Garcinia KOLA extract, pharmaceutical composition thereof, methods of making the extract and treatments using the same

Abstract

Presented herein are methods of treating attention deficit hyperactivity disorder (ADHD), methods of treating depression, methods of treating an anxiety disorder, and methods of ameliorating cognitive impairment associated with a disorder or disease such as neurodegenerative disorders, ADHD, and schizophrenia, each comprising administering to a subject pharmaceutical compositions comprising an organic solvent-aqueous extract of Garcinia kola seeds. Also disclosed are methods of producing an organic solvent-aqueous extract of Garcinia kola seeds.

Description

GARCINIA KOLA EXTRACT, PHARMACEUTICAL COMPOSITION THEREOF, METHODS OF MAKING THE EXTRACT AND TREATMENTS USING THE SAMEPRIORITY

[0001] This application claims priority to U.S. Provisional Application No. 63 / 656,101 filed on June 5, 2024 and U.S. Provisional Application No. 63,691,684 filed on September 6, 2024 both of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention is directed to methods of treating attention deficit hyperactivity disorder (ADHD), methods of treating depression, methods of treating an anxiety disorder, and methods of ameliorating cognitive impairment associated with a disorder or disease such as, for example, schizophrenia, ADHD, or a neurodegenerative disorder, each comprising administering to a subject a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds. The present invention is also directed to methods of producing an organic solvent-aqueous extract of Garcinia kola seeds.BACKGROUND

[0003] Garcinia kola, also known as bitter kola or G. kola, is a flowering plant of the plant family Clusiaceae found in moist tropical forests throughout West and Central Africa, and is common in parts of Ghana, Cameroon, Nigeria, Democratic Republic of Congo, and Sierra Leone. The fruit, seeds, and bark of Garcinia kola has been traditionally used for centuries by folk healers for ailments such as liver disorders, bronchitis, throat infections, colic, head or chest colds, and cough. It is believed to have purgative, antiparasitic, and antimicrobial properties. Garcinia kola contains a complex mixture of phenolic compounds such as biflavonoids, xanthones, and benzophenones. The biflavonoid complex kolaviron is the predominant constituent in Garcinia kola, and contains biflavanones such as GB1, GB2, and kolaflavanone. However, other compounds found in Garcinia kola may have important effects, and the complex mixture likely acts in a synergistic manner to produce therapeutic response. Further, there are several neuropsychiatric diseases, disorders, and conditions, including the cognitive impacts and negative symptoms of such diseases, for which adequate treatments, therapies, or cures are needed.

[0004] For example, cognitive deficits are a core feature of schizophrenia, account for much of the impaired functioning associated with the disorder, and are not alleviated by existing treatments. In addition, cognitive impairment is often one of the earliest and most persistent symptoms of schizophrenia, manifesting as early as a decade before the onset of more prominent symptoms like hallucinations and delusions. Almost all currently approved pharmacological treatments for schizophrenia exert their effects via antagonism of the dopamine D2 receptor. This mechanism of action is efficacious for symptoms that are thought to be driven by excessive striatal dopamine signaling, such as hallucinations and delusions. However, antipsychotic medications have little impact on cognitive impairments in schizophrenia, perhaps because the latter are related to different pathophysiological processes. McCutcheon, R.A., Keefe, R.S.E. & McGuire, P.K. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry 28, 1902-1918 (2023). And at present, there are no approved treatments directed to addressing the cognitive impairment.

[0005] Accordingly, there remains a need for pharmaceutical compositions and methods for treating neuropsychiatric disorders, as well as a need for methods of producing extracts of Garcinia kola. These needs and others are met by the present invention.SUMMARY

[0006] Disclosed herein are methods of ameliorating cognitive impairment associated with schizophrenia as well as other disorders or disease associated with cognitive impairment, such as, for example, neurodegenerative diseases like Alzheimer’s and Parkinson’s. Such methods comprise administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a composition comprising one or more biflavonoids or flavonoids that include kolaviron.

[0007] Also disclosed herein are methods of treating, such as by improving cognitive performance and more particularly, executive function, in subjects with attention deficit hyperactivity disorder (ADHD) comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds. Such methods can comprise administering the pharmaceutical composition as an adjunct to a primary ADHD pharmaceutical therapy.

[0008] Also disclosed herein are methods of producing an organic solvent-aqueous extract of Garcinia kola seeds.

[0009] Also disclosed herein are methods of treating depression in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds.

[0010] In a further aspect, the pharmaceutical composition is administered to a subject in need thereof in combination with standard therapies for treatment of schizophrenia, ADHD, or a neurodegenerative disorder, or in combination with standard therapies for the treatment of comorbidities associated with schizophrenia, ADHD, or a neurodegenerative disorder, such as anxiety, depression, or cognitive impairment (e.g. executive dysfunction).

[0011] Also disclosed herein are methods of treating an anxiety disorder or alleviating anxiety in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds.

[0012] Also disclosed herein are methods of treating or ameliorating negative symptoms of schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds, wherein the negative symptoms are selected from alogia, avolition, anhedonia, social withdrawal, and blunted affect. In an embodiment, the negative symptom is avolition.

[0013] In one aspect, the patient being treated has failed other treatments or does not tolerate other treatments or the treatments may have risk of long term adverse effects, including anti -depressants, anti-psychotics, ADHD medication or anti-anxiety medication. In such scenarios, the pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds can replace a therapy previously administered to the subject.

[0014] In other embodiment, the pharmaceutical composition can be used as an adjunct to a primary therapy for ADHD, schizophrenia, dementia, Parkinson’s, or Alzheimer’s. The patient is administered other treatments, including anti-depressants, anti-psychotics, ADHD medication oranti-anxiety medication, in combination with a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds.

[0015] In one aspect, disclosed are methods of producing an organic solvent-aqueous extract of Garcinia kola seeds comprising the steps of: a. exposing dried seeds or dried seed tissue from Garcinia kola to a first organic solvent-aqueous solvent to form a first liquid phase and a first solid phase; b. separating the first solid phase from the first liquid phase; and c. evaporating the solvent from the first liquid phase to form a concentrate of the liquid phase.

[0016] Other embodiments are disclosed infra.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a chart showing details for each mouse (ml-m80 and ml02-ml06) included in the study using [18F]FDG scans to assess the effect of Garcinia kola seed extract on brain glucose metabolism. The details for each mouse in the chart include its weight, blood glucose level, injected activity, time between injection and imaging start and SUV (standard uptake value).

[0018] FIGS. 2A-2G depict brain scan image averages for each study group obtained via18F]FDG-microPET which show the effects of Garcinia kola seed extract using SUV (standard uptake value) as the semi-quantitative measure. The study groups are the vehicle (injection of carrier), control (no injection), and dosed groups, namely, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 200 mg doses. Times of scans after dosing indicated on figures for the dosed groups.

[0019] FIGS. 3A-3G depict brain scan image averages for each study group obtained via18F]FDG-microPET which show the effects of Garcinia kola seed extract using SUVr (standard uptake value ratio - reference point is the pons portion of the brainstem) as the semi-quantitative measure. The study groups are the vehicle, control, and dosed groups, namely, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 200 mg doses. Times of scans after dosing indicated on figures for the dosed groups.

[0020] FIGS. 4A-4F depict Voxel-wise images showing the average percentage of change of [18F]FDG-SUV for the dosed groups compared to the vehicle group at 60 min., 120 min., 240 min., and 24 hours.

[0021] FIGS. 5A-5F depict Voxel-wise images showing the average percentage of change of [18F]FDG-SUVr for the dosed groups compared to the vehicle group at 60 min., 120 min., 240 min., and 24 hours.

[0022] FIGS. 6A-6F depict plots showing the group mean regional FDG SUV values for the frontal cortex, temporoparietal cortex, hippocampus, striatum, thalamus, and hypothalamus of each study group.

[0023] FIGS. 7A-7F depict plots showing the group mean regional FDG SUVr values for the frontal cortex, temporoparietal cortex, hippocampus, striatum, thalamus, and hypothalamus of each study group.

[0024] FIGS. 8A-8U depict symmetric heatmaps showing the average metabolic connectivity across previously delineated Voxel-wise images for the control, vehicle, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg dose groups.

[0025] FIG. 9A-9B depict plots showing the percent spontaneous alternation data obtained for a T-maze alternation task.

[0026] FIG. 10A-10B depict plots showing individual mice data for the dark-light test.

[0027] FIG. 11 A-l IB depict plots showing group mice data for the dark-light test.

[0028] FIG. 12A-12B depict plots showing individual and group mice data for the forced swim test.DETAILED DESCRIPTIONI. Definitions

[0029] Where a term is provided in the singular, the inventors also contemplate aspects of the invention described by the plural of that term. As used in this specification and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise, e.g., "a compound" includes a plurality of compounds. Thus, for example, a reference to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0030] “Ameliorate,” “amelioration,” “improvement” or the like refers to, for example, a detectable improvement or a detectable change consistent with improvement that occurs in a subject or in at least a minority of subjects, e.g., in at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between about any two of these values. Such improvement or change may be observed in treated subjects as compared to subjects not treated with a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self-assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement. Amelioration may be transient, prolonged or permanent or it may be variable at relevant times during or after a pharmaceutical composition comprising the organic solvent-aqueous extract of Garcinia kola seeds is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within timeframes described infra, or about 1 hour after the administration or use of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds to about 7 days, 2 weeks, 28 days, or 1, 3, 6, 9 months or more after a subject(s) has received such treatment.

[0031] As used herein, the term “organic solvent-aqueous extract” refers to an extract in which an extraction solvent system used during the extraction process to obtain the extract includes both water and at least one organic solvent. The extraction solvent system can comprise a blend of solvents (cosolvents) of water and at least one organic solvent or a sequence of solvents such as water used in the extraction after or before at least one organic solvent is used, thereafter combining the solvents (with extract) to obtain the organic solvent-aqueous extract. The extraction solvent system can comprise a series of different cosolvents that are used in sequence and thereafter combined to obtain the organic solvent-aqueous extract. The extract solvent system that is a blend of solvents comprising, for example, by weight, at least 0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or at least 90% water and the remainder the at least one organic solvent. An “organic solvent” is a solvent at standard pressure and room temperature that contains only oxygen(s), carbon(s), hydrogen(s), or nitrogen(s). Preferably organic solvents are water miscible. Organic solvents can be methanol, ethanol, propanol, acetone, acetic acid,tetrahydrofuran (THF), acetonitrile, or mixtures thereof. References to the weight of an extract through this disclosure refer to the weight of the dry extract.

[0032] As used herein, the term “alcohol-aqueous extract” refers to an organic solvent- aqueous extract in which the organic solvent is an alcohol which is used to obtain the extract. The extract solvent system can comprise, for example, by weight, at least 0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% water or any value therebetween and the remainder at least one alcohol. Alcohol can be ethanol, methanol, propanol, or combinations thereof.

[0033] As used herein, “subject” includes an animal, including a human, such as adult or pediatric humans.

[0034] The language “an effective amount” of a compound or extract refers to an amount of a compound or extract which is effective, upon single or multiple dose administration to the subj ect to treat an indication or ameliorate a symptom thereof.

[0035] The term “administering” is introducing a pharmaceutical composition to a subject to perform its intended function. Routes of administering that may be used include oral, sublingual, buccal, injection, inhalation, and topical. The pharmaceutical preparations may be given by forms suitable for each administration route. For example, oral preparations can be administered in liquid or capsule form. Oral administration is preferred. Depending on the route of administration, a pharmaceutical composition can be coated with or disposed in a selected material to protect it from natural conditions that may detrimentally affect its ability to perform its intended function. A pharmaceutical composition in accordance with the present disclosure can be administered alone, or in conjunction with either another agent or agents as described above or with a pharmaceutically-acceptable carrier, or both.

[0036] Administration "in combination with" or “co-administered with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

[0037] The phrase “pharmaceutically acceptable” refers to, an active ingredient, excipient, carrier, or any other component of a dosage form that is within the scope of sound medicaljudgment, suitable for use in the intended administration mode, e.g., oral, in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0038] The phrase “pharmaceutically-acceptable carrier” includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.

[0039] The term “treat” or “treatment” as used herein is intended to include the reduction or amelioration of the progression, severity, and / or duration of a condition or one or more symptoms of the condition, e.g., attention deficit hyperactivity disorder (ADHD), depression, an anxiety disorder, cognitive impairment associated with a disorder or disease, including schizophrenia, or negative symptoms (e.g., avolition) associated with a disorder or disease, such as schizophrenia.II. Organic Solvent -Aqueous Extract of Garcinia Kola Seeds

[0040] Garcinia kola contains a complex mixture of phenolic compounds, including biflavonoids, xanthones, and benzophenones. The biflavonoid complex known as kolaviron is the predominant constituent in G. kola, and is a mixture containing the biflavanones Garcinia biflavonoid 1 (GB1), Garcinia flavonoid 2 (GB2), and kolaflavanone. The chemical structure of kolaviron is shown below as Formula I.

[0041] Studies have previously analyzed the chemical composition of G. kola. For example, Unegbu VN et al. analyzed methanolic, ethanolic, and aqueous extracts of Garcinia kola and detected the presence of phenols, flavonoids, steroids, glycosides, tanins, saponins, alkaloids, anthraquinolones, phlobatanin, and terpenoids. Without wishing to be bound by theory, it is believed that the compounds present in the Garcinia kola extract described herein, including the kolaviron complex, likely act in a synergistic manner to produce a therapeutic response for the indications as described herein.

[0042] An extract comprising or consisting of Garcinia kola seeds, in accordance with the present disclosure is an organic solvent-aqueous extract, such as an alcohol-aqueous extract (e.g., methanol-aqueous or ethanol-aqueous) or acetone-aqueous extract. In embodiments, the extract is a whole seed extract. In embodiments, the extract is obtained from a Garcinia kola biomass that is at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% Garcinia kola seeds by weight.

[0043] In embodiments, the organic solvent-aqueous extract, such as the alcohol-aqueous extract, comprises one or more biflavonoids. In embodiments, the organic solvent-aqueous extract of Garcinia kola seeds comprises at least 40% of biflavanoids by total dry extract mass. For example, the organic solvent-aqueous extract can comprise in terms of weight at least 40%, 45%, 50%, 60%, 70%, 80%, or at least 90% biflavonoids of the total dry extract mass. In embodiments, the organic solvent-aqueous extract of Garcinia kola seeds comprises at least 40% of biflavanoids and flavonoids by total dry extract mass. For example, the organic solvent-aqueous extract can comprise in terms of weight at least 40%, 45%, 50%, 60%, 70%, 80%, or at least 90% biflavonoids and flavonoids of the total dry extract mass. In other embodiments, the organic solvent-aqueous extract comprises less than 50% kolaviron. For example, the organic- solvent aqueous extract can comprise 10-50%, 10-30%, 20-45%, 20-40% or 30-40% of kolaviron by weight.

[0044] In embodiments, the organic solvent-aqueous extract comprises kolaviron. Kolaviron is a complex which contains Garcinia biflavanoid 1, Garcinia biflavanoid 2, and kolaflavanone. In embodiments, the organic solvent-aqueous extract comprises, in terms of dry weight %, 20% to 30% Garcinia biflavanoid (GB1). In embodiments, the organic solvent-aqueous extract comprises in terms of dry weight % of the total dry extract mass, 20% to 30% Garcinia biflavanoid (GB2).In embodiments, the organic solvent-aqueous extract comprises in terms of dry weight % of the total dry extract mass, 1.0% to 5.0% kolaflavanone. In embodiments, the organic solvent-aqueous extract comprises, in terms of dry weight % of the total dry extract mass, 20-30% Garcinia biflavanoid 1 and 20-30% Garcinia biflavanoid 2, and optionally 1.0% to 5.0% kolaflavanone.

[0045] The organic solvent-aqueous extract can also comprise, in addition to kolaviron, other biflavonoids such as amentoflavone and binaringenin. In some embodiments, the extract further comprises, in terms of dry weight % of the total dry extract mass, one or more of the following compounds: 0.25% to 1.5% amentoflavone, 0.25% to 1.0% binaringenin, 0.25% to 1.0% garcinianin, and 0.25% to 1.0% kolaflavone.

[0046] In embodiments, the organic solvent-aqueous extract can also comprise one or more compounds that are not biflavonoids, such as a tocopherol, a tocotrienol, a flavonoid, a saponin, kolanone, garcinol, and garcinoic acid, which are also naturally occurring in Garcinia kola seeds. In embodiments, the organic solvent-aqueous extract further comprises garcinoic acid, garcinol, and / or D-tocotrienol. In embodiments, the organic solvent-aqueous extract comprises a tocopherol. In embodiments, the organic solvent-aqueous extract further comprises at least one of a flavonoid and / or a saponin. In embodiments, the organic solvent-aqueous extract further comprises garcinoic acid. In embodiments, the organic solvent-aqueous extract of Garcinia kola seeds results from an extraction process described herein.

[0047] In some embodiments, a method of treatment comprises the administration to a subject in need thereof an effective amount of an organic solvent-aqueous extract of Garcinia kola seeds. In some embodiments, a method of treatment comprises the administration to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent- aqueous extract of Garcinia kola seeds.III. Pharmaceutical Compositions

[0048] Another aspect of the current disclosure are pharmaceutical compositions comprising the organic solvent-aqueous extract of Garcinia kola seeds as described above. (Disclosures of embodiments in this application with reference to an extract are referring to an extract of Garcinia kola seeds.) The pharmaceutical compositions can comprise an amount of the extract that is effective to treat the indications described herein.

[0049] The pharmaceutical composition can comprise any weight percent of the organic solvent-aqueous extract of Garcinia kola seeds. In some embodiments, the pharmaceutical composition comprises a weight percent of from about 30 % to about 100 % of the organic solvent- aqueous extract of Garcinia kola seeds (wt of dry extract / wt of pharmaceutical composition). The pharmaceutical composition can comprise any weight percent in a range of the listed exemplary values. The pharmaceutical composition can comprise a weight percent of the organic solvent- aqueous extract of Garcinia kola seeds of, for example, from about 30 % to about 99 %, from about 30 % to about 95 %, from about 30 % to about 80 %, from about 30 % to about 70 %, from about 30 % to about 60 %, from about 30 % to about 50 %, from about 40 % to about 100 %, from about 40 % to about 80 %, from about 40 % to about 60 %, from about 50 % to about 99%, from about 50 % to about 95% , from about 50 % to about 80 %, from about 50 % to about 70 %, from about 60 % to about 99 %, from about 60 % to about 95 %, from about 60 % to about 90 %, from about 60 % to about 80 %, from about 70 % to about 99%, from about 70 % to about 95 %, from about 70 % to about 90 %, from about 70 % to about 80%, from about 80 % to about 99 %, from about 80 % to about 95 %, or from about 80 % to about 90 %.

[0050] An alternative embodiment of the pharmaceutical composition can be one that comprises one or more biflavonoids or flavonoids including kolaviron. The one or more flavonoids or biflavonoids can further include biflavonoids or flavonoids selected from amentoflavone, kolaflavone, binaringenin, and garcinianin. In one embodiment, the one or more biflavonoids or flavonoids comprise kolaviron, amentoflavone, kolaflavone, binaringenin, and garcinianin. In the composition, the kolaviron can be 70% to 100% by weight of the total mass of the one or more biflavonoids or flavonoids, such as about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% wt / wt. In some embodiments, the kolaviron, amentoflavone, kolaflavone, binaringenin, and garcinianin can together be 75% to 100% by weight of the total mass of the one or more biflavonoids or flavonoids, such as about 75%, 80%, 85%, 90%, 95%, 98%, or 99% wt / wt. In some embodiments, the one or more biflavonoids or flavonoids are 80% to 95% kolaviron, 0.5% to 3% amentoflavone, 0.5% to 2.0% binaringenin, 0.5% to 2.0% garcinianin, and 0.5% to 2.0% kolaflavone by weight of the total mass of the one or more biflavonoids or flavonoids. In addition to the biflavonoids or flavonoids, the composition can further comprise an effective amount of one or more antioxidants selected from a tocotrienol, garcinol, tocopherol, kolanone, garcinoic acid,and saponin. In embodiments, the biflavonoids, flavonoids, and / or antioxidants are not extracted from Garcinia kola. In other embodiments, the biflavonoids, flavonoids, and / or antioxidants are extracted from seeds, flowers, leaves, stems, roots, and / or bark of Garcinia kola.

[0051] Either of the above embodiments of pharmaceutical composition can be formulated in any dosage form. For example, the pharmaceutical composition can be formulated in solid, semisolid, liquid, or aerosol dosage form. In some embodiments, the pharmaceutical composition is formulated as an oral dosage form. In further embodiments, the pharmaceutical composition is formulated as a solid oral dosage form.

[0052] In certain embodiments, the pharmaceutical compositions can further comprise a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, alcohols such as ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0053] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0054] In preparing either of the above embodiments of pharmaceutical compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders,disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.

[0055] Either pharmaceutical composition embodiment can further comprise a sweetener. A sweetener may be added to improve the palatability and acceptability of the pharmaceutical composition by giving it a sweet taste. The sweetener may be any sweetening agent conventionally known in the art for use in pharmaceutical compositions.

[0056] The pharmaceutical compositions described herein can comprise additional excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, or flavoring agent. Compositions may be formulated for selected coated and uncoated tablets, hard and soft gelatin or HMPC capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet, and chewing gums.

[0057] A pharmaceutical composition can comprise 150 mg to 1000 mgIV. Methods of Treating Attention Deficit Hyperactivity Disorder

[0058] Provided herein are methods of treating attention deficit hyperactivity (ADHD) in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as described above, such as one comprising an organic solvent- aqueous extract of Garcinia kola seeds or comprising the one or more biflavonoids or flavonoids. Treating can comprise improving cognitive performance, especially executive function and / or attention.

[0059] Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition which is characterized by excessive amounts of inattention, impulsivity, and in some cases, hyperactivity. ADHD is classified into three major types. Combined type ADHD, the most common type of ADHD, is characterized by impulsive and hyperactive behaviors, as well as inattention and distractibility. Inattentive ADHD, the second most common type of ADHD, is characterized primarily by inattention and distractibility without hyperactivity. Lastly, hyperactive-impulsive ADHD, the least common type of ADHD, is characterized by impulsive and hyperactive behaviors without inattention and distractibility. In some embodiments, thesubject is being treated for attention deficit hyperactivity disorder being inattentive, hyperactive- impulsive, or combined type attention deficit hyperactivity disorder.

[0060] ADHD is associated with various co-morbidities, such as depression, anxiety, or substance use disorder (SUD). In one embodiment, the treatment of co-morbidities associated with ADHD such as depression, anxiety, or SUD comprise administering the pharmaceutical composition as described herein alone or in combination with ADHD medications, such as small molecules approved by a federal drug agency (e.g., FDA) to treat ADHD.

[0061] Studies have found that attention deficit hyperactivity disorder is associated with hypometabolism in the frontal cortex of the brain. Without wishing to be bound by theory, it is believed that the organic solvent-aqueous extract of Garcinia kola seeds which comprise kolaviron with other biflavonoids, tocotrienols, and flavonoids as described herein, when administered to a subject with ADHD, induces metabolism in the frontal cortex and promotes increased brain connectivity between neural network regions. Thus, the pharmaceutical compositions described herein have therapeutic potential for disorders marked by hypometabolism in the frontal cortex, such as ADHD.

[0062] In some embodiments, the subject being treated for attention deficit hyperactivity disorder can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0063] Some patients taking stimulants and other types of drugs traditionally used to treat ADHD can develop, after extended use, tolerance to the ADHD drug. This typically results in the need to dose increase over time to maintain efficacy. This increase in dose can lead to an increase in side effects and risks from the drug , including dependency, cardiovascular side effects, and other long-term health concerns. This increase in tolerance is a particular issue with the patient population being treated with stimulants. Furthermore, there are long-term health concerns with the use of stimulants for the treatment of ADHD. The pharmaceutical composition as describedherein may offer a safer long-term alternative treatment for ADHD compared to conventional stimulants, with less long-term health risks and side effects.

[0064] To counter this need to increase dose of a primary ADHD drug, another aspect of this disclosure is to administer a pharmaceutical composition as described herein as an adjunct therapy in combination with a primary ADHD pharmaceutical therapy. The combination treatment can begin in lieu of increasing the dose of the primary ADHD drug or can begin at the outset of treatment so as to start at a lower dose of the primary ADHD drug. Similarly, the combination treatment can be used in the midst of treatment of the primary ADHD drug and the combination treatment comprises a reduced dose of the primary ADHD drug as compared to the dose prior to beginning the combination treatment. In other embodiments, the patient does not tolerate the ADHD drug due to adverse effects or the ADHD drug is not effective to treat the ADHD in the patient.

[0065] The primary ADHD drug can be at least one drug selected from a stimulant, an alpha- adrenergic agonist, or a norepinephrine reuptake inhibitor. Examples of stimulants suitable for the treatment of ADHD include, but are not limited to, methylphenidate, dexmethylphenidate, amphetamines, serdexmethylphenidate, and lisdexamfetamine, or a combination thereof. Examples of alpha-adrenergic agonists suitable for the treatment of ADHD include, but are not limited to, clonidine and guanfacine. Examples of norepinephrine reuptake inhibitors suitable for the treatment of ADHD include, but are not limited to, atomoxetine and viloxazine. Examples of tricyclic antidepressant suitable for the treatment of ADHD include, but are not limited to, desipramine, imipramine, and nortriptyline. In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a stimulant, an alpha- adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0066] When the pharmaceutical composition is administered in combination with a stimulant, administration of the pharmaceutical composition may prevent the need for stimulant dose escalation. In some embodiments, the subject was previously being treated for or is simultaneously being treated for an attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor. In some embodiments, the pharmaceutical composition is co-administered with at least one drugselected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor. In embodiments, the subject is intolerant to and / or resistant to the at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and is administered the pharmaceutical composition described herein. In embodiments, a pharmaceutical composition as described herein is administered as an adjunct to primary ADHD drug therapy selected from dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, lisdexamfetamine, guanfacine clonidine, atomoxetine, and viloxazine.

[0067] In some embodiments, the subject is administered a daily dose of the composition as described herein, such as the one comprising an organic solvent-aqueous extract comprising the one or more biflavonoids or flavonoids. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the organic solvent-aqueous extract is from about 0.5 mg / kg to 20 mg / kg. (All references to weight of the extract throughout this disclosure is dry weight. Thus, mg / kg is mg of dry weight of the extract per kg of the subject.) The daily dose of the organic solvent-aqueous extract can be, for example, from about 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 15 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 20 mg / kg, 1.5 mg / kg to 8 mg / kg, 1.5 mg / kg to 10 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 10 mg / kg, 4 mg / kg to 15 mg / kg, 4 mg / kg to 10 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 8 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 20 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 16 mg / kg, 8 mg / kg to 20 mg / kg, 10 mg / kg to 20 mg / kg, 12 mg / kg to 20 mg / kg, 12 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg.

[0068] In some embodiments, the pharmaceutical composition comprising the organic solvent-aqueous extract is administered 1, 2, or 3 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, or 3 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0069] Thus, in embodiments, the administered dose or single dosage form of the organic solvent-aqueous extract can be, for example, from can be from 0.5 mg / kg to 20 mg / kg. The administered dose or single dosage form can be, for example, from 1 mg / kg to 15 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 9 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 3 mg / kg,3 mg / kg to 15 mg / kg, 3 mg / kg to 13 mg / kg, 3 mg / kg to 10 mg / kg, 3 mg / kg to 9 mg / kg, 3 mg / kg to 8 mg / kg, 3 mg / kg to 5 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 8 mg / kg, 8 mg / kg to 15 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 9 mg / kg, 9 mg / kg to 15 mg / kg, 9 mg / kg to 13 mg / kg, 9 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 13 mg / kg to 15 mg / kg, 10 mg / kg to 20 mg / kg, or 15 mg / kg to 20 mg / kg. In embodiments, for an adult or 70 kg human, the administered dose or single dosage form of the organic solvent-aqueous extract can be 200 mg to 1000 mg of the organic solvent-aqueous extract, or more particularly, 285 mg to 850 mg.

[0070] In some embodiments, treating attention deficit hyperactivity disorder in a subject comprises administering the pharmaceutical composition comprising the organic solvent-aqueous extract during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for attention deficit hyperactivity disorder, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0071] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased metabolism, a proxy for synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., attention deficit hyperactivity disorder. Although the exact cause of attention deficit hyperactivity disorder is unknown, without wishing to be bound by theory, studies have found that attention deficit hyperactivity disorder is associated with weaker function and structure of the frontal cortex circuits in the brain.

[0072] In some embodiments, administration of the pharmaceutical composition causes increased activation in the frontal cortex region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG). In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 5% to about 50% higher than theactivity prior to initial administration. The activity in the frontal cortex region of the subj ect’ s brain can be about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 20%, about 5% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 20%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 50%, about 30% to about 40%, or about 40% to about 50% higher than the activity prior to initial administration. In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 10% to about 40% higher than the activity prior to initial administration.

[0073] In certain embodiments, the subject being treated for attention deficit hyperactivity disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

[0074] In some embodiments, the subject being treated for attention deficit hyperactivity disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0075] In some embodiments, the subject being treated for attention deficit hyperactivity disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.

[0076] In some embodiments, the method comprises multiple administrations of the pharmaceutical compositions, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0077] Besides the behavioral symptoms of ADHD, ADHD is associated with a range of cognitive deficits. Examples of cognitive deficits associated with ADHD which may be improvedby administration of an effective amount of a pharmaceutical composition as described herein, such as one comprising an organic solvent-aqueous extract of Garcinia kola seeds as described herein include attention deficits, memory problems (such as working memory), executive function deficits, reduced inhibition, emotional regulation deficits, concentration problems, or a combination thereof.

[0078] In some embodiments, the executive function deficit can be treated by administration of an effective amount of a pharmaceutical composition as described herein, such as one comprising an organic solvent-aqueous extract of Garcinia kola seeds. The treatment of executive function deficit can comprise administering the pharmaceutical composition alone or in combination with ADHD medications such as stimulants.V. Methods of Treating Depression

[0079] Provided herein are methods of treating depression in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds, as described above.

[0080] Depression is a disorder characterized by persistently depressed mood, low self- esteem, and loss of interest or pleasure in normally enjoyable activities. Depression can negatively affect a person’s personal life, work life, or education, and can cause issues with a person’s eating habits, sleeping habits, and overall health. Depression is believed to be caused by a combination of genetic, environmental, and psychological factors. Depression as defined herein can correspond to one or more types of depression, such as, for example, major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, atypical depression, and treatment resistant depression. Although the exact cause of depression is unknown, dysregulation of activity in the hippocampus, frontal cortex, cingulate cortex, nucleus accumbens, and amygdala regions of the brain are suspected. Without wishing to be bound by theory, it is believed that the organic solvent-aqueous extract of Garcinia kola seeds described herein, when administered to a subject with depression, induces metabolism in the frontal cortex cingulate cortex, nucleus accumbens amygdala regions, and / or hippocampus and promotes increased brain connectivity between neural network regions, such as the frontal cortex. Thus, the organic solvent-aqueous extract of Garcinia kola seeds describedherein has therapeutic potential for disorders marked by hypometabolism in the frontal cortex, such as depression.

[0081] In some embodiments, the subject being treated for depression can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0082] The pharmaceutical composition can be administered for the treatment of depression alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for depression with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

[0083] Examples of selective serotonin reuptake inhibitors suitable for the treatment of depression include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone.

[0084] Examples of serotonin-norepinephrine reuptake inhibitors suitable for the treatment of depression include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine.

[0085] Examples of norepinephrine and specific serotonergic antidepressant suitable for the treatment of depression include, but are not limited to, aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline / teciptiline.

[0086] Examples of tricyclic antidepressants suitable for the treatment of depression include, but are not limited to, clomipramine, amoxapine, amitriptyline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, and protriptyline.

[0087] Examples of serotonin antagonist and reuptake inhibitors suitable for the treatment of depression include, but are not limited to, etoperidone, lorpiprazole, mepiprazole, nefazodone, and trazodone.

[0088] Examples of monoamine oxidase inhibitors suitable for the treatment of depression include, but are not limited to, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, pirlindole, rasagiline, selegiline, and safinamide.

[0089] In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

[0090] In embodiments, the subject to be administered is already taking a therapeutic for depression, including a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor. In embodiments, the subject to be administered has become intolerant of, for example, due to adverse effects, of the therapeutic for depression and / or the therapeutic is not effective in the subject.

[0091] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the organic solvent-aqueous extract is from about 0.5 mg / kg to 20 mg / kg. (All references to weight of the extract throughout this disclosure is dry weight. Thus, mg / kg is mg of dry weight of the extract per kg of the subject.) The daily dose of the organic solvent-aqueous extract can be, for example, from about 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 15 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 20 mg / kg, 1.5 mg / kg to 8 mg / kg, 1.5 mg / kg to 10 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kgto 10 mg / kg, 4 mg / kg to 15 mg / kg, 4 mg / kg to 10 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 8 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 20 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 16 mg / kg,8 mg / kg to 20 mg / kg, 10 mg / kg to 20 mg / kg, 12 mg / kg to 20 mg / kg, 12 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg.

[0092] In some embodiments, the pharmaceutical composition is administered 1, 2, or 3 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, or 3 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0093] Thus, in embodiments, the administered dose or single dosage form of the organic solvent-aqueous extract can be, for example, from can be from 0.5 mg / kg to 20 mg / kg. The administered dose or single dosage form can be, for example, from 1 mg / kg to 15 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 9 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 13 mg / kg, 3 mg / kg to 10 mg / kg, 3 mg / kg to 9 mg / kg, 3 mg / kg to 8 mg / kg, 3 mg / kg to 5 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 8 mg / kg, 8 mg / kg to 15 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 9 mg / kg, 9 mg / kg to 15 mg / kg,9 mg / kg to 13 mg / kg, 9 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 13 mg / kg to 15 mg / kg, 10 mg / kg to 20 mg / kg, or 15 mg / kg to 20 mg / kg. In embodiments, for an adult or 70 kg human, the administered dose or single dosage form of the organic solvent-aqueous extract can be 200 mg to 1000 mg of the organic solvent-aqueous extract, or more particularly, 285 mg to 850 mg.

[0094] In some embodiments, treating depression in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for depression, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0095] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantifymetabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased metabolism, a proxy for synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., depression. Although the exact cause of attention deficit hyperactivity disorder is unknown, without wishing to be bound by theory, studies have found that attention deficit hyperactivity disorder is associated with weaker function and structure of the frontal cortex circuits in the brain.

[0096] In some embodiments, administration of the pharmaceutical composition causes increased activation in the frontal cortex region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy -D-glucose (FDG). In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 5% to about 50% higher than the activity prior to initial administration. The activity in the frontal cortex region of the subject’s brain can be about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 20%, about 5% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 20%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 50%, about 30% to about 40%, or about 40% to about 50% higher than the activity prior to initial administration. In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 10% to about 40% higher than the activity prior to initial administration.

[0097] In certain embodiments, the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

[0098] In some embodiments, the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0099] In some embodiments, the subject being treated for depression is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.

[0100] Schizophrenia is a mental disorder which is characterized by delusions, hallucinations, disorganized thinking and behavior, and flat or inappropriate affect. Patients with schizophrenia are at an increased risk for the development of depression relative to the general population. Depression is associated with a less favorable patient course and poorer outcomes compared to patients with schizophrenia without depression. In some embodiments, the subject being treated for depression with an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds is treated for depression associated with schizophrenia.VI. Methods of Treating an Anxiety Disorder

[0101] Provided herein are methods of treating an anxiety disorder in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as described above, such as one comprising an organic solvent-aqueous extract of Garcinia kola seeds or one or more biflavonoids and flavonoids . In some embodiments, the organic solvent- aqueous extract of Garcinia kola seeds is produced using methods described herein.

[0102] Anxiety disorders are characterized by intense, excessive, and persistent worry or fear about everyday situations. The symptoms resulting from this abnormal level of worry or fear can interfere with daily functions, such as job performance, schoolwork, and relationships. Often, anxiety disorders involve repeated episodes of intense anxiety and fear or terror that reach a peak within minutes. These episodes are also known as panic attacks. The constellation of symptomsof anxiety disorders depend on the type but as whole, symptoms can include restlessness, difficulty controlling feelings of worry, difficulty concentrating, increased heart rate, heart palpitations, irritability, trembling, tingling, having a sense of impending danger, panic, or doom, feeling nervous or out of control, hyperventilation, sleep issues, fatigue, feelings of self-consciousness or fear that others will judge negatively, rigid body posture or overly soft voice, difficulty making eye contact or being around unfamiliar people, and gastrointestinal problems. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, and medication-induced anxiety disorder. In some embodiments, the subject is being treated for an anxiety disorder being generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, or medication-induced anxiety disorder.

[0103] Although the exact causes of anxiety disorders are unknown, frontal cortex, amygdala and the hypothalamus regions of the brain likely play key roles in stress responses, and by extension, anxiety. In embodiments, administration of the pharmaceutical composition causes increased activation in at least one of: the frontal cortex, amygdala and hypothalamus regions of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy- D-glucose (FDG) during treatment comprising administration of the pharmaceutical composition. In some embodiments, the subject being treated for an anxiety disorder can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0104] The pharmaceutical composition can be administered for the treatment of an anxiety disorder alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for an anxiety disorder with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for an anxiety disorderwith at least one drug selected from a selective serotonin reuptake inhibitor, a serotoninnorepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor.

[0105] Examples of selective serotonin reuptake inhibitors suitable for the treatment of an anxiety disorder include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone.

[0106] Examples of serotonin norepinephrine reuptake inhibitors suitable for the treatment of an anxiety disorder include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine.

[0107] Examples of tricyclic antidepressants suitable for the treatment of an anxiety disorder include, but are not limited to, clomipramine, amoxapine, amitriptyline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, and protriptyline.

[0108] Examples of benzodiazepines suitable for the treatment of an anxiety disorder include, but are not limited to, clonazepam, alprazolam, lorazepam, bromazepam, oxazepam, chlordiazepoxide, clorazepate, and diazepam.

[0109] Examples of beta-blockers suitable for the treatment of an anxiety disorder include, but are not limited to, acebutolol, bisoprolol, carvedilol, propranolol, atenolol, and metoprolol.

[0110] Examples of monoamine oxidase inhibitors suitable for the treatment of an anxiety disorder include, but are not limited to, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, pirlindole, rasagiline, selegiline, and safinamide.

[0111] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the organic solvent-aqueous extract is from about 0.5 mg / kg to 20 mg / kg. (All references to weight of the extract throughout this disclosure is dry weight. Thus, mg / kg is mg of dry weight of the extract per kg of the subject.) The daily dose of the organic solvent-aqueous extract can be, for example, from about 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 15 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 20 mg / kg,1.5 mg / kg to 8 mg / kg,1.5 mg / kg to 10 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 10 mg / kg, 4 mg / kg to 15 mg / kg, 4 mg / kg to 10 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 8 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 20 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 16 mg / kg,8 mg / kg to 20 mg / kg, 10 mg / kg to 20 mg / kg, 12 mg / kg to 20 mg / kg, 12 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg.

[0112] In some embodiments, the pharmaceutical composition is administered 1, 2, or 3 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, or 3 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0113] Thus, in embodiments, the administered dose or single dosage form of the organic solvent-aqueous extract can be, for example, from can be from 0.5 mg / kg to 20 mg / kg. The administered dose or single dosage form can be, for example, from 1 mg / kg to 15 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 9 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 13 mg / kg, 3 mg / kg to 10 mg / kg, 3 mg / kg to 9 mg / kg, 3 mg / kg to 8 mg / kg, 3 mg / kg to 5 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 8 mg / kg, 8 mg / kg to 15 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 9 mg / kg, 9 mg / kg to 15 mg / kg,9 mg / kg to 13 mg / kg, 9 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 13 mg / kg to 15 mg / kg, 10 mg / kg to 20 mg / kg, or 15 mg / kg to 20 mg / kg. In embodiments, for an adult or 70 kg human, the administered dose or single dosage form of the organic solvent-aqueous extract can be 200 mg to 1000 mg of the organic solvent-aqueous extract, or more particularly, 285 mg to 850 mg.

[0114] In some embodiments, treating an anxiety disorder in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for an anxiety disorder, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0115] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased metabolism, a proxy for synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., anxiety disorders.

[0116] In some embodiments, administration of the pharmaceutical composition causes increased activation in the frontal cortex region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG). In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 5% to about 50% higher than the activity prior to initial administration. The activity in the frontal cortex region of the subj ecf s brain can be about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 20%, about 5% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 20%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 50%, about 30% to about 40%, or about 40% to about 50% higher than the activity prior to initial administration. In some embodiments, the activity in the frontal cortex region of the subject’s brain is about 10% to about 40% higher than the activity prior to initial administration.

[0117] In certain embodiments, the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a betablocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug. In a certain embodiment, the subject being treated for the anxiety disorder has been and continues to be on an anti-anxiolytic drug and further is administered the pharmaceutical composition described herein.

[0118] In some embodiments, the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a betablocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0119] In some embodiments, the subj ect being treated for an anxiety disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.

[0120] Up to 65% of people with schizophrenia have anxiety. Symptoms of schizophrenia, such as hallucinations and delusions, can contribute to feelings of anxiety for patients with schizophrenia. One of the most common anxiety disorders to affect patients with schizophrenia is social anxiety disorder (SAD), or fear related to social situations. Schizophrenia can also be co- morbid with anxiety disorders such as obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and panic disorder. In some embodiments, the subject being treated for anxiety with an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds is treated for anxiety associated with schizophrenia.VII. Methods of Ameliorating Cognitive Impairment Associated with a Disorder or Disease

[0121] Provided herein are methods of ameliorating cognitive impairment associated with a disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition as described herein, such as one comprising an organic solvent-aqueous extract of Garcinia kola seeds or one comprising the one or more biflavonoids or flavonoids including kolaviron. Examples of disorders or diseases which have associated cognitive impairment include, but are not limited to neurodegenerative disorders and schizophrenia.

[0122] Cognition is the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses. It encompasses all aspects of intellectual functions, such as perception, attention, memory, judgment, problem solving, and comprehension and production of language. Cognitive skills relate to the ability to perform executive functions such as reasoning, planning, language, and social interactions. “Cognitive impairment” is an inclusive term used to describe the impairment of any such aspects or intellectual functions associated with cognition, including executive function. A patient with cognitive impairment may have trouble with memory, concentration, planning, or making decisions that affect daily life.

[0123] Cognitive impairment can be caused by a variety of factors, which can be genetic, environmental, old age, etc. In some instances, cognitive impairment is correlated with oxidative stress and neuroinflammation that is an effect of the disorder or disease with which the cognitive impairment is associated. Cognitive impairment may also be associated with hypometabolism in the hippocampus region of the brain. Executive function skills are regulated predominantly by the neurons of the prefrontal cortex which is part of the frontal cortex. Without wishing to be bound by theory, it is believed that the organic solvent-aqueous extract of Garcinia kola seeds described herein, when administered to a subject with cognitive impairment, may minimize the effects of oxidative stress and neuroinflammation, and may induce hypermetabolism in the hippocampus and / or prefrontal cortex. Cognitive impairment and treatment of cognitive impairment can be assessed by standard assessment scales, such as, for example, Self-Administered Gerocognitive Exam, mini-cog, Montreal Cognitive Assessment, Mini-Mental State Examination, General Practitioner Assessment of Cognition, Six-Item Cognitive Impairment Test, Alzheimer's Disease Assessment Scale - Cognitive, standard ADHD assessment test and scales, intelligence assessment test and scales, and executive function test and scales.

[0124] Impairment of executive function is a hallmark of many diseases, includingADHD, depression, and anxiety previously discussed, as well as indications such as autism spectrum disorder, traumatic brain injury, dementias, substance abuse, schizophrenia and obsessive-compulsive disorder.

[0125] In some embodiments, the subject can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0126] The pharmaceutical composition can be administered for the amelioration of cognitive impairment associated with a disorder or disease alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for cognitive impairment associated with a disorder with the pharmaceutical composition and at least one other drug, including drugs for the disease or disorder or for cognitive impairment. Included are treatment of subjects who are on a therapeutic for the disease or disorder, including where the subject is administered the drug for the disease or disorder or to treat or ameliorate the cognitive impairment and are administered and effective amount of the pharmaceutical composition described herein. In embodiments, the subject is not tolerant of the drug for the treatment of the disease or disorder or the cognitive impairment or that drug is not effective or has lost effectiveness for the treatment of the disease or disorder or the cognitive impairment and is administered an effective amount of the pharmaceutical composition disclosed herein.

[0127] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the organic solvent-aqueous extract is from about 0.5 mg / kg to 20 mg / kg. (All references to weight of the extract throughout this disclosure is dry weight. Thus, mg / kg is mg of dry weight of the extract per kg of the subject.) The daily dose of the organic solvent-aqueous extract can be, for example, from about 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 15 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 20 mg / kg, 1.5 mg / kg to 8 mg / kg, 1.5 mg / kg to 10 mg / kg, 3 mg / kg to 20 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 10 mg / kg, 4 mg / kg to 15 mg / kg, 4 mg / kg to 10 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 8 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to15 mg / kg, 5 mg / kg to 20 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 16 mg / kg, 8 mg / kg to 20 mg / kg, 10 mg / kg to 20 mg / kg, 12 mg / kg to 20 mg / kg, 12 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg.

[0128] In some embodiments, the pharmaceutical composition is administered 1, 2, or 3 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, or 3 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0129] Thus, in embodiments, the administered dose or single dosage form of the organic solvent-aqueous extract can be, for example, from can be from 0.5 mg / kg to 20 mg / kg. The administered dose or single dosage form can be, for example, from 1 mg / kg to 15 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg to 9 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 15 mg / kg, 3 mg / kg to 13 mg / kg, 3 mg / kg to 10 mg / kg, 3 mg / kg to 9 mg / kg, 3 mg / kg to 8 mg / kg, 3 mg / kg to 5 mg / kg, 4 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, 5 mg / kg to 15 mg / kg, 5 mg / kg to 13 mg / kg, 5 mg / kg to 10 mg / kg, 5 mg / kg to 9 mg / kg, 5 mg / kg to 8 mg / kg, 8 mg / kg to 15 mg / kg, 8 mg / kg to 13 mg / kg, 8 mg / kg to 10 mg / kg, 8 mg / kg to 9 mg / kg, 9 mg / kg to 15 mg / kg, 9 mg / kg to 13 mg / kg, 9 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 13 mg / kg to 15 mg / kg, 10 mg / kg to 20 mg / kg, or 15 mg / kg to 20 mg / kg. In embodiments, for an adult or 70 kg human, the administered dose or single dosage form of the organic solvent-aqueous extract can be 200 mg to 1000 mg of the organic solvent-aqueous extract, or more particularly, 285 mg to 850 mg.

[0130] In some embodiments, ameliorating cognitive impairment associated with a disorder or disease in a subject comprises administering an effective amount of the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for a neurodegenerative disorder, or from a drug to a drug comprising the pharmaceutical composition as described herein. In embodiments, the subject either can no longer tolerate a drug for treatment of the disease or disorder, for example, due to adverse effects, and / or the drug is no longer effective or has reduced effectiveness for the treatment of the disease or disorder so the subject is administered an effective amount of the pharmaceutical composition described herein.

[0131] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased metabolism, as a proxy for synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with cognitive impairment. Although the exact causes of cognitive impairment is unknown, without wishing to be bound by theory, studies have shown that the hippocampus regions of the brain likely play key roles.

[0132] In some embodiments, the subject being administered the pharmaceutical composition is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects. In other embodiments, the subject is on an existing or standard treatment prior to treatment with the pharmaceutical composition comprising an organic solvent- aqueous extract of Garcinia kola seeds.

[0133] Other disorders where administering an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds may ameliorate or prevent cognitive impairment include those where a drug or treatment causes such cognitive impairment. Examples of such drugs or treatments include, but are not limited to, chemotherapy (chemobrain), antiretroviral therapies, hepatitis treatments, benzodiazepines, antidepressants, anti convulsive agents, antipsychotics, antihistamines, sleep aid medication, incontinence drugs, antimuscarinics, corticosteroids, diphenhydramine, high blood pressure medications, pain medications, and statins.

[0134] Other disorders where cognitive impairment is observed include viral infections, bacterial infections, long COVID, schizophrenia, and epilepsy.

[0135] In some embodiments, the disorder or disease is autism spectrum disorder, substance abuse disorder, schizophrenia, obsessive-compulsive disorder, or a cognitive impairment disorder resulting from a traumatic brain injury.A. Neurodegenerative Disorders

[0136] The above described method for ameliorating cognitive impairment can be administered to subjects with a neurodegenerative disorder. Neurodegenerative disorders are conditions that gradually damage and destroy portions of a subject’s nervous system, especially areas of the brain. These disorders typically develop slowly, with the effects and symptoms tending to appear later in life. Examples of neurodegenerative disorders include, but are not limited to, Alzheimer’s disease, Parkinson's disease, Huntington's disease, and spinocerebellar ataxia. The symptoms of neurodegenerative disorders vary widely on the type of disorder. Many of these neurodegenerative disorders have cognitive impairment associated with the disorder. Dementiatype diseases, such as Alzheimer’s, are characterized by confusion, memory loss, trouble thinking or concentrating, and behavior changes. Parkinson’s disease is also frequently associated with cognitive impairment.

[0137] Specific dementias where administering an effective amount of a pharmaceutical composition as described herein, such as one comprising an organic solvent-aqueous extract of Garcinia kola seeds may ameliorate , prevent, or slow the rate of decline in cognitive impairment including frontal temporal dementia, frontal temporal dementia with parkinsonism, Lewy body dementia, mild cognitive impairment, mild to moderate cognitive impairment, and vascular dementia.

[0138] In some embodiments, the disorder is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, and spinocerebellar ataxia.

[0139] In some embodiments, the subject was previously being treated for or is simultaneously being treated for a neurodegenerative disorder with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

[0140] In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

[0141] Suitable cholinesterase inhibitors for the treatment of neurodegenerative disorders include, but are not limited to, rivastigmine, donepezil, and galantamine.

[0142] Suitable N-m ethyl -D-aspartate receptor antagonists for the treatment of neurodegenerative disorders include, but are not limited to, memantine,

[0143] In some embodiments, the subject being administered the pharmaceutical composition as described herein has been previously or is currently being treated for a neurodegenerative disorder with at least one drug selected from a cholinesterase inhibitor or a N- methyl-D-aspartate (NDMA) receptor antagonist and has been identified as a subject that has experienced or is experiencing treatment resistance or intolerance to the at least one drug.A. Schizophrenia

[0144] The above described method for ameliorating cognitive impairment can be administered to subjects with schizophrenia. As discussed above, schizophrenia is a mental disorder characterized by hallucinations, such as visual and auditory hallucinations, delusions, disorganized thinking, flat or inappropriate affect, and cognitive impairment (i.e., cognitive deficit). Cognitive impairment is typically the first symptom to present and often years before the more pronounced symptoms like hallucinations and delusions present. Cognitive impairment can present in the pre-teen or teenage years with symptoms worsening gradually . More pronounced symptoms, particularly those referred to as positive symptoms, typically onset during young adulthood. There is no cure for schizophrenia, but medical professionals can help manage the symptoms to improve quality of life. Treatment is typically lifelong and includes a combination of medications and psychological and social therapy.

[0145] The symptoms of schizophrenia are usually classified into positive, negative, and cognitive symptoms (namely, cognitive impairments). Positive symptoms include any change in behavior or thoughts, such as hallucinations and delusions. Negative symptoms refers to behaviors or emotions which are deficient or lacking in patients with schizophrenia. Examples of negative symptoms associated with schizophrenia include, but are not limited to, alogia, avolition, anhedonia, social withdrawal, and blunted affect. In some embodiments, the administration of an effective dose of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds as described herein is for the treatment of a negative symptom associated withschizophrenia, such as those selected from alogia, avolition, anhedonia, social withdrawal, and blunted affect.

[0146] The term “avolition” as used herein refers to a negative symptom associated with schizophrenia characterized by lack of motivation or ability to do tasks or activities which have an end goal. Patients with schizophrenia are at an increased risk for avolition, and can experience difficulties in maintaining a job or caring for personal health and hygiene. In some embodiments, the administration of an effective dose of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds as described herein is for the treatment of avolition associated with schizophrenia.

[0147] Cognitive impairments are one of the core symptoms of schizophrenia. Examples of cognitive impairments associated with schizophrenia which may be ameliorated by administration of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds as described herein include attention deficits, memory problems, processing speed deficits, executive functioning deficits, social cognition deficits, learning deficits, or a combination thereof. Ameliorating cognitive impairment in schizophrenia can comprise improving one or more cognitive functions selected from memory (such as working memory), attention, executive functioning, reasoning, decision making, and processing speed.

[0148] In addition to ameliorating cognitive impairment, pharmaceutical compositions described herein can also provide a neuroprotective effect that slows the rate of progression of schizophrenia. In embodiments, pharmaceutical compositions described herein can be used to ameliorate cognitive impairment and slow the rate of progression in schizophrenia, particularly when administered during the early stages in the pre-teen (10-12) or teen years by administering the pharmaceutical compositions as described herein in a manner described herein.

[0149] Medications which are most often prescribed for the treatment of schizophrenia are anti-psychotic drugs. These drugs ease symptoms such as hallucinations and delusions. Antipsychotic medications are generally grouped into “first-generation,” “typical,” or “conventional” antipsychotics, and newer, “second-generation” or “atypical” anti-psychotics. Atypical antipsychotics are currently more widely used for the treatment of schizophrenia. In someembodiments, the pharmaceutical composition is co-administered with at least one atypical antipsychotic drug.

[0150] In some embodiments, the pharmaceutical composition is co-administered with at least one atypical anti-psychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

[0151] In some embodiments, the subject was previously being treated for or is simultaneously being treated with at least one atypical anti-psychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

[0152] In embodiments, the subj ect has become resistant to or intolerant of an anti-psychotic drug, including an atypical anti-psychotic drug. In embodiments, the subject who is administered an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds has been on anti-psychotic therapies and continues anti-psychotic therapies after initiating treatment with the pharmaceutical composition described herein. In other embodiments, the subject is resistant to or is intolerant of an atypical anti-psychotic therapy and initiates treatment with the pharmaceutical composition disclosed herein as an alternative therapy or in combination with a lower dose of the anti-psychotic therapy.II, Methods of Producing Pharmaceutical Compositions

[0153] Provided herein are methods of producing pharmaceutical compositions comprising an effective amount of an organic solvent-aqueous extract of Garcinia kola seeds.

[0154] In one embodiment, the method comprises the steps of: a. exposing dried seeds or dried seed tissue from Garcinia kola to a first extraction solvent comprising first organic solvent and water to form a first liquid phase and a first solid phase; b. separating the first solid phase from the first liquid phase; and c. evaporating at least a portion of the extraction solvent from the first liquid phase to form a concentrate of the liquid phase.

[0155] Examples of organic solvents which can be used as the first organic solvent-aqueous solvent can be ethanol, methanol, isopropyl, butanol, acetone, acetonitrile, or combinations thereof. In some embodiments, the first organic solvent comprises or consists of an alcohol. In some embodiments, the alcohol comprises or consists of methanol.

[0156] In some embodiments, the extraction solvent comprises from 50% to 100% methanol. The extraction solvent can comprise, for example, from 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 70%, 70% to 100%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 99%, 80% to 95%, 80% to 90%, 90% to 100%, 90% to 99%, or 90% to 95% methanol and the remainder being water. In some embodiments, extraction solvent comprises from 50% to 100% water. The extraction solvent can comprise, for example, from 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 70%, 70% to 100%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 99%, 80% to 95%, 80% to 90%, 90% to 100%, 90% to 99%, or 90% to 95% water and the remainder being alcohol, such as methanol.

[0157] In some embodiments, the extraction solvent comprises from 50% to 100% methanol and from 50% to 100% water.

[0158] In some embodiments, the concentrate of the liquid phase is further powderized to form the organic solvent-aqueous extract of Garcinia kola seeds.

[0159] In some embodiments, the method further comprises exposing the first solid phase to the first extraction solvent described above to form a second liquid phase and a second solid phase; and combining the first liquid phase and the second liquid phase to form a pooled liquid phase and evaporating at least a portion of the first extraction solvent to produce the concentrate of the liquid phase.

[0160] In some embodiments, the method further comprises exposing the second solid phase to the first extraction solvent described above to form a third liquid phase and a third solid phase; and combining the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid phase and evaporating at least a portion of the extraction solvent to produce the concentrate of the liquid phase.

[0161] In some embodiments, the method further comprises exposing the third solid phase to the first extraction solvent described above to form a fourth liquid phase; and combining the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid and evaporating at least a portion of the extraction solvent to produce the concentrate of the liquid phase.

[0162] In some embodiments, the method further comprises exposing the fourth solid phase to the first extraction solvent to form a fifth liquid phase; and combining the fifth liquid phase, the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to produce the concentrate of the liquid phase.

[0163] In some embodiments, the concentrate of the liquid phase is a slurry. The slurry can comprise a mixture of denser solids being Garcinia kola whole seeds, Garcinia kola seed parts, or a combination thereof in a solvent.

[0164] In some embodiments, the method further comprises: solubilizing the concentrate of the liquid phase in water to precipitate water insoluble compounds; and separating the water insoluble compounds from the concentrate of the liquid phase. Examples of water insoluble compounds which can be precipitated and separated from the concentrate of the liquid phase include, but are not limited to, tannins and fats.

[0165] In some embodiments, the concentrate of the liquid phase is exposed to an adsorbent material being a gel resin, a non-ionic macroporous resin, an ion-exchange resin, or a combination thereof. In further embodiments, the adsorbent material is washed with an impurity-eluting solvent to remove unwanted components from the adsorbent material. The solvent can be, for example, water, or an alcohol-aqueous solvent comprising less than 50%, 40%, 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or less than 1% alcohol. Examples of impurities which can be removed from the adsorbent material include, but are not limited to, sugars, carbohydrates, fats, and proteins.

[0166] In some embodiments, the adsorbent material is eluted with an extract-eluting solvent to release the desired components, such as bioflavonoids, to form an eluted concentrate. In some embodiments, the eluting solvent comprises from 50% to 80% ethanol. The extract-eluting solvent can comprise, for example, from 50% to 75%, 50% to 70%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%, 70% to 80%, 70% to 75%, or 75% to 80% ethanol. The extract-eluting solventcan comprise, for example, 50%, 55%, 60%, 65%, 70%, 75%, or 80% ethanol. In some embodiments, the extract-eluting solvent is an alcohol-water mixture comprising from 50% to 80% ethanol. The extract-eluting solvent can be, for example, an alcohol-water mixture comprising from 50% to 75%, 50% to 70%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%, 70% to 80%, 70% to 75%, or 75% to 80% ethanol. The extract-eluting solvent being an alcohol-water mixture can comprise, for example, 50%, 55%, 60%, 65%, 70%, 75%, or 80% ethanol.

[0167] In some embodiments, fractions of the eluted concentrate can be combined to form a pooled mixture. In a further embodiment, the pooled mixture is volume reduced to form a concentrated mixture.

[0168] In some embodiments, the eluted concentrate, the pooled mixture thereof, or the concentrated mixture is dried using a drying technology. The drying technology further removes or evaporates excess solvent. Examples of suitable drying technologies include spray drying, belt drying, or freeze drying.

[0169] The eluted concentrate, the pooled mixture thereof, the concentrated mixture, or the dried product of any of the foregoing can be mixed with a pharmaceutically acceptable excipient to form the pharmaceutical composition. Examples of pharmaceutically acceptable excipients include, but are not limited to, one or more of a diluting agent, a binding agent, a lubricating agent, a disintegrating agent, coloring agent, or a flavoring agent.Embodiments

[0170] Embodiment 1 : A method of ameliorating cognitive impairment associated with schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0171] Embodiment 2: The method of embodiment 1, wherein the cognitive impairment is selected from attention deficits, memory problems, processing speed deficits, executive functioning deficits, social cognition deficits, learning deficits, or a combination thereof.

[0172] Embodiment 3: The method of embodiment 1 or 2, wherein the pharmaceutical composition is co-administered with at least one atypical anti-psychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

[0173] Embodiment 4: The method according to any of embodiments 1-3, wherein the subject was previously being treated for or is simultaneously being treated with at least one atypical antipsychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

[0174] Embodiment 5: The method according to any of embodiments 1-4, wherein the pharmaceutical composition is an oral dosage form.

[0175] Embodiment 6: The method according to any of embodiments 1 -5, wherein the extract is a whole seed extract.

[0176] Embodiment 7: The method according to any of embodiments 1-6, wherein the extract comprises a biflavonoid.

[0177] Embodiment 8: The method according to any of embodiments 1-7, wherein the biflavonoid is kolaviron.

[0178] Embodiment 9: The method according to any of embodiments 1-8, wherein the extract comprises a tocopherol and / or tocotrienol.

[0179] Embodiment 10: The method according to any of embodiments 1-9, wherein the extract further comprises at least one of a flavonoid and / or a saponin.

[0180] Embodiment 11 : The method according to any of embodiments 1-10, wherein the extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0181] Embodiment 12: The method according to any of embodiments 1-11, wherein the subject is a mammal.

[0182] Embodiment 13: The method according to any of embodiments 1-12, wherein the subject is a human.

[0183] Embodiment 14: The method according to any of embodiments 1-13, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg.

[0184] Embodiment 15: The method according to embodimentl4, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0185] Embodiment 16: The method according to any of embodiments 1-15, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0186] Embodiment 17: The method according to any one of embodiments 1-16, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0187] Embodiment 18: The method according to any one of embodiments 1-17, wherein the subject is a juvenile or 10-15 years of age or wherein the subject has yet to develop paranoia, hallucinations, or delusions.

[0188] Embodiment 19: A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0189] Embodiment 20: The method according to embodiment 19, wherein the pharmaceutical composition is an oral dosage form.

[0190] Embodiment 21 : The method according to embodiments 19 or 20, wherein the organic solvent-aqueous extract is a whole seed extract.

[0191] Embodiment 22: The method according to any one of embodiments 19-21, wherein the organic solvent -aqueous extract comprises a biflavonoid.

[0192] Embodiment 23: The method according to embodiment 22, wherein the biflavonoid is kolaviron.

[0193] Embodiment 24: The method according to any one of embodiments 19-23, wherein the organic solvent-aqueous extract comprises a tocopherol and / or tocotrienol.

[0194] Embodiment 25: The method according to any one of embodiments 19-24, wherein the organic solvent -aqueous extract further comprises at least one of a flavonoid, and / or a saponin.

[0195] Embodiment 26: The method according to any one of embodiments 19-25, wherein organic solvent -aqueous extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0196] Embodiment 27: The method according to any one of embodiments 19-26, wherein the subject is a mammal.

[0197] Embodiment 28: The method according to any one of embodiments 19-27, wherein the subject is a human.

[0198] Embodiment 29: The method according to any one of embodiments 19-28, wherein the administered daily dose of the organic solvent -aqueous extract is from about 0.5 mg / kg to 20 mg / kg.

[0199] Embodiment 30: The method according to embodiment 29, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0200] Embodiment 31 : The method according to any one of embodiments 19-30, wherein the attention deficit hyperactive disorder is inattentive, hyperactive-impulsive, or combined type attention deficit hyperactive disorder.

[0201] Embodiment 32: The method according to any one of embodiments 19-31, wherein the subject was previously being treated for or is simultaneously being treated for an attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0202] Embodiment 33: The method according to any one of embodiments 19-32, wherein the pharmaceutical composition is co-administered with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0203] Embodiment 34: The method according to embodiment 32 or 33, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, lisdexamfetamine, or a combination thereof.

[0204] Embodiment 35: The method according to embodiment 32 or 33, wherein the alpha- adrenergic agonist is guanfacine or clonidine.

[0205] Embodiment 36: The method according to embodiment 32 or 33, wherein the norepinephrine reuptake inhibitor is atomoxetine or viloxazine.

[0206] Embodiment 37: The method according to any one of embodiments 19-36, wherein the administration of the pharmaceutical composition causes increased activity in the frontal cortex region of the subject’s brain relative to activity prior to initial administration, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG).

[0207] Embodiment 38: The method according to embodiment 37, wherein the activity in the frontal cortex region of the subject’s brain is about 5% to 50% higher than the activity prior to initial administration.

[0208] Embodiment 39: The method according to embodiment 38, wherein the activity in the frontal cortex region of the subject’s brain is about 10% to 40% higher than the activity prior to initial administration.

[0209] Embodiment 40: The method according to any of embodiments 19-39, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0210] Embodiment 41 : The method according to any one of embodiments 19-40, wherein treating ADHD in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for treating ADHD to another medication for treating ADHD or when the subject is tapering a dose or administration frequency of a medication for treating ADHD.

[0211] Embodiment 42: The method according to any one of embodiments 19-41, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0212] Embodiment 43: A method of treating depression in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent -aqueous extract of Garcinia kola seeds.

[0213] Embodiment 44: The method according to embodiment 43, wherein the pharmaceutical composition is an oral dosage form.

[0214] Embodiment 45: The method according to embodiment 43 or 44, wherein the organic solvent -aqueous extract is a whole seed extract.

[0215] Embodiment 46: The method according to any one of embodiments 43-45, wherein the organic solvent -aqueous extract comprises a biflavonoid.

[0216] Embodiment 47: The method according to embodiment 46, wherein the biflavonoid is kolaviron.

[0217] Embodiment 48: The method according to any one of embodiments 43-47, wherein the organic solvent-aqueous extract comprises a tocopherol and / or tocotrienol.

[0218] Embodiment 49: The method according to any one of embodiments 43-48, wherein the organic solvent -aqueous extract further comprises at least one of a flavonoid and / or a saponin.

[0219] Embodiment 50: The method according to any one of embodiments 43-49, wherein organic solvent -aqueous extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0220] Embodiment 51 : The method according to any one of embodiments 43-50, wherein the subject is a mammal.

[0221] Embodiment 52: The method according to any one of embodiments 43-51, wherein the subject is a human.

[0222] Embodiment 53: The method according to any one of embodiments 43-52, wherein the administered daily dose of the organic solvent -aqueous extract is from about 0.5 mg / kg to about 20 mg / kg.

[0223] Embodiment 54: The method according to embodiment 53, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0224] Embodiment 55: The method according any one of embodiments 43-54, wherein the subject is being treated for depression with at least one antidepressant drug selected from a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a noradrenaline and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

[0225] Embodiment 56: The method according any one of embodiments 43-55, wherein the pharmaceutical composition is co-administered with at least one antidepressant drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

[0226] Embodiment 57: The method according to any one of embodiments 43-56, wherein the administration of the pharmaceutical composition causes increased activity in the frontal cortex region of the subject’s brain relative to activity prior to initial administration, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG).

[0227] Embodiment 58: The method according to embodiment 57, wherein the activity in the frontal cortex region of the subject’s brain is about 5% to 50% higher than the activity prior to initial administration.

[0228] Embodiment 59: The method according to embodiment 58, wherein the activity in the frontal cortex region of the subject’s brain is about 10% to 40% higher than the activity prior to initial administration.

[0229] Embodiment 60: The method according to any of embodiments 43-59, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0230] Embodiment 61 : The method according to any one of embodiments 43-60, wherein treating depression in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for treating depression to another medication for treating depression or when the subject is tapering a dose or administration frequency of a medication for treating depression.

[0231] Embodiment 62: The method according to any one of embodiments 43-61, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0232] Embodiment 63: A method of treating an anxiety disorder in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent -aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0233] Embodiment 64: The method according to embodiment 63, wherein the pharmaceutical composition is an oral dosage form.

[0234] Embodiment 65: The method according to embodiment 63 or 64, wherein the organic solvent -aqueous extract is a whole seed extract.

[0235] Embodiment 66: The method according to any one of embodiments 63-65, wherein the organic solvent -aqueous extract comprises a biflavonoid.

[0236] Embodiment 67: The method according to embodiment 66, wherein the biflavonoid is kolaviron.

[0237] Embodiment 68: The method according to any one of embodiments 63-67, wherein the organic solvent -aqueous extract comprises a tocopherol and / or tocotrienol.

[0238]

[0239] Embodiment 69: The method according to any one of embodiments 63-68, wherein the organic solvent -aqueous extract further comprises at least one of a flavonoid and / or a saponin.

[0240] Embodiment 70: The method according to any one of embodiments 63-69, wherein organic solvent -aqueous extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0241] Embodiment 71 : The method according to any one of embodiments 63-70, wherein the subject is a mammal.

[0242] Embodiment 72: The method according to any one of embodiments 63-71, wherein the subject is a human.

[0243] Embodiment 73: The method according to any one of embodiments 63-72, wherein the administered daily dose of the organic solvent -aqueous extract is from about 0.5 mg / kg to about 20 mg / kg.

[0244] Embodiment 74: The method according to embodiment 73, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0245] Embodiment 75: The method according to any one of embodiments 63-74, wherein the subject is being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor.

[0246] Embodiment 76: The method according any one of embodiments 63-75, wherein the pharmaceutical composition is co-administered with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor.

[0247] Embodiment 77: The method according to any of embodiments 63-76, wherein the anxiety disorder is selected from generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, and medication-induced anxiety disorder.

[0248] Embodiment 78: The method according to embodiment 77, wherein the anxiety disorder is generalized anxiety disorder (GAD).

[0249] Embodiment 79: The method according to any one of embodiments 63-78, wherein the administration of the pharmaceutical composition causes increased activity in the frontal cortexregion of the subject’s brain relative to activity prior to initial administration, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG).

[0250] Embodiment 80: The method according to embodiment 79, wherein the activity in the frontal cortex region of the subject’s brain is about 5% to 50% higher than the activity prior to initial administration.

[0251] Embodiment 81 : The method according to embodiment 80, wherein the activity in the frontal cortex region of the subject’s brain is about 10% to 40% higher than the activity prior to initial administration.

[0252] Embodiment 82: The method according to any of embodiments 63-81, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0253] Embodiment 83: The method according to any one of embodiments 63-82, wherein treating depression in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for treating an anxiety disorder to another medication for treating an anxiety disorder or when the subject is tapering a dose or administration frequency of a medication for treating an anxiety disorder.

[0254] Embodiment 84: The method according to any one of embodiments 63-83, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0255] Embodiment 85: A method of ameliorating cognitive impairment associated with a disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent -aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0256] Embodiment 86: The method according to embodiment 85, wherein the pharmaceutical composition is an oral dosage form.

[0257] Embodiment 87: The method according to embodiment 85 or 86, wherein the extract is a whole seed extract.

[0258] Embodiment 88: The method according to any one of embodiments 85-87, wherein the extract comprises a biflavonoid.

[0259] Embodiment 89: The method according to embodiment 88, wherein the biflavonoid is kolaviron.

[0260] Embodiment 90: The method according to any one of embodiments 85-89, wherein the extract comprises a tocopherol and / or tocotrienol.

[0261] Embodiment 91 : The method according to any one of embodiments 85-90, wherein the extract further comprises at least one of a flavonoid and / or a saponin.

[0262] Embodiment 92: The method according to any one of embodiments 85-91, wherein extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0263] Embodiment 93: The method according to any one of embodiments 85-92, wherein the subject is a mammal.

[0264] Embodiment 94: The method according to any one of embodiments 85-93, wherein the subject is a human.

[0265] Embodiment 95: The method according to any one of embodiments 85-94, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg.

[0266] Embodiment 96: The method according to embodiment 95, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0267] Embodiment 97: The method according to any of embodiments 85-96, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0268] Embodiment 98: The method according to any one of embodiments 85-97, wherein ameliorating cognitive impairment associated with a disorder or disease in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for ameliorating cognitive impairment to another medication for amelioratingcognitive impairment or when the subject is tapering a dose or administration frequency of a medication for ameliorating cognitive impairment.

[0269] Embodiment 99: The method according to any one of embodiments 85-98, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0270] Embodiment 100: The method according to any of embodiments 85-99, wherein the subject was previously being treated for or is simultaneously being treated with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

[0271] Embodiment 101 : The method according to any of embodiments 85-100, wherein the pharmaceutical composition is co-administered with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

[0272] Embodiment 102: The method according to any of embodiments 85-101, wherein the disorder is a neurodegenerative disorder selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, and spinocerebellar ataxia or wherein the disorder is epilepsy or wherein the disorder is Long CO VID.

[0273] Embodiment 103: A pharmaceutical composition comprising an organic solvent- aqueous extract of Garcinia kola seeds, wherein the extract comprises, in terms of dry weight %, 20-30% Garcinia hydroxybiflavanonol 1 and 20-30% Garcinia hydroxybiflavanonol 2, wherein the organic solvent can comprise ethanol, methanol, or acetonitrile.

[0274] Embodiment 104: The pharmaceutical composition of embodiment 103, wherein the composition further comprises, in terms of dry weight %, 0.25-1.5% amentoflavone, 1.0-5.0% kolaflavanone, 0.25-1.0% binaringenin, 0.25-1.0% garcinianin, and 0.25-1.0% kolaflavone.

[0275] Embodiment 105: The pharmaceutical composition of embodiment 103 or 104, wherein biflavanoids are at least 40% of the total dry extract mass.

[0276] Embodiment 106: The pharmaceutical composition according to any of embodiments 103-105, wherein the organic solvent-aqueous extract further comprises garcinoic acid, garcinol, and / or D-tocotrienol.

[0277] Embodiment 107: A method of making an organic solvent-aqueous extract of Garcinia kola seeds comprising the steps of:

[0278] exposing dried seeds or dried seed tissue from Garcinia kola to a first organic solvent- aqueous solvent to form a first liquid phase and a first solid phase;

[0279] separating the first solid phase from the first liquid phase; and

[0280] evaporating the solvent from the first liquid phase to form a concentrate of the liquid phase.

[0281] Embodiment 108: The method of embodiment 107, wherein the first organic solvent- aqueous solvent is a first alcohol-aqueous solvent comprising from 50% to 100% methanol and from 50% to 100% water.

[0282] Embodiment 109: The method of embodiment 107 or 108, further comprising powderizing the concentrate to form the extract.

[0283] Embodiment 110: The method according to any of embodiments 108 or 109, further comprising exposing the first solid phase to the first alcohol-aqueous solvent to form a second liquid phase and a second solid phase; and combining the first liquid phase and the second liquid phase to form a pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

[0284] Embodiment 111: The method according to embodiment 110, further comprising exposing the second solid phase to the first alcohol-aqueous solvent to form a third liquid phase and a third solid phase; and combining the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

[0285] Embodiment 112: The method according to embodiment 111, further comprising exposing the third solid phase to the first alcohol-aqueous solvent to form a fourth liquid phase; and combining the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid and evaporating the solvent to produce the concentrate of the liquid phase.

[0286] Embodiment 113: The method according to embodiment 112, further comprising exposing the fourth solid phase to the first alcohol-aqueous solvent to form a fifth liquid phase; and combining the fifth liquid phase, the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to produce the concentrate of the liquid phase.

[0287] Embodiment 114: The method according to any of embodiments 107-113, wherein the concentrate of the liquid phase is a slurry.

[0288] Embodiment 115: The method according to any of embodiments 107-114, wherein the method further comprises:

[0289] solubilizing the concentrate of the liquid phase in water to precipitate water insoluble compounds; and

[0290] separating the water insoluble compounds from the concentrate of the liquid phase.

[0291] Embodiment 116: The method according to any of embodiments 107-1 15, wherein the concentrate of the liquid phase is exposed to an absorbent material selected from a gel resin, a nonionic macroporous resin, an ion-exchange resin, or a combination thereof.

[0292] Embodiment 117: The method according to embodiment 116, wherein the adsorbent material is washed with a second solvent to remove impurities.

[0293] Embodiment 118: The method according to embodiment 116 or 117, wherein the concentrate of the liquid phase is exposed to a gel resin, non-ionic macroporous resin, ionexchange resin, or a combination thereof is eluted with a third solvent to form an eluted concentrate.

[0294] Embodiment 119: The method according to embodiment 118, wherein fractions of the eluted concentrate of the liquid phase are combined to form a pooled mixture.

[0295] Embodiment 120: The method according to embodiment 119, wherein the pooled mixture is volume reduced to form a concentrated mixture.

[0296] Embodiment 121 : The method according to embodiment 120, wherein the concentrated mixture is combined with pharmaceutically acceptable excipients or bioavailability enhancers to produce a standard dosage of a pharmaceutical composition.

[0297] Embodiment 122: The method according to embodiment 120 or 121, wherein the concentrated mixture is dried using spray drying, belt drying, freeze drying, or a combination thereof.

[0298] Embodiment 123: An extract produced by the method according to any of embodiments 107-122.

[0299] Embodiment 124: A method of treating anxiety associated with schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0300] Embodiment 125: The method according to embodiment 124, wherein the subject is a mammal.

[0301] Embodiment 126: The method according embodiment 124 or 125, wherein the subject is a human.

[0302] Embodiment 127: The method according to any of embodiments 124-126, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg.

[0303] Embodiment 128: The method according to embodiment 127, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0304] Embodiment 129: The method according to any of embodiments 124-128, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0305] Embodiment 130: The method according to any one of embodiments 124-129, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0306] Embodiment 131 : A method of treating depression associated with schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of apharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron

[0307] Embodiment 132: The method according to embodiment 131, wherein the subject is a mammal.

[0308] Embodiment 133 : The method according embodiment 131 or 132, wherein the subject is a human.

[0309] Embodiment 134: The method according to any of embodiments 131-133, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg.

[0310] Embodiment 135: The method according to embodiment 134, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0311] Embodiment 136: The method according to any of embodiments 131-135, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0312] Embodiment 137: The method according to any one of embodiments 131-136, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0313] Embodiment 138: A method of improving cognitive performance in a subject with attention deficit hyperactivity disorder (ADHD) comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent - aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

[0314] Embodiment 139: The method of embodiment 138, wherein the improvement in cognitive performance is selected from attention deficits, memory problems, executive functioning deficits, reduced inhibition, emotional regulation deficits, concentration problems, or a combination thereof.

[0315] Embodiment 140: The method of 138 or 139, wherein the attention deficit hyperactive disorder is inattentive, hyperactive-impulsive, or combined type attention deficit hyperactive disorder.

[0316] Embodiment 141 : The method according to any one of embodiments 138-140, wherein the subject was previously being treated for or is simultaneously being treated for an attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0317] Embodiment 142: The method according to any one of embodiments 138-141, wherein the pharmaceutical composition is co-administered with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0318] Embodiment 143: The method according to embodiment 141 or 142, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, lisdexamfetamine, or a combination thereof.

[0319] Embodiment 144: The method according to embodiment 141 or 142, wherein the alpha-adrenergic agonist is guanfacine or clonidine.

[0320] Embodiment 145: The method according to embodiment 141 or 142, wherein the norepinephrine reuptake inhibitor is atomoxetine or viloxazine.

[0321] Embodiment 146: The method according to any of embodiments 138-145, wherein the pharmaceutical composition is an oral dosage form.

[0322] Embodiment 147: The method according to any of embodiments 138-146, wherein the extract is a whole seed extract.

[0323] Embodiment 148: The method according to any of embodiments 138-145, wherein the extract comprises a biflavonoid.

[0324] Embodiment 149: The method according to embodiment 148, wherein the biflavonoid is kolaviron.

[0325] Embodiment 150: The method according to any of embodiments 138-149, wherein the extract comprises a tocopherol and / or tocotrienol.

[0326] Embodiment 151 : The method according to any of embodiments 138-150, wherein the extract further comprises at least one of a flavonoid and / or a saponin.

[0327] Embodiment 152: The method according to any of embodiments 138-151, wherein the extract further comprises garcinoic acid and / or kolanone and / or garcinol.

[0328] Embodiment 153: The method according to any of embodiments 138-152, wherein the subject is a mammal.

[0329] Embodiment 154: The method according to any of embodiments 138-151, wherein the subject is a human.

[0330] Embodiment 155: The method according to any of embodiments 138-154, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg.

[0331] Embodiment 156: The method according to embodiment 155, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

[0332] Embodiment 157: The method according to any of embodiments 138-156, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

[0333] Embodiment 158: The method according to any one of embodiments 138-157, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

[0334] Embodiment 159: A method of treating a negative symptom associated with schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent -aqueous extract of Garcinia kola seeds according to any of embodiments 107-122.

[0335] Embodiment 160: The method of embodiment 159, wherein the negative symptom is avolition.

[0336] Embodiment 161 : The method of any one of embodiments 1-106 or 124-160, wherein the subject is resistant to or intolerant of a drug that is standard therapy for the symptom, disease or disorder.

[0337] Embodiment 162: A method according to any one of embodiments 1 -102 and 124 to 161, wherein the pharmaceutical composition is a pharmaceutical composition according to any one of embodiments 103 to 106.

[0338] Embodiment 163: A method according to any one of embodiments 1 -102 and 124 to 161, wherein the pharmaceutical composition comprises an organic solvent -aqueous extract according to embodiment 123.

[0339] Embodiment 164: A pharmaceutical composition comprising one or more biflavonoids and flavonoids comprising kolaviron, amentoflavone, kolaflavanone, binaringenin, garcinianin, and kolaflavone, wherein kolaviron is 70% to 100% by weight of the total mass of the one or more biflavonoids or flavonoids.

[0340] Embodiment 165: The pharmaceutical composition according to embodiment 164, wherein the kolaviron can be 80% to 98% wt / wt of the total mass of the one or more biflavonoids or flavonoids.

[0341] Embodiment 166: The pharmaceutical composition according to embodiment 164 or 165, wherein the kolaviron, amentoflavone, kolaflavone, binaringenin, and garcinianin can together be 75% to 100% or 75% to 98% by weight of the total mass of the one or more biflavonoids or flavonoids.

[0342] Embodiment 167: The pharmaceutical composition according to embodiment 164, wherein the one or more biflavonoids or flavonoids are 80% to 95% kolaviron, 0.5% to 3% amentoflavone, 0.5% to 2.0% binaringenin, 0.5% to 2.0% garcinianin, and 0.5% to 2.0% kolaflavone by weight of the total mass of the one or more biflavonoids or flavonoids.

[0343] Embodiment 168: The pharmaceutical composition according to any one of the embodiments 164-167, further comprising one or more antioxidants selected from a tocotrienol, garcinol, kolanone, garcinoic acid, and saponin or including tocotrienol, garcinol, tocopherol, kolanone, garcinoic acid, saponin, or a combination thereof.

[0344] Embodiment 169: The pharmaceutical composition according to embodiment 168, wherein the amount of the one or more antioxidants in the composition are about 20% to 40% by weight of the total weight of the one or more biflavonoids or flavonoids.

[0345] Embodiment 170: The pharmaceutical composition according to any one of the embodiments 164-169, wherein the biflavonoids, flavonoids, and / or antioxidants are extracted from seeds, flowers, leaves, stems, roots, and / or bark of Garcinia kola.

[0346] Embodiment 171 : The pharmaceutical composition according to any one of the embodiments 164-170, wherein composition is in a single dosage form and the mass of the one or more biflavonoids or flavonoids is 100 mg to 500 mg per single dosage form.

[0347] Embodiment 172: A method according to any one of embodiments 1 -102 and 124 to 161, wherein the pharmaceutical composition is a pharmaceutical composition according to any one of embodiments 164-170.Ill ExamplesExample 1 - Extraction of Garcinia kola Seeds

[0348] Dried seed tissue from Garcinia kola (whole or powdered) is first soaked, agitated, and exposed to 50-100% methanol / water by volume in order to extract components such as biflavonoids, saponins, cardiac glycosides, tannins, tocopherols, tocotrienol and essential oils. Next, the solid portion of the biomass above a certain size, such as 10-25 microns, is filtered from the solvent. The solid portion is then re-extracted using the same solvent and filtering process. The extraction process can be repeated sequentially up to five times. The solvent from each extraction step is then combined into a pooled extract. The pooled extract is then evaporated to concentrate to dryness or to a slurry. The concentrated extract is then re-suspended in water to cause precipitation or phase separation of water insoluble components such as tannins and / or oils. The aqueous phase of the re-suspended extract is then filtered to remove the water insoluble components. Next, the aqueous phase of the re-suspended extract is exposed to an adsorbent material such as a gel resin, a non-ionic macroporous resin, an ion-exchange resin (cationic or anionic), or a combination thereof. This step allows for the adsorption and concentration of the desired Garcinia kola secondary metabolites onto the adsorbent material. The adsorbent materialis then washed with a solvent such as water or low concentration alcohol to remove impurities such as sugars, carbohydrates, oils, and proteins from the adsorbent material. A different solvent, such as 50-80% ethanol, is used to elute the absorbent material to produce the desired profile of the organic solvent-aqueous extract. Optionally, fractions produced from the washing and elution of the adsorbent material can be combined. The combined fractions or pooled extract is then evaporated to produce a concentrated mixture.

[0349] Drying technology, such as spray drying, belt drying, freeze drying, or a combination thereof, can be utilized to further evaporate solvent from the pooled concentrated extract. The standardized dry extract is then powderized.

[0350] The biflavonoid / flavonoid profile of the organic solvent-aqueous extract obtained from the above-described process is detailed in Table 1. Total biflavonoids constitute at least 40% of the total dry extract mass.Table 1

[0351] The extract further comprises various antioxidants including tocotrienol, garcinol, kolanone, garcinoic acid, and saponin. Pharmaceutically acceptable excipients or bioavailability enhancers can then be mixed with the concentrated mixture to produce a standardized dosage of the organic solvent-aqueous extract of Garcinia kola seeds.Example 2 -FDG-PET Studies After Oral Administration of Garcinia kola Extract

[0352] Multiple static18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG- PET) imaging experiments were conducted in mice after orally receiving an extract of Garcinia kola seeds in different doses and being scanned at different times.

[0353] Methods

[0354] Mice were kept in a room with a controlled temperature (21 °C) under a 12 h light / dark cycle (lights on 7 a.m.) and had access to food and water ad libitum. Every day, food was removed 7 a.m. and scans started 10 a.m. The short fasting period was implemented to avoid stress, but also to reduce any potential interaction between food and the extract. An extract dosage form was prepared solubilizing the extract prepared in accordance with Example 1 in 5% ethanol and 5% polysorbate 20 (Tween®). Adult male mice received the extract dosage form via gavage at doses of 25, 50, 75, 100, 150, and 200 mg / Kg. Brain metabolism was assessed with18F-FDG-PET imaging at different time points after the extract administration as shown in Table 2.Table 2

[0355] Blood glucose was also assessed to correct for potential transport competition with [18F]FDG. Mice received an intravenous injection of [18F]FDG and were maintained awake, freely moving, for a 40-minute uptake period, followed by a 10-minute static acquisition under isoflurane anesthesia. Body temperature was maintained at 36.5 ± 1 °C, and vital signs, including respiration, heart rate, and body temperature, were monitored throughout scanning procedures. Individual summaries for each mouse are depicted in FIG. 1 and include the weight, blood glucose level, injected activity, time between injection and imaging start and SUV (standard uptake value) of the mice in the study.

[0356] Image Analysis

[0357] Imaging analysis was conducted using Mine-tools(https: / / www.bic.mni.mcgi 11. ca / ServicesSoftware / Se,icesSofiwareMincToolKit accessed on May 7, 2024). Micro-PET images were manually co-registered to a standard mice histological magnetic resonance template. Standard Uptake Values (SUVs) were calculated using the following equation: SUV = (radioactivity) / (dose injected / body weight) and Standardized Uptake Value Ratio (SUVr) was calculated with pons as the pseudo reference region.

[0358] Regional SUV and SUVr were extracted from delimited volumes of interest (VOIs), defined on the mice template for the following brain regions: frontal cortex (CxF), temporoparietal cortex (CxTP), hippocampus, striatum, thalamus, hypothalamus. In addition, local maxima (brain area with the maximum SUV / SUVr value), voxelwise analyses, and metabolic connectivity were also conducted. Visual readings and statistical significance of p < 0.05 were used to evaluate differences between groups.

[0359] Effects of Garcinia kola Seed Extract using SUV as the semi -quantitative measure

[0360] The effects of Garcinia kola seed extract on brain glucose metabolism was assessed by [18F]FDG-microPET using SUV as the semi-quantitative measure. The brain glucose map images are shown in FIG. 2A-2G. FIG. 2A shows the mean standardized uptake value (SUV) of control and vehicle groups (N=8). FIG. 2B shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 25 mg / kg groups at 4 time points: 60 minutes, 120 minutes, 240 minutes, and 24 hours. A noticeable increase in [18F]FDG uptake was observed at all time points. FIG. 2C shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 50 mg / kg groups at 4 time points: 60 minutes, 120 minutes, 240 minutes, and 24 hours. A noticeable increase in [18F]FDG uptake was observed at 60 and 120 minutes (N=8). FIG. 2D shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 75 mg / kg groups at 4 time points: 60 minutes, 120 minutes, 240 minutes, and 24 hours. A noticeable increase in18F]FDG uptake was observed at 240 minutes. FIG. 2E shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 100 mg / kg groups at 4 time points: 60 minutes, 120 minutes, 240 minutes, and 24 hours. A noticeable increase in [18F]FDG uptake was observed at 60, 120 and 240 minutes (N=8 ). FIG. 2 F shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 150 mg / kg groups at 4 time points: 60 minutes, 120 minutes, 240 minutes, and 24 hours. FIG. 2G shows the mean standardized uptake value (SUV) of Garcinia kola seed extract 200 mg / kg in the 60-minute group, 120 minutes, 240 minutes, and 24 hours (N=5).

[0361] The visual readings indicated an effect of vehicle injection compared to control. Stress caused by animal manipulation and / or the ethanol in the dosage form could contribute to this difference. Thus, all comparisons were made among vehicle and drug-tested groups. Visual reading indicated a widespread increase in brain glucose metabolism in 25, 50, and 100 mg / kg at 60 minutes after administering the Garcinia kola seed extract, but no effect was seen with 75, 150, and 200 mg / kg. At 120 minutes, an increase was observed for 25, 50, and 100 mg / kg. At 240 minutes, the increase was still present in the animals that received 25, 75, and 100 mg / kg. At 24h, the brain glucose metabolism was consistent with the vehicle group’s brain glucose metabolism.

[0362] Effects of Garcinia kola Seed Extract using SUVr as the quantitative measure

[0363] The effects of Garcinia kola seed extract on brain glucose metabolism was assessed by18F]FDG-microPET using SUVr as the quantitative measure. FIG. 3A-3G show brain glucosemaps for this study. FIG. 3A shows the mean standardized uptake value ratio (SUVr) of control and vehicle groups. FIG. 3B shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 25 mg / kg groups in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours. FIG. 3C shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 50 mg / kg groups, in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours. FIG. 3D shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 75 mg / kg groups in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours. FIG. 3E shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 100 mg / kg groups in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours. FIG. 3F shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 150 mg / kg groups in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours. FIG. 3G shows the mean standardized uptake value ratio (SUVr) of Garcinia kola seed extract 200 mg / kg in 4 time points: 60 minutes, 120 minutes, 240 minutes and 24 hours.

[0364] Visual reading indicated an effect of vehicle injection compared to control (no injection). This observation is compatible with stress caused by animal manipulation. Thus, all comparisons were made between vehicle and tested groups. Visual reading indicated a widespread increase in brain glucose metabolism in 25, 50 and 100 mg / kg 60 minutes after administering the Garcinia kola seed extract, but no effect of 200 mg was seen. At 120 minutes, an increase is observed for 25 and 100 mg / kg. At 240 minutes, the increase was still present in the animals that received 25, 50, and 100 mg / kg. At 24 h, the brain glucose metabolism is consistent with the vehicle group’s brain glucose metabolism.

[0365] Voxel-Wise Analysis: Voxel-Wise analysis was performed for visualization of the percentage of change of18F]FDG-SUV and18F]FDG-SUVr.

[0366] FIG. 4A-4F shows voxel-wise images representing the percentage of change of18F]FDG-SUV. FIG. 4A shows the percentage of change between vehicle and 25 mg / kg group The 25 mg / kg group presented a few small clusters (small brain areas) of glucose metabolism increase, between 5 and 30%. FIG. 4B shows the percentage of change between vehicle and the 50 mg / kg group. The 60 and 120 min groups presented several clusters of increased glucose metabolism in the range of between 5 and 30% (N = 8). FIG. 4C shows the percentage of changebetween vehicle and the 75 mg / kg group. The 75mg / kg - 60min group presented a few clusters of increased glucose metabolism between 5 and 20%. Also, 75mg / kg - 240 min group presented several clusters of increased glucose metabolism between 5 and 30%., (N = 8).

[0367] FIG. 4D shows the percentage of change between vehicle and the 100 mg / kg group. The lOOmg / kg - 60 min, 120 min and 240 min groups presented several clusters of glucose metabolism increase between 5 and 50%, (N = 8). FIG. 4E shows the percentage of change between vehicle and the 150 mg / kg group. The 150 mg / kg - 240 min and 24 h groups presented several clusters of glucose metabolism increase between 5 and 25% (N = 8). FIG. 4F shows the percentage of change between vehicle and the 200 mg / kg group. No changes from vehicles were seen with the 200 mg / kg group.

[0368] The visual perception was corroborated by the percentage of change maps. The dose of 25 mg caused an increase in brain glucose metabolism in all groups. The dose of 50 mg caused an increase in brain glucose metabolism at 60 and 120 minutes but no changes at 240 minutes and 24 h. The dose of 75mg caused an increase in brain glucose metabolism majority at 240 minutes. The dose of 100 mg caused an increase in brain glucose metabolism at 60, 120, and 240 minutes but no changes at 24 h. The peak effect can be seen in the prefrontal cortex, reaching more than a 40 % increase (white clusters depicted on the brain surfaces).

[0369] FIG. 5A- 5F shows voxel-wise images representing the percentage of change of18F]FDG-SUVr. FIG. 5A shows the percentage of change between vehicle and 25 mg / kg group. The 25mg / kg group presented a few small clusters of increased glucose metabolism, between 5 and 10%. FIG. 5B shows the percentage of change between vehicle and 50 mg / kg group. The 50 mg / kg group presented a few small clusters of glucose metabolism increase, between 5 and 10%. FIG. 5C shows the percentage of change between vehicle and the 75 mg / kg group. The 75mg / kg - 240min group presented a few small clusters of glucose metabolism increase, between 5 and 10%. FIG. 5D shows the percentage of change between vehicle and 100 kg / kg group. The lOOmg / kg group presented several clusters of glucose metabolism increase, between 5 and 22.5%. FIG. 5E shows the percentage of change between vehicle and the 150 mg / kg group. The 150mg / kg - 120min group presented a few small clusters of glucose metabolism increase, between 5 and 10%. FIG. 5F shows the percentage of change between vehicle and 200 mg / kg group. The200mg / kg - 60min group presented a few small clusters of glucose metabolism increase, between 5 and 10%.

[0370] The visual perception was corroborated by the percentage of change maps. The dose of 25 mg / kg caused small increases in all times. The dose of 50 mg / kg caused small increases in delimited brain regions at 60, 120, and 240 minutes, but no changes at 24 h. The 75mg / kg group presented a small increase in brain glucose metabolism at 240 minutes. The dose of 100 mg / kg caused an increase in brain glucose metabolism at 60, 120, 240 min, and 24 h. The 150 mg / kg group presented a small increase in brain glucose metabolism at 120 minutes. The 200 mg / kg group presented a small increase in brain glucose metabolism at 60 minutes. The peak effect can be seen in the prefrontal cortex, reaching more than a 15 % increase (blue clusters depicted on the brain surfaces).

[0371] FIG. 6A-6F are plots showing group mean regional FDG SUV values for the frontal cortex (FIG. 6A), temporoparietal cortex (FIG. 6B), hippocampus (FIG. 6C), striatum (FIG. 6D), thalamus (FIG. 6E), and hypothalamus (FIG. 6F). Points under the shaded square indicate values that surpass the mean of the vehicle. Data are presented as mean values ± S.E.M and individual scatter plots. Conventional VOI analyses did not reveal differences among groups. FIG. 6A shows frontal cortex (CxF) means regional FDG SUV values in vehicle, water, 25 mg / kg (60, 120, 240min and 24h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60, 120, 240min and 24h). N = 8 for25, 50, 75, 100 and 150 mg / kg and N =5 for 200 mg / kg. FIG. 6B shows temporoparietal cortex (CxTP) means regional FDG SUV values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60, 120, 240min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 6C shows hippocampus means regional FDG SUV values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60, 120, 240min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 6D shows striatum means regional FDG SUV values invehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60, 120, 240min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 6E shows thalamus means regional FDG SUV values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60 , 120, 240min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 6F shows hypothalamus means regional FDG SUV values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240min and 24h), 75 mg / kg (60, 120, 240min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240min and 24h) and 200 mg / kg (60 , 120, 240min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7A-7F are plots showing group mean regional FDG SUVr values for the frontal cortex (FIG. 7A), temporoparietal cortex (FIG. 7B), hippocampus (FIG. 7C), striatum (FIG. 7D), thalamus (FIG. 7E), and hypothalamus (FIG. 7F). Points under the shaded square indicate values that surpass the mean of the vehicle. Conventional VOI analyses did not reveal statistically significant differences among groups. Data are presented as mean values ± S.E.M and individual scatter plots. FIG. 7A shows the frontal cortex (CxF) means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240 min and 24h), 75 mg / kg (60, 120, 240 min and 24h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24h) and 200 mg / kg (60, 120, 240 min and 24h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7B shows the temporoparietal cortex (CxTP) means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240 min and 24 h), 75 mg / kg (60, 120, 240 min and 24 h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24 h) and 200 mg / kg (60, 120, 240 min and 24 h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7C shows the hippocampus means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240 min and 24 h), 75 mg / kg (60, 120, 240 min and 24 h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24 h) and 200 mg / kg (60, 120, 240 min and 24 h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7D shows the striatum means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and24 h), 50 mg / kg (60, 120, 240 min and 24 h), 75 mg / kg (60, 120, 240 min and 24 h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24 h) and 200 mg / kg (60, 120, 240 min and 24 h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7E shows the thalamus means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240 min and 24 h), 75 mg / kg (60, 120, 240 min and 24 h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24 h) and 200 mg / kg (60, 120, 240 min and 24 h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg. FIG. 7F shows the hypothalamus means regional FDG SUVr values in vehicle, water, 25 mg / kg (60, 120, 240 min and 24 h), 50 mg / kg (60, 120, 240 min and 24 h), 75 mg / kg (60, 120, 240 min and 24 h), 100 mg / kg (60, 120, 240 min and 24 h), 150 mg / kg (60, 120, 240 min and 24 h) and 200 mg / kg (60, 120, 240 min and 24 h). N = 8 for 25, 50, 75, 100 and 150 mg / kg, and N =5 for 200 mg / kg.

[0372] Metabolic Connectivity

[0373] Matric correlation heatmaps showing metabolic connectivity across previously delineated VOIs were generated (FIG. 8A-8U). As previously defined, comparisons were made between vehicle and test groups. The doses of 50, 75, 100 and 150 mg increased metabolic connectivity, with a peak effect at 240 minutes. Due to the small sample size (n = 5), no analyses were made with the 200 mg group.

[0374] In total, the data show that Garcinia kola extract of the present disclosure reshapes the neuronal network in areas found to be defective in the mental disorders and neurodegenerative diseases as described herein.

[0375] Conclusions

[0376] The results of these experiments provide an in vivo demonstration that the organic solvent-aqueous extract of Garcinia kola seeds induces increases in brain metabolism believed to be due to increased synaptic activity, particularly in the frontal cortex. More specifically, animals treated with the organic solvent-aqueous extract at 100 mg / kg dose (60 min) exhibited regions in the cortex with as much as a 40% increase in FDG-PET signal compared to vehicles. Consistently, animals treated with the organic solvent-aqueous extract at 50 mg / kg dose (60 min) also exhibited regions in the cortex with an increase in FDG-PET signal, ranging from 5 to 30%. The metabolic network analyses identified a hyperconnectivity in 50, 75, 100 and 150 groups with a peak effectat 240 minutes. As these were acute experiments, it is fair to expect that changes in connectivity would be further clear with repetitive dosing. These mice doses are equivalent to 280 - 567 mg for a 70 kg man. The experiments show that effects are seen for at least 4 hours after the ingestion and with residual effects after 24 h with the higher dose.

[0377] From a clinical perspective, there is potential for the therapeutic use of the organic solvent-aqueous extract of Garcinia kola seeds for conditions marked by hypometabolism in the frontal cortex. Notably, based on the literature, Attention Deficit / Hyperactivity Disorder (ADHD), generalized anxiety (GAD) and major depression disorder (MDD) are associated with decreased prefrontal cortex activity (Baeken et al, 2018; Bush et al, 2005; Fu, 2018). Cognitive deficits in schizophrenia are also believed to be associated with hypo glutamate functioning in the frontal cortex. Given the brain areas affected by the extract include the hippocampus, there is also potential to treat cognitive deficits associated with several conditions, including schizophrenia and many neurodegenerative disorders.

[0378] Example 3: T-maze Alternation Task to Assess Effect of Garcinia kola Seed Extract on Cognitive Impairment

[0379] The T-maze alternation task was used to assess the effect of Garcinia kola seed extract on cognitive impairment. In this task, mice were placed in the starting arm of a T-maze and are trained to alternate between the left and right arms on consecutive trials. The ability to alternate successfully relies on spatial working memory. MK-801, also known as dizocilpine, is an NMDA receptor antagonist which was administered to induce cognitive deficits. Donezepil, a known memory enhancing drug, was administered as a positive control. 60 CD-I mice were used. They were randomly distributed to different experimental groups as shown in Table 3 below (10 animals per group). The organic solvent-aqueous Garcinia kola seed extract, also referred to here as MB2500, was administered at 3 dosages - 50, 100, and 150 mg / kg in Groups 4, 5, and 6, respectively.Table 3

[0380] The animals were treated using the oral gavage route of administration 120 minutes before the test. After treatment they are numbered with permanent ink on the tail and returned to the cage (at least one animal per treatment group per cage). The formulations are coded by a third party; the experimenter is thus blinded to the treatment groups. The T-maze alternation performance was expressed as a percentage of alternation between Left and Right arm visits with cut-off time set as 10 min. The raw results for each mice are shown in FIG. 9A. A bar graph showing the percent in spontaneous alternation for each group is shown in FIG. 9B, and the tabulated results are shown in Table 4 below. The administered dosages of the Garcinia kola seed extract of 100 mg / kg and 150 mg / kg were found to reverse MK-801 -induced cognitive deficit.Table 4***, p < 0.001 , as compared to MK-801 (0.1 mg / kg) / Vehicle groupExample 4: Light-Dark Test to Assess Effect of Garcinia kola Seed Extract on Anxiety

[0381] A Light-Dark test was used to assess the effect of the organic solvent-aqueous Garcinia kola extract on anxiety. The light-dark test is a behavioral test used to assess anxiety-like behavior in mice by observing their preference for dark versus bright areas. Mice naturally prefer darker spaces and tend to avoid brightly lit areas. The apparatus contains a dark chamber and a brightly lit chamber, and mice are allowed to move freely between the two chambers. The number of entries into the illuminated chamber and the duration of time spent there are indices of anxiety in mice. Diazepam, a pharmaceutical agent known to treat anxiety, was administered as a positive control. 60 CD-I mice were used, and the mice were randomly distributed to different experimental groups (12 animals per group) as outlined in Table 5 below. The organic solvent- aqueous Garcinia kola seed extract, also referred to here as MB2500, was administered at 3 dosages - 50, 100, and 150 mg / kg in Groups 3, 4, and 5, respectively.Table 5

[0382] The animals were treated using the oral gavage route of administration 120 minutes before the test. After treatment, they are numbered with permanent ink on the tail and returned to the cage (at least one animal per treatment group per cage). The formulations were coded by a third party. Thus, the experimenter is blinded to the treatment groups. The results for each mice are shown in FIG. 10A (entries into the lit box) and FIG. 10B (time spent in the lit box). Bar graphs showing the results for each group are shown in FIG. 11A (entries into the lit box) and FIG. 11B (time spent in the lit box). The results for each group are tabulated in Table 6 below. An effect is observe with MB2500 at the two higher doses (Group 4 and 5).Table 6

[0383] *, p<0.05 as compared to Vehicle group

[0384] **, p<0.01 as compared to Vehicle group

[0385] ***, p<0.001 as compared to Vehicle group

[0386] Example 5: Forced Swim Test to Assess Effect of Garcinia kola Seed Extract on volition

[0387] A forced swim test was conducted to assess the effect of the organic solvent-aqueous Garcinia kola extract on volition. The forced swim test is a rodent behavioral test used to evaluate volition or depressive-like behavior. Mice are placed in an inescapable transparent tank that is filled with water, and their escape related mobility is measured. Imipramine, a pharmaceutical known for the treatment of depression, was administered as a positive control. Clozapine, which is an anti-psychotic and evidence suggests a positive effect on avolition associated with schizophrenia, was also used as a positive control. 60 CD-I mice were used, and they were randomly distributed to different experimental groups (12 animals per group) according to Table 7.Table 7

[0388] The animals were treated using the oral gavage route of administration 120 minutes before the test. After treatment, they are numbered with permanent ink on the tail and returned to the cage (at least one animal per treatment group per cage). The formulations were coded by a third party. Thus, the experimenter is blinded to the treatment groups. The immobility time results for each mice are shown in FIG. 12A. A bar graph depicting the results for each group is shown in FIG. 12B, and the results are tabulated in Table 8 below. For groups 4-6, a dose effect is observed, namely, the immobility time decreases with increasing dose.Table 8

[0389] References

[0390] Hoh CK. Clinical use of FDG PET. Nucl Med Biol. 2007 Oct;34(7):737-42.

[0391] Baeken C, Wu GR, De Raedt R. Dorsomedial frontal cortical metabolic differences of comorbid generalized anxiety disorder in refractory major depression: A [18F] FDG PET brain imaging study. J Affect Disord. 2018 Feb;227:550-553.

[0392] Bush G, Valera EM, Seidman LJ. Functional neuroimaging of attention- deficit / hyperactivity disorder: a review and suggested future directions. Biol Psychiatry. 2005 Jun 1;57(11): 1273-84.

[0393] Fu C, Zhang H, Xuan A, Gao Y, Xu J, Shi D. A combined study of18F-FDG PET- CT and fMRI for assessing resting cerebral function in patients with major depressive disorder. Exp Ther Med. 2018 Sep; 16(3): 1873- 1881.

[0394] All publications, patents, and patent applications cited herein are hereby incorporated herein by reference in their entirety.

Claims

What is claimed is:

1. A method of ameliorating cognitive impairment associated with schizophrenia in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

2. The method of claim 1, wherein the cognitive impairment is selected from attention deficits, memory problems, processing speed deficits, executive functioning deficits, social cognition deficits, learning deficits, or a combination thereof.

3. The method of claim 1 or 2, wherein the pharmaceutical composition is coadministered with at least one atypical anti-psychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

4. The method according to any of claims 1-3, wherein the subject was previously being treated for or is simultaneously being treated with at least one atypical anti-psychotic drug selected from aripiprazole, aripiprazole lauroxil, amisulpride, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, levomepromazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.

5. The method according to any one of claims 1-4, wherein the subject is a juvenile or 10-15 years of age and / or wherein the subject has yet to develop paranoia, hallucinations, or delusions.

6. A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject comprising administering to a subject in need thereof an effective amount of apharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

7. The method according to claim 6, wherein the attention deficit hyperactive disorder is inattentive, hyperactive-impulsive, or combined type attention deficit hyperactive disorder.

8. The method according to any one of claims 6-7, wherein the subject was previously being treated for or is simultaneously being treated for an attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

9. The method according to any one of claims 6-8, wherein the pharmaceutical composition is co-administered with at least one drug selected from: a stimulant, an alpha- adrenergic agonist, or a norepinephrine reuptake inhibitor.

10. The method according to claim 8 or 9, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, lisdexamfetamine, or a combination thereof.

11. The method according to claim 8 or 9, wherein the alpha-adrenergic agonist is guanfacine or clonidine.

12. The method according to claim 8 or 9, wherein the norepinephrine reuptake inhibitor is atomoxetine or viloxazine.

13. The method according to any one of claims 1-12, wherein the administration of the pharmaceutical composition causes increased activity in the frontal cortex region of the subject’s brain relative to activity prior to initial administration, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG).

14. The method according to claim 13, wherein the activity in the frontal cortex region of the subject’s brain is about 5% to 50% higher than the activity prior to initial administration.

15. The method according to claim 14, wherein the activity in the frontal cortex region of the subject’s brain is about 10% to 40% higher than the activity prior to initial administration.

16. The method according to any one of claims 6-15, wherein treating ADHD in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for treating ADHD to another medication for treating ADHD or when the subject is tapering a dose or administration frequency of a medication for treating ADHD.

17. A method of ameliorating cognitive impairment associated with a disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an organic solvent -aqueous extract of Garcinia kola seeds or a pharmaceutical composition comprising one or more biflavonoids or flavonoids including kolaviron.

18. The method according to claim 17, wherein ameliorating cognitive impairment associated with a disorder or disease in a subject comprises administering the pharmaceutical composition during a period when the subject is transitioning from one medication for ameliorating cognitive impairment to another medication for ameliorating cognitive impairment or when the subject is tapering a dose or administration frequency of a medication for ameliorating cognitive impairment.

19. The method according to any of claims 17-18, wherein the subject was previously being treated for or is simultaneously being treated with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

20. The method according to any of claims 17-19, wherein the pharmaceutical composition is co-administered with at least one drug selected from a cholinesterase inhibitor or a N-methyl-D-aspartate (NDMA) receptor antagonist.

21. The method according to any of claims 17-20, wherein the disorder is a neurodegenerative disorder selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, and spinocerebellar ataxia.

22. The method according to any one of claims 1 to 21, wherein the pharmaceutical composition is an oral dosage form.

23. The method according to any one of claims 1-22, wherein the extract is a whole seed extract.

24. The method according to any one of claims 1-23, wherein the extract comprises a biflavonoid.

25. The method according to claim 24, wherein the biflavonoid is kolaviron.

26. The method according to any one of claims 1-25, wherein the extract comprises a tocopherol and / or tocotrienol.

27. The method according to any one of claims 1-26, wherein the extract further comprises at least one of a flavonoid and / or a saponin.

28. The method according to any one of claims 1-27, wherein extract further comprises garcinoic acid and / or kolanone and / or garcinol.

29. The method according to any one of claims 1-28, wherein the subject is a mammal.

30. The method according to any one of claims 29, wherein the subject is a human.

31. The method according to any one of claims 1-30, wherein the administered daily dose of the extract is from about 0.5 mg / kg to about 20 mg / kg or 3 mg / k to 14 mg / kg.

32. The method according to claim 31, wherein an administered dose of the organic solvent-aqueous extract is about 0.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, or 20 mg / kg.

33. The method according to any of claims 1-32, wherein the method comprises multiple administrations of the pharmaceutical composition, wherein the interval of time between each administration is 8, 12, 16, 20, or 24 hours.

34. The method according to any one of claims 1-33, wherein the pharmaceutical composition is administered 1, 2, or 3 times a day.

35. A pharmaceutical composition comprising an organic solvent-aqueous extract of Garcinia kola seeds, wherein the extract comprises, in terms of dry weight %, 20-30% Garcinia hydroxybiflavanonol 1 and 20-30% Garcinia hydroxybiflavanonol 2, wherein the organic solvent can comprise ethanol, methanol, or acetonitrile.

36. The pharmaceutical composition of claim 35, wherein the composition further comprises, in terms of dry weight %, 0.25-1.5% amentoflavone, 1.0-5.0% kolaflavanone, 0.25- 1.0% binaringenin, 0.25-1.0% garcinianin, and 0.25-1.0% kolaflavone.

37. The pharmaceutical composition of claim 35 or 36, wherein biflavanoids are at least 40% or 40% to 65% of the total dry extract mass.

38. The pharmaceutical composition according to any of claims 35-37, wherein the organic solvent-aqueous extract further comprises garcinoic acid, garcinol, and / or D-tocotrienol.

39. A method of making an organic solvent-aqueous extract of Garcinia kola seeds comprising the steps of:a. exposing dried seeds or dried seed tissue from Garcinia kola to a first organic solvent-aqueous solvent to form a first liquid phase and a first solid phase; b. separating the first solid phase from the first liquid phase; and c. evaporating the solvent from the first liquid phase to form a concentrate of the liquid phase.

40. The method of claim 39, wherein the first organic solvent-aqueous solvent is a first alcohol-aqueous solvent comprising from 50% to 100% methanol and from 50% to 100% water.

41. The method of claim 39 or 40, further comprising powderizing the concentrate to form the extract.

42. The method according to any of claims 40 or 41, further comprising exposing the first solid phase to the first alcohol-aqueous solvent to form a second liquid phase and a second solid phase; and combining the first liquid phase and the second liquid phase to form a pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

43. The method according to claim 42, further comprising exposing the second solid phase to the first alcohol-aqueous solvent to form a third liquid phase and a third solid phase; and combining the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

44. The method according to claim 43, further comprising exposing the third solid phase to the first alcohol-aqueous solvent to form a fourth liquid phase; and combining the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to form a pooled liquid and evaporating the solvent to produce the concentrate of the liquid phase.

45. The method according to claim 44, further comprising exposing the fourth solid phase to the first alcohol-aqueous solvent to form a fifth liquid phase; and combining the fifth liquid phase, the fourth liquid phase, the third liquid phase, the second liquid phase, and the first liquid phase to produce the concentrate of the liquid phase.

46. The method according to any of claims 39-45, wherein the concentrate of the liquid phase is a slurry.

47. The method according to any of claims 39-46, wherein the method further comprises: i. solubilizing the concentrate of the liquid phase in water to precipitate water insoluble compounds; and ii. separating the water insoluble compounds from the concentrate of the liquid phase.

48. The method according to any of claims 39-47, wherein the concentrate of the liquid phase is exposed to an absorbent material selected from a gel resin, a non-ionic macroporous resin, an ion-exchange resin, or a combination thereof.

49. The method according to claim 48, wherein the adsorbent material is washed with a second solvent to remove impurities.

50. The method according to claim 48 or 49, wherein the concentrate of the liquid phase is exposed to a gel resin, non-ionic macroporous resin, ion-exchange resin, or a combination thereof is eluted with a third solvent to form an eluted concentrate.

51. The method according to claim 50, wherein fractions of the eluted concentrate of the liquid phase are combined to form a pooled mixture.

52. The method according to claim 51 , wherein the pooled mixture is volume reduced to form a concentrated mixture.

53. The method according to claim 52, wherein the concentrated mixture is combined with pharmaceutically acceptable excipients or bioavailability enhancers to produce a standard dosage of a pharmaceutical composition.

54. The method according to claim 52 or 53, wherein the concentrated mixture is dried using spray drying, belt drying, freeze drying, or a combination thereof.

55. An extract produced by the method according to any of claims 39-54.

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