Coca leaf extract for neuropsychiatric disorders

Abstract

Methods for treating narcolepsy, attention deficit hyperactivity disorder (ADHD), depression, and anxiety disorders, each comprising the step of administering a pharmaceutical composition containing coca whole leaf extract to the target. Methods for producing coca whole leaf extract are also disclosed.

Description

Technical Field

[0001] Field of the Invention The present invention is directed to a method of treating narcolepsy, a method of treating attention deficit hyperactivity disorder (ADHD) comprising the step of reducing cognitive impairment associated with ADHD, a method of treating depression, and a method of treating anxiety disorder, each of which comprises the step of administering to a subject a pharmaceutical composition comprising a whole coca leaf extract. The present invention is also directed to a method of producing a whole coca leaf extract.

Background Art

[0002] Background Indigenous peoples in the Andean highlands of South America have cultivated and chewed the leaves of two cultivated coca plant species, in particular Erythroxylum coca Lam and Erythroxylum novogranatense, for thousands of years. Chewing the coca leaves of Erythroxylum coca Lam and Erythroxylum novogranatense leads to the release of one or more coca alkaloids, which can produce a stimulant effect on the user. Of greatest pharmacological interest is a group of about 15 alkaloids, among which cocaine is the most well-known and characterized. However, secondary alkaloids may have significant effects on their own, and when the whole leaf is utilized, they are highly likely to act in a synergistic manner in the central nervous system to produce a therapeutic response. Furthermore, there are several neuropsychiatric diseases, disorders, and conditions for which appropriate treatments, therapies, or remedies are needed. Accordingly, there remains a need for pharmaceutical compositions and methods for treating neuropsychiatric disorders, as well as methods for producing whole coca leaf extracts. These needs and other needs are satisfied by the present invention.

Summary of the Invention

Problem to be Solved by the Invention

[0003] Summary Disclosed herein are methods for treating narcolepsy, methods for treating ADHD including a step of reducing cognitive impairment associated with attention deficit hyperactivity disorder (ADHD), methods for treating depression, and methods for treating anxiety, each comprising the step of administering a pharmaceutical composition comprising a whole coca leaf extract to a subject. Methods for producing a whole coca leaf extract are also disclosed herein. [Means for solving the problem]

[0004] In one embodiment, a method for treating narcolepsy in a subject is disclosed, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to the subject in need.

[0005] In one embodiment, a method for treating attention deficit hyperactivity disorder (ADHD), comprising the step of administering an effective amount of a pharmaceutical composition comprising coca whole leaf extract to a subject in need thereof, is disclosed.

[0006] In one embodiment, a method for treating depression in a subject is disclosed, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to the subject in need.

[0007] In one embodiment, a method for treating an anxiety disorder in a subject is disclosed, comprising the step of administering to the subject in need of such treatment a certain amount of a pharmaceutical composition containing a whole coca leaf extract.

[0008] In one embodiment, a method for producing a whole coca leaf extract is disclosed, comprising the steps of: a. exposing the leaves of a plant of the family Erythroxylaceae, for example, a dried powder thereof, to a first 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.

[0009] Other embodiments are disclosed below. [Modes for carrying out the invention]

[0010] Detailed explanation I. Definition Where a term is provided in the singular form, the inventors also envision aspects of the invention described by the plural form of that term. As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include references to multiple things unless the context explicitly indicates otherwise; for example, “a compound” includes multiple compounds. Thus, for example, a reference to “a method” includes one or more methods and / or steps of the kind described herein and / or which would be apparent to those skilled in the art by reading this disclosure.

[0011] "Reduction," "mitigation," and "improvement" refer to a detectable improvement or a detectable change consistent with improvement that occurs in, for example, a subject or at least a small number of subjects, in an approximate range of, for example, at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, or any two of these values. Such improvement or change can be observed in subjects treated with a pharmaceutical composition containing coca whole leaf extract, compared to untreated subjects, where the untreated subjects have or are susceptible to the same or similar disease, condition, symptoms, etc. The reduction of disease, condition, symptoms, or assay parameters can be determined subjectively or objectively, for example, by self-assessment by the subject, by assessment by a clinician, or by performing an appropriate assay or measurement. The relief may be transient, long-term, or permanent, and may vary during or at appropriate times thereafter while the pharmaceutical composition containing coca whole leaf extract is administered to the subject or used in the assay or other method described herein or in the references cited herein, for example, within the timeframes described below, or from about one hour after administration or use of the pharmaceutical composition containing coca whole leaf extract to about seven days, two weeks, 28 days, or one month, three months, six months, nine months or longer after the subject has received such treatment.

[0012] For example, "modulation," such as symptoms, molecular levels, or biological activity, refers to a detectable increase or decrease in symptoms, activity, etc. Such an increase or decrease can be observed in subjects treated with a pharmaceutical composition containing coca whole leaf extract compared to untreated subjects, where the untreated subjects have or are susceptible to the same or similar diseases, conditions, symptoms, etc. Such an increase or decrease may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000%, or more, or within any range between any two of these values. Modulation can be determined subjectively or objectively. Modulation may be transient, prolonged, or permanent, and may vary during or at appropriate times thereafter while the pharmaceutical composition containing coca whole leaf extract is administered to a subject or used in the assay or other method described herein or in the references cited herein, for example, within the time periods described below, or from about one hour after administration or use of the pharmaceutical composition containing coca whole leaf extract to about two weeks, 28 days, three months, six months, nine months or longer after the subject received the pharmaceutical composition containing coca whole leaf extract.

[0013] As used herein, “subject” includes animals, including humans, such as adults or children.

[0014] The term "effective dose" of a compound refers to the amount of a pharmaceutical composition containing coca whole leaf extract that is effective when administered to a target subject in a single or multiple dose.

[0015] The terms "administration" or "administering" include the route through which a pharmaceutical composition containing coca whole leaf extract is introduced to a target and exerts its intended function. Examples of usable routes of administration include oral, sublingual, buccal, injection, inhalation, and topical administration. Pharmaceutical preparations can be given in a form appropriate to each route of administration. For example, these preparations may be administered in liquid or capsule form. Oral administration is preferred. Depending on the route of administration, pharmaceutical compositions containing coca whole leaf extract may be coated with or placed within a selected material to protect them from natural conditions that may adversely affect their ability to exert their intended function. Pharmaceutical compositions containing coca whole leaf extract may be administered alone or in combination with any or both of the above-mentioned drugs, drugs, or pharmaceutically acceptable carriers.

[0016] Administration "in combination with" or "concurrently administered with" one or more additional therapeutic agents includes concurrent (parallel) administration and sequential administration in any order.

[0017] The term "pharmaceutically acceptable" means a pharmaceutical composition, composition, and / or dosage form containing coca whole leaf extract as described herein, wherein the active ingredient, excipient, carrier, or any other component of the dosage form is suitable, within the bounds of sound medical judgment, for use in the intended mode of administration, e.g., oral administration, and is appropriate for contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, and other problems and complications, in a reasonable benefit-risk ratio.

[0018] The term "pharmaceutically acceptable carrier" includes pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, which are involved in transporting or carrying a chemical substance of interest from one organ or part of the body to another organ or part of the body.

[0019] As used herein, the term "treat" or "treatment" is intended to include reducing or alleviating the progression, severity, and / or duration of a condition or one or more symptoms of a condition, such as narcolepsy, attention deficit hyperactivity disorder (ADHD) and cognitive impairment associated with ADHD, depression, or anxiety disorders.

[0020] The term "obtaining" as in "obtaining a pharmaceutical composition comprising a whole coca leaf extract" is intended to include purchasing, synthesizing, isolating, extracting, or otherwise acquiring the pharmaceutical composition comprising the whole coca leaf extract.

[0021] II. Whole coca leaf extract There are two known cultivated species of coca crops, one of which is Erythroxylum coca, including the varieties of Erythroxylum coca var. coca and Erythroxylum coca var. ipadu, and the other is Erythroxylum novogranatense, including the varieties of Erythroxylum novogranatense var. novogranatense and Erythroxylum novogranatense var. truxillense. In various embodiments, the whole coca leaf extract is extracted from Erythroxylum coca var. coca, Erythroxylum coca var. ipadu, Erythroxylum novogranatense var. novogranatense, Erythroxylum novogranatense var. truxillense, or a combination thereof.

[0022] According to the present disclosure, the whole coca leaf extract comprises at least two alkaloids naturally occurring in coca leaves, and one or more compounds that are also naturally present in coca leaves but are not alkaloids, which account for at least 5% w / w of the extract, such as minerals, vitamins, essential oils, diterpenes, triterpenes, flavonoids, tannins, or polyphenols. In various embodiments, the extract comprises a combination of two or more alkaloids and one or more of minerals, vitamins, essential oils, diterpenes, triterpenes, flavonoids, tannins, or polyphenols that naturally occur in coca leaves. In various embodiments, the whole coca leaf extract is obtained from the extraction methods described herein.

[0023] In some embodiments, the method of treatment comprises administering an effective amount of the whole coca leaf extract to a subject in need thereof. In some embodiments, the method of treatment comprises administering an effective amount of a pharmaceutical composition comprising the whole coca leaf extract to a subject in need thereof. Alkaloids naturally occurring in the coca plant include cocaine and methylecgonine cinnamate, and depending on the species, may further include some combinations of benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, tropacocaine, truxilline, cuscohygrine, dihydrocuscohygrine, hygrine, and nicotine. In various embodiments, the whole coca leaf extract contains cocaine and methylecgonine cinnamate. In various embodiments, the whole coca leaf extract contains two or more of cocaine, methylecgonine cinnamate, benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, tropacocaine, truxilline, cuscohygrine, dihydrocuscohygrine, hygrine, and nicotine. The whole coca leaf extract contains the alkaloids in an amount of the whole coca leaf extract that is considered to be administrable as a dose to a human subject, where the alkaloids are detectable by assay methods known in the art.

[0024] The primary active alkaloid present in cultivated species of the genus Coca, or in the leaves of the Coca plant, is cocaine. Depending on the species of Coca plant, cocaine is generally found in amounts ranging from approximately 0.3% to 2.4% by weight of the Coca leaf, typically around 0.8% by weight. Coca leaves of all varieties also contain the secondary alkaloid methyl ecgonine cinnamate. In some embodiments, methyl ecgonine cinnamate exists as a cis isomer, a trans isomer, or a combination thereof.

[0025] In addition, coca leaves may contain various other alkaloids, such as benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, tropacocaine, tolxyline, cuscohigrin, dihydrocuscohigrin, higrin, and nicotine. Considering the properties of the coca extract as a whole, other alkaloids may also be present. In various embodiments, the whole coca leaf extract further comprises at least one of benzoylecgonine, tolxyline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohigrin, dihydrocuscohigrin, or higrin. The presence, relative proportion, and total amount of these additional alkaloids vary depending on the coca plant variety. Therefore, to adjust for the presence and concentration of desired alkaloids, the whole coca leaf extract can be extracted from the leaves of a combination of coca plant varieties.

[0026] In one embodiment, the whole coca leaf extract contains cocaine in an amount of about 80% by weight or less of the extract, including the dry weight of the extract. The whole coca leaf extract may contain, for example, about 0.5% by weight or less, 1% by weight or less, 2% by weight or less, 5% by weight or less, 8% by weight or less, 10% by weight or less, 20% by weight or less, 30% by weight or less, 40% by weight or less, 50% by weight or less, 60% by weight or less, 70% by weight or less, or about 80% by weight or less. In some embodiments, the whole coca leaf extract may contain cocaine in a range derived from any two of the exemplary values ​​listed above. For example, whole coca leaf extract may contain cocaine in the range of approximately 0.5% to 8% by weight, approximately 0.5% to 25% by weight, approximately 0.5% to 50% by weight, approximately 0.5% to 80% by weight, approximately 5% to 30% by weight, approximately 5% to 50% by weight, approximately 5% to 80% by weight, approximately 10% to 50% by weight, approximately 10% to 80% by weight, approximately 20% to 50% by weight, approximately 20% to 80% by weight, approximately 30% to 60% by weight, approximately 30% to 80% by weight, approximately 40% to 70% by weight, or approximately 50% to 80% by weight.

[0027] In one embodiment, the coca whole leaf extract contains methyl ecgonine cinnamate. The coca whole leaf extract may contain trans-methyl ecgonine cinnamate or cis-methyl ecgonine cinnamate in any amount up to 20% by weight of the extract, including the dry weight of the extract. In some embodiments, the coca whole leaf extract may contain methyl ecgonine cinnamate in amounts, for example, about 0.001% to about 20% by weight, 0.001% to about 15% by weight, about 0.001% to about 1% by weight, about 0.001% to about 5% by weight, about 0.001% to about 0.1% by weight, about 0.001% to about 0.01% by weight, about 1% to about 3% by weight, about 0.01% to about 1% by weight, about 0.01% to about 0.1% by weight, about 0.5% to about 1% by weight, or about 5% to about 15% by weight.

[0028] Coca whole leaf extract may contain any alkaloids naturally present in coca leaves. In various embodiments, coca whole leaf extract may further contain at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscoxhigrin, dihydrocuscoxhigrin, or higrin.

[0029] Furthermore, as mentioned above, coca leaves also contain vitamins, minerals, diterpenes, triterpenes, flavonoids, tannins, and polyphenols. Therefore, coca whole leaf extract may contain one or more of the vitamins, minerals, diterpenes, triterpenes, flavonoids, tannins, and polyphenols. In some embodiments, coca whole leaf extract contains vitamins. In some embodiments, coca whole leaf extract contains minerals. Coca whole leaf extract may contain any vitamin or mineral naturally present in coca leaves. In some embodiments, coca whole leaf extract further contains vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

[0030] Furthermore, whole coca leaves contain at least one essential oil. Therefore, in various embodiments, whole coca leaf extracts may contain any essential oil naturally present in coca leaves. In one embodiment, the whole coca leaf extract may contain an essential oil such as wintergreen oil.

[0031] Mai. Pharmaceutical composition In some embodiments, the treatment method includes administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

[0032] The pharmaceutical composition can be formulated in any dosage form. For example, the pharmaceutical composition can be formulated as a solid, 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.

[0033] In some embodiments, the pharmaceutical composition further comprises an alkalizing agent. While we do not wish to be bound by theory, it is thought that alkalizing agents can promote the release of alkaloids from leaves or convert them into active or absorbable forms. In the stomach, the high pH brought about by the alkalizing agent can promote gastric absorption of active compounds or inhibit gastric degradation. Examples of suitable alkalizing agents included in the pharmaceutical compositions described herein include, but are not limited to, sodium bicarbonate, calcium oxide, or potassium hydroxide. The pH of the alkalizing agent can be any alkaline pH greater than about 7. The pH of the alkalizing agent may be, for example, 7.5, 8, 9, 10, 11, 12, 13, or higher. In further embodiments, the pH of the alkalizing agent may be any pH within the range derived from any two of the exemplary values ​​listed above. For example, the pH of the alkalizing agent may be in the range of approximately 7 to 8, 7 to 10, 7 to 13, 7 to 14, 8 to 11, 8 to 13, 9 to 12, 9 to 14, 10 to 12, 10 to 13, or 10 to 14. In some embodiments, the pH of the alkalizing agent is approximately 10 to 13.

[0034] The pharmaceutical composition may contain any weight percent of whole coca leaf extract. In some embodiments, the pharmaceutical composition contains about 30% to about 100% by weight of whole coca leaf extract. The pharmaceutical composition may contain any weight percent within the range derived from the listed exemplary values. For example, the pharmaceutical composition may contain about 30% to about 99%, about 30% to about 95%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 40% to about 100%, about 40% to about 80%, about 40% to about 60%, about 50% to about 99%, about 50% to about 95%, about 50% to about 80%, about 50% to about 7 It may contain whole coca leaf extract in weight percent of 0%, approximately 60%-99%, approximately 60%-95%, approximately 60%-90%, approximately 60%-80%, approximately 70%-99%, approximately 70%-95%, approximately 70%-90%, approximately 70%-80%, approximately 80%-99%, approximately 80%-95%, or approximately 80%-90%.

[0035] In certain embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to a sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or media include water, alcohols such as ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Compounds can be formulated with a pharmaceutically acceptable carrier or diluent, as well as any other known adjuvants and excipients, according to conventional methods, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0036] The pharmaceutical carriers used may be solids, liquids, or gases. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include liquid sugar, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0037] When preparing pharmaceutical compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycol, oil, alcohol, flavoring agents, preservatives, colorants, etc., can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; on the other hand, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants can be used to form oral solid preparations such as powders, capsules, and tablets.

[0038] In certain embodiments, the pharmaceutical composition may further contain a sweetener. The sweetener may be added to improve the palatability and acceptability of the pharmaceutical composition by providing it with sweetness. The sweetener may be any sweetener conventionally known in the art for use in pharmaceutical compositions.

[0039] The pharmaceutical compositions described herein may contain one or more additional excipients, such as diluents, binders, lubricants, disintegrants, colorants, or flavoring agents. The compositions can be formulated for selected coated and uncoated tablets, hard and soft gelatin or HMPC capsules, sugar-coated tablets, lozenges, wafer sheets, pellets and powders in sealed packets, and chewing gum.

[0040] IV. Treatment Methods for Narcolepsy A method for treating narcolepsy in a subject is provided herein, comprising the step of administering an effective amount of a pharmaceutical composition containing the above-mentioned whole coca leaf extract to a subject in need thereof.

[0041] Narcolepsy is a chronic neurological condition characterized by a impaired ability to regulate the sleep-wake cycle. Symptoms often include excessive daytime sleepiness, short episodes of unconscious sleep, inability to remain awake for extended periods, and cataplexy. Narcolepsy is classified into two main types. A diagnosis of type 1 narcolepsy is characterized by a subject either having low levels of the brain hormone hypocretin or reporting cataplexy, also known as sudden muscle weakness. A diagnosis of type 2 narcolepsy is characterized by a subject exhibiting symptoms of narcolepsy without cataplexy. In some embodiments, subjects are treated for narcolepsy, which is either type 1 or type 2. In further embodiments, subjects are treated for daytime somnolence, characterized by excessive sleepiness while awake. Conditions such as narcolepsy and idiopathic hypersomnia are thought to affect hormones involved in promoting wakefulness, thereby causing daytime sleepiness. Sleep disorders such as obstructive sleep apnea (OSA), restless limb syndrome, and periodic limb movement disorder are known to cause sleep fragmentation. Similarly, people with circadian rhythm disorders experience a discrepancy between their internal clock and the time they should be awake.

[0042] In some embodiments, the subjects receiving treatment for narcolepsy may be vertebrates such as mammals, fish, birds, reptiles, or amphibians. Therefore, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not imply any specific age or sex. Therefore, it is intended to include adult and neonatal subjects, as well as fetuses, regardless of whether they are male or female. In one embodiment, the subject is a mammal. In further embodiments, the subject is a human.

[0043] The pharmaceutical composition may be administered alone or in combination with other drugs and / or the pharmaceutical composition for the treatment of narcolepsy. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject receives treatment for narcolepsy with the pharmaceutical composition and at least one other drug. In various embodiments, the subject receives treatment for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate.

[0044] Examples of stimulants suitable for treating narcolepsy include, but are not limited to, modafinil, almodafinil, souliamfetol, pitrisant, methylphenidate, and amphetamines.

[0045] Examples of selective serotonin reuptake inhibitors suitable for the treatment of narcolepsy include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, fluvoxamine CR, paroxetine, paroxetine CR, and sertraline.

[0046] Examples of serotonin-norepinephrine reuptake inhibitors suitable for the treatment of narcolepsy include, but are not limited to, desvenlafaxine, duloxetine, venlafaxine, venlafaxine XR, milnacipran, and levomirnacipran.

[0047] Examples of tricyclic antidepressants suitable for treating narcolepsy include, but are not limited to, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine.

[0048] Examples of benzodiazepine receptor agonists suitable for the treatment of narcolepsy include, but are not limited to, triazolam, temazepam, estazolam, lorazepam, zolpidem, zaleplon, and zopiclone.

[0049] Examples of gamma-hydroxybutyrate suitable for the treatment of narcolepsy include, but are not limited to, oxybate calcium, oxybate magnesium, oxybate potassium, and oxybate sodium.

[0050] In some embodiments, the pharmaceutical composition is administered concurrently with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate.

[0051] In some embodiments, a daily dose of the pharmaceutical composition is administered to the subject. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of coca whole leaf extract is approximately 1 g to approximately 500 g of coca whole leaf equivalents. That is, the administered extract contains an alkaloid concentration equivalent to approximately 1 g to approximately 500 g of dried leaves. The daily dose of coca whole leaf extract may include any dose within the range derived from the listed exemplary values. The daily dose of whole coca leaf extract is, for example, approximately 1g to 400g leaf equivalent, approximately 1g to 300g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 100g leaf equivalent, approximately 1g to 90g leaf equivalent, approximately 1g to 70g leaf equivalent, approximately 1g to 50g leaf equivalent, approximately 1g to 30g leaf equivalent, approximately 1g to 15g leaf equivalent, approximately 10g to 500g leaf equivalent, approximately 10g to 400g leaf equivalent, approximately 10g to 300g leaf equivalent, approximately 10g to 200g leaf equivalent, and approximately 10g to 100g leaf equivalent. It may be approximately 10g to 80g leaf equivalent, approximately 10g to 60g leaf equivalent, approximately 10g to 40g leaf equivalent, approximately 20g to 500g leaf equivalent, approximately 20g to 300g leaf equivalent, approximately 20g to 100g leaf equivalent, approximately 20g to 70g leaf equivalent, approximately 20g to 50g leaf equivalent, approximately 100g to 500g leaf equivalent, approximately 100g to 300g leaf equivalent, approximately 40g to 100g leaf equivalent, approximately 40g to 80g leaf equivalent, approximately 40g to 60g leaf equivalent, approximately 50g to 100g leaf equivalent, or approximately 50g to 80g leaf equivalent.

[0052] In some embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day, or as needed. In further embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day. In yet another embodiment, the pharmaceutical composition is administered as needed.

[0053] In some embodiments, treatment of narcolepsy in a subject includes the step of administering a pharmaceutical composition during a transition period between drug therapies. The pharmaceutical compositions described herein may be administered as treatment when a subject transitions from one drug to another, transitions from one drug to a state where the subject no longer receives treatment for narcolepsy, or transitions from one drug to a drug containing the pharmaceutical composition described herein.

[0054] FDG-PET, or [ 18 Positron emission tomography (PET) using [F]-fluorodeoxy-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 that is injected into the body. Like glucose, FDG is taken up by cells and results in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormal decreases or increases in synaptic activity in various regions of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders (e.g., narcolepsy). The exact cause of narcolepsy is unknown, but it is considered a clinical syndrome of hypothalamic dysfunction, although we do not wish to be bound by theory. In some embodiments, the administration of a pharmaceutical composition is [ 18 Positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in the perifornix hypothalamic region of the target brain.

[0055] In certain embodiments, subjects receiving treatment for narcolepsy with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate, and who have experienced or are experiencing an adverse reaction to at least one of these drugs.

[0056] In some embodiments, subjects receiving treatment for narcolepsy with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate, and who have experienced or are experiencing treatment resistance to at least one of these drugs.

[0057] In some embodiments, the subject receiving treatment for narcolepsy is refractory to and / or intolerant of existing or standard treatments. In further embodiments, the subject is intolerant of existing or standard treatments due to adverse effects.

[0058] V. How to treat Attention Deficit Hyperactivity Disorder A method for treating attention deficit hyperactivity disorder (ADHD) in a subject is provided herein, comprising the step of administering an effective amount of a pharmaceutical composition containing the above-mentioned whole coca leaf extract to a subject in need of such treatment.

[0059] Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by excessive inattention, impulsivity, and, in some cases, hyperactivity. ADHD is classified into three main types. The most common type, combined ADHD, is characterized by impulsive and hyperactive behavior, as well as inattention and distractibility. The second most common type, inattentive ADHD, is characterized primarily by inattention and distractibility without hyperactivity. Finally, the least common type, hyperactive-impulsive ADHD, is characterized by impulsive and hyperactive behavior without inattention and distractibility. In some embodiments, the subject receives treatment for attention-deficit hyperactivity disorder, which may be inattentive, hyperactive-impulsive, or combined ADHD.

[0060] Also provided herein is a method for alleviating cognitive impairment associated with attention deficit hyperactivity disorder (ADHD) in a subject, comprising the step of administering to a subject in need thereof an effective amount of a pharmaceutical composition containing the above-mentioned whole coca leaf extract.

[0061] Cognition is the mental activity or process of acquiring knowledge and understanding through thought, experience, and sensation. It encompasses all aspects of intellectual functioning, 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 interaction. "Cognitive impairment" is a broad term used to describe any impairment of any such aspect or intellectual function related to cognition, including executive functions. Individuals with cognitive impairment may have trouble with memory, concentration, planning, or decision-making, which can affect their daily lives. Cognitive impairment, and the treatment of cognitive impairment, can be assessed using standardized assessment scales, such as tests for assessing intelligence and / or cognitive function, standard ADHD assessment scales, and executive function scales.

[0062] Examples of ADHD-related cognitive impairments that may be alleviated by administration of pharmaceutical compositions containing coca whole leaf extract as described herein include, but are not limited to, attention deficit, working memory impairment, executive function impairment, reaction time delay, logical reasoning impairment, problem-solving impairment, planning impairment, and information integration problems.

[0063] In some embodiments, the cognitive impairment treated by administering an effective dose of the pharmaceutical composition comprising the whole coca leaf extract described herein is executive function disorder. Treatment of executive function disorder may include the step of administering the pharmaceutical composition alone or in combination with ADHD medications such as stimulants. Over time, patients may develop tolerance to the effects of stimulants, which can lead to increased doses. Stimulants, while effective, carry significant risks, including dependence, cardiovascular side effects, and other long-term health concerns. When the pharmaceutical composition is administered in combination with a stimulant, the administration of the pharmaceutical composition can prevent the need to increase or decrease the effective dose of the stimulant.

[0064] In some embodiments, subjects receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD may be vertebrates such as mammals, fish, birds, reptiles, or amphibians. Accordingly, subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not indicate a specific age or sex. Accordingly, it is intended to include adult and neonatal subjects, as well as fetuses, whether male or female. In one embodiment, the subject is a mammal. In further embodiments, the subject is a human.

[0065] The pharmaceutical composition may be administered alone or in combination with other drugs and / or the pharmaceutical composition for the treatment of cognitive impairment associated with attention deficit hyperactivity disorder or ADHD. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for attention deficit hyperactivity disorder with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors.

[0066] Examples of stimulants appropriate for the treatment of ADHD or ADHD-related cognitive impairment include, but are not limited to, methylphenidate, dexmethylphenidate, amphetamine, celdexmethylphenidate, and lisdexamfetamine, or combinations thereof.

[0067] Examples of alpha-adrenergic agonists suitable for the treatment of ADHD or ADHD-related cognitive impairment include, but are not limited to, clonidine and guanfacine.

[0068] Examples of norepinephrine reuptake inhibitors suitable for the treatment of ADHD or ADHD-related cognitive impairment include, but are not limited to, atomoxetine and biloxazine.

[0069] Examples of tricyclic antidepressants suitable for the treatment of ADHD or ADHD-related cognitive impairment include, but are not limited to, desipramine, imipramine, and nortriptyline.

[0070] In some embodiments, the pharmaceutical composition is administered concurrently with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors.

[0071] In some embodiments, a daily dose of the pharmaceutical composition is administered to the subject. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of coca whole leaf extract is approximately 1 g to approximately 500 g of coca whole leaf equivalents. That is, the administered extract contains an alkaloid concentration equivalent to approximately 1 g to approximately 500 g of dried leaves. The daily dose of coca whole leaf extract may include any dose within the range derived from the listed exemplary values. The daily dose of whole coca leaf extract is, for example, approximately 1g to 400g leaf equivalent, approximately 1g to 300g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 100g leaf equivalent, approximately 1g to 90g leaf equivalent, approximately 1g to 70g leaf equivalent, approximately 1g to 50g leaf equivalent, approximately 1g to 30g leaf equivalent, approximately 1g to 15g leaf equivalent, approximately 10g to 500g leaf equivalent, approximately 10g to 400g leaf equivalent, approximately 10g to 300g leaf equivalent, approximately 10g to 200g leaf equivalent, and approximately 10g to 100g leaf equivalent. It may be approximately 10g to 80g leaf equivalent, approximately 10g to 60g leaf equivalent, approximately 10g to 40g leaf equivalent, approximately 20g to 500g leaf equivalent, approximately 20g to 300g leaf equivalent, approximately 20g to 100g leaf equivalent, approximately 20g to 70g leaf equivalent, approximately 20g to 50g leaf equivalent, approximately 100g to 500g leaf equivalent, approximately 100g to 300g leaf equivalent, approximately 40g to 100g leaf equivalent, approximately 40g to 80g leaf equivalent, approximately 40g to 60g leaf equivalent, approximately 50g to 100g leaf equivalent, or approximately 50g to 80g leaf equivalent.

[0072] In some embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day, or as needed. In further embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day. In yet another embodiment, the pharmaceutical composition is administered as needed.

[0073] In some embodiments, treatment of cognitive impairment associated with attention deficit hyperactivity disorder or ADHD in a subject includes the step of administering a pharmaceutical composition during a transition period between drug therapies. The pharmaceutical compositions described herein may be administered as treatment when a subject transitions from one drug to another, transitions from one drug to a state where treatment for attention deficit hyperactivity disorder is no longer received, or transitions from one drug to a drug containing the pharmaceutical composition described herein.

[0074] FDG-PET, or [ 18 Positron emission tomography (PET) using [F]-fluorodeoxy-D-glucose (FDG) is a medical imaging technique that enables clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog that is injected into the body. Like glucose, FDG is taken up by cells and results in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormal decreases or increases in synaptic activity in various regions of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder). The exact cause of attention deficit hyperactivity disorder is unknown, and although we do not wish to be bound by theory, studies have found that attention deficit hyperactivity disorder is associated with weakness in the function and structure of prefrontal cortical circuits in the brain. In some embodiments, the administration of a pharmaceutical composition is [ 18 Positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in the prefrontal cortex region of the target brain.

[0075] In certain embodiments, subjects receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD using the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD using at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and who have experienced or are experiencing adverse reactions to at least one drug.

[0076] In some embodiments, subjects receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD using the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD using at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and who have experienced or are experiencing treatment resistance to at least one drug.

[0077] In some embodiments, subjects receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder or ADHD are refractory to and / or intolerant of existing or standard treatments. In further embodiments, subjects are intolerant of existing or standard treatments due to adverse effects.

[0078] VI. Methods for treating depression A method for treating depression in a subject is provided herein, comprising the step of administering an effective amount of a pharmaceutical composition containing the above-mentioned whole coca leaf extract to a subject in need thereof.

[0079] Depression is a disorder characterized by persistent depressed mood, low self-esteem, and loss of interest in and pleasure in activities that are normally enjoyable. Depression can negatively impact a person's personal life, work, or education, and can cause problems with a person's eating habits, sleep habits, and overall health. Depression is thought to be caused by a combination of genetic, environmental, and psychological factors. Depression as defined herein may correspond to one or more types of depression, such as major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, atypical depression, and treatment-resistant depression.

[0080] In some embodiments, the subjects receiving treatment for depression may be vertebrates such as mammals, fish, birds, reptiles, or amphibians. Accordingly, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not indicate a specific age or sex. Accordingly, it is intended to include adult and neonatal subjects, as well as fetuses, regardless of whether they are male or female. In one embodiment, the subject is a mammal. In further embodiments, the subject is a human.

[0081] The pharmaceutical composition may be administered alone or in combination with other drugs and / or the pharmaceutical composition for the treatment of depression. 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 selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, monoamine oxidase inhibitors, or combinations thereof.

[0082] Examples of selective serotonin reuptake inhibitors suitable for treating depression include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and bilazodone.

[0083] Examples of serotonin-norepinephrine reuptake inhibitors suitable for treating depression include, but are not limited to, desvenlafaxine, duloxetine, levomirnacipran, milnacipran, and venlafaxine.

[0084] Examples of norepinephrine-specific serotonergic drugs suitable for treating depression include, but are not limited to, aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline / tesiptiline.

[0085] Examples of tricyclic antidepressants suitable for treating depression include, but are not limited to, clomipramine, amoxapine, amitriptyline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, and protriptyline.

[0086] Examples of serotonin antagonists and reuptake inhibitors suitable for treating depression include, but are not limited to, etoperidone, lorpiprazole, mepiprazole, nefazodone, and trazodone.

[0087] Examples of monoamine oxidase inhibitors suitable for the treatment of depression include, but are not limited to, isocarboxazide, hydracarbazine, phenelzine, tranylcypromine, bifemelan, methylthioninium chloride, moclobemide, pyrrindol, rasagiline, selegiline, and safinamides.

[0088] In some embodiments, the pharmaceutical composition is administered concurrently with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, monoamine oxidase inhibitors, or combinations thereof.

[0089] In some embodiments, a daily dose of the pharmaceutical composition is administered to the subject. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of coca whole leaf extract is approximately 1 g to approximately 500 g of coca whole leaf equivalents. That is, the administered extract contains an alkaloid concentration equivalent to approximately 1 g to approximately 500 g of dried leaves. The daily dose of coca whole leaf extract may include any dose within the range derived from the listed exemplary values. The daily dose of whole coca leaf extract is, for example, approximately 1g to 400g leaf equivalent, approximately 1g to 300g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 100g leaf equivalent, approximately 1g to 90g leaf equivalent, approximately 1g to 70g leaf equivalent, approximately 1g to 50g leaf equivalent, approximately 1g to 30g leaf equivalent, approximately 1g to 15g leaf equivalent, approximately 10g to 500g leaf equivalent, approximately 10g to 400g leaf equivalent, approximately 10g to 300g leaf equivalent, approximately 10g to 200g leaf equivalent, and approximately 10g to 100g leaf equivalent. It may be approximately 10g to 80g leaf equivalent, approximately 10g to 60g leaf equivalent, approximately 10g to 40g leaf equivalent, approximately 20g to 500g leaf equivalent, approximately 20g to 300g leaf equivalent, approximately 20g to 100g leaf equivalent, approximately 20g to 70g leaf equivalent, approximately 20g to 50g leaf equivalent, approximately 100g to 500g leaf equivalent, approximately 100g to 300g leaf equivalent, approximately 40g to 100g leaf equivalent, approximately 40g to 80g leaf equivalent, approximately 40g to 60g leaf equivalent, approximately 50g to 100g leaf equivalent, or approximately 50g to 80g leaf equivalent.

[0090] In some embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day, or as needed. In further embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day. In yet another embodiment, the pharmaceutical composition is administered as needed.

[0091] In some embodiments, treatment of depression in a subject includes the step of administering a pharmaceutical composition during a transition period between drug therapies. The pharmaceutical compositions described herein may be administered as treatment when a subject transitions from one drug to another, transitions from one drug to a state where they no longer receive treatment for depression, or transitions from one drug to a drug containing the pharmaceutical composition described herein.

[0092] FDG-PET, or [ 18 Positron emission tomography (PET) using [F]-fluorodeoxy-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 that is injected into the body. Like glucose, FDG is taken up by cells and results in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormal decreases or increases in synaptic activity in various regions of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders (e.g., depression). The exact cause of depression is unknown, and although we do not wish to be bound by theory, studies have shown that dysregulation of activity in the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens-amygdala regions of the brain appears to correlate with the disorder. In some embodiments, administration of a pharmaceutical composition is performed during treatment involving the administration of the pharmaceutical composition. 18 Positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in at least one of the following regions of the brain: the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens-amygdala.

[0093] In certain embodiments, subjects receiving treatment for depression with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for depression with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, or monoamine oxidase inhibitors, and who have experienced or are experiencing an adverse reaction to at least one drug.

[0094] In some embodiments, subjects receiving treatment for depression with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for depression with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, or monoamine oxidase inhibitors, and who have experienced or are experiencing treatment resistance to at least one drug.

[0095] In some embodiments, subjects receiving treatment for depression are refractory to and / or intolerant of existing or standard treatments. In further embodiments, subjects are intolerant of existing or standard treatments due to adverse effects.

[0096] VII. How to treat anxiety disorders A method for treating anxiety disorders in a subject is provided herein, comprising the step of administering an effective amount of a pharmaceutical composition containing the above-mentioned whole coca leaf extract to a subject in need thereof.

[0097] Anxiety disorders are characterized by intense, excessive, and persistent worry. Often, anxiety disorders involve recurrent episodes of intense anxiety and fear or terror that peak within minutes. These episodes are also known as panic attacks. Symptoms of anxiety disorders include increased heart rate, a sense of imminent danger, panic or misfortune, irritability, hyperventilation, sleep disturbances, and gastrointestinal disturbances. 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 drug-induced anxiety disorders. In some embodiments, the patient receives treatment for an anxiety disorder that is generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, or drug-induced anxiety disorder.

[0098] In some embodiments, the subjects receiving treatment for anxiety disorders may be vertebrates such as mammals, fish, birds, reptiles, or amphibians. Accordingly, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not indicate a specific age or sex. Accordingly, it is intended to include adult and neonatal subjects, as well as fetuses, regardless of whether they are male or female. In one embodiment, the subject is a mammal. In further embodiments, the subject is a human.

[0099] The pharmaceutical composition may be administered alone or in combination with other drugs and / or the pharmaceutical composition for the treatment of anxiety disorders. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is receiving treatment for narcolepsy with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is receiving treatment for anxiety disorders with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors.

[0100] Examples of selective serotonin reuptake inhibitors appropriate for the treatment of anxiety disorders include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and bilazodone.

[0101] Examples of serotonin-norepinephrine reuptake inhibitors appropriate for the treatment of anxiety disorders include, but are not limited to, desvenlafaxine, duloxetine, levomirunacipran, milnacipran, and venlafaxine.

[0102] Examples of tricyclic antidepressants suitable for treating anxiety disorders include, but are not limited to, clomipramine, amoxapine, amitriptyline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, and protriptyline.

[0103] Examples of benzodiazepines suitable for treating anxiety disorders include, but are not limited to, clonazepam, alprazolam, lorazepam, bromazepam, oxazepam, chlordiazepoxide, clorazepate, and diazepam.

[0104] Examples of beta-blockers suitable for treating anxiety disorders include, but are not limited to, acebutolol, bisoprolol, carvedilol, propranolol, atenolol, and metoprolol.

[0105] Examples of monoamine oxidase inhibitors suitable for treating anxiety disorders include, but are not limited to, isocarboxazide, hydracarbazine, phenelzine, tranylcypromine, bifemelan, methylthioninium chloride, moclobemide, pyrrindol, rasagiline, selegiline, and safinamide.

[0106] In some embodiments, a daily dose of the pharmaceutical composition is administered to the subject. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of coca whole leaf extract is approximately 1 g to approximately 500 g of coca whole leaf equivalents. That is, the administered extract contains an alkaloid concentration equivalent to approximately 1 g to approximately 500 g of dried leaves. The daily dose of coca whole leaf extract may include any dose within the range derived from the listed exemplary values. The daily dose of whole coca leaf extract is, for example, approximately 1g to 400g leaf equivalent, approximately 1g to 300g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 200g leaf equivalent, approximately 1g to 100g leaf equivalent, approximately 1g to 90g leaf equivalent, approximately 1g to 70g leaf equivalent, approximately 1g to 50g leaf equivalent, approximately 1g to 30g leaf equivalent, approximately 1g to 15g leaf equivalent, approximately 10g to 500g leaf equivalent, approximately 10g to 400g leaf equivalent, approximately 10g to 300g leaf equivalent, approximately 10g to 200g leaf equivalent, and approximately 10g to 100g leaf equivalent. It may be approximately 10g to 80g leaf equivalent, approximately 10g to 60g leaf equivalent, approximately 10g to 40g leaf equivalent, approximately 20g to 500g leaf equivalent, approximately 20g to 300g leaf equivalent, approximately 20g to 100g leaf equivalent, approximately 20g to 70g leaf equivalent, approximately 20g to 50g leaf equivalent, approximately 100g to 500g leaf equivalent, approximately 100g to 300g leaf equivalent, approximately 40g to 100g leaf equivalent, approximately 40g to 80g leaf equivalent, approximately 40g to 60g leaf equivalent, approximately 50g to 100g leaf equivalent, or approximately 50g to 80g leaf equivalent.

[0107] In some embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day, or as needed. In further embodiments, the pharmaceutical composition is administered once, two, three, four, five, or six times a day. In yet another embodiment, the pharmaceutical composition is administered as needed.

[0108] In some embodiments, treatment of anxiety disorder in a subject includes the step of administering a pharmaceutical composition during a transition period between drug therapies. The pharmaceutical compositions described herein may be administered as treatment when a subject transitions from one drug to another, transitions from one drug to a state where they no longer receive treatment for anxiety disorder, or transitions from one drug to a drug containing a pharmaceutical composition described herein.

[0109] FDG-PET, or [ 18 Positron emission tomography (PET) using [F]-fluorodeoxy-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 that is injected into the body. Like glucose, FDG is taken up by cells and results in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormal decreases or increases in synaptic activity in various regions of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders (e.g., anxiety disorders). The exact cause of anxiety disorders is unknown, and although we do not wish to be bound by theory, studies have indicated that the amygdala and hypothalamic regions of the brain likely play important roles in stress responses and, consequently, in anxiety. In some embodiments, the administration of a pharmaceutical composition is performed during treatment involving the administration of the pharmaceutical composition. 18 Positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) show increased activation in at least one of the amygdala and hypothalamic regions of the target brain.

[0110] In certain embodiments, subjects receiving treatment for anxiety disorders with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for anxiety disorders with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors, and who have experienced or are experiencing adverse reactions to at least one drug.

[0111] In some embodiments, subjects receiving treatment for anxiety disorders with the pharmaceutical compositions described herein are identified as subjects who have previously received or are currently receiving treatment for anxiety disorders with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors, and who have experienced or are experiencing treatment resistance to at least one drug.

[0112] In some embodiments, subjects receiving treatment for anxiety disorders are refractory to and / or intolerant of existing or standard treatments. In further embodiments, subjects are intolerant of existing or standard treatments due to adverse effects.

[0113] VIII. Method for producing pharmaceutical compositions A method for producing a pharmaceutical composition containing an effective amount of coca whole leaf extract is provided herein.

[0114] In one embodiment, the method includes the steps of: a. exposing the leaves of a plant of the Coccaceae family, or a dried powder thereof, to a first 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.

[0115] In some embodiments, the liquid-phase concentrate is further powdered to form a whole coca leaf extract.

[0116] In some embodiments, the method further includes the steps of exposing a first solid phase to a 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 a concentrate of the liquid phase.

[0117] In some embodiments, the solvent is selected from C1-C4 alcohols, ketones, water, or a combination thereof. Suitable first solvents include, but are not limited to, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, isobutanol, sec-butanol, tert-butyl alcohol, acetone, methyl ethyl ketone, or water. The first solvent may have any pH. In some embodiments, the first solvent is one or more acids selected from the group consisting of acetic acid, adipic acid, ascorbic acid, phosphoric acid, aluminum ammonium sulfate, dibasic ammonium citrate, monobasic ammonium citrate, calcium citrate, calcium fumarate, calcium gluconate, dibasic calcium phosphate, calcium phosphate, hydrochloric acid, monobasic sulfuric acid, tribasic calcium phosphate, citric acid, fumaric acid, gluconic acid, magnesium fumarate, malic acid, phosphoric acid, potassium bitartrate, potassium citrate, potassium fumarate, sodium citrate, sodium fumarate, sodium gluconate, sodium lactate, potassium sodium sodium hexametaphosphate, potassium sodium tartrate, potassium sodium tripolyphosphate, sodium tetrabasic sodium pyrophosphate, sodium tripolyphosphate, and tartaric acid, and is controlled to a specific pH. In further embodiments, the first solvent is controlled to a specific pH with one or more bases selected from the group consisting of ammonium bicarbonate, ammonium carbonate, ammonium hydroxide, calcium acetate, calcium carbonate, calcium chloride, calcium hydroxide, calcium lactate, calcium oxide, dibasic calcium phosphate, monobasic calcium phosphate, magnesium carbonate, potassium aluminum sulfate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, dibasic potassium phosphate, tetrabasic potassium pyrophosphate, tribasic potassium phosphate, potassium tripolyphosphate, sodium acetate, acidic sodium pyrophosphate, aluminum sodium phosphate, aluminum sodium sulfate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, and tribasic sodium phosphate.

[0118] In some embodiments, the method includes the steps of: a. exposing a second solid phase to a solvent to form a third liquid phase and a third solid phase; and b. combining the third liquid phase, the first liquid phase and the second liquid phase to form a pooled liquid phase, evaporating the solvent to produce a concentrate of the liquid phase.

[0119] In some embodiments, the method includes the steps of: a. exposing a third solid phase to a solvent to form a fourth liquid phase and a fourth solid phase; and b. combining the fourth liquid phase with the first, second, and third liquid phases to form a pooled liquid phase, evaporating the solvent to produce a concentrate of the liquid phases.

[0120] In some embodiments, the method includes the steps of: a. exposing a fourth solid phase to a solvent to form a fifth liquid phase and a fifth solid phase; and b. combining the fifth liquid phase with the first, second, third, and fourth liquid phases to form a pooled liquid phase, evaporating the solvent to produce a concentrate of the liquid phases.

[0121] In some embodiments, the liquid phase concentrate is a slurry. The slurry may contain a high-density solid mixture of whole coca leaf extract, coca leaf solids, or a combination thereof in a solvent.

[0122] In certain embodiments, the concentrate of the liquid phase is exposed to a second solvent to form a resolubilizable mixture, where the second solvent is different from the solvent to which the leaves were exposed. Suitable examples of the second solvent include, but are not limited to, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, isobutanol, sec-butanol, tert-butyl alcohol, acetone, methyl ethyl ketone, or water. The second solvent may have any pH. In some embodiments, the second solvent is controlled to a specific pH between 1 and 14. In some embodiments, the second solvent is one or more acids selected from the group consisting of acetic acid, adipic acid, ascorbic acid, phosphoric acid, aluminum ammonium sulfate, dibasic ammonium citrate, monobasic ammonium citrate, calcium citrate, calcium fumarate, calcium gluconate, dibasic calcium phosphate, calcium phosphate, hydrochloric acid, monobasic sulfuric acid, tribasic calcium phosphate, citric acid, fumaric acid, gluconic acid, magnesium fumarate, malic acid, phosphoric acid, potassium bitartrate, potassium citrate, potassium fumarate, sodium citrate, sodium fumarate, sodium gluconate, sodium lactate, potassium sodium sodium hexametaphosphate, potassium sodium tartrate, potassium sodium tripolyphosphate, sodium tetrabasic sodium pyrophosphate, sodium tripolyphosphate, and tartaric acid, and is controlled to a specific pH between 1 and 14.In further embodiments, the first solvent is controlled to a specific pH with one or more bases selected from the group consisting of ammonium bicarbonate, ammonium carbonate, ammonium hydroxide, calcium acetate, calcium carbonate, calcium chloride, calcium hydroxide, calcium lactate, calcium oxide, dibasic calcium phosphate, monobasic calcium phosphate, magnesium carbonate, potassium aluminum sulfate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, dibasic potassium phosphate, tetrabasic potassium pyrophosphate, tribasic potassium phosphate, potassium tripolyphosphate, sodium acetate, acidic sodium pyrophosphate, aluminum sodium phosphate, aluminum sodium sulfate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, and tribasic sodium phosphate.

[0123] In various embodiments, when the concentrate is exposed to a second solvent, two immiscible layers are formed, and the method includes the step of separating the layer containing the second solvent from the other layer.

[0124] In some embodiments, the concentrate of the liquid phase exposed to the second solvent is exposed to an adsorbent material, which is a gel resin, a nonionic macroporous resin, an ion exchange resin, or a combination thereof. In further embodiments, the adsorbent material is washed with the second solvent to remove impurities from the adsorbent material. In some embodiments, the adsorbent material is eluted with the second solvent.

[0125] The liquid-phase concentrate can be mixed with pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include, but are not limited to, one or more of diluents, binders, lubricants, disintegrants, colorants, or flavorings. In certain embodiments, the liquid-phase concentrate is mixed with an alkalizing agent. As described above, alkalizing agents can promote the release of alkaloids from the leaves or convert them into active or absorbable forms. In the stomach, the high pH brought about by the alkalizing agent can promote gastric absorption of the active compound or inhibit gastric degradation. Examples of suitable alkalizing agents included in the pharmaceutical compositions described herein include, but are not limited to, sodium bicarbonate, calcium oxide, or potassium hydroxide. The pH of the alkalizing agent can be any alkaline pH greater than about 7. The pH of the alkalizing agent may be, for example, 7.5, 8, 9, 10, 11, 12, 13, or higher. In further embodiments, the pH of the alkalizing agent may be any pH within the range derived from any two of the exemplary values ​​listed above. For example, the pH of the alkalizing agent may be in the range of about 7 to about 8, about 7 to about 10, about 7 to about 13, about 7 to about 14, about 8 to about 11, about 8 to about 13, about 9 to about 12, about 9 to about 14, about 10 to about 12, about 10 to about 13, or about 10 to about 14. In some embodiments, the pH of the alkalizing agent is about 10 to about 13.

[0126] In certain embodiments, the liquid-phase concentrate or other pharmaceutical product is not mixed with the alkalizing agent.

[0127] In some embodiments, the liquid-phase concentrate is dried using a drying technique. The drying technique further removes or evaporates excess solvent. Examples of suitable drying techniques include spray drying, belt drying, or freeze-drying. [Examples]

[0128] IX. Examples [Examples]

[0129] Extraction of whole coca leaves To extract or dissolve components of coca leaves, including tropane alkaloids, pyrrolidine alkaloids, essential oils, and flavonoids, dried whole coca leaves are first exposed to a solvent. Next, the undissolved portion of the biomass is filtered from the solvent. Subsequently, the undissolved portion in the solvent is re-extracted using the same solvent and filtration method. This extraction method can be repeated up to five times consecutively. Next, the solvents from each extraction step are combined to form a pooled extract. The solvent is evaporated to dryness or a concentrated slurry is formed. Subsequently, the slurry or dried extract can be resuspended in a different or similar solvent and then filtered. Next, the resuspended extract is exposed to a resin such as a gel resin, a nonionic macroporous resin, or an ion exchange resin. Subsequently, the resin is washed to elute the extracted fractions, which are then combined to produce a liquid-phase concentrate. The liquid-phase concentrate is combined with an alkalizing agent and pharmaceutically acceptable excipients. The solvent is evaporated from the mixture using drying techniques such as spray drying, belt drying, or freeze-drying. Finally, the dried extract is powdered. [Examples]

[0130] Effects of whole coca leaf extract on brain parameters associated with narcolepsy as measured by FDG-PET A pharmaceutical composition containing whole coca leaf extract will be tested in mice using positron emission tomography (PET) to evaluate in vivo brain metabolism as an indicator of synaptic activity and information exchange (connectivity) in target brain regions associated with narcolepsy. Previous studies have found that narcolepsy is associated with functional and structural weakness of the perifornix hypothalamus in the brain.

[0131] Mice will be administered fluorodeoxyglucose (FDG), a radioactive glucose analog, and PET brain scans will be performed before and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. Compared to PET scans performed before administration, it is expected that increased metabolic activity in the perifornix hypothalamic region of the brain will be observed in PET scans performed after administration. [Examples]

[0132] Safety and efficacy testing of a pharmaceutical composition containing whole coca leaf extract for the treatment of narcolepsy. This study evaluates the efficacy, safety, and tolerability of a pharmaceutical composition containing coca whole leaf extract in adults with narcolepsy.

[0133] Protocol: Patients to be treated with whole coca leaf extract will be randomly assigned to either a treatment group or a control group. Patients in the treatment group will receive a solid oral dosage form of whole coca leaf extract 1 to 6 times a day (approximately 1 g to approximately 500 g leaf equivalent). Patients in the control group will not receive whole coca leaf extract at any point in this study.

[0134] Eligibility criteria: Patients eligible to participate in the study must meet the following criteria: willingness and ability to provide written informed consent; male or female aged 18 years or older; diagnosed with narcolepsy within the past five years; female of childbearing age must have a negative pregnancy test result at the time of informed consent; subjects may or may not currently be receiving medication for narcolepsy; subjects currently receiving medication for narcolepsy may self-report being unresponsive to treatment or having a significant side effect profile. Patients ineligible to participate in the study include breastfeeding women; individuals currently suffering from sleep disorders such as sleep apnea syndrome or periodic limb movement disorder; patients with neurodegenerative or cerebrovascular diseases; or patients consuming caffeine in amounts equivalent to six or more cups of tea, four or more cups of coffee, or nine or more cans of soda per day.

[0135] Effectiveness variable: Primary outcome measure: Epworth Sleepiness Scale (ESS) [Evaluation period: 14 days]. Range: 0-24, lower scores indicate better outcomes.

[0136] Patient Global Impression of Change (PGI-C) [Evaluation period: 14 days]. PGI-C is an evaluation scale completed by the subject from screening to the final visit (at every visit). [Examples]

[0137] Effects of whole coca leaf extract on brain parameters associated with attention deficit hyperactivity disorder (ADHD) as measured by FDG-PET. A pharmaceutical composition containing whole coca leaf extract will be tested in mice using positron emission tomography (PET) to evaluate in vivo brain metabolism as an indicator of synaptic activity and information exchange (connectivity) in target brain regions associated with ADHD. Previous studies have found that attention deficit hyperactivity disorder (ADHD) is associated with weakness in the function and structure of prefrontal cortical circuits in the brain, particularly abnormalities in the striatal frontofrontal network. Furthermore, PET has identified multiple low-metabolic brain regions, including the prefrontal cortex and cingulate cortex, suggesting consistent synaptic dysfunction in individuals exhibiting ADHD.

[0138] Mice will be administered fluorodeoxyglucose (FDG), a radioactive glucose analog, and PET brain scans will be performed before and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. Compared to PET scans performed before administration, an increase in metabolic activity in the prefrontal cortex region of the brain is expected to be observed in PET scans performed after administration. [Examples]

[0139] Safety and efficacy testing of a pharmaceutical composition containing whole coca leaf extract for the treatment of ADHD. This study evaluates the efficacy, safety, and tolerability of pharmaceutical compositions containing coca whole leaf extract in adults and children with attention deficit hyperactivity disorder (ADHD).

[0140] Protocol: Patients to be treated with whole coca leaf extract will be randomly assigned to either a treatment group or a control group. Patients in the treatment group will receive a solid oral dosage form of whole coca leaf extract 1 to 6 times a day (approximately 1 g to approximately 500 g leaf equivalent). Patients in the control group will not receive whole coca leaf extract at any point in this study.

[0141] Eligibility criteria: Patients eligible to participate in the study must meet the following criteria: willingness and ability to provide written informed consent; male or female aged 18 or older, or male or female aged 5-18 with a signed and dated consent form from a parent or legal guardian; meet the ADHD criteria (including primarily inattentive, hyperactive, or combined) of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) as confirmed by the Adult ADHD Clinical Diagnostic Scale (ACDS) version 1.2; women of childbearing age must have a negative pregnancy test result at the time of informed consent; subjects may or may not currently be receiving medication for ADHD; subjects currently receiving medication for ADHD may self-report being unresponsive to treatment or having a significant side effect profile. Patients ineligible for the study include breastfeeding women; individuals with a current comorbid mental disorder that requires treatment with a drug prohibited in this study or that could interfere with the efficacy or safety evaluation. Examples include, but are not limited to, psychotic disorders, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, a current major depressive episode, or post-traumatic stress disorder; or individuals with a known or current history of structural cardiac abnormalities.

[0142] Effectiveness variable: Primary outcome measure: Change from baseline in the ADHD Investigator Symptom Rating Scale (AISRS) [Evaluation period: 8 weeks, weekly evaluation]. The AISRS for adults is an 18-item clinician assessment scale that evaluates individual ADHD symptoms on a scale from 0 (none) to 3 (severe). The total score ranges from 0 (no ADHD symptoms) to 54 (very severe ADHD symptoms). A negative change from baseline indicates improvement. [Examples]

[0143] Effects of whole coca leaf extract on brain parameters associated with depression as measured by FDG-PET A pharmaceutical composition containing coca whole leaf extract will be tested in mice using positron emission tomography (PET) to evaluate in vivo brain metabolism as an indicator of synaptic activity and information exchange (connectivity) in target brain regions associated with depression. Previous studies have found that depression is associated with weakness in the function and structure of circuits in the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens-amygdal region of the brain.

[0144] Mice will be administered fluorodeoxyglucose (FDG), a radioactive glucose analog, and PET brain scans will be performed before and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. Compared to PET scans performed before administration, increased metabolic activity is expected to be observed in the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens-amygdala regions of the brain in PET scans performed after administration. [Examples]

[0145] Safety and efficacy testing of a pharmaceutical composition containing whole coca leaf extract for the treatment of depression. This study evaluates the efficacy, safety, and tolerability of a pharmaceutical composition containing whole coca leaf extract in adults with depression.

[0146] Protocol: Patients to be treated with whole coca leaf extract will be randomly assigned to either a treatment group or a control group. Patients in the treatment group will receive a solid oral dosage form of whole coca leaf extract 1 to 6 times a day (approximately 1 g to approximately 500 g leaf equivalent). Patients in the control group will not receive whole coca leaf extract at any point in this study.

[0147] Eligibility criteria: Patients eligible for a single trial may be: willing and able to provide written informed consent; male or female 18 years of age or older; must meet the current criteria for depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); women of childbearing age must have a negative pregnancy test result at the time of informed consent; subjects may or may not be currently receiving medication for depression; subjects may be currently receiving medication for depression and self-report being unresponsive to treatment or having a significant side effect profile. Patients ineligible for the trial include breastfeeding women; individuals with a history of schizophrenia or other psychotic disorders; and individuals with suicidal ideation.

[0148] Effectiveness variable: Primary outcome measure: Change in Montgomery-Asberg Depression Rating Scale score [Evaluation period: 24 hours, 2 weeks, 4 weeks, and 8 weeks]. The Montgomery-Asberg Depression Rating Scale (MADARS) is a 10-item assessment tool used to evaluate depressive symptoms and changes in any of these symptoms in adults. Each of the 10 items is evaluated on a scale of 0 to 6 using different descriptors. These individual item scores are summed up to form a total score ranging from 0 to 60, with higher scores indicating poorer health outcomes. MADARS provides a general measure of the level of depression. [Examples]

[0149] Effects of whole coca leaf extract on brain parameters associated with anxiety disorder as measured by FDG-PET A pharmaceutical composition containing whole coca leaf extract will be tested in mice using positron emission tomography (PET) to evaluate in vivo brain metabolism as an indicator of synaptic activity and connectivity in target brain regions associated with anxiety disorders. Previous studies have found that depression is associated with functional and structural vulnerabilities in the amygdala and hypothalamic regions of the brain.

[0150] Mice will be administered fluorodeoxyglucose (FDG), a radioactive glucose analog, and PET brain scans will be performed before and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. Compared to PET scans performed before administration, increased metabolic activity in the amygdala and hypothalamic regions of the brain is expected to be observed in PET scans performed after administration. [Examples]

[0151] Safety and efficacy testing of pharmaceutical compositions containing whole coca leaf extract for the treatment of anxiety disorders This study evaluates the efficacy, safety, and tolerability of a pharmaceutical composition containing whole coca leaf extract in adults with anxiety disorders.

[0152] Protocol: Patients to be treated with whole coca leaf extract will be randomly assigned to either a treatment group or a control group. Patients in the treatment group will receive a solid oral dosage form of whole coca leaf extract 1 to 6 times daily (approximately 1 to 500 g leaf equivalent). Patients in the control group will not receive whole coca leaf extract at any point in the study, but will receive a placebo tablet that appears identical to a pharmaceutical composition containing whole coca leaf extract.

[0153] Eligibility criteria: Patients eligible to participate in the study must meet the following criteria: willingness and ability to provide written informed consent; male or female aged 18 years or older; and have one of the following major Axis I disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5): panic disorder with or without agoraphobia, social anxiety disorder, anxiety disorder not otherwise specified, adjustment disorder with anxiety, adjustment disorder with mixed anxiety and depression, specific phobia, generalized anxiety disorder, separation anxiety, or substance-induced anxiety disorder; women of childbearing age must have a negative pregnancy test result at the time of informed consent; subjects may or may not currently be receiving medication for an anxiety disorder; subjects currently receiving medication for an anxiety disorder may self-report being unresponsive to treatment or having a significant side effect profile. Patients who are ineligible for the study include breastfeeding women; patients with medical contraindications that prevent adequate exposure, such as cardiovascular disease or autoimmune disease; and patients who currently or have previously had schizophrenia, psychosis, or bipolar disorder.

[0154] Effectiveness variable: Primary outcome measure: Change from baseline in the total score of the Hamilton Rating Scale for Anxiety (HAM-A) [Evaluation period: 8 weeks].

[0155] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

1. A method for treating narcolepsy in a subject, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

2. The method according to claim 1, wherein the whole coca leaf extract contains cocaine in an amount of about 80% by weight or less of the extract.

3. The method according to claim 1 or 2, wherein the coca whole leaf extract contains methyl ecgonine cinnamate.

4. The method according to any one of claims 1 to 3, wherein the whole leaf extract of coca is extracted from Coca genus Coca variety, Coca genus Ipadu variety, Coca genus Novogranatense variety, Coca genus Novogranatense variety, or a combination thereof.

5. The method according to any one of claims 1 to 4, wherein the pharmaceutical composition is formulated as an oral dosage form.

6. The method according to claim 5, wherein the oral dosage form is a solid oral dosage form.

7. The method according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises an alkalizing agent.

8. The method according to claim 7, wherein the alkalizing agent is sodium bicarbonate, calcium oxide, or potassium hydroxide.

9. The method according to claim 7 or 8, wherein the pH of the alkalizing agent is approximately 10 to approximately 13.

10. The method according to any one of claims 1 to 9, wherein the pharmaceutical composition comprises about 30% to about 100% by weight of whole coca leaf extract.

11. The method according to any one of claims 1 to 10, wherein the whole coca leaf extract further comprises at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscohigrin, dihydrocuscohigrin, or higrin.

12. The method according to any one of claims 1 to 11, wherein methyl ecgonine cinnamate exists as a cis isomer, a trans isomer, or a combination thereof.

13. The method according to any one of claims 1 to 12, wherein the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

14. The method according to any one of claims 1 to 13, wherein the coca whole leaf extract comprises at least one essential oil.

15. The method according to any one of claims 1 to 14, wherein the narcolepsy is type 1 or type 2 narcolepsy.

16. The method according to any one of claims 1 to 15, wherein the subject is experiencing daytime sleepiness.

17. The method according to any one of claims 1 to 16, wherein the subject is a mammal.

18. The method according to claim 17, wherein the subject is a human.

19. The method according to any one of claims 1 to 18, wherein the subject is being treated for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate.

20. The method according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered concurrently with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or gamma-hydroxybutyrate.

21. The method according to any one of claims 1 to 20, wherein the daily dose of coca whole leaf extract administered to the subject is approximately 1 g leaf equivalent to approximately 500 g leaf equivalent of the whole leaf extract.

22. The method according to any one of claims 1 to 21, wherein the pharmaceutical composition is administered once, two, three, four, five, or six times per day, or as needed.

23. The administration of the pharmaceutical composition is [ １８ The method according to any one of claims 1 to 22, wherein positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in the perifornix hypothalamic region of the target brain.

24. The method according to any one of claims 1 to 23, wherein the treatment of narcolepsy in a subject includes the step of administering a pharmaceutical composition during a transition period to drug therapy.

25. A method for treating attention deficit hyperactivity disorder in a subject, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

26. The method according to claim 25, wherein the whole coca leaf extract contains cocaine in an amount of about 80% by weight or less of the extract.

27. The method according to claim 25 or 26, wherein the whole coca leaf extract contains methyl ecgonine cinnamate.

28. The method according to any one of claims 25 to 27, wherein the whole leaf extract of coca is extracted from Coca genus Coca variety, Coca genus Ipadu variety, Coca genus Novogranatense variety, Coca genus Novogranatense variety, or a combination thereof.

29. The method according to any one of claims 25 to 28, wherein the pharmaceutical composition is formulated as an oral dosage form.

30. The method according to claim 29, wherein the oral dosage form is a solid oral dosage form.

31. The method according to any one of claims 25 to 30, wherein the pharmaceutical composition further comprises an alkalizing agent.

32. The method according to claim 31, wherein the alkalizing agent is sodium bicarbonate, calcium oxide, or potassium hydroxide.

33. The method according to claim 31 or 32, wherein the pH of the alkalizing agent is approximately 10 to approximately 13.

34. The method according to any one of claims 25 to 33, wherein the pharmaceutical composition comprises about 30% to about 100% by weight of whole coca leaf extract.

35. The method according to any one of claims 25 to 34, wherein the whole coca leaf extract further comprises at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscohigrin, dihydrocuscohigrin, or higrin.

36. The method according to any one of claims 25 to 35, wherein methyl ecgonine cinnamate exists as a cis isomer, a trans isomer, or a combination thereof.

37. The method according to any one of claims 25 to 36, wherein the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

38. The method according to any one of claims 25 to 37, wherein the coca whole leaf extract comprises at least one essential oil.

39. The method according to any one of claims 25 to 38, wherein the attention deficit hyperactivity disorder is inattentive type, hyperactive-impulsive type, or combined type of attention deficit hyperactivity disorder.

40. The method according to any one of claims 25 to 39, wherein the subject is a mammal.

41. The method according to claim 40, wherein the subject is a human.

42. The method according to any one of claims 25 to 41, wherein the subject is being treated for attention deficit hyperactivity disorder with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors.

43. The method according to any one of claims 25 to 42, wherein the pharmaceutical composition is administered concurrently with at least one drug selected from an stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

44. The method according to claim 42 or 43, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, celdexmethylphenidate, lisdexamfetamine, or a combination thereof.

45. The method according to claim 42 or 43, wherein the alpha-adrenergic agonist is guanfacine or clonidine.

46. The method according to claim 42 or 43, wherein the norepinephrine reuptake inhibitor is atomoxetine or biloxazine.

47. The method according to any one of claims 25 to 46, wherein the daily dose of coca whole leaf extract administered to the subject is approximately 1 g leaf equivalent to approximately 500 g leaf equivalent of the whole leaf extract.

48. The administration of the pharmaceutical composition is [ １８ The method according to any one of claims 25 to 47, wherein positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in the prefrontal cortical region of the target brain.

49. The method according to any one of claims 25 to 48, wherein the treatment of ADHD in a subject includes the step of administering a pharmaceutical composition during a transition period to drug therapy.

50. A method for treating depression in a subject, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

51. The method according to claim 50, wherein the whole coca leaf extract contains cocaine in an amount of about 10% by weight or less of the extract.

52. The method according to claim 50 or 51, wherein the coca whole leaf extract contains methyl ecgonine cinnamate.

53. The method according to any one of claims 50 to 52, wherein the whole leaf extract of coca is extracted from Coca genus Coca variety, Coca genus Ipadu variety, Coca genus Novogranatense variety, Coca genus Novogranatense variety, or a combination thereof.

54. The method according to any one of claims 50 to 53, wherein the pharmaceutical composition is formulated as an oral dosage form.

55. The method according to claim 54, wherein the oral dosage form is a solid oral dosage form.

56. The method according to any one of claims 50 to 55, wherein the pharmaceutical composition further comprises an alkalizing agent.

57. The method according to claim 56, wherein the alkalizing agent is sodium bicarbonate, calcium oxide, or potassium hydroxide.

58. The method according to claim 56 or 57, wherein the pH of the alkalizing agent is approximately 10 to approximately 13.

59. The method according to any one of claims 50 to 58, wherein the pharmaceutical composition comprises about 30% to about 100% by weight of whole coca leaf extract.

60. The method according to any one of claims 50 to 59, wherein the whole coca leaf extract further comprises at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscohigrin, dihydrocuscohigrin, or higrin.

61. The method according to any one of claims 50 to 60, wherein methyl ecgonine cinnamate exists as a cis isomer, a trans isomer, or a combination thereof.

62. The method according to any one of claims 50 to 61, wherein the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

63. The method according to any one of claims 50 to 62, wherein the coca whole leaf extract comprises at least one essential oil.

64. The method according to any one of claims 50 to 63, wherein the subject is receiving treatment for depression with at least one antidepressant selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic / specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, monoamine oxidase inhibitors, or combinations thereof.

65. The method according to any one of claims 50 to 64, wherein the pharmaceutical composition is administered concurrently with at least one antidepressant selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine-acting / specific serotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist / reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

66. The method according to any one of claims 50 to 65, wherein the subject is a mammal.

67. The method according to claim 66, wherein the subject is a human.

68. The method according to any one of claims 50 to 67, wherein the daily dose of coca whole leaf extract administered to the subject is approximately 1 g leaf equivalent to approximately 500 g leaf equivalent of the whole leaf extract.

69. The administration of the pharmaceutical composition occurs during treatment including the administration of the pharmaceutical composition. １８ The method according to any one of claims 50 to 68, wherein positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) cause increased activation of at least one of the following regions of the brain: the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens / amygdala.

70. The method according to any one of claims 50 to 69, wherein the treatment of depression in a subject includes the step of administering a pharmaceutical composition during a transition period to pharmacotherapy.

71. A method for treating anxiety disorder in a subject, comprising the step of administering a certain amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

72. The method according to claim 71, wherein the whole coca leaf extract contains cocaine in an amount of about 10% by weight or less of the extract.

73. The method according to claim 71 or 72, wherein the coca whole leaf extract contains methyl ecgonine cinnamate.

74. The pharmaceutical composition according to any one of claims 71 to 73, wherein the whole leaf extract of coca is extracted from Coca serrata variety, Coca serrata ypadu variety, Coca serrata novogranatense variety, Coca serrata novogranatense variety, or a combination thereof.

75. A pharmaceutical composition according to any one of claims 71 to 74, which is formulated as an oral dosage form.

76. The pharmaceutical composition according to claim 75, wherein the oral dosage form is a solid oral dosage form.

77. A pharmaceutical composition according to any one of claims 71 to 76, wherein the composition further comprises an alkalizing agent.

78. The pharmaceutical composition according to claim 77, wherein the alkalizing agent is sodium bicarbonate, calcium oxide, or potassium hydroxide.

79. The pharmaceutical composition according to claim 77 or 78, wherein the pH of the alkalizing agent is in the range of about 10 to about 13.

80. A pharmaceutical composition according to any one of claims 71 to 79, comprising approximately 30% to approximately 100% by weight of coca whole leaf extract.

81. The pharmaceutical composition according to any one of claims 71 to 80, wherein the whole leaf extract of coca further comprises at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscohigrin, dihydrocuscohigrin, or higrin.

82. The pharmaceutical composition according to any one of claims 71 to 81, wherein methyl ecgonine cinnamate is present as a cis isomer, a trans isomer, or a combination thereof.

83. The pharmaceutical composition according to any one of claims 71 to 82, wherein the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

84. The pharmaceutical composition according to any one of claims 71 to 83, further comprising a whole coca leaf extract and at least one essential oil.

85. The method according to any one of claims 71 to 84, 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 drug-induced anxiety disorder.

86. The method according to any one of claims 71 to 85, wherein the subject is a mammal.

87. The method according to claim 86, wherein the subject is a human.

88. The method according to any one of claims 71 to 87, wherein the subject is being treated for an anxiety disorder with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors.

89. The method according to any one of claims 71 to 88, wherein the pharmaceutical composition is administered concurrently with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine, a beta-blocker, a buspirone, or a monoamine oxidase inhibitor.

90. The method according to any one of claims 71 to 89, wherein the daily dose of coca whole leaf extract administered to the subject is approximately 1 g leaf equivalent to approximately 500 g leaf equivalent of the whole leaf extract.

91. The administration of the pharmaceutical composition occurs during treatment including the administration of the pharmaceutical composition. １８ The method according to any one of claims 71 to 90, wherein positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in at least one of the amygdala and hypothalamic regions of the target brain.

92. The method according to any one of claims 71 to 91, wherein the treatment of anxiety in a subject includes the step of administering a pharmaceutical composition during a transition period to pharmacotherapy.

93. The method according to any one of claims 1 to 92, wherein the whole leaf extract is an aqueous extract obtained by extracting from coca leaves with an aqueous extract solution having a pH greater than 8, 9, 10, 11, 12, or 12.5, or a pH of 10 to 13.

94. a. Exposing the leaves of a plant of the Coccaceae family, or its dried powder, to a first solvent to form a first liquid phase and a first solid phase; b. The step of separating the first solid phase from the first liquid phase; c. A step of evaporating the solvent from the first liquid phase to form a concentrate of the liquid phase; Coca whole leaf extract produced by a method including the following.

95. The method according to claim 94, further comprising the step of pulverizing the concentrate to form a whole coca leaf extract.

96. The steps of exposing the first solid phase to a solvent to form a second liquid phase and a second solid phase; and A step of combining the first liquid phase and the second liquid phase to form a pooled liquid phase, and evaporating the solvent to produce a concentrate of the liquid phase; The method according to claim 94, further comprising:

97. The method according to claim 94 or 96, wherein the solvent is selected from C1-C4 alcohols, ketones, water, or a combination thereof.

98. The method according to any one of claims 94 to 97, further comprising the step of adjusting the pH of the liquid phase or solvent with at least one acid selected from acetic acid, adipic acid, ascorbic acid, phosphoric acid, aluminum ammonium sulfate, dibasic ammonium citrate, monobasic ammonium citrate, calcium citrate, calcium fumarate, calcium gluconate, dibasic calcium phosphate, calcium phosphate, hydrochloric acid, monobasic sulfuric acid, tribasic calcium phosphate, citric acid, fumaric acid, gluconic acid, magnesium fumarate, malic acid, phosphoric acid, potassium bitartrate, potassium citrate, potassium fumarate, sodium citrate, sodium fumarate, sodium gluconate, sodium lactate, potassium sodium sodium hexametaphosphate, potassium sodium tartrate, potassium sodium tripolyphosphate, sodium tetrabasic sodium pyrophosphate, sodium tripolyphosphate, tartaric acid, or any combination thereof.

99. The method according to any one of claims 94 to 98, further comprising the step of adjusting the pH of the liquid phase or solvent with at least one base selected from ammonium bicarbonate, ammonium carbonate, ammonium hydroxide, calcium acetate, calcium carbonate, calcium chloride, calcium hydroxide, calcium lactate, calcium oxide, dibasic calcium phosphate, monobasic calcium phosphate, magnesium carbonate, potassium aluminum sulfate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, dibasic potassium phosphate, tetrabasic potassium pyrophosphate, tribasic potassium phosphate, potassium tripolyphosphate, sodium acetate, acidic sodium pyrophosphate, aluminum sodium phosphate, aluminum sodium sulfate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, tribasic sodium phosphate, or any combination thereof.

100. a. Exposing the second solid phase to a solvent to form a third liquid phase and a third solid phase; and b. The third liquid phase, the first liquid phase, and the second liquid phase are combined to form a pooled liquid phase, and the solvent is evaporated to produce a concentrate of the liquid phase; The method according to claim 94, including the method described in claim 94.

101. a. Exposing the third solid phase to a solvent to form a fourth liquid phase and a fourth solid phase; and b. The step of combining the fourth liquid phase with the first, second, and third liquid phases to form a pooled liquid phase, and evaporating the solvent to produce a concentrate of the liquid phase; The method according to claim 100, including the method described in claim 100.

102. a. Exposing the fourth solid phase to a solvent to form a fifth liquid phase and a fifth solid phase; and b. The step of combining the fifth liquid phase with the first, second, third, and fourth liquid phases to form a pooled liquid phase, and evaporating the solvent to produce a concentrate of the liquid phase; The method according to claim 101, including the method described in claim 101.

103. The method according to any one of claims 94 to 102, wherein the concentrate of the liquid phase is a slurry.

104. The method according to any one of claims 94 to 103, comprising the step of exposing a concentrate of the liquid phase to a second solvent to form a resolubilizable mixture, wherein the second solvent is different from the solvent to which the leaves were exposed.

105. The method according to claim 104, wherein when the concentrate is exposed to a second solvent, two immiscible layers are formed, and the method includes the step of separating the layer containing the second solvent from the other layer.

106. The method according to claim 104, wherein the concentrate of the liquid phase exposed to the second solvent is controlled to a specific pH between 1 and 14.

107. The method according to any one of claims 104 to 106, wherein the concentrate of the liquid phase exposed to the second solvent is exposed to an adsorbent material which is a gel resin, a nonionic macroporous resin, an ion exchange resin, or a combination thereof.

108. The method according to claim 107, wherein the adsorbent material is washed with a second solvent to remove impurities from the adsorbent material.

109. The method according to claim 107, wherein the adsorbent material is eluted with a second solvent.

110. The method according to any one of claims 94 to 109, wherein the concentrate of the liquid phase is mixed with a pharmaceutically acceptable excipient or alkalizing agent.

111. The method according to any one of claims 94 to 110, wherein the concentrate of the liquid phase is dried using a drying technique.

112. The method according to claim 111, wherein the drying technique is selected from spray drying, belt drying, or freeze-drying.

113. The method according to any one of claims 1 to 24, wherein a subject receiving treatment for narcolepsy with the pharmaceutical composition described herein has been identified as a subject who has previously received or is currently receiving treatment for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate, and has experienced or is experiencing an adverse reaction to said at least one drug.

114. The method according to any one of claims 1 to 24, wherein a subject receiving treatment for narcolepsy with the pharmaceutical composition described herein has previously received or is currently receiving treatment for narcolepsy with at least one drug selected from stimulants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepine receptor agonists, or gamma-hydroxybutyrate, and has been identified as a subject who has experienced or is experiencing treatment resistance to the at least one drug.

115. The method according to any one of claims 1 to 24, wherein a subject receiving treatment for narcolepsy is refractory to and / or intolerant to existing or standard treatments.

116. The method according to claim 115, wherein the subject is intolerant to existing or standard treatments due to adverse effects.

117. The method according to any one of claims 25 to 49, wherein a subject receiving treatment for attention deficit hyperactivity disorder with the pharmaceutical composition described herein has been identified as a subject who has previously received or is currently receiving treatment for attention deficit hyperactivity disorder with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and has experienced or is experiencing an adverse reaction to said at least one drug.

118. The method according to any one of claims 25 to 49, wherein a subject receiving treatment for attention deficit hyperactivity disorder with the pharmaceutical composition described herein has previously received or is currently receiving treatment for attention deficit hyperactivity disorder with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and has been identified as a subject who has experienced or is experiencing treatment resistance to the at least one drug.

119. The method according to any one of claims 25 to 49, wherein a subject receiving treatment for attention deficit hyperactivity disorder is refractory to and / or intolerant of existing or standard treatments.

120. The method according to claim 119, wherein the subject is intolerant to existing or standard treatments due to adverse effects.

121. The method according to any one of claims 50 to 70, wherein a subject receiving treatment for depression with the pharmaceutical composition described herein has previously received or is currently receiving treatment for depression with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, or monoamine oxidase inhibitors, and has been identified as a subject who has experienced or is experiencing an adverse reaction to the at least one drug.

122. The method according to any one of claims 50 to 70, wherein a subject receiving treatment for depression with the pharmaceutical composition described herein has previously received or is currently receiving treatment for depression with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-specific serotonergic antidepressants, tricyclic antidepressants, serotonin antagonists / reuptake inhibitors, or monoamine oxidase inhibitors, and has been identified as a subject who has experienced or is experiencing treatment resistance to the at least one drug.

123. The method according to any one of claims 50 to 70, wherein a subject receiving treatment for depression is refractory to and / or intolerant to existing or standard treatments.

124. The method according to claim 123, wherein the subject is intolerant to existing or standard treatments due to adverse effects.

125. The method according to any one of claims 71 to 92, wherein a subject receiving treatment for an anxiety disorder with the pharmaceutical composition described herein has previously received or is currently receiving treatment for an anxiety disorder with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors, and has been identified as a subject who has experienced or is experiencing an adverse reaction to the at least one drug.

126. The method according to any one of claims 71 to 92, wherein a subject receiving treatment for an anxiety disorder with the pharmaceutical composition described herein has previously received or is currently receiving treatment for an anxiety disorder with at least one drug selected from selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, benzodiazepines, beta-blockers, buspirone, or monoamine oxidase inhibitors, and has been identified as a subject who has experienced or is experiencing treatment resistance to the at least one drug.

127. The method according to any one of claims 71 to 92, wherein a subject receiving treatment for an anxiety disorder is refractory to and / or intolerant of existing or standard treatments.

128. The method according to claim 127, wherein the subject is intolerant to existing or standard treatments due to adverse effects.

129. The method according to any one of claims 1 to 92 and 113 to 159, wherein the whole coca leaf extract is the whole coca leaf extract according to any one of claims 94 to 112.

130. A method for reducing ADHD-related cognitive impairment in a subject, comprising the step of administering an effective amount of a pharmaceutical composition containing coca whole leaf extract to a subject in need thereof.

131. The method according to claim 130, wherein the cognitive impairment is selected from attention deficit, working memory impairment, executive function impairment, reaction time delay, logical reasoning impairment, problem-solving impairment, planning impairment, and / or information integration problems.

132. The method according to claim 130 or 131, wherein the whole coca leaf extract contains cocaine in an amount of about 80% by weight or less of the extract.

133. The method according to any one of claims 130 to 132, wherein the whole coca leaf extract contains methyl ecgonine cinnamate.

134. The method according to any one of claims 130 to 133, wherein the whole leaf extract of coca is extracted from Coca variety of the genus Coca, Coca variety of the genus Coca, Coca variety of the genus Coca, Coca variety of the species Coca novogranatense, Coca variety of Coca torxilense, or a combination thereof.

135. The method according to any one of claims 130 to 134, wherein the pharmaceutical composition is formulated as an oral dosage form.

136. The method according to claim 135, wherein the oral dosage form is a solid oral dosage form.

137. The method according to any one of claims 130 to 136, wherein the pharmaceutical composition further comprises an alkalizing agent.

138. The method according to claim 137, wherein the alkalizing agent is sodium bicarbonate, calcium oxide, or potassium hydroxide.

139. The method according to claim 137 or 138, wherein the pH of the alkalizing agent is approximately 10 to approximately 13.

140. The method according to any one of claims 130 to 139, wherein the pharmaceutical composition comprises about 30% to about 100% by weight of whole coca leaf extract.

141. The method according to any one of claims 130 to 140, wherein the whole coca leaf extract further comprises at least one of benzoylecgonin, tolxylin, hydroxytropacocaine, tropacocaine, ecgonin, cuscohigrin, dihydrocuscohigrin, or higrin.

142. The method according to any one of claims 130 to 141, wherein methyl ecgonine cinnamate exists as a cis isomer, a trans isomer, or a combination thereof.

143. The method according to any one of claims 130 to 142, wherein the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorus.

144. The method according to any one of claims 130 to 143, wherein the coca whole leaf extract comprises at least one essential oil.

145. The method according to any one of claims 130 to 144, wherein the attention deficit hyperactivity disorder is inattentive type, hyperactive-impulsive type, or combined type of attention deficit hyperactivity disorder.

146. The method according to any one of claims 130 to 145, wherein the subject is a mammal.

147. The method according to claim 146, wherein the subject is a human.

148. The method according to any one of claims 130 to 147, wherein the subject has reduced cognitive impairment associated with attention deficit hyperactivity disorder using at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors.

149. The method according to any one of claims 130 to 148, wherein the pharmaceutical composition is administered concurrently with at least one drug selected from an stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

150. The method according to claim 148 or 149, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, celdexmethylphenidate, lisdexamfetamine, or a combination thereof.

151. The method according to claim 148 or 149, wherein the alpha-adrenergic agonist is guanfacine or clonidine.

152. The method according to claim 148 or 149, wherein the norepinephrine reuptake inhibitor is atomoxetine or biloxazine.

153. The method according to any one of claims 130 to 152, wherein the daily dose of coca whole leaf extract administered to the subject is approximately 1 g leaf equivalent to approximately 500 g leaf equivalent of the whole leaf extract.

154. The administration of the pharmaceutical composition is [ １８ The method according to any one of claims 130 to 153, wherein positron emission tomography (PET) measurements using [F]-fluorodeoxy-D-glucose (FDG) induce increased activation in the prefrontal cortical region of the target brain.

155. The method according to any one of claims 130 to 154, wherein the reduction of ADHD-related cognitive impairment in a subject comprises the step of administering a pharmaceutical composition during a transition period to pharmacotherapy.

156. The method according to any one of claims 130 to 155, wherein a subject receiving treatment for cognitive impairment related to attention deficit hyperactivity disorder using the pharmaceutical composition described herein is identified as a subject who has previously received or is currently receiving treatment for cognitive impairment related to attention deficit hyperactivity disorder using at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and who has experienced or is experiencing an adverse reaction to the at least one drug.

157. The method according to any one of claims 130 to 156, wherein a subject receiving treatment for cognitive impairment related to attention deficit hyperactivity disorder using the pharmaceutical composition described herein has been identified as a subject who has previously received or is currently receiving treatment for cognitive impairment related to attention deficit hyperactivity disorder with at least one drug selected from stimulants, alpha-adrenergic agonists, or norepinephrine reuptake inhibitors, and has experienced or is experiencing treatment resistance to the at least one drug.

158. The method according to any one of claims 130 to 157, wherein a subject receiving treatment for cognitive impairment associated with attention deficit hyperactivity disorder is refractory to and / or intolerant of existing or standard treatments.

159. The method according to claim 158, wherein the subject is intolerant to existing or standard treatments due to adverse effects.

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