CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This claims the benefit of United States Provisional Patent Application No. 63/108,439 filed October 31, 2020, the entirety of which is incorporated herein by reference.

BACKGROUND

Field of the Invention

[2] This relates generally to compositions for the treatment of interstitial cystitis ("IC) and related urinary tract problems that involve bladder pain syndrome ("BPS"). More particularly this relates to nutraceutical and/or pharmaceutical compositions comprising cannabis extracts and mushroom extracts for the treatment of IC/BPS.

Description of Related Art

[3] Interstitial cystitis is a chronic condition characterized by pressure in the bladder that can lead to a sense of urgency to urinate, or an increase is frequency. It is typically accompanied by pain that can range from mild discomfort to severe pain in the bladder and sometimes, the pelvis. Interstitial cystitis ("IC") is part of a spectrum of conditions called painful bladder syndrome or bladder pain syndrome ("BPS"), and often, chronic pelvic pain syndrome. There is not a single, universally agreed-upon clinical definition of interstitial cystitis.

[4] In patients with IC, the bladder wall becomes inflamed and irritated. This can cause the bladder to have reduced ability to expand to hold urine without pain. In more severe cases of IC, patients may feel the need to urinate 50 or more times a day. In addition to chronic pain, chronic or repeated bouts of IC can result in long-term consequences, including sleep disruption, sexual dysfunction and intimacy problems, and emotional troubles including depression, thereby impacting quality of life. Long-term consequences can also include decreased bladder capacity as the bladder can become stiff and scarred in chronic cases.

[5] The average age of onset of IC is 30 - 40 years. It is more common in women, and the symptoms may be more bothersome or even more severe during menstruation. Some estimates suggest as many as 8 million women in the U.S. suffer with interstitial cystitis. Fair skin and/or red hair are also associated with increased likelihood of an IC diagnosis. Men with IC can also experience pain in the penis and scrotum, although prostate inflammation is sometimes the actual underlying clause rather than IC.

[6] The specific etiology of IC is unknown, but it is believed to be multifactorial. Some reports suggest vulnerable bladder epithelial lining may induce leaks that irritate and inflame the bladder wall. The symptoms often can show as a urinary tract infection, but in the general case, IC is present without infection. Infections, however, can aggravate IC. At present there are no known cures, but various treatments and therapies are available, including managing the symptoms. Treatments can include physical therapy, nerve stimulation, oral pharmaceuticals, bladder distention, and instillation procedures, as well as acupuncture, and in some cases, surgical interventions.

[7] Oral medications may include NSAIDs such as ibuprofen, or naproxen, drugs to relax the bladder and/or block pain (such as amitriptyline or imipramine), and/or antihistamines to reduce urinary urgency and/or frequency. One drug, pentosan polysulfate sodium, is believed to be involved in protecting or restoring the inner bladder surface or the bladder wall, has been approved by the FDA specifically for interstitial cystitis. While it may work, the course of therapy may be 6 months before any relief is achieved.

[8] Surgical intervention options range from relatively minimally invasive procedures such as bladder hydrodistension, and fulguration to remove ulcerated tissue, to bladder resection, catheterization, and bladder augmentation.

[9] Instillation of medicines directly to the bladder through a catheter is approved for treatment. Traditionally, dimethyl sulfoxide ("DMSO") has been used in instillation procedures. Instillation can also be performed with other medicaments including sodium bicarbonate, lidocaine, pentosan, and/or heparin. The latter may be alkalinized (buffered) prior to use. Use of sodium hyaluronate or hyaluronic acid as an instillate is used in multiple countries, but not currently approved in the US. Other compounds have been reported useful or are being tested in various clinical trials includes, singly or in various "bladder cocktails", gentamicin, triamcinolone, bupivacaine, hydrocortisone, sodium chondroitin sulfate, liposomes, and misoprostol. Some of these compounds are believed to act on the bladder wall to protect or restore it, while others are intended to address pain and urination issues. In a typical instillation procedure, the patient receives the instillate (in some case via an 'at home' procedure) and is instructed to work to retain the fluid for 30 minutes or more.

[10] Notwithstanding the availability of the present treatments, there is an ongoing need for new therapeutics that are useful for treating interstitial cystitis.

SUMMARY

[11] In a first of the several aspects of this disclosure, the inventor has discovered that certain pharmaceutical and/or nutraceutical compositions generally comprising extracts of cannabis and extracts of mushrooms in various combinations are useful in treating interstitial cystitis.

[12] The mushroom or mushroom extract present in the compositions is from any edible or medicinal mushroom species. The edible or medicinal mushroom in various embodiments comprises one or more of Agaricus bisporus, A. blazei, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, A. confluens, Amanita muscaria, Antrodia camphorate, Boletus badius, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Caripia montagnei, Clitocybe maxima, Cordyceps cicadicola, C. gunnii, C. liangshanensis, C. militaris, C. pruinose, C. sinensis, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Pomes fomentarius, Fomitopsis pinicola, Funalia trogii, Ganoderma lucidum, Geastrum saccatum, Grifola frondosa, Hericium erinaceus, Inocybe umbrinella, Inonotus olbiquus, Lactarius deliciosus, L. flavidulus, L. rufus, Lentinula edodes, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus ostreatus, P. pulmonarius, Poria cocos, Schizophyllum commune, Suillus placidus, Trametes versicolor, or Termitomyces albuminosus.

[13] The cannabis extracts present in the compositions can be derived from any Cannabis spp. and may include any cannabinoids. The cannabis extracts may further comprise any number of useful terpenes and/or flavonoids.

[14] The compositions optionally include other nutraceutical or botanical compounds to provide additional functionality or support for the bladder or urinary tract. Examples include compound such as herbal extracts from one or more of Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, corn silk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, or combinations thereof. Additional compounds contemplated for use herein comprise S- adenosylmethionine, methylfolate, polyphenols, D-mannose, antioxidants, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically available form thereof, or combinations thereof.

[15] The combination compositions further optionally comprise one or more solvents, including but not limited to dimethyl sulfoxide or related amphipathic solvents, or other solvent capable of dissolving poorly soluble polar and nonpolar molecules and which are relatively nontoxic in mammals and specifically humans. For example, dihydrolevoglucosenone cyrene (sold commercially as "CYRENE") has been reported to be nontoxic, nonmutagenic, and relatively safe and is contemplated for use herein.

[16] In cases of IC with chronic pain that has been, e.g., recalcitrant to other treatments, the compositions may include one or more serotonergic psychedelics as defined herein below. Serotonergic psychedelics useful herein include both tryptamine derivative and analogues and phenylethylamine derivatives and analogues, with affinity or avidity for any of the 5-HT receptors. Such compounds may be useful in a single or periodic treatment to resolve chronic pain in patients, particularly where the underlying cause of the pain has been treated or ameliorated.

[17] The inventor has surprisingly discovered that a composition comprising an extract from one or more edible or medicinal mushrooms and a cannabis extract, in combination, has many benefits for treatment of interstitial cystitis. The compositions provide certain useful properties, such as effectiveness (including over a long period of time), low toxicity, no serious side effects, and good tolerance on the part of a wide range of subjects. [18] In yet another aspect, methods are provided for optimizing a composition for use in treatment of a subject suffering from a disease comprising interstitial cystitis, BPS, an inflammatory process of the bladder, or bladder cancer. The methods generally employ the use of artificial intelligence algorithms, such as classification algorithms, regression algorithms, clustering algorithms, or a combination thereof.

[19] The methods generally comprise:

[20] a) providing data on the therapeutic effect on the disease process of each of:

[21] i) a plurality of edible or medicinal mushrooms, mushroom extracts, or components thereof;

[22] ii) a plurality of cannabis extracts, at least partially purified cannabinoids, or combinations thereof;

[23] iii) a plurality of terpenes, flavonoids, or other components extracted from Cannabis, or combinations thereof; and optionally,

[24] iv) DMSO, or one or more pharmaceutically acceptable solvents having useful amphipathic properties;

[25] v) a plurality of herbal extracts for supporting urinary tract function; or

[26] vi) a plurality of optional ingredients comprising one or more antioxidants, polyphenols, D-mannose, S-adenosylmethionine, methylfolate, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically-available form thereof, or combinations thereof;

[27] b) using an artificial intelligence algorithm to analyze the data for the mushrooms or extracts, cannabinoids, and other components; and

[28] c) generating one or more base profiles of compositions optimized for therapeutic treatment of the disease;

[29] d) optionally, using the artificial intelligence algorithm to analyze the data for the combination compositions and the optional ingredients, and

[30] e) generating one or more complete profiles of compositions with and without the optional ingredients. [31] The disease generally comprises a bladder condition or process for which other treatment options are limited or nonexistent.

[32] The data for use in the artificial intelligence algorithm can be obtained from original experiments or literature review.

[33] In a final aspect, this disclosure provides methods for treating a disease process in a patient in need thereof. The methods generally comprise the step of administering a composition comprising at least one edible or medicinal mushroom or extract thereof, and at least one cannabis extract or cannabinoid, in combination, to the patient. Additional compounds such as terpenes, flavonoids, or other compounds derived from cannabis may be included, as may other herbal or nutraceutical compounds or compositions useful in supporting healthy bladder or urinary tract functions, or in treating bladder or urinary tract conditions. The combinations may be administered directly, by any route. Preferred routes, particularly for treatment of interstitial cystitis, or where a solvent such as DMSO is included are administration through instillation, particularly in connection with hydrodistension of the bladder. In some embodiments, the at least one Cannabis extract or cannabinoid can be conveniently administered separately from, sequentially to, or simultaneously with the edible or medicinal mushroom or mushroom extract. The at least one edible or medicinal mushroom or extract thereof is also administered separately from, sequentially to, or simultaneously with the cannabis cannabinoid.

[34] These and/or further aspects, features, and advantages of the present invention will become apparent to those skilled in the art in view of this disclosure.

DETAILED DESCRIPTION

[35] Provided herein are compositions and methods for treating interstitial cystitis or other bladder disease processes. The methods are applicable to acute or chronic conditions in a subject. Surprisingly, the compositions allow a modern practitioner to combine the benefits of certain compounds found in edible and medicinal mushrooms (such as used for centuries in Chinese and other traditional medicine practices, and by e.g. herbalists throughout the world), with the positive benefits of another natural substance, cannabis, also used for centuries. The compositions further include certain beneficial compounds derived from Cannabis and other natural or synthetic sources, and other nutraceutical or pharmaceutical compounds, particularly nutraceutical compounds known to be supportive of bladder and urinary tract functions. Used properly, these compositions have little risk, few side effects, and are effective for producing measurable and lasting results in patients suffering from interstitial cystitis or related chronic bladder inflammation or other bladder disease.

Definitions & Abbreviations

[36] Unless expressly defined otherwise, all technical and scientific terms, terms of art, and acronyms used herein have the meanings commonly understood by one of ordinary skill in the art in the field(s) of the invention, or in the field(s) where the term is used. In accordance with this description, the following abbreviations and definitions apply.

[37] As used herein, "interstitial cystitis" means any disease that is on the spectrum of bladder pain syndrome.

[38] The term "bladder disease" as used herein includes both acute and chronic conditions including interstitial cystitis, bladder pain syndrome ("BPS"), an inflammatory process of the bladder or urinary tract, prolonged or repeated bladder or urinary tract infections ("UTIs"), inflammation of the epithelial tissues of the bladder or urinary tract, or bladder cancer.

[39] "Serotonergic psychedelics" as used herein mean any of the family of compounds that interact with serotonin pathways in the nervous system, particularly with the class of 5-HT receptors that recognize serotonin compounds, and which produce hallucinogenic effects in a subject. Serotonergic psychedelics can be naturally occurring or synthetically produced.

[40] As the skilled artisan will appreciate, as used herein the term "edible" does not mean merely capable of being eaten. In that overly broad sense, even poisonous or toxic mushrooms are 'edible' however lethal or sickening or the like. In contrast "edible mushrooms" is used herein in the sense of mushrooms that are used traditionally or in modern times as sources of food, nutrients, nutraceuticals, flavors, and the like. Edible mushrooms are neither toxic nor poisonous as consumed. [41] "Medicinal mushrooms" as used herein means any mushroom species that has been used traditionally or in modern times as a source of medicinal or therapeutic benefits, healing properties, and / or healthful compounds. It should be noted that the medicinal mushrooms may not be edible in all embodiments herein, and may in fact be poisonous if eaten, however, one or more extracts therefrom or components extracted or isolated therefrom may be perfectly useful herein.

[42] Notwithstanding the foregoing exception(s), generally, mushrooms that are edible or medicinal may be grouped together, as there may be many crossovers and it may be difficult to clearly distinguish between the two groups. Examples of edible and / or medicinal mushrooms useful herein include mushrooms of the genera Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Pomes, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus. Species of particular interest include Agaricus blazei, A. bisporus, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, Amanita muscaria, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Cordyceps militaris, C. pruinose, Caripia montagnei, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Fomitopsis pinicola, Grifola frondosa, Ganoderma lucidum, Geastrum saccatum, Inonotus obliquus, Lactarius deliciosus, L. rufus, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus pulmonarius, Poria cocos, and Termitomyces albuminosus.

[43] More generally edible and/or medicinal mushrooms can be useful in connection with the current disclosure for treating inflammation, directly or indirectly. For example, the therapeutic uses may include: preventing and/or treating bladder diseases, helping recover from treatments or surgical interventions with respect to such diseases, particularly those with significant toxicity or side effects, stimulating and / or supporting the immune system, reducing or mitigating chronic pain associated with such bladder diseases; or reducing or mitigating the psychological affects (e.g. depression, sexual problems, quality of life perceptions, or the like) of a chronic and painful disease, generally promoting of health, providing antioxidant functionality, stimulating or promoting immune system health, or the like.

[44] Reishi mushrooms have been reported to calm the central nervous system and/or have neuroprotective effect, stimulate the immune system, and act as a prebiotic to support gut health. Reishi has been reported to have a beneficial effect on the adrenals, and to be anxiolytic; reducing anxiety and promoting sleep. Reishi has also been associated with improved memory, and sharpened concentration and focus. Lion's Mane reportedly calms mental activity and modulates certain neurotransmitters. Cordyceps has been reported to have adaptagenic properties and stimulate the adrenals glands and modulates the nervous system. For purposes herein, the publication by Elsayed, Elsayed A et al. entitled "Mushrooms: a potential natural source of anti-inflammatory compounds for medical applications." (Mediators of Inflammation Vol. 2014 (2014): 805841. doi:10.1155/2014/805841) provides a list of anti-inflammatory mushrooms and active components therein. Any of the mushrooms or anti-inflammatory components described in the publication, which is incorporated herein by reference, may be useful herein.

[45] "Cannabis" or "Cannabis spp." as used herein refers to any plant of the genus Cannabis, including plants that may be classified as Cannabis sativa, Cannabis indica, or Cannabis ruderalis. It is well known that despite the foregoing list, some experts believe that there are only 2 species, and still others consider that there is only a single species (generally, C. sativa'). Whatever nomenclature is used, for purposes of this disclosure, "Cannabis" includes all possible members of the genus, without regard to the species to which they are assigned.

[46] As used herein 'cannabinoids' means any of a class of compounds that generally can interact with one or more cannabinoid receptors, including the receptors of the endocannabinoid system, in particular, CB1 and CB2. Cannabinoids include e.g., phytocannabinoids and synthetic cannabinoids. Phytocannabinoids are found in several plant species, especially Cannabis spp. Among the most prevalent and most studied cannabinoids are tetrahydrocannabinol (THC), and cannabidiol (CBD). However, there are at least ~120 known cannabinoids that have been identified in Cannabis within certain classes including the tetrahydrocannabinols, cannabidiols (including e.g. cannabidiol (CBD) and cannabidivarin (CBDV)), cannabigerols, cannabinols, cannabichromenes, and cannabinodiol. Other cannabinoids, such as cannabicyclol, cannabieslsoin, and cannabitriol are currently classed as 'miscellaneous' by some researchers. THC is not only a major cannabinoid in Cannabis spp., it is generally the compound responsible for the psychoactive effects of consuming Cannabis. However, other cannabinoids, such as cannabinol may also be at least mildly psychoactive. Certain other cannabinoids such as CBD may help regulate or attenuate the psychoactive effects of other cannabinoids. For purposes herein, compositions may be created with various ratios of cannabinoids, such as the ratio of CBD to THC or other ratios depending the specific person or the specific condition being treated. Synthetic cannabinoids may also be useful herein. Certain such synthetic cannabinoids are presently FDA-approved, such as MARINOL, SYNDROS, and CESAMET and can be readily incorporated into the compositions and emulsions. Similarly, FDA- approved cannabinoid compounds, such as EPIDIOLEX, a purified, plant- derived (i.e. non-synthetic) cannabidiol may also be useful herein.

[47] "Herbal extracts" as used herein comprise extracts from one or more of Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, corn silk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, and/or combinations thereof. Such herbal extracts may support or improve bladder and urinary tract function.

[48] Additional nutraceutical compounds that may support or improve normal bladder and urinary tract functions include but are not limited S- adenosylmethionine, methylfolate, polyphenols, D-mannose, antioxidants, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically available form thereof, or combinations thereof. [49] As used herein, "curcuminoids" means any of the compounds associated with turmeric or curcumin, as derived rhizome of the plant Curcuma longa, or synthetic versions or derivative thereof. Curcuminoids include but are not limited to curcumin (aka diferuloylmethane), analogs of curcumin such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), turmerones, and turmeric oil. Also include are metabolites of curcumin such as tetrahydrocurcumin (THCU), hexahydrocurcumin, and octahydrocurcumin.

[50] Conjugates, such as curcumin glucuronide and curcumin sulfate, are also included herein. Conjugation may also provide opportunities for improved delivery of curcumins herein, for example, conjugation to peptide carriers, or polylactic-co-gly colic acid [PLGA]; as well as complexation with essential oils; coadministration with piperine; and encapsulation into nanoparticles, liposomes, phytosomes, polymeric micelles, and cyclodextrins may also be useful herein.

[51] As used herein, "terpenes" means any of the organic compounds commonly known as terpenes or terpenoids. Terpenes are generally aromatic compounds classified as isoprene derivatives. Terpenes suitable for use herein include hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, sesquaterpenes, tetraterpenes, polyterpenes, and norisoprenoids. Exemplary terpenes that are particularly useful herein include alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, and valencene. In other embodiments phytol, limonene, humulene, myrcene, cineol, phellandrene, caryophyllene, terpinolene, linalool, ocimene, pinene, or a combination thereof are presently preferred.

[52] As used herein, "flavonoids" includes any of the class of polyphenolic molecules containing 15 carbon atoms that are naturally produced in plants and are soluble in water. Also included herein as "flavonoids" are natural or synthetic derivative or analogs thereof that have biological activity. Flavonoids of use herein can generally be divided in to 6 groups of structurally related compounds: chaicones, flavones, isoflavonoids, flavanones, anthoxanthins, and anthocyanins. Also useful are flavanols and catechins, as well as glucosides or other derivatives or analogs of any of the foregoing. The flavonoids are found in most fruits and vegetables, particular colorful ones. They are also prevalent in legumes (including soybeans), grains, green and black teas, as well as red wine.

[53] Flavonoids have numerous functions in plants, and act as important cell messengers. Various flavonoids are believed to provide healthful benefits and functions to humans such as anti-cancer, anti-inflammatory, anti-allergic, and antioxidant properties. They may also be cardio-protective, cholesterol-lowering, and anti-atherosclerotic. Natural or synthetic flavonoids from any source may be used herein. Generally natural flavonoids are preferred. Flavonoids isolated from Cannabis, such as cannaflavins A, B, and or C, are of interest in certain applications, as are vitexin, isovitexin, apigenin, kaempferol, quercetin, orientin, and luteolin, as well as the catechins found in Cannabis.

[54] "Traditional Jamaican medicinal plants" means any plant that has been used in traditional or indigenous medicine or herbalism practices in Jamaica or other Caribbean states. The book, “Common Medicinal Plants of Portland, Jamaica" by Thomas and Austin, provides a useful list of a number of such plants. The book was published in its second edition in 2010 by CIEER and is incorporated herein by reference. For purposes herein, the definition of such traditional Jamaican medicinal plants" expressly excludes Cannabis spp.

[55] As used herein, "subject-specific" data are data that pertain to a specific subject or patient's health status and/or disease condition. "Bioinformatic data" as used herein are data pertaining to the genome, transcriptome, proteome, metabolome, or any portion thereof, for a specific subject. In preferred embodiments, subject-specific data can be used to "personalize" a treatment.

[56] As used herein "compositions" and "in combination" are used to indicate that a composition may be a single composition comprising all components in a single e.g. container, bottle, package, or portion, or such compositions may comprise different components in separate containers, bottles, packages, or portions. E.g. Composition A might include bottle 1, which is administered to a subject. Composition B might include bottle 2 and bottle 4, where bottles A and B have different components within them. Composition B can be administered to a subject by providing both bottle 2 and bottle 3 simultaneously, or providing the bottles sequentially, one after the other. Alternatively, Composition B can be administered by providing bottles 2 and 3 separately, by different route of administration, or by the same route of administration with a given period of time. E.g. bottles 2 and 4 must be given within not more than 4 hours, or not more than 2 hours in certain embodiments. The two bottles of Composition B may have to be administered within 1 hour, 30 minutes, or 15 minutes in other embodiments. By allowing the compositions to be combined at the time of administration rather than in the packaging, bottle, or the like, certain problems and potential interactions may be avoided. Bottle 2 may require refrigeration or have a short shelf life, while bottle 3 is shelf stable. Or bottle 3 may precipitate. Bottle 2 may be best instilled and need to be pharmaceutical grade, while bottle 3 may be administered orally and be a nutraceutical or dietary supplement formulation that is food grade. The skilled artisan will appreciate the potential pitfalls, difficulties, and / or regulatory challenges of combining the components of the compositions herein. Administering the components together or within a given time frame of each other allows the overall composition to have its affect in the subject without the requirement that the components be combined in a single bottle, package, portion, or the like.

[57] As used herein, the singular form of a word includes the plural, and vice versa, unless the context clearly dictates otherwise. Thus, the references "a", "an", and "the" are generally inclusive of the plurals of the respective terms. For example, reference to "a composition" or "a mushroom extract" includes a plurality of such "compositions" or "mushroom extracts."

[58] The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. Likewise, the terms "include", "including" and "or" should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Further, forms of the terms "comprising" or "including" are intended to include embodiments encompassed by the phrases "consisting essentially of" and "consisting of". Similarly, the phrase "consisting essentially of" is intended to include embodiments encompassed by the phrase "consisting of".

[59] Where used herein, ranges are provided in shorthand, so as to avoid having to list and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.

[60] The methods and devices and / or other advances disclosed here are not limited to particular methodology, protocols, and/or structures described herein because, as the skilled artisan will appreciate, they may vary. Further, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to, and does not, limit the scope of that which is disclosed or claimed.

[61] Although any devices, methods, articles of manufacture, or other means or materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred compositions, methods, articles of manufacture, or other means or materials are described herein.

[62] All patents, patent applications, publications, technical and/or scholarly articles, and other references cited or referred to herein are in their entirety incorporated herein by reference to the extent permitted under applicable law. Any discussion of those references is intended merely to summarize the assertions made therein. No admission is made that any such patents, patent applications, publications or references are prior art, or that any portion thereof is either relevant or material to the patentability of what is claimed herein.

Applicant specifically reserves the right to challenge the accuracy and pertinence of any assertion that such patents, patent applications, publications, and other references are prior art, or are relevant, and/or material.

Abbreviations

[63] The following abbreviations apply unless indicated otherwise:

APM: "Apollon Medical" strain of C. sativa

CBD: cannabidiol;

CBG: cannabigerol;

CBN: cannabinol;

DMT: N,N-Dimethyl tryptamine;

5-HT: 5-hydroxytryptamine;

KNN: K Nearest Neighbor; NK: natural killer cells;

NS AID: nonsteroidal anti-inflammatory drugs;

OCD: obsessive compulsive disorder;

SVM: Support Vector Machines; and

THC: tetrahydrocannabinol.

Detailed Description of Illustrative Embodiments

[64] In a first of its several aspects, compositions generally comprising one or more edible or medicinal mushrooms or extracts, fractions, isolates, or components thereof are provided. The compositions alternatively or further generally comprise one or more cannabis extracts, or purified or partially purified cannabinoids.

[65] In various embodiments, the edible or medicinal mushroom(s) comprise one or more of the species Agaricus blazei, A. bisporus, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, Amanita muscaria, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Cordyceps militaris, C. pruinose, Caripia montagnei, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Fomitopsis pinicola, Grifola frondosa, Ganoderma lucidum, Geastrum saccatum, Inonotus obliquus, Lactarius deliciosus, L. rufus, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus pulmonarius, Poria cocos, and Termitomyces albuminosus. The mushroom(s) in other embodiments comprise one or more species such as Albatrellus confluens, Antrodia camphorate, Boletus badius, Clitocybe maxima, Cordyceps sinensis, Cordyceps liangshanensis, Cordyceps gunnii, Cordyceps cicadicola, Pomes fomentarius, Funalia trogii, Hericium erinaceus, Inocybe umbrinella, Lactarius flavidulus, Pleurotus ostreatus, Schizophyllum commune, Suillus placidus, or Trametes versicolor, Cordyceps sinensis, C. liangshanensis, C. gunnii, or C. cicadicola.

[66] More generally, mushrooms of the genera Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Fames, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus may be useful herein.

[67] These mushrooms are all well-known edible and / or medicinal mushrooms with a long history of use. Without limiting the invention to any particular theory of operation, mushrooms, such as Reishi, shitake, maitake, turkey tail, and many others have a plethora of beneficial and potentially therapeutic compounds present in them. For example, the polysaccharides, peptides, and/or other small molecules in various mushrooms have been shown to regulate the production of certain molecular mediators of inflammation and functions of immune cells (e.g. B- and/or T-cells) as well as pro-inflammatory lymphocytes, T-helper cells, T- killer cells, and macrophages. For example, the beta-1,3 D-glucans from certain mushrooms and other glycans may suppress cytokines such as interleukins tumor necrosis factor (TNF-a), and still other compounds

[68] Regardless of the mechanism(s) responsible, the compositions preferably comprise the benefits of such edible or medicinal mushroom(s) as described above.

[69] The edible or medicinal mushrooms or extracts can be present as fresh mushrooms, or as a dried mushroom or extract thereof, a lyophilized mushroom preparation, a mushroom powder, or an aqueous or alcohol extract (e.g. an ethanolic or other alcohol extract) of mushroom. Extracts for purposes herein can include hot- or cold-water extracts. Mushroom concentrates, or partially purified or even extensively purified mushroom fractions, or fully purified components or isolates from a mushroom are also useful herein.

[70] In certain embodiments, preferably, various extracts, concentrates, or partially purified fractions, or the like, are enriched for one or more advantageous mushroom component, or compounds with desirable effects on treatment of inflammation, immune status, or general health. In one embodiment, the extract, concentrate, partially purified fraction, or the like are enriched for one or more phenolic acids, flavonoids, triterpenes, carotenoids, stilbenes, sterols, fatty acids, lignans, chitosan, polyphenols, polysaccharides, glycosides, glucans, polysaccharide-protein complexes, glycoproteins, polysaccharopeptide, krestin, tocopherols, peptides, cyclic peptides, or other amino compounds found in the mushroom. [71 ] While certain edible and / or medicinal mushrooms have been explored for their use in supporting or improving bladder function, the inventors have discovered that by providing mushroom extracts with additional compounds such as cannabinoids, terpenes, flavonoids, and other components, antiviral and other benefits can be derived from the treatments with better outcomes and fewer side effects.

[72] The compositions in various embodiments therefor also include cannabinoids, comprising one or more of cannabidiol (CBD), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), or tetrahydrocannabinol (THC).

[73] In certain embodiments, the cannabinoids are derived from hemp, or the THC content is removed from the cannabinoids such that THC is present in the composition at less than about 0.3 percent. In various embodiments, the THC content may be less than 0.2%, or even less than 0.1% of the composition.

[74] In other embodiments, the ratio of cannabinoids is set in the compositions. For example, in certain embodiments, the ratio of CBD to THC ranges from about 1:5 to about 30:1 or more. In other embodiments the ratio may range from about 1:2 to about 10:1. In still other embodiments, the ratio of CBD to THC may be about 1:1 to 5:1. In other cases, the ratio of e.g. CBD to CBG or CBN may be set based on any of a variety of factors, including the health status of the subject being treated, the symptoms of the subject, the condition(s) being treated, and or one or more physiological or genetic criteria.

[75] In certain embodiments the compositions may be provided in completely customized or personalized formulations for each person being treated - i.e. as personalized medicines. In such cases, the compositions may be adjusted based on initial or subsequent blood work, enzyme test results, bioinformatic data (including measurements of e.g. the genome, transcriptome, proteome, metabolome, or any portion thereof, for a subject), the nature of the inflammation, specific markers, antigen, or mediators of the interstitial cystitis or bladder disease process, specific symptomology, or the like. The formulation of the compositions may also be changed based on the results from an initial treatment, subsequent treatment, or based on subsequent tests.

[76] In various presently preferred embodiments, the cannabinoids are derived from Cannabis spp. or an extract thereof. Cannabis can generally be concentrated or extracted (e.g. via mechanical or chemical means) to obtain cannabinoids. Mechanical means of extracting oils from plants, such as pressing, have been used for centuries, and may be suitable for use herein. Extraction via chemical means includes extraction with various volatile solvents that range from hydrocarbon solvents such as butane, hexanes, or propane, to supercritical fluids, alcohol (e.g. isopropanol, butanol, or ethanol), steam, or even water. Two very common methods are extraction with supercritical carbon dioxide, or ethanol, both of which are particularly useful herein. Extracts can be also be distilled e.g. to remove additional compounds of interest, or to concentrate them. Certain components can be removed, e.g. by treatment with steam to strip certain volatiles, which can be captured as an additional component from the Cannabis.

[77] In various embodiments, cannabinoids present in an ethanolic extract or supercritical CO ₂ extract of Cannabis sativa are preferred for use herein. The extract comprises one or more of Ringo's Gift, OG Kush, Strawberry Cough, Orange Cookies, Jack Herer-derived strains (e.g. Black Jack, Super Jack, JI, and XJ13), and the Lemon family of strains of Cannabis sativa. In other embodiments, the extracts comprise Ringo's Gift, Harle Tsu, ACDC, Charlotte's Web, The Gift, or Pineberry strains. Proprietary strains commercially available from Apollon Formularies, are also useful herein, including but not limited to "Apollon Medical" ("APM").

[78] The compositions, in various embodiments, include terpenes comprising one or more monoterpenes, one or more sesquiterpenes, or a combination thereof. The terpenes generally comprise one or more of alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene oxide, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, or valencene.

[79] In one embodiment, the terpenes comprise phytol, limonene, humulene, myrcene, cineol, phellandrene, caryophyllene, terpinolene, linalool, ocimene, pinene, or a combination thereof. In other embodiments, the terpenes preferably comprise one or more of limonene, myrcene, beta-caryophyllene, linalool, alpha pinene, or a combination thereof. In one embodiment the terpenes include beta- ocimene, 1,8-cineole, alpha-pinene and / or beta-pinene, linalool, limonene, phytol, humulene, myrcene, phellandrene, caryophyllene, terpinolene, linalool, or other cineols or ocimenes, or any combination thereof, and the strains used to isolate terpenes are high in those terpenes, relative to other strains.

[80] In presently preferred embodiments, the terpenes are derived from Cannabis spp. or an extract thereof. The terpenes can be derived from any source and in certain embodiments, they can be present in steam distillate or an ethanolic extract of Cannabis sativa.

[81] The compositions in certain embodiments include extracts of Cannabis spp., such as C. sativa, as a source of cannabinoids and/or terpenes. In various embodiments, the extract comprises compounds from one or more C. sativa strains, Of current interest are Ringo's Gift, OG Kush, Strawberry Cough, Orange Cookies, Jack Herer-derived strains, Lemon family strains, Harle Tsu, ACDC, Charlotte's Web, The Gift, or Pineberry strains. In other embodiments, the extract comprises compounds from proprietary Apollon Formularies' C. sativa strains, which may be strain dependent and adapted for specific therapeutic purposes.

[82] In other embodiments, the compositions feature extracted or enriched cannabinoids from Cannabis comprising one or more of cannabidiol (CBD), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), or tetrahydrocannabinol (THC). In some embodiments, preferred ratios of various cannabinoids to other cannabinoid present are set forth (see above). In particular, in can be useful to control the ratio of non-psychoactive to psychoactive cannabinoids to maximize the benefits of both types. In other embodiments, there are little to no psychoactive cannabinoids present (e.g. THC <0.3%). In such embodiments, C. sativa plants that are hemp are particularly useful.

[83] In various other embodiments, the compositions may further comprise one or more flavonoids. The flavonoids can comprise chaicones, flavones, isoflavonoids, flavanones, anthoxanthins, anthocyanins, flavonols, or glucosides or other biologically active derivatives or analogs thereof, and combinations of any number of the foregoing. In certain embodiments, flavonoids are included in the compositions are isolated or derived from a plant, mushroom, or other natural source. [84] In another embodiment, the composition still further comprises an extract or fraction from one or more traditional Jamaican medicinal plants other than Cannabis spp. Any of the traditional Jamaican or Carribbean medicinal plants may be useful herein. Examples of Jamaican plants useful herein include ackee, aloe vera, avocado, breadflower, ginger, leaf of life, sorrel, soursop, tamarind, and trumpet. In one embodiment, the traditional medicinal plants comprise Jamaican sorrel Hibiscus sabdariffa), guinea hen weed (Petiveria alliacea), and/or soursop (Annona murata). In a presently preferred embodiments, the compositions include a whole plant extract, or an extract from any parts or portion thereof including but not limited to leaves (dried, fresh, or extracted), stems, flowers, roots, fruit, seeds, or the like.

[85] The compositions in certain embodiments may comprise one or more serotonergic psychedelics, for example as part of a mushroom extract or fraction. Such compounds may be particularly useful for disrupting chronic pain in patients suffering therefrom due to chronic interstitial cystitis or bladder pain syndrome. Moreover, such compositions may help a patient overcome certain psychological ramifications (such as depression or problems with intimacy) resulting from prolonged pain and suffering, chronic pelvic pain, and the like). They may be particular useful where the underlying physical pain has been treated successfully but psychological issues persist.

[86] In terms of compounding the compositions, the skilled artisan will appreciate that methods of maximizing the efficacy of the composition such as by enhancing the bioavailability of one or more components, or by providing the components in optimized ratios, for example one component to another with which it interacts, or each component to the others in ratio(s) that optimize the absorption into the gut or bloodstream, or enhance the therapeutic effect of the composition. The skilled artisan will also understand that some information useful in improving the compounding may be obtained empirically.

[87] In various embodiments, the compositions, or one or more components thereof, may be solubilized, micronized, provided as, for example, extracts, powders, lyophilized powders, concentrates, tinctures, essential oils, aqueous or lipid suspensions, emulsions, microemulsions, or nano-emulsions, or in whole or part as liposomal, vesicular, or other delivery systems. As described below, the compounding or formulation of any of the compositions provided herein may be optimized for the intended delivery route.

[88] The compositions may be administered and delivered as pharmaceuticals, however, it is also contemplated that one or more of the compositions may be formulated for administration and delivery by oral routes that include as food and beverages, including solid, semisolid, and liquid foods, such as smoothies, shakes, pudding, broths, teas, and soups. The food and or beverage compositions can also include hot, cold, or even frozen foods (such as frozen desserts). The compositions may also be administered by instillation either via a practitioner, or at home using a urinary catheter kit.

[89] In another aspect of the disclosure, provided are methods of treating a subject suffering from a bladder disease. The methods generally comprise administering a therapeutically effective dose of a composition to the subject. The composition typically comprises one or more edible or medicinal mushrooms or an extract, fraction, or isolate thereof, and one or more cannabinoids, in various combinations. The compositions may optionally comprise an amphipathic solvent such as DMSO. In such cases, preferred routes of administration include direct bladder instillation with a urinary catheter, particularly with bladder hydrodistension.

[90] The bladder disease in various embodiments comprises interstitial cystitis or another bladder disease, such as bladder cancer, prolonged or repeated bladder infection(s) or UTIs, or inflammation of the epithelial tissues of the bladder or urinary tract.

[91] The composition for use in the methods is generally as described above for the first aspect. The description of the compositions above is incorporated by reference herein for purposes of the present methods.

[92] In various embodiments, the compositions for use in the methods further comprise one or more optional ingredients comprising e.g. herbal extracts from Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, corn silk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, and/or combinations thereof. The compositions may further comprise nutraceutical or vitamins or the like such as polyphenols, antioxidants, D-mannose, S-adenosylmethionine, methylfolate, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically-available form thereof. In still other embodiments fish oil, primrose oil, or an extract of one or more of black cumin, Echinacea, Astralagus, sorrel, ginger, ginseng, bee propolis, bee pollen, honey, fenugreek, goldenseal, licorice, coriander, tomato, carrot, sweet potato, broccoli, green tea, rosemary, hazelnut, walnut, wheat germ, pomegranate, or date, or any combination thereof, can also be included. Garlic extract, alpha lipoic acid (ALA), conjugated linoleic acid (CLA), phytoestrogens, soy isoflavones, selenium, zinc, copper, magnesium, niacin, and/or nicotinamide are also contemplated for use herein.

[93] The terpenes for use with the compositions can comprise one or more monoterpenes, one or more sesquiterpenes, or a combination thereof. In various embodiments, the terpenes comprise one or more of alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene oxide, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, or valencene. Also useful are related polyphenols such as chlorogenic acid. In other embodiments, the terpenes can comprise beta- ocimene, 1,8-cineole, alpha-pinene and / or beta-pinene, linalool, limonene, phytol, humulene, myrcene, phellandrene, caryophyllene, terpinolene, linalool, or other cineols or ocimenes, or any combination thereof,

[94] In certain preferred embodiments, the terpenes are derived from Cannabis spp. or an extract thereof. The terpenes can be present in steam distillate or an ethanolic extract of Cannabis sativa, and can comprise limonene, myrcene, betacaryophyllene, linalool, alpha pinene, or a combination thereof, in some embodiments. The Cannabis sativa in one embodiment includes one or more of Ringo's Gift, OG Kush, Strawberry Cough, Orange Cookies, Jack Herer-derived strains or extract formulations (e.g. Black Jack, Super Jack, JI, and XJ13), and the Lemon family of strains of Cannabis sativa. In other embodiments Ringo's Gift, Harle Tsu, ACDC, Charlotte's Web, The Gift, or Pineberry strains or extract formulations are useful. Proprietary strains or extract formulations commercially available from Apollon Formularies are also useful herein.

[95] The compositions for use with the methods also may comprise one or more flavonoids that can be chaicones, flavones, isoflavonoids, flavanones, anthoxanthins, anthocyanins, flavonols, or glucosides or other biologically active derivatives or analogs thereof, and preferably they are from a plant, mushroom, or other natural source.

[96] Presently preferred flavonoids include cannaflavin A, cannaflavin B, or cannaflavin C, vitexin, isovitexin, apigenin, kaempferol, quercetin, orientin, luteolin, a catechin found in Cannabis, or a combination of any of the foregoing.

[97] In certain embodiments, the methods further comprise one or more steps of administering an additional therapeutically effective dose of the composition.

[98] Preferably the additional administering steps are performed on a periodic basis of any frequency or schedule. For example, the administration or dosing can conveniently be on e.g. a daily, thrice weekly, twice weekly, weekly, biweekly, monthly, bimonthly, quarterly, semi-annual, or annual basis. The administration need not be the same over every period of time. By way of nonlimiting example, administration could be daily for a week, then weekly for a month. Or the administration could be every 4 months for a year, then every 6 months thereafter. Similarly, the actual amount of the composition or dosage administration can vary. For example, a monthly dosage schedule could feature a dose of x for the first dosage each quarter, and a dose of O.lx for the remaining months in each quarter.

[99] Just as the composition can be 'personalized', so can the administration or dosing schedule. Thus, in various embodiments, the methods further comprise the step of periodically assessing one or more of the subject's medication levels, enzyme levels, or other indicators of physiological health or status, genetic markers or metabolic markers or mediator presence, or the like, in order to determine the periodic basis for administration.

[100] The methods provide for administration of the compositions via any useful route, including parenteral (intravenous, intra-arterial, intramuscular, intraperitoneal, or subcutaneous), oral, nasal, ocular, transmucosal (buccal, vaginal, or rectal), transdermal, or via inhalation. Presently preferred for treatment of interstitial cystitis is direct instillation into the bladder, e.g. via a urinary catheter. The compositions are relatively safe enough that they can be adapted for home use by the patient, who is also directed to administer the compositions and then to retain the mixture in the bladder for at least 30 minutes if possible (so as to maximize exposure to bladder tissues, allow for transport to the bladder wall, and to mitigate or alleviate the inflammation of the bladder epithelial cells. In another embodiment, the composition may be administered by multiple routes of administration in the same patient e.g., one aspect of the compositions might be given by direct bladder instillation via urinary catheter while another aspect of the compositions might be administered orally or sublingually.

[101] Commercial kits can be provided for home administration. The kits can include one or more catheters and any connections useful therefore, as well as detailed instructions for the instillation process and / or hydrodistension of the bladder in a home setting.

[102] It should be noted that the route of dosing or administration of compositions can vary over the course of treating a subject or patient with multiple steps of treatment, as well as from subject to subject, or with different types of bladder disease. For example, administration via one route may be useful when administering a larger dose and a different route may be useful for smaller doses. Or, administration via a particular route may be appropriate initially, with subsequent doses conveniently administered through another route.

[103] In one embodiment, the method further comprises a step of providing to the subject additional treatment of the interstitial cystitis or other bladder disease comprising: i) one or more doses of a pharmacological agent to reduce pain; ii) one or more doses of an antibiotic; iii) one or more treatments to expand the bladder mechanically; iv) one or more other treatments specifically provided to support the subject during recovery from the interstitial cystitis or other bladder disease process; or any combination of any of the foregoing. [104] The additional compositions further optionally comprise any combination of one or more of polyphenols, antioxidants, D-mannose, S-adenosylmethionine, methylfolate, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically available form thereof.

[105] In various embodiments of the methods:

[106] i) the one or more edible or medical mushrooms comprise Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Pomes, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus;

[107] ii) the cannabinoids comprise one or more of cannabidiol (CBD), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), or tetrahydrocannabinol (THC).

[108] In one embodiment, the compositions are specifically for treating interstitial cystitis and the compositions further comprises DMSO, CYRENE, or another amphipathic solvent.

[109] In another embodiment, the compositions further comprise one or more herbal extracts comprising from Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, corn silk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, or any combinations thereof.

[110] In another embodiment the compositions further comprise terpenes comprising one or more of alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene oxide, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, or valencene; and [111] iv) flavonoids comprising one or more of chai cones, flavones, isoflavonoids, flavanones, anthoxanthins, anthocyanins, flavonols, or glucosides or other biologically active derivatives or analogs thereof.

[112] In one embodiment the terpenes preferably comprise beta-ocimene, 1,8- cineole, alpha-pinene and/or beta-pinene, linalool, limonene, phytol, humulene, myrcene, phellandrene, caryophyllene, terpinolene, linalool, or other cineols or ocimenes, or any combination thereof.

[113] In one embodiment of the methods, the composition further comprises an extract or fraction from one or more traditional Jamaican medicinal plants other than Cannabis spp. The traditional medicinal plants comprise Jamaican sorrel Hibiscus sabdariffa), guinea hen weed (Petiveria alliacea), or soursop (Annona murata) in certain embodiments.

[114] The skilled artisan will appreciate that the methods are flexible as set forth herein, an aspect which is particularly useful given the varied and nature of the bladder diseases and conditions which they are intended to treat.

[115] In yet another aspect of the disclosure, methods of optimizing a composition for use in treatment of a subject suffering from interstitial cystitis or a bladder disease process using artificial intelligence are provided herein. The methods generally comprise, for each disease process of interest, or for each subject in need of therapeutic compositions for such disease process:

[116] a) providing data on the therapeutic effect on the disease process of each of:

[117] i) a plurality of edible or medicinal mushrooms, mushroom extracts, or components thereof;

[118] ii) a plurality of cannabis extracts, at least partially purified cannabinoids, or combinations thereof;

[119] iii) a plurality of terpenes, flavonoids, or other components extracted from Cannabis, or combinations thereof; and optionally,

[120] iv) DMSO, or one or more pharmaceutically acceptable solvents having useful amphipathic properties;

[121] b) using an artificial intelligence algorithm to analyze the data for the mushrooms or extracts, cannabinoids, and other components; and [122] c) generating one or more base profiles of compositions optimized for therapeutic treatment of the disease.

[123] The methods can further comprise the additional steps of: d) providing data on the therapeutic effect on the disease process of any or all of:

[124] v) a plurality of herbal extracts for supporting urinary tract function; or

[125] vi) a plurality of optional ingredients comprising one or more antioxidants, polyphenols, D-mannose, S-adenosylmethionine, methylfolate, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically available form thereof, or combinations thereof;

[126] e) using the artificial intelligence algorithm to analyze the data for the optional ingredients, and

[127] f) using the base profiles and the analysis of the data for the optional ingredients to generate one or more complete profiles of compositions with and without the optional ingredients.

[128] Generally, the data for the method are obtained from original experiments and/or reviews of the relevant scientific literature.

[129] The artificial intelligence algorithm can comprise any useful software or algorithm approach capable of making the distinctions required. In various embodiments, the algorithm comprises a classification algorithm, a regression algorithm, a clustering algorithm, or a combination thereof.

[130] In one embodiment, the methods comprise a classification algorithm that is a naive Bayes algorithm, decision tree, random forest algorithm, Support Vector Machines, or K Nearest Neighbor algorithm.

[131] In another embodiment, the methods comprise a regression algorithm that is a liner regression, lasso regression, logistic regression, or multivariate regression.

[132] In yet another embodiment, the methods comprise a clustering algorithm that is a K-means clustering, fuzzy C-means algorithm, expectation-maximization algorithm, or hierarchical clustering algorithm. [133] The skilled artisan will appreciate that the methods are designed to optimize the compositions, and that such optimization as set forth above can be with respect to each particular disease. However, the compositions can also be optimized for, and a profile of relevant compositions generated for each particular subject, e.g. for a 'personalized medicine' approach.

[134] Thus, also provided herein are the methods comprising the additional step of providing subject-specific data comprising, e.g. initial or subsequent blood work, enzyme test results, bioinformatic data (including measurements of e.g. the genome, transcriptome, proteome, metabolome, or any portion thereof, for a subject), specific symptomology, or the like. The artificial intelligence algorithm is then used to further optimize the composition based on those data in addition to the disorder-specific data. The optimized formulation of the compositions may also be changed based on data from the results from an initial treatment, subsequent treatment, or based on subsequent tests of the subject.

[135] The plurality of edible or medicinal mushrooms, mushroom extracts, or components for which data are analyzed generally comprise one or more of the species Agaricus blazei, Albatrellus confluens, Antrodia camphorate, Boletus badius, Clitocybe maxima, Cordyceps militaris, Flanulina velutipes, Pomes fomentarius, Punalia trogii, Ganoderma lucidum, Grifola frondosa, Hericium erinaceus, Inocybe umbrinella, Inonotus olbiquus, Lactarius flavidulus, Lentinula edodes, Phellinus linteus, Pleurotus ostreatus, Schizophyllum commune, Suillus placidus, Trametes versicolor, Cordyceps sinensis, C. liangshanensis, C. gunnii, or C. cicadicola.

[136] In other embodiments, the mushroom or mushroom extract can comprise Agaricus bisporus, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, Amanita muscaria, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Cordyceps pruinose, Caripia montagnei, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Plammulina velutipes, Fomitopsis pinicola, Ganoderma lucidum, Geastrum saccatum, Inonotus obliquus, Lactarius deliciosus, L. rufus, Lentinus edodes, L. polychrous, Lyophyllum decastes, Pholiota nameko, Pleurotus pulmonarius, Poria cocos, and Termitomyces albuminosus.

[137] More generally, the mushroom or mushroom extract can come from any the following species: Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Pomes, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus.

[138] The skilled artisan will appreciate that once data for particular mushroom species or extracts, or particular Cannabis species or extracts are known, those data may be stored and the algorithm will naturally be able to access more and better information as the data set grows. Similarly, as various curcuminoids, terpenes, flavonoids, or the like are characterized with respect to their effect on different aspects of different disease conditions, the method will produce better results in terms of compositions that could not otherwise be readily formulated. Data related to various disease conditions and symptoms, and satisfactory or desirable compounds for treating such symptoms and underlying disease conditions will also help the algorithm generate better composition profiles over time.

[139] The scope of the invention is set forth in the claims appended hereto, subject, for example, to the limits of language. Although specific terms are employed to describe the invention, those terms are used in a generic and descriptive sense and not for purposes of limitation. Moreover, while certain presently preferred embodiments of the claimed invention have been described herein, those skilled in the art will appreciate that such embodiments are provided by way of example only. In view of the teachings provided herein, certain variations, modifications, and substitutions will occur to those skilled in the art. It is therefore to be understood that the invention may be practiced otherwise than as specifically described, and such ways of practicing the invention are either within the scope of the claims, or equivalent to that which is claimed, and do not depart from the scope and spirit of the invention as claimed.