WO2021207466A1 - Diagnosing and treating fibromyalgia - Google Patents

Abstract

The invention relates to diagnosing and treating autoimmune disorders such as fibromyalgia. Some embodiments of the invention relate to methods, systems, assays and kits for diagnosing the autoimmune disorder such as fibromyalgia. The invention also relates to methods, systems and assays for determining treatments for fibromyalgia, for example, an assay for determining effective compositions and dosages.

Description

DIAGNOSING AND TREATING FIBROMYALGIA

Claim of Priority under 35 U.S.C. §119

[0001] The present Application for Patent claims priority to Provisional Application No. 63/007,798 entitled “DIAGNOSING AND TREATING FIBROMYALGIA” filed April 9, 2020 and assigned to the assignee hereof and hereby expressly incorporated by reference herein.

BACKGROUND

Field

[0002] The invention relates to diagnosing and treating autoimmune disorders such as fibromyalgia. Some embodiments of the invention relate to methods, systems, assays and kits for diagnosing the autoimmune disorder such as fibromyalgia. The invention also relates to methods, systems and assays for determining treatments for fibromyalgia, for example, an assay for determining effective compositions and dosages.

Background

[0003] Fibromyalgia was likely first described by Sir William Gowers as fibrositis in the early 1900s, a condition characterized as soft tissue pain that could wander in the body, and which was aggravated by overuse. In the 1980s, fibromyalgia became the preferred term due to a failure to identify inflammation or other objective changes in tissue biopsies from affected patients. Formal diagnostic parameters (Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62(5):600-10. DOI: 10.1002/acr.20140; the entire contents of which are fully incorporated herein) were established thereafter. While a recent report indicated the presence of small fiber neuropathy in a subset of patients with fibromyalgia symptoms (Caro XJ, Winter EF. The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain. Curr Pain Headache Rep 2015; 19(12):55. DOI: 10.1007/sl 1916-015-0527-7; the entire contents of which are fully incorporated by reference herein) creating possible diagnostic confusion, this finding by no means explains all such cases. Fibromyalgia is noteworthy for its characteristic painful nodules dubbed as trigger points that are particularly prevalent in the shoulder and neck that are frequently of sufficient severity to limit physical activity. The disorder has a clear association with depression and anxiety, but debate surrounds the timing and relationship of these comorbidities. Like migraine, it is more prevalent in women and invariably disrupts sleep. The disorder remains controversial in some quarters, but it is nonetheless the most common diagnosis in American rheumatology practices. Many authorities now posit a central sensitization consistent with neuropathic pain at the root of the syndrome. In Italy, it was noted that fibromyalgia, like migraine, was associated with secondary hyperalgesia, that is, a lowered threshold to pain in areas adjacent to the primarily affected parts, for which the authors suggested pharmacological NMD A blockade for what they interpreted as a deficit in serotonergic analgesia (further information can be found in Russo EB. Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett 2004;25(l-2):31-39 and Russo EB. Clinical endocannabinoid deficiency reconsidered: Current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis and Cannabinoid Research 2016;1:154-165. DOI: 10.1089/can.2016.0009; the entire contents of each of the foregoing are fully incorporated by reference herein).

SUMMARY

[0004] Fibromyalgia has been hypothesized to relate to a “clinical endocannabinoid deficiency” that could be linked to a genetic susceptibility or be an acquired disorder after injury. The invention relates to the finding that fibromyalgia and other disorders with unexplained etiology are autoimmune manifestations in which the points of attack are cannabinoid receptors (CB1 or CB2). This can be analogous to similar pathophysiologic mechanisms related to autoimmune conditions affecting other receptor systems, e.g., acetylcholine receptors in myasthenia gravis and the NMDA receptor in anti-NMDA receptor encephalitis. Further information can be found in Russo E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro endocrinology letters, 25(1-2), 31-39; and Russo E. B. (2016). Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis and cannabinoid research, 1(1), 154-165; the entireties of which are hereby incorporated by reference herein for all purposes.

[0005] Embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia including providing a biological sample from a subject; detecting a presence of an anti-CBl or an anti-CB2 antibody in the biological sample with an assay; and determining a presence or likely presence of fibromyalgia if the presence of anti-CBl or anti-CB2 antibody is detected. Other embodiments of the invention relate to a method of treating fibromyalgia including administering a composition that inhibits an anti-CBl or anti-CB2 antibody to a subject with fibromyalgia. For example, synthesized anti-auto-antibodies can be administered as a treatment for the disorder. In some embodiments, the composition is identified by the assay used for diagnosing or monitoring a subject for fibromyalgia.

[0006] Some embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia. In some embodiments, the method can include providing a biological sample from a subject and detecting the presence of an anti-CB 1 or an anti-CB2 antibody in the biological sample with an assay. In some embodiments, the presence of an anti-CB 1 or an anti-CB2 antibody can be indicative of a presence or likely presence of fibromyalgia in the patient.

[0007] Some embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia that can include providing a biological sample from a subject and detecting a level of anti-CB 1 or anti-CB2 antibodies in the biological sample with an assay. In some embodiments, a significantly higher level of anti-CB 1 or an anti-CB2 antibodies compared to a level in a control sample can be indicative of a presence or likely presence of fibromyalgia in the patient.

[0008] In some embodiments, the sample can be serum. In some embodiments, the assay can be an ELISA.

[0009] Some embodiments of the invention relate to a system for diagnosing or monitoring a subject for fibromyalgia using a method disclosed herein. In some embodiments, the system can include an immunoassay. In some embodiments, the system further includes a computer.

[0010] Some embodiments of the invention relate to a kit for diagnosing or monitoring a subject for fibromyalgia using a method disclosed herein. The kit can include reagents for an immunoassay. [0011] Some embodiments of the invention relate to a method of determining a therapy for fibromyalgia for a subject in need thereof. In some embodiments, the method can include measuring a binding affinity of a composition to CB 1 or CB2 and selecting a composition with a higher binding affinity to CB1 compared to an anti-CBl autoimmune antibody or a higher binding affinity to CB2 compared to an anti-CB2 autoimmune antibody, or both.

[0012] Some embodiments of the invention relate to a method of treating fibromyalgia that can include administering the composition selected in the method disclosed above that inhibits an anti-CB 1 or anti-CB2 antibody to a subject with fibromyalgia. In some embodiments, the method can further include administration of a prebiotic or a probiotic or both.

DETAILED DESCRIPTION

[0013] Methods for diagnosing and treating autoimmune disorders such as fibromyalgia, among others are provided. Some embodiments of the invention relate to methods, systems, assays and kits for diagnosing the autoimmune disorder such as fibromyalgia. The disclosure also provides methods, systems and assays for determining treatments for fibromyalgia, for example, an assay for determining effective compositions and dosages.

Diagnosing

[0014] Methods and systems of diagnosing fibromyalgia are provided. In some embodiments, the method can include providing a biological sample from a subject; detecting a presence of an anti-CBl or an anti-CB2 antibody in the biological sample; and determining a presence or likely presence of fibromyalgia if the presence of anti- CB 1 or anti-CB2 antibody is detected.

[0015] In some embodiments, the method can include providing a biological sample from a subject, detecting a level of anti-CBl or anti-CB2 antibodies in the biological sample, and determining a presence or likely presence of fibromyalgia if the level of an anti-CBl or anti-CB2 antibody is higher than an established control level. In some embodiments, the established control level is a level of anti-CBl or anti-CB2 antibodies within two standard deviations of anti-CBl or anti-CB2 antibody levels from subjects without fibromyalgia. [0016] In some embodiments, the method includes providing a biological sample from a subject; detecting a level of anti-CBl or anti-CB2 antibodies in the biological sample; and determining a presence or likely presence of fibromyalgia if the level of anti-CB 1 or anti-CB2 antibodies is significantly higher than an established control level. In some embodiments the established control level is a level of anti-CBl or anti-CB2 antibodies from subjects without fibromyalgia.

[0017] As used herein, “significantly higher” means a significant increase in value. For example, a “significantly higher” anti-CBl or anti-CB2 antibody level can mean that the antibody level in a subject is higher than the antibody level measured in an normal biological sample (i.e., a biological sample of a healthy subject) by 10% or more, 30% or more, 70% or more, or 100% or more.

[0018] As used herein, the term “level” of a component refers to the quantity or concentration of a component present in a sample. Component levels can be measured using any of a variety of well known techniques. The level is typically determined by measuring protein levels, but alternatively the level can be determined in some cases by measuring mRNA levels, which may be followed by conversion of mRNA levels into predicted protein levels.

[0019] The system can include an isolated biological sample from a subject and an assay for detecting in the biological sample, a presence or level of an anti-CBl or anti- CB 2 antibody.

[0020] The assay can be any assay that can detect an antibody and/or measure levels of an antibody, such as an immunoassay. For example, the assay can be, but not be limited to, an enzyme-linked immunosorbent assay (ELISA), radio-immunoassay, automated immunoassay, cytometric bead assay, immunoprecipitation assay, and/or the like. The ELISA can be, but not be limited to quantitative, indirect ELISA, sandwich ELISA, competitive ELISA, multiple and portable ELISA, and/or the like.

[0021] In some embodiments, the assay includes a first reagent to react with the biological sample, a second reagent (e.g., secondary antibody) to react with the anti- CBl or anti-CB2 antibody, and a substrate. In some embodiments, the first reagent is CB1 or CB2 or a fragment thereof, which will react with the anti-CBl or anti-CB 2 antibody if present in the biological sample. In some embodiments, the second reagent includes a label to produce a signal to indicate the presence of the anti-CBl or anti-CB2 antibody. In some embodiments, the label is a radiolabel, a chromophore, a fluorophore, a quantum dot, an enzyme, horseradish peroxidase (HRP), an alkaline phosphatase (AP), biotin, or a combination thereof. In some embodiments, the label is an enzyme that will react with the substrate. In some embodiments, the first reagent is on a solid phase (e.g., plate, multi-well plate).

[0022] In some embodiments, the assay includes a first reagent to react with the anti- CB1 or anti-CB2 antibody. In some embodiments, the first reagent includes a label to produce a signal to indicate the presence of the anti-CBl or anti-CB2 antibody. In some embodiments, the label is a radiolabel, a chromophore, a fluorophore, a quantum dot, an enzyme, HRP, an AP, biotin, or a combination thereof. In some embodiments, the reagent is on a solid phase (e.g., plate, multi-well plate).

[0023] In some embodiments, the system further includes a machine for determining a presence or likely presence of fibromyalgia if the presence of an anti-CBl or anti-CB2 antibody is detected. In some embodiments, the machine is a computer. In some embodiments, the computer includes a display element for displaying whether there is a presence or absence of fibromyalgia.

[0024] In some embodiments, the system further includes a machine for determining a presence or likely presence of fibromyalgia if the level of anti-CBl or anti-CB2 antibodies is higher than an established control level. In some embodiments, the established control level is a level of anti-CBl or anti-CB2 antibodies within two standard deviations of anti-CBl or anti-CB2 antibody levels from subjects without fibromyalgia. In certain embodiments, the method further includes analyzing the biological sample for a level of anti-CBl or anti-CB2 antibodies.

[0025] In some embodiments, the anti-CBl or anti-CB2 antibody detected in these methods or systems is an antibody that binds specifically to CB 1 or CB2.

[0026] In some embodiments, the anti-CBl or anti-CB2 antibody is an antibody that binds specifically to a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 residue peptide that has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB 1 or CB2.

[0027] In another embodiment, the anti-CB 1 or anti-CB2 antibody binds specifically to a polypeptide comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 residues that has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB 1 or CB2.

[0028] In another embodiment, the anti-CB 1 or anti-CB2 antibody binds specifically to a polypeptide comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB1 or CB2.

[0029] In some embodiments, detecting the presence or absence of the antibody is performed on a biological sample obtained from the subject. The biological sample can be blood, serum, stool, lymph fluid, cerebral, fluid, tissue fluid (such as bone marrow or thymus fluid) and respiratory fluid including nasal and pulmonary fluid and bronchoalveolar lavage, or the like, obtained from the subject. One of ordinary skill in the art will readily appreciate methods and systems that can be used to detect the presence or absence of an antibody that binds specifically to CB 1 or CB2, or a fragment thereof. These methods and systems include but are not limited to ELISA, immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), radioimmunoassays, and affinity purification.

[0030] In some embodiments, CB1 or a fragment thereof or CB2 or a fragment thereof is used as a substrate to bind anti-CR antibodies.

[0031] In certain embodiments, detecting the presence or absence of an antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof can be performed by contacting CB 1 or a fragment thereof or CB2 or a fragment thereof to a biological sample obtained from the subject to isolate the antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof, wherein the isolation of the antibody that binds specifically to CB 1 or a fragment thereof or CB2 or a fragment thereof indicates the presence of the antibody and the lack of isolation of the antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof indicates the lack of the antibody. In some embodiments, the fragment CB1 or CB2 can be the fragments as described herein. As an example, an affinity matrix comprising CB 1 or a fragment thereof or CB2 or a fragment thereof can be bound to a solid support; the biological sample can be contacted to the affinity matrix to produce an affinity matrix- antibody complex (if the antibody is present); the affinity matrix- antibody complex can be separated from the remainder of the biological sample; and the antibody can be released from the affinity matrix. In another example, a label (e.g., fluorescent label) can be placed on CB1 or a fragment thereof or CB2 or a fragment thereof; the labeled CB1 or a fragment thereof or CB2 or a fragment thereof can be contacted with a biological sample to allow the antibody (if present) to bind specifically to the labeled CB1 or a fragment thereof or CB2 or a fragment thereof. In some embodiments, the labeled CB1 or a fragment thereof or CB2 or a fragment thereof can be separated out and analyzed for its binding to the antibody.

[0032] Some embodiments of the invention relate to an assay used in any of the foregoing methods.

[0033] Some embodiments of the invention relate to a kit using any of the foregoing methods.

Treatment

[0034] Some embodiments provide for a method of determining a therapy for fibromyalgia for a subject in need thereof using a method, system, assay and/or kit disclosed above and herein. For example, in some embodiments, the method can include an assay used to determine compositions of a substance that has higher binding affinities to CB1 and CB2 compared to an anti-CBl or anti-CB2 autoimmune antibody. The method can include an assay to determine synergistic combinations of substances by comparing binding affinities of various combinations of the substances. As a further example, in some embodiments, the method is used to determine effectivity of various dosages.

[0035] The assay can be any binding assay known in the art used to determine binding affinities. For example, enzyme-linked immunoassays (ELISA), radioimmunoassays (RIAs), competitive binding assays, and the like can be utilized. The ELISA can include, but not be limited to indirect ELISA, sandwich ELISA, competitive ELISA, multiple and portable ELISA as described above.

[0036] In some embodiments, the method can include determining effectivity of an anti- CB1 or anti-CB2 antibody neutralizing or inhibiting agent for administering the anti- CBl or CB2 antibody neutralizing or inhibiting agent to a subject in need thereof to neutralize or inhibit the anti-CBl or anti-CB2 antibody. In some embodiments, the anti- CBl or anti-CB2 antibody neutralizing or inhibiting agent is a compound capable of binding and activating CB 1 or CB2 with a higher affinity than an anti-CB 1 or anti-CB2 antibody. In some embodiments, the compound is a cannabinoid in concentrations sufficient to competitively bind the CB1 and/or CB2 and/or otherwise change the conformation at CB1 and/or CB2 sufficient to interfere with binding of autoantibody. In some embodiments, the anti-CBl or anti-CB2 antibody neutralizing or inhibiting agent is a compound capable of binding to the anti-CBl or CB2 antibody and neutralizing or inhibiting its function.

[0037] In some embodiments, the method can include determining efficacy of an agent to change CB1 or CB2 from an inactive state to an active state for administering the agent to a subject in need thereof to treat fibromyalgia. In some embodiments, the agent to change CB 1 or CB2 from an inactive state to an active state is a compound capable of activating CB1 or CB2. The compound can be a cannabinoid. In some embodiments, the method can include determining effectivity of a CB1 or CB2 agonist for administering the CB 1 or CB2 agonist to a subject in need thereof to treat fibromyalgia. In certain embodiments, the CB 1 or CB2 agonist can be a cannabinoid.

[0038] The cannabinoid in any method described herein can be The cannabinoid can be, for example, one or more of cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-C1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B ), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol-C4 (THC-C4), delta-9- tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta-9-tetrahydrocannabiorcol (THC-C1), delta-7-cis-iso-tetrahydrocannabivarin, delta-8-tetrahydrocannabinolic acid (A8-THCA), delta-8-tetrahydrocannabinol (A8-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannnabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN), cannabinol methylether (CBNM), cannabinol-C4 (CBN — C4), cannabivarin (CBV), cannabinol-C2 (CBN — C2), cannabiorcol (CBN — Cl), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), lO-ethoxy-9- hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy-delta-6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), dehydrocannabifuran (DCBF), cannabifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10- oxo-delta-6a-tetrahydrocannabinol (OTHC), delta-9-cis-tetrahydrocannabinol (cis- THC), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano- 2H-l-benzoxocin-5-methanol (OH-iso-HHCV), cannabiripsol (CBR) and trihydroxy- delta-9-tetrahydrocannabinol (triOH-THC), or the like.

[0039] In some embodiments, the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of the agents described herein. “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.

[0040] In some embodiments, the pharmaceutical compositions according to the invention can be formulated for delivery via any route of administration. “Route of administration” can refer to any administration pathway known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal or parenteral. “Transdermal” administration can be accomplished using a topical cream or ointment or by means of a transdermal patch. Via the topical route, the pharmaceutical compositions based on compounds according to the invention can be formulated for treating the skin and mucous membranes and are in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid vesicles or polymer vesicles or polymer patches and hydrogels allowing controlled release. These topical-route compositions can be either in anhydrous form or in aqueous form depending on the clinical indication. “Parenteral” refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the compositions can be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders. Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release. Via the parenteral route, the compositions can be in the form of solutions or suspensions for infusion or for injection. The compositions can also be administered by vaporization or the like.

[0041] The pharmaceutical compositions according to the invention can also contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier can be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it can come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0042] The pharmaceutical compositions according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

[0043] The pharmaceutical preparations are made following the conventional techniques of pharmacy and can include milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation can be administered directly p.o. or filled into a soft gelatin capsule.

[0044] The pharmaceutical compositions according to the invention can be delivered in a therapeutically effective amount. The precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance, by monitoring a subject's response to administration of a compound and adjusting the dosage accordingly. For additional guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000), which is hereby incorporated by reference in its entirety.

[0045] Some embodiments provide for a method of treating a subject for fibromyalgia including detecting the presence of anti-CB 1 or anti-CB2 antibodies and administering a composition to the subject. In some embodiments, the composition is a composition as described herein and/or a composition determined by any of the methods disclosed herein.

[0046] In some embodiments, the method can include administration of prebiotics and/or probiotics in addition to the composition.

[0047] Embodiments of the invention relate to various treatment protocols. Treatment protocols can involve use of cannabis-based medicines via oral, oromucosal, and/or topical routes. Treatment protocols can include synthesis of a biological pharmaceutical to serve as an anti-auto-antibody to inactivate endogenous substances in the fibromyalgia patient. This can be administered via periodic intravenous infusion, and/or via the oral route. Treatment protocols can include optimized lifestyle adjustments including, but not limited to, low-impact aerobic exercise and dietary manipulation to include prebiotics and/or probiotics.

[0048] An example of a putative cannabis-based treatment can relate to use of THC due to its analgesic and sleep-promoting properties, as well as positive effects on the gut microbiome to reduce autoimmune responses. Similarly, cannabidiol (CBD) can affect auto-antibody binding to the CB1 receptor via its known ability to act as a negative allosteric modulator. [0049] In addition to fibromyalgia, the methods can be used in connection with other autoimmune disorders as defined herein, including, but not limited to, arthritis (acute and chronic, rheumatoid arthritis including juvenile-onset rheumatoid arthritis and stages such as rheumatoid synovitis, gout or gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, menopausal arthritis, estrogen-depletion arthritis, and ankylosing spondylitis/rheumatoid spondylitis), autoimmune lymphoproliferative disease, inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, atopy including atopic diseases such as hay fever and Job's syndrome, dermatitis including contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, hives, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, and atopic dermatitis, x-linked hyper IgM syndrome, allergic intraocular inflammatory diseases, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, myositis, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as systemic sclerosis, multiple sclerosis (MS) such as spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, ataxic sclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (for example, Crohn's disease, autoimmune- mediated gastrointestinal diseases, gastrointestinal inflammation, colitis such as ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), bowel inflammation, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, graft-versus-host disease, angioedema such as hereditary angioedema, cranial nerve damage as in meningitis, herpes gestationis, pemphigoid gestationis, pruritis scroti, autoimmune premature ovarian failure, sudden hearing loss due to an autoimmune condition, IgE- mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis and limbic and/or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as chronic or acute glomerulonephritis such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), including Type I and Type II, and rapidly progressive GN (RPGN), proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis including balanitis circumscripta plasmacellularis, balanoposthitis, erythema annulare centrifugum, erythema dyschromicum perstans, eythema multiform, granuloma annulare, lichen nitidus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, lichen planus, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, food allergies, drug allergies, insect allergies, rare allergic disorders such as mastocytosis, allergic reaction, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma such as asthma bronchiale, bronchial asthma, and auto-immune asthma, conditions involving infiltration of T cells and chronic inflammatory responses, immune reactions against foreign antigens such as fetal A-B-0 blood groups during pregnancy, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, lupus, including lupus nephritis, lupus cerebritis, pediatric lupus, non-renal lupus, extra-renal lupus, discoid lupus and discoid lupus erythematosus, alopecia lupus, SLE, such as cutaneous SLE or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and lupus erythematosus disseminatus, juvenile onset (Type I) diabetes mellitus, including pediatric IDDM, adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, diabetic retinopathy, diabetic nephropathy, diabetic colitis, diabetic large-artery disorder, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including lymphomatoid granulomatosis, agranulocytosis, vasculitides (including large- vessel vasculitis such as polymyalgia rheumatica and giant-cell (Takayasu's) arteritis, medium-vessel vasculitis such as Kawasaki's disease and polyarteritis nodosa/periarteritis nodosa, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis such as fibrinoid necrotizing vasculitis and systemic necrotizing vasculitis, ANCA-negative vasculitis, and ANCA-associated vasculitis such as Churg-Strauss syndrome (CSS), Wegener's granulomatosis, and microscopic polyangiitis), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia(s), cytopenias such as pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, Alzheimer's disease, Parkinson's disease, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen- antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, motoneuritis, allergic neuritis, Behcet's disease/syndrome, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid or pemphigus such as pemphigoid bullous, cicatricial (mucous membrane) pemphigoid, skin pemphigoid, pemphigus vulgaris, paraneoplastic pemphigus, pemphigus foliaceus, pemphigus mucus -membrane pemphigoid, and pemphigus erythematosus, epidermolysis bullosa acquisita, ocular inflammation, preferably allergic ocular inflammation such as allergic conjunctivis, linear IgA bullous disease, autoimmune- induced conjunctival inflammation, autoimmune polyendocrinopathies, Reiter's disease or syndrome, thermal injury due to an autoimmune condition, preeclampsia, an immune complex disorder such as immune complex nephritis, antibody-mediated nephritis, neuroinflammatory disorders, polyneuropathies, chronic neuropathy such as IgM polyneuropathies or IgM-mediated neuropathy, thrombocytopenia (as developed by myocardial infarction patients, for example), including thrombotic thrombocytopenic purpura (TTP), post-transfusion purpura (PTP), heparin-induced thrombocytopenia, and autoimmune or immune-mediated thrombocytopenia including, for example, idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, scleritis such as idiopathic cerato- scleritis, episcleritis, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases including thyroiditis such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, Grave's eye disease (ophthalmopathy or thyroid- associated ophthalmopathy), polyglandular syndromes such as autoimmune polyglandular syndromes, for example, type I (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis such as allergic encephalomyelitis or encephalomyelitis allergica and experimental allergic encephalomyelitis (EAE), myasthenia gravis such as thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant-cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, pneumonitis such as lymphoid interstitial pneumonitis (LIP), bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac or Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia such as mixed cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsed or relapsing polychondritis, pulmonary alveolar proteinosis, keratitis such as Cogan's syndrome/nonsyphilitic interstitial keratitis, Bell's palsy, Sweet's disease/syndrome, rosacea autoimmune, zoster-associated pain, amyloidosis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal or segmental or focal segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia greata, alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, e.g., due to anti-spermatozoan antibodies, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, parasitic diseases such as leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, fibrosing mediastinitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, SCID, acquired immune deficiency syndrome (AIDS), echovirus infection, sepsis (systemic inflammatory response syndrome (SIRS)), endotoxemia, pancreatitis, thyroxicosis, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant-cell polymyalgia, chronic hypersensitivity pneumonitis, conjunctivitis, such as vernal catarrh, keratoconjunctivitis sicca, and epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia- reperfusion injury, transplant organ reperfusion, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway/pulmonary disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders (cerebral vascular insufficiency) such as arteriosclerotic encephalopathy and arteriosclerotic retinopathy, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica (sympathetic ophthalmitis), neonatal ophthalmitis, optic neuritis, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired spenic atrophy, non-malignant thymoma, lymphofollicular thymitis, vitiligo, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomemlar basement membrane disease, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, poly endocrine failure, autoimmune polyglandular syndromes, including polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), cardiomyopathy such as dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpumlent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, allergic sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, spondyloarthropathies, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott- Aldrich syndrome, ataxia telangiectasia syndrome, angiectasis, autoimmune disorders associated with collagen disease, rheumatism such as chronic arthrorheumatism, lymphadenitis, reduction in blood pressure response, vascular dysfunction, tissue injury, cardiovascular ischemia, hyperalgesia, renal ischemia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, ischemic re-perfusion disorder, reperfusion injury of myocardial or other tissues, lymphomatous tracheobronchitis, inflammatory dermatoses, dermatoses with acute inflammatory components, multiple organ failure, bullous diseases, renal cortical necrosis, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, narcolepsy, acute serious inflammation, chronic intractable inflammation, pyelitis, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis.

[0050] In addition to fibromyalgia, the methods can be used in connection with disorders known to be co-morbid with fibromyalgia that affect a subject, including, but not limited to, disorders linked to clinical endocannabinoid deficiency, for example, migraine, irritable bowel syndrome, post-traumatic stress disorder (PTSD), autism, intractable depression, and/or the like (Russo 2004; Russo 2016).

EXAMPLES

Example 1

[0051] A study is done to identify possible autoantibodies to CB1 or CB2 in fibromyalgia as compared to control patients. The study includes 100 patients fulfilling the American College of Rheumatology (ACR) Revised 2010 criteria for diagnosis of fibromyalgia and 100 control patients without fibromyalgia. Serum is collected from all patients and examined for presence or absence of antibodies to human CB1 and CB2 receptors. Exclusion Criteria: El. Patient / Subject less than 18 years old; E2. Pregnant or breast-feeding women (to eliminate possibility of changes in immunity attributable to those conditions); E3. Patients with known autoimmune disorders; E4. Patients on steroids or other immunosuppressive drugs; E5. Patients with severe chronic migraine, irritable bowel syndrome, severe psychiatric disorder, Lyme disease or Epstein-Barr virus; E6. Patients with history of fibromyalgia that do not meet the ACR revised 2010 criteria for diagnosis of fibromyalgia upon screening (e.g., asymptomatic fibromyalgia patients); E7. Subjects without prior history or formal diagnosis of fibromyalgia that meet ACR revised 2010 criteria for diagnosis of fibromyalgia upon screening; E8. Subjects with a history of problems during phlebotomy; E9. Subjects taking regular use of anti-coagulants.

Example 2 [0052] Experiments are done to compare levels of anti-CBl or anti-CB2 antibodies in the serum of patients with fibromyalgia compared to healthy subjects. The primary screen is ELISA for antibodies against CB1 or CB2 receptor extracellular domains. Plates are coated with GST fusion proteins corresponding to the extracellular domains of each cannabinoid receptor and testing the serum for antibody /antigen interaction over a range of dilutions. Positives are verified by screening serum by Western blot against human CB1 and CB2 receptor lysates. Immunostaining of human CB1 or CB2- expressing HEK cells are performed to confirm results. A statistically significant difference was found in auto-antibody expression against CB1 and/or CB2 in fibromyalgia patients as compared to controls.

Example 3

[0053] Experiments are done to determine if anti-CBl antibodies from patients with fibromyalgia will bind with HA-tagged hCBl receptors transiently expressed in HEK293 cells. Dilution of control serum that minimizes non-specific binding is determined by pooling samples of control serum (healthy patients without fibromyalgia) and incubated with CB1-HEK 293 cells at the following dilutions: 1:30, 1:100, 1:300, 1:1000, and 1:3000. The dilution that minimizes background staining is selected. General background staining and staining of CB1 receptors is differentiated. Using this dilution, fibromyalgia samples and control serum are pooled and tested to determine if any of the fibromyalgia (or control) pools specifically label CB1R (by co-localization with antibody labeling the HA tag). This is repeated with different concentrations of antibody until acceptable background levels (control = fibromyalgia) are achieved. Patients that produce anti-CB 1 antibodies are identified by deconvolving the strongest 3 pools from fibromyalgia patients (30 samples at the dilution determined above). The 5 strongest serum samples identified above are titered. Dilutions from 1:30 to 1:30,000 in ½ log (= 7 samples) steps are examined to determine the titer of the antibodies against the CB1R. Anti-CBl and/or CB2 antibodies from fibromyalgia patients were found to bind the HA-tagged hCB 1 or CB2 receptors.

Example 4

[0054] This example relates to diagnosing Crohn disease. The presence of an anti-CB 1 or an anti-CB2 antibody is tested in a biological sample from a patient. If the presence of anti-CBl or anti-CB2 antibody is detected, the presence or likely presence of Crohn disease in the subject is determined.

Example 5

[0055] This example relates to diagnosing ulcerative colitis. The presence of an anti- CBl or an anti-CB2 antibody is tested in a biological sample from a patient. If the presence of anti-CB 1 or anti-CB2 antibody is detected, the presence or likely presence of ulcerative colitis in the subject is determined.

Example 6

[0056] This example relates to an antibody binding inhibition assay to determine effective agents for treatment of an autoimmune disorder. The assay uses various cannabinoids and/or other small molecules to identify effective agents to inhibit the autoimmune antibody binding. In a preliminary experiment, a panel of all available cannabinoids in semi-purified or purified form is used in a competitive binding assay in which immobilized CB1 and CB2 receptors are first contacted with the panel of cannabinoids at varying concentrations. Optional washes are conducted in some of the samples to indicate binding stringencies of the various cannabinoids. The contacting step and optional washing step is followed by addition of autoimmune antibody collected from patients or raised in model-system animals. Antibody binding to CB1 and CB2 is measured by binding of a secondary antibody permitting quantitative detection of the complex of the receptor, primary antibody, and secondary antibody.

[0057] In a second set of experiments, extracts of cannabis flower of multiple chemotypic profiles are used in place of the single cannabinoids in a range of dilutions. Other aspects of the experiment are held constant.

[0058] In a third set of experiments, one or more libraries of diverse small molecules is used in place of the cannabinoids. In one such experiment, the library of small molecules includes a large number of essential oils, many of which are known to have affinity for G-protein coupled receptors (GPCRs); CB1 and CB2 are both members of the large family of GPCRs, and so the essential oils constitute a diverse and inexpensive, readily available source of small molecules for such an analysis.

[0059] Upon review of the data from the experiments conducted, the cannabinoids, extracts, and other small molecules that are most effective at interfering with autoantibody binding are identified and further quantitative binding analyses are conducted to identify the top effective agents.

Example 7

[0060] This example relates to treating a patient with an autoimmune disorder. Volunteer patients are administered a composition with the effective agents identified in Example 6, in various doses. Safety issues are addressed by administering the effective agents within dosage ranges already known to be tolerated by humans in other uses of the effective agents. Particularly in the case of cannabinoids and essential oils, there are abundant data on human uses and tolerated ranges of dosage. Efficacy of the effective agents is assessed, ranked, and optionally correlated with other patient criteria such as age, gender, genotype, and the like. Amelioration of symptoms of the autoimmune disorder is observed in some of the patients, and further trials are designed based upon these data.

Example 8

[0061] A patient with an autoimmune disorder is treated with a cannabis-based treatment using THC due to its analgesic and sleep-promoting properties, as well as its positive effects on the gut microbiome to reduce autoimmune responses (further details can be found in Russo EB. Cannabis Therapeutics and the Future of Neurology. Frontiers in Integrative Neuroscience 2018;12:1-11. DOI: 10.3389/fnint.2018.00051; the entire contents of the foregoing are fully incorporated by reference herein). Beneficial effects are observed. The study is expanded to a larger number of patients for quantitative determination of dose/response, taking into account the approach to safety of dosage ranges as discussed in Example 7. Other patient characteristics as discussed in Example 7 are also noted for larger personalized-medicine studies.

Example 9

[0062] A patient with an autoimmune disorder is treated with a cannabis-based treatment using CBD which affects auto-antibody binding to the CB1 receptor via its ability to act as a negative allosteric modulator (further details can be found in Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 2015;172(20):4790-805. DOI: 10.1111/bph.13250; the entire contents of the foregoing are fully incorporated by reference herein). Amelioration of symptoms is noted and further studies are conducted as described in Example 8.

Example 10

[0063] A patient with an autoimmune disorder is treated with an optimized cannabis- based preparation combining components such as low-dose THC, higher dose CBD, plus select cannabis terpenoids including caryophyllene for analgesia and reduced inflammation without sedation, and linalool for anti-anxiety benefits (additional information can be found in Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7): 1344-64. (In eng). DOI: 10.1111/j.1476-5381.2011.01238.x; Russo EB, Marcu J. Cannabis pharmacology: The usual suspects and a few promising leads. Advances in Pharmacology 2017;80:71-138. DOI: 10.1016/bs.apha.2017.03.004; and Lewis MA, Russo EB, Smith KM. Pharmacological Foundations of Cannabis Chemovars. Planta Med 2018;84(4):225-233. DOI: 10.1055/s-0043-122240; the entire contents of each of the foregoing are fully incorporated by reference herein. Beneficial results are noted and the study is expanded as described in Example 8.

[0064] The various methods and techniques described above provide a number of ways to carry out the application. Of course, it is to be understood that not necessarily all objectives or advantages described are achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by including one, another, or several other features.

[0065] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

[0066] Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

[0067] In some embodiments, any numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the disclosure are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and any included claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are usually reported as precisely as practicable.

[0068] In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain claims) are construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application. [0069] Variations on preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

[0070] All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting effect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.

[0071] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for diagnosing or monitoring a subject for fibromyalgia comprising providing a biological sample from a subject; detecting the presence of an anti-CBl or an anti-CB2 antibody in the biological sample with an assay; wherein the presence of an anti-CB 1 or an anti-CB2 antibody is indicative of a presence or likely presence of fibromyalgia in the patient.

2. A method for diagnosing or monitoring a subject for fibromyalgia comprising providing a biological sample from a subject; detecting a level of anti-CB 1 or anti-CB2 antibodies in the biological sample with an assay; wherein a significantly higher level of anti-CBl or an anti-CB2 antibodies compared to a level in a control sample is indicative of a presence or likely presence of fibromyalgia in the patient.

3. The method of claims 1 or 2, wherein the sample is serum.

4. The method of claims 1 or 2, wherein the assay is an ELISA.

5. A system for diagnosing or monitoring a subject for fibromyalgia using the method of claims 1 or 2 comprising an immunoassay.

6. The system of claim 5 further comprising a computer.

7. A kit for diagnosing or monitoring a subject for fibromyalgia using the method of claims 1 or 2 comprising reagents for an immunoassay.

8. A method of determining a therapy for fibromyalgia for a subject in need thereof comprising measuring a binding affinity of a composition to CB 1 or CB2 and selecting a composition with a higher binding affinity to CB 1 compared to an anti-CB 1 autoimmune antibody or a higher binding affinity to CB2 compared to an anti-CB2 autoimmune antibody, or both.

9. A method of treating fibromyalgia comprising administering the composition selected in claim 8 that inhibits an anti-CBl or anti-CB2 antibody to a subject with fibromyalgia.

10. The method of claim 9 further comprising administration of a prebiotic or a probiotic or both.