrin. The size of the cyclodextrin molecule, and therefore the "pore" formed by the cyclodextrin molecule, is dictated by the number of glucose units in the polymer. Thus, a- cyclodextrin has the smallest pore, while y-cyclodextrin has the largest, a-cyclodextrin is known to sequester small molecules, while P-cyclodextrin and y-cyclodextrin sequester larger poly- and heterocyclic compounds.

[0063] Cyclodextrins have found applications in pharmaceutical delivery systems. As a "host" for "guest" drug molecules, these inclusion (clathrate) complexes have shown increased aqueous solubility for pharmaceuticals with intrinsically low aqueous solubility (Jones; U.S. Pat. No. 4,555,504).

[0064] As used herein, the terms "a-cyclodextrin," refers to a cyclic polysaccharide including six glucose subunits that are cyclically linked via a- 1,4 intersubunit linkages. The term can be used in the context of a single monomeric compound, e.g., a compound that includes one a-cyclodextrin. The term can also be used in the context of a polymer, e.g., a co-polymer that includes a-cyclodextrin co-monomers. The term can be used to refer to monomeric a-cyclodextrin compounds or to a-cyclodextrin co-polymers. The glucose subunits of the a-cyclodextrin moieties can be naturally occurring sugars, in their reduced or oxidized forms. In some instances, the glucose subunits of the a-cyclodextrin are a-D-glucopyranoside units. The a-cyclodextrin moieties can be modified. A modified a-cyclodextrin is a moiety (e.g., a monomer or co-polymer) that includes at least one modified glucose subunit. Modifications of interest include, but are not limited to, modification at a 2-, 3- and/or 6-hydroxyl groups of a glucose unit (e.g., alkylation or acylation with any convenient linking moiety), substitution or transformation of a hydroxyl group (e.g., a 2-, 3- and/or 6-hydroxyl group) with an alternative functional group (e.g., an amine, a thiol, an aldehyde, a ketone, an azide, a carboxylic acid, an active ester, an isocyanate, an isothiocyanate, etc.). a-Cyclodextrin moieties can include an optional linker for attachment to a co-polymer or other moiety of interest. The linkage can be covalent (e.g., via biohydrolyzable bonds, e.g., esters, amides, carbamates, and carbonates). a-Cyclodextrin moieties can further include one or more carbohydrate moieties, in some cases, simple carbohydrate moieties such as galactose, attached to the cyclic core, either directly (i.e., via a carbohydrate linkage) or through a linker group. The glucose subunits of the a-cyclodextrin can be the same or different. In some cases, one or more of the glucose subunits is modified to provide for covalent linking of the a-cyclodextrin to a moiety of interest.

[0065] P-Cyclodextrin consists of seven glucose units linked by a- 1,4 glycosidic bonds into a macrocycle with a hydrophobic cavity. HP-P-CD is a substituted P-CD at 2-position with a 2-hydroxy propyl group. Each cyclodextrin has its own ability to form inclusion complexes with specific guests into the hydrophobic cyclodextrin cavity.

[0066] Chemical modification of cyclodextrins is known to modulate their properties. Electroneutral cyclodextrins have been described by Parmerter et al (U.S. Pat. No. 3,453,259), and Gramera et al (U.S. Pat. No. 3,459,731), the disclosures of which are hereby incorporated by reference herein in their entireties. These are obtained by the condensation reaction of cyclodextrins with various epoxides or organic halides.

[0067] Other derivatives include cyclodextrins with cationic properties (Parmerter (I); U.S. Pat. No. 3,453,257), insoluble crosslinked cyclodextrins (Solms; U.S. Pat. No. 3,420,788), and cyclodextrins with anionic properties (Parmerter (II); U.S. Pat. No. 3,426,011), the disclosures of which are hereby incorporated by reference herein in their entireties. Among the cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorus acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiophosphinic acids, and sulfonic acids (see Parmerter (II), supra), have been appended to the parent cyclodextrin.

[0068] Cyclodextrins contemplated by the present disclosure include, without limitation, the following: a, P, y-cyclodextrins, methylated cyclodextrins, hydroxypropyl-P-cyclodextrin (HPBCD), hydroxyethyl-P-cyclodextrin (HEBCD), branched cyclodextrins, and sulfoalkyl ether cyclodextrins, such as sulfobutyl ether-P-cyclodextrins, dihydropropyl cyclodextrins, and sulfoalkyl ether cyclodextrins, such as sulfobutyl ether- P-cyclodextrin (SBECD). The cyclodextrins can be unsubstituted or substituted in whole or in part as known in the art; mixtures of cyclodextrins are also useable in accordance with the present disclosure. The preferred cyclodextrins for the depot formulation of the disclosure include y-cyclodextrin, HPBCD, SBECD or mixtures thereof; SBECD being most preferred.

[0069] Particular non-limiting examples of cyclodextrins include a-cyclodextrin, P- cyclodextrin, y-cyclodextrin, and 5-cyclodextrin, and derivatives of each of these classes of cyclodextrins. Particular examples of cyclodextrin derivatives, include hydroxypropylated a- cyclodextrin, hydroxypropylated P-cyclodextrin, hydroxypropylated y-cyclodextrin, hydroxyethylated a-cyclodextrin, hydroxyethylated P-cyclodextrin, hydroxyethylated y- cyclodextrin, hydroxyisopropylated a-cyclodextrin, hydroxyisopropylated P-cyclodextrin, hydroxyisopropylated y-cyclodextrin, carboxymethylated a-cyclodextrin, carboxymethylated P- cyclodextrin, carboxymethylated y-cyclodextrin, carboxyethylated a-cyclodextrin, carboxyethylated P-cyclodextrin, carboxyethylated y-cyclodextrin, octyl succinated-a- cyclodextrin, octyl succinated-P-cyclodextrin, octyl succinated-y-cyclodextrin, acetylated-a- cyclodextrin, acetylated- P-cyclodextrin, acetylated-y-cyclodextrin, sulfated-a-cyclodextrin, sulfated-P-cyclodextrin, and sulfated-y-cyclodextrin. Other particular examples of cyclodextrins derivatives include the following P-cyclodextrin derivatives: 2,3-dimethyl-6-aminomethyl-a- cyclodextrin, 6-azido- a-cyclodextrin, 6-bromo-P-cyclodextrin, 6A,6B-dibromo-P-cyclodextrin, 6A,6B-diiodo-P-cyclodextrin, 6-O-maltosyl-P-cyclodextrin, 6-iodo-a-cyclodextrin, 6-tosyl-P- cyclodextrin, peracetyl-maltosyl-P-cyclodextrin, 6-t-butyldimethylsilyl-P-cyclodextrin, 2,3- diacetyl-6-butyldimethylsilyl-P-cyclodextrin, 2,6-dibutyl-3-acetyl-P-cyclodextrin, 2,6-dibutyl-P- cyclodextrin, 2,6-t-butyl-dimethylsilyl-P-cyclodextrin, and 2,6-di-O-methyl-3-allyl-P- cyclodextrin. Exemplary cyclodextrins include a, P, and y cyclodextrin, hydroxy propyl -beta- cyclodextrin, sulfobutyl ether-beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta cyclodextrin, C 1 -24-alkyl-gamma-cyclodextrin, and C 1 -24-hydroxyalkyl-gamma-cyclodextrin.

[0070] Finally, the mixture is converted to a dry material (step 60). In some embodiments, the conversion to the dry material is facilitated by spray drying, pulse atomization spray drying, or rotary evaporation.

[0071] EXAMPLE

[0072] A molar excess of cyclodextrin to expected heterocycle quantity is prepared as part of the solvent extraction system based on total biomass weight.

[0073] In one example, 100 g of mushroom fruiting body biomass is homogenized and added into a 1 Liter solution of 0.1 Molar acetate buffer with a pH of 4.8 and a freshly prepared 2% solution of enzymes consisting of chitinase, 1,6-glucanase, and 1,3-glucanase, for a total of 20 mg of combined enzymes and stirred for 3 hours at 50° Celsius.

[0074] In one example, the solution of 100g of homogenized mushrooms has an estimated content of Psilocybin and Psilocin of 650 mg and 85 mg respectively. A 10% molar excess of Hydroxypropyl-Beta-Cyclodextrin weighing 4,293 mg is added to the solution to complex with the Psilocin and Psilocybin to prevent oxidative degradation.

[0075] In one example, the 1 Liter solution of homogenized mushrooms and cyclodextrins are vacuum filtered to remove the biomass and the subsequent solution dried to a solid powder by way of a spray dryer. The solid resulting product is quantified by HPLC and used for further processing into solid dosage forms or other consumable products.

[0076] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

[0077] Although the present disclosure has been described with reference to a number of illustrative embodiments, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure. More particularly, reasonable variations and modifications are possible in the component parts and/or arrangements of the subject combination arrangement within the scope of the foregoing disclosure, the drawings, and the appended claims without departing from the spirit of the disclosure. In addition to variations and modifications in the component parts and/or arrangements, alternative uses will also be apparent to those skilled in the art.

Claims

1. A particle comprising one or more natural product - cyclodextrin complexes, wherein the natural product of the one or more natural product - cyclodextrin complexes is derived from psilocybin mushrooms.

2. The particle of claim 1, wherein the natural product derived from the psilocybin mushrooms are selected form the group consisting of include baeocystin, norbaeocystin, N,N-dimethyltryptamine, 5 -hydroxy tryptamine (serotonin), 5-hydroxytryptophan, psilocybin and psilocin.

3. The particle any one of the preceding claims, wherein the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of a- cyclodextrins, P-cyclodextrins, y-cyclodextrins, and 5-cyclodextrins, and combinations thereof.

4. The particle of any one of claims 1 - 2, wherein the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of hydroxypropylated a-cyclodextrin, hydroxypropylated P-cyclodextrin, hydroxypropylated y-cyclodextrin, hydroxyethylated a-cyclodextrin, hydroxyethylated P-cyclodextrin, hydroxyethylated y-cyclodextrin, hydroxyisopropylated a-cyclodextrin, hydroxyisopropylated P-cyclodextrin, hydroxyisopropylated y-cyclodextrin, carboxymethylated a-cyclodextrin, carboxymethylated P-cyclodextrin, carboxymethylated y-cyclodextrin, carboxyethylated a-cyclodextrin, carboxyethylated P-cyclodextrin, carboxyethylated y-cyclodextrin, octyl succinated-a-cyclodextrin, octyl succinated-P- cyclodextrin, octyl succinated-y-cyclodextrin, acetylated-a-cyclodextrin, acetylated-P- cyclodextrin, acetylated-y-cyclodextrin, sulfated-a-cyclodextrin, sulfated- P-cyclodextrin, and sulfated-y-cyclodextrin.

5. The particle of any one of claims 1 - 2, wherein the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of 2,3-dimethyl-6- aminomethyl-a-cyclodextrin, 6-azido-a-cyclodextrin, 6-bromo-P-cyclodextrin, 6A,6B- dibromo-P-cyclodextrin, 6A,6B-diiodo-P-cyclodextrin, 6- 0-mal tosyl- P-cyclodextrin, 6- iodo-a-cyclodextrin, 6-tosyl- P-cyclodextrin, peracetyl-maltosyl-P-cyclodextrin, 6-t- butyldimethylsilyl-P-cyclodextrin, 2,3-diacetyl-6-butyldimethylsilyl-P-cyclodextrin, 2,6- dibutyl-3-acetyl-P-cyclodextrin, 2,6-dibutyl-P-cyclodextrin, 2,6-t-butyl-dimethylsilyl-P- cyclodextrin, and 2,6-di-O-methyl-3-allyl-P-cyclodextrin. The particle of any one of claims 1 -2 , wherein the cyclodextrin of the one or more natural product - cyclodextrin complexes is selected from the group consisting of hydroxypropyl- beta-cyclodextrin, sulfobutyl ether-beta- cyclodextrin, heptakis(2,6-di-O-methyl)-beta cyclodextrin, Cl-24-alkyl-gamma-cyclodextrin, and Cl-24-hydroxyalkyl-gamma- cyclodextrin. The particle any one of the preceding claims, further comprising one or more antioxidants. The particle of claim 7, wherein the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, cysteine and its salts. The particle of claim 7, further comprising ascorbic acid. A spray-dried particle comprising a psilocybin - cyclodextrin complex. The spray-dried particle of claim 10, wherein the spray-dried particle further comprises at least one natural product - cyclodextrin complex other than the psilocybin - cyclodextrin complex. The spray-dried particle of any one of claims 10 - 11, further comprising one or more antioxidants. The spray-dried particle of claim 12, wherein the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, cysteine and its salts. A method of preparing a particle comprising a psilocybin-cyclodextrin complex, comprising: (i) processing psilocybin mushrooms; (ii) transferring the processed psilocybin mushrooms to a solution comprising (a) one or more solvents; (b) one or more enzymes; and (c) one or more cyclodextrins; and (d) converting the solution to a dry, particulate material. The method of claim 14, wherein the processing of the psilocybin mushrooms comprises homogenizing the psilocybin mushrooms. The method of claim 15, wherein the homogenization comprises at least one of grinding, chopping, and mechanical shearing. The method of any one of claims 14 - 16, wherein the one or more solvents are selected from the group consisting of water, methanol, ethanol, and combinations thereof. The method of any one of claims 14 - 17, wherein the solution further comprises a buffer. The method of claim 18, wherein the buffer has a pH ranging from between about 4 and about 5.5. The method of claim 18, wherein the buffer is selected from the group consisting of acetate, carbonate, phosphate, Tris-HCl, acetic acid, tris buffer, and phosphate buffer. The method of any one of claims 14 - 20, wherein the one or more enzymes are selected from the group consisting of chitinase, 1,6-glucanase, 1,3-glucanase, and combinations thereof. The method of any one of claims 14 - 20, wherein the one or more cyclodextrins are selected from the group consisting of a-cyclodextrins, P-cyclodextrins, y-cyclodextrins, and 5-cyclodextrins, and combinations thereof. The method of any one of claims 14 - 22, wherein the one or more cyclodextrins are selected from the group consisting of hydroxypropylated a-cyclodextrin, hydroxypropylated P-cyclodextrin, hydroxypropylated y-cyclodextrin, hydroxyethylated a-cyclodextrin, hydroxyethylated P-cyclodextrin, hydroxyethylated y-cyclodextrin, hydroxyisopropylated a-cyclodextrin, hydroxyisopropylated P-cyclodextrin, hydroxyisopropylated y-cyclodextrin, carboxymethylated a-cyclodextrin, carboxymethylated P-cyclodextrin, carboxymethylated y-cyclodextrin, carboxyethylated a-cyclodextrin, carboxyethylated P-cyclodextrin, carboxyethylated y-cyclodextrin, octyl succinated-a-cyclodextrin, octyl succinated-P-cyclodextrin, octyl succinated-y- cyclodextrin, acetylated-a-cyclodextrin, acetylated-P-cyclodextrin, acetylated-y- cyclodextrin, sulfated-a-cyclodextrin, sulfated-P-cyclodextrin, and sulfated-y- cyclodextrin. The method of any one of claims 14 - 22, wherein the one or more cyclodextrins are selected from the group consisting of 2,3-dimethyl-6-aminomethyl-a-cyclodextrin, 6- azido-a-cyclodextrin, 6-bromo-P-cyclodextrin, 6A,6B-dibromo-P-cyclodextrin, 6A,6B- diiodo-P-cyclodextrin, 6-O-maltosyl-P-cyclodextrin, 6-iodo-a-cyclodextrin, 6-tosyl-P- cyclodextrin, peracetyl-maltosyl-P-cyclodextrin, 6-t-buty Idi methy 1 si 1 yl- P-cyclodextrin, 2,3-diacetyl-6-butyldimethylsilyl-P-cyclodextrin, 2,6-dibutyl-3-acetyl-P-cyclodextrin, 2,6-dibutyl-P-cyclodextrin, 2,6-t-butyl-dimethylsilyl-P-cyclodextrin, and 2,6-di-O-methyl- 3-allyl-P-cyclodextrin. The method of any one of claims 14 - 22, wherein the one or more cyclodextrins are selected from the group consisting of hydroxypropyl-beta- cyclodextrin, sulfobutyl ether- beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta cyclodextrin, Cl-24-alkyl-gamma- cyclodextrin, and Cl-24-hydroxyalkyl-gamma-cyclodextrin. The method of any one of claims 14 - 25, wherein the solution further comprises one or more antioxidants. The method of claim 26, wherein the one or more antioxidants are selected from ascorbic acid and its salts, tocopherols, cysteine and its salts. The method of any one of claims 14 - 27, wherein the converting of the solution including the processed psilocybin mushrooms to the dry material comprises one or more of spray drying, pulse atomization spray drying, or rotary evaporation. A particle comprising one or more natural product - cyclodextrin complexes, wherein the natural product of the one or more natural product - cyclodextrin complexes is derived from psilocybin mushrooms and wherein the natural product - cyclodextrin complexes comprise a mixture of two different cyclodextrins. The particle of claim 29, wherein the two different cyclodextrins are provided in a 1 : 1 ratio.