Coca leaf extract for neuropsychiatric disorders

Abstract

Presented herein are methods of treating narcolepsy, methods of treating attention deficit hyperactivity disorder (ADHD), methods of treating depression, and methods of treating an anxiety disorder, each comprising administering to a subject pharmaceutical compositions comprising a whole coca leaf extract. Also disclosed are methods of producing a whole coca leaf extract.

Description

COCA LEAF EXTRACT FOR NEUROPSYCHIATRIC DISORDERSFIELD OF THE INVENTION

[0001] The present invention is directed to methods of treating narcolepsy, methods of treating attention deficit hyperactivity disorder (ADHD), including ameliorating cognitive impairment associated with ADHD, methods of treating depression, and methods of treating an anxiety disorder, each comprising administering to a subject a pharmaceutical composition comprising a whole coca leaf extract. The present invention is also directed to methods of producing a whole coca leaf extract.BACKGROUND

[0002] For thousands of years, the indigenous people of the Andean regions of South America have cultivated and chewed on the leaves of the coca plant, particularly the two domesticated species of Erythroxylum coca Lam and Erythroxylum novogranatense . Chewing coca leaves from Erythroxylum coca Lam and Erythroxylum novogranatense can lead to the release of one or more coca alkaloids, producing a stimulus effect on the user. Of greatest pharmacological interest is a group of about 15 or so alkaloids, of which cocaine is the most well-known and characterized. However, the secondary alkaloids may have important effects of their own, and likely act in a synergistic manner in the central nervous to produce therapeutic responses when the whole leaf is utilized. Further, there are several neuropsychiatric diseases, disorders, and conditions for which adequate treatments, therapies, or cures are needed. Accordingly, there remains a need for pharmaceutical compositions and methods for treating neuropsychiatric disorders, as well as a need for methods of producing whole coca leaf extracts. These needs and others are met by the present invention.SUMMARY

[0003] Disclosed herein are methods of treating narcolepsy, methods of treating attention deficit hyperactivity disorder (ADHD), including ameliorating cognitive impairment associated with ADHD, methods of treating depression, and methods of treating anxiety comprising administering to a subject pharmaceutical compositions comprising a whole coca leaf extract. Also disclosed herein are methods of producing a whole coca leaf extract.

[0004] In one aspect, disclosed are methods of treating narcolepsy in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract.

[0005] In one aspect, disclosed are methods of treating attention deficit hyperactivity disorder (ADHD), including ameliorating cognitive impairment associated with ADHD, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising whole coca leaf extract.

[0006] In one aspect, disclosed are methods of treating depression in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract.

[0007] In one aspect, disclosed are methods of treating an anxiety disorder in a subject comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising whole coca leaf extract.

[0008] In one aspect, disclosed are methods of producing a whole coca leaf extract comprising the steps of: a. exposing leaves of a plant from the family Erythroxylaceae, such as 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 infra.DETAILED DESCRIPTIONI. Definitions

[0010] Where a term is provided in the singular, the inventors also contemplate aspects of the invention described by the plural of that term. As used in this specification and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise, e.g., "a compound" includes a plurality of compounds. Thus, for example, a reference to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0011] “Ameliorate,” “amelioration,” “improvement” or the like refers to, for example, a detectable improvement or a detectable change consistent with improvement that occurs in a subject or in at least a minority of subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between about any two of these values. Such improvement or change may be observed in treated subjects as compared to subjects not treated with a pharmaceutical composition comprising a whole coca leaf extract, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self-assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement. Amelioration may be transient, prolonged or permanent or it may be variable at relevant times during or after a pharmaceutical composition comprising a whole coca leaf extract is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within timeframes described infra, or about 1 hour after the administration or use of a pharmaceutical composition comprising a whole coca leaf extract to about 7 days, 2 weeks, 28 days, or 1, 3, 6, 9 months or more after a subject(s) has received such treatment.

[0012] The “modulation” of, e.g., a symptom, level or biological activity of a molecule, or the like, refers, for example, that the symptom or activity, or the like is detectably increased or decreased. Such increase or decrease may be observed in treated subjects as compared to subjects not treated with a pharmaceutical composition comprising a whole coca leaf extract, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Such increases or decreases 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 may be determined subjectively or objectively. Modulation may be transient, prolonged or permanent or it may be variable at relevant times during or after a pharmaceutical composition comprising a whole coca leaf extract is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within times descried infra, or about 1 hour of the administration or use of a pharmaceutical compositioncomprising a whole coca leaf extract to about 2 weeks, 28 days, 3, 6, 9 months or more after a subject(s) has received a pharmaceutical composition comprising a whole coca leaf extract.

[0013] As used herein, “subject” includes an animal, including a human, such as adult or pediatric humans.

[0014] The language “an effective amount” of a compound refers to an amount of a pharmaceutical composition comprising a whole coca leaf extract which is effective, upon single or multiple dose administration to the subject.

[0015] The term “administration” or “administering” includes routes of introducing a pharmaceutical composition comprising a whole coca leaf extract to a subject to perform its intended function. Examples of routes of administration that may be used include oral, sublingual, buccal, injection, inhalation, and topical.. The pharmaceutical preparations may be given by forms suitable for each administration route. For example, these preparations are administered in liquid or capsule form. Oral administration is preferred. Depending on the route of administration, a pharmaceutical composition comprising a whole coca leaf extract can be coated with or disposed in a selected material to protect it from natural conditions that may detrimentally affect its ability to perform its intended function. A pharmaceutical composition comprising a whole coca leaf extract can be administered alone, or in conjunction with either another agent or agents as described above or with a pharmaceutically-acceptable carrier, or both.

[0016] Administration "in combination with" or “co-administered with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

[0017] The phrase “pharmaceutically acceptable” refers to a pharmaceutical composition, comprising a whole coca leaf extract as described herein, compositions containing a whole coca leaf extract, and / or dosage forms which are, an active ingredient, excipient, carrier, or any other component of a dosage form that is within the scope of sound medical judgment, suitable for use in the intended administration mode, e.g., oral, in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0018] The phrase “pharmaceutically-acceptable carrier” includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.

[0019] The term “treat” or “treatment” as used herein is intended to include the reduction or amelioration of the progression, severity, and / or duration of a condition or one or more symptoms of the condition, e.g., narcolepsy, attention deficit hyperactivity disorder (ADHD), including cognitive impairment associated with ADHD, depression, or an anxiety disorder.

[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 a pharmaceutical composition comprising a whole coca leaf extract.II. Whole Coca Leaf Extract

[0021] There are two known cultivated species of coca crops, Erythroxylum coca, which includes the varieties Erythroxylum coca var. coca and Erythroxylum coca var. ipadu, and Erythroxylum novogranatense , which includes the varieties 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] A whole coca leaf extract, in accordance with the present disclosure, comprises at least 2 alkaloids naturally occurring in coca leaves and one or more compounds that are not alkaloids, such asa mineral, vitamin, essential oil, diterpene, triterpene, flavonoid, tannin, or polyphenol, which are also naturally occurring in coca leaves and is at least 5% w / w of the extract. In embodiments, the extract comprises combinations of 2 or more alkaloids and one or more of a mineral, vitamin, essential oil, diterpene, triterpene, flavonoid, tannin, or polyphenol naturally occurring in coca leaves. In embodiments, the whole coca leaf extract results from an extraction process described herein.

[0023] In some embodiments, a method of treatment comprises the administration to a subject in need thereof an effective amount of a whole coca leaf extract. In some embodiments, a method of treatment comprises the administration to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract. The naturally occurring alkaloids in coca plants include cocaine and methylecgonine cinnamate and can further include, depending on the species, some combination of benzoylecgonine, ecgonidine, ecgonine, hydroxytropacocaine, tropacocaine, truxilline, cuscohygrine, dihydrocuscohygrine, hygrine, and nicotine. In embodiments, the whole coca leaf extract contains cocaine and methylecgonine cinnamate. In 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. A whole coca leaf extract contains an alkaloid if it is detectable by assay methods known in the art in an amount of whole coca leaf extract that could be administered as a dose to a human subject.

[0024] The principal active alkaloid present in the leaves of cultivated Erythroxylum species, or the coca plant, is cocaine. Depending on the variety of the coca plant, cocaine is generally found in the amount of about 0.3 % to about 2.4 % by weight of the coca leaf, typically about 0.8 % by weight of the coca leaf. All varieties of coca leaves also contain the secondary alkaloid methylecgonine cinnamate. In some embodiments, methylecgonine cinnamate is present as a cis-isomer, a trans-isomer, or a combination thereof.

[0025] In addition, coca leaves can contain a variety of other alkaloids, such as benzoyl ecgonine, ecgonidine, ecgonine, hydroxytropacocaine, tropacocaine, truxilline, cuscohygrine, dihydrocuscohygrine, hygrine, and nicotine. Given the nature of the whole coca extract, other alkaloids are also present. In various embodiments, the whole coca leaf extract further comprises at least one of: benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine. The presence, relative percentages, and total amounts of these additional alkaloids differ based on the variety of the coca plant. Accordingly, the whole coca leaf extract can be extracted from the leaves of a combination of coca plant varieties to tailor the presence and concentrations of desired alkaloids.

[0026] In one embodiment, the whole coca leaf extract comprises cocaine in an amount of no more than about 80 % by weight of the extract, including by dry weight of extract. The whole coca leaf extract can comprise, for example, no more than about 0.5 %, 1 %, 2 %, 5 %, 8 %, 10 %, 20%, 30 %, 40 %, 50 %, 60 %, 70 %, or about 80 % by weight. In some embodiments, the whole coca leaf extract can comprise cocaine in a range derived from any two of the above listed exemplary values. For example, the whole coca leaf extract can comprise cocaine in a range of from about 0.5 % to about 8 % by weight, about 0.5 % to about 25 % by weight, about 0.5 % to about 50 % by weight, about 0.5 % to about 80 % by weight, about 5 % to about 30 % by weight, from about 5 % to about 50 % by weight, from about 5 % to about 80 % by weight, about 10 % to about 50 % by weight, about 10 % to about 80 % by weight, about 20 % to about 50 % by weight, about 20 % to about 80 % by weight, about 30 % to about 60 % by weight, about 30 % to about 80 % by weight, about 40 % to about 70 % by weight, or about 50 % to about 80 % by weight.

[0027] In one embodiment, the whole coca leaf extract comprises methylecgonine cinnamate. The whole coca leaf extract can comprise trans- or cis- methylecognine cinnamate in any amount of up to 20 % by weight of extract, including dry weight of extract. In some embodiments, the whole coca leaf extract can comprise methylecognine cinnamate in an amount of, for example, from 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] The whole coca leaf extract can comprise any alkaloids which are naturally present in coca leaves. In various embodiments, the whole coca leaf extract further comprises at least one of: benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

[0029] Additionally, as alluded to above, coca leaves also comprise vitamins, minerals, diterpenes, triterpenes, flavonoids, tannins, and polyphenols. Accordingly, the whole coca leaf extract comprises can comprise one or more of vitamins, minerals, diterpenes, triterpenes,flavonoids, tannins, and polyphenols. In some embodiments, the whole coca leaf extract comprises vitamins. In some embodiments, the whole coca leaf extract comprises minerals. The whole coca leaf extract can comprise any vitamin or mineral which is naturally present in coca leaves. In some embodiments, the whole coca leaf extract further comprises vitamin A, riboflavin, vitamin E, calcium, iron, and / or phosphorous.

[0030] Additionally, whole coca leaves comprise at least one essential oil. Accordingly, in embodiments, the whole coca leaf extract can comprise any essential oil which is naturally present in coca leaves. In one embodiment, the whole coca leaf extract can comprise essential oils such as, for example, wintergreen oil.III. Pharmaceutical Compositions

[0031] In some embodiments, a method of treatment comprises the administration to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract.

[0032] The pharmaceutical composition can be formulated in any dosage form. For example, the pharmaceutical composition can be formulated in 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. Without wishing bound by theory, it is believed that alkalizing agents may promote release of the alkaloids from the leaves or convert them to active or absorbable forms. In the stomach, the high pH provided by the alkalizing agent may facilitate gastric absorption or inhibit gastric breakdown of the active compounds. Examples of suitable alkalizing agents to be 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 can be, for example, 7.5, 8, 9, 10, 11, 12, 13, or more. In further embodiments, the pH of the alkalizing agent can be any pH in a range derived from any two of the above listed exemplary values. For example, the pH of the alkalizing agent can be in a range of from about 7 to about 8, from about 7 to about 10, fromabout 7 to about 13, from about 7 to about 14, from about 8 to about 11, from about 8 to about 13, from about 9 to about 12, from about 9 to about 14, from about 10 to about 12, from about 10 to about 13, or from about 10 to about 14. In some embodiments, the pH of the alkalizing agent is from about 10 to about 13.

[0034] The pharmaceutical composition can comprise any weight percent of the whole coca leaf extract. In some embodiments, the pharmaceutical composition comprises a weight percent of from about 30 % to about 100 % of the whole coca leaf extract. The pharmaceutical composition can comprise any weight percent in a range derived from the listed exemplary values. The pharmaceutical composition can comprise a weight percent of the whole coca leaf extract of, for example, from about 30 % to about 99 %, from about 30 % to about 95 %, from about 30 % to about 80 %, from about 30 % to about 70 %, from about 30 % to about 60 %, from about 30 % to about 50 %, from about 40 % to about 100 %, from about 40 % to about 80 %, from about 40 % to about 60 %, from about 50 % to about 99%, from about 50 % to about 95% , from about 50 % to about 80 %, from about 50 % to about 70 %, from about 60 % to about 99 %, from about 60 % to about 95 %, from about 60 % to about 90 %, from about 60 % to about 80 %, from about 70 % to about 99%, from about 70 % to about 95 %, from about 70 % to about 90 %, from about 70 % to about 80%, from about 80 % to about 99 %, from about 80 % to about 95 %, or from about 80 % to about 90 %.

[0035] In certain embodiments, the pharmaceutical compositions can further comprise a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, alcohols such as ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington:The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0036] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0037] In preparing the pharmaceutical compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.

[0038] In certain embodiments, the pharmaceutical composition can further comprise a sweetener. A sweetener may be added to improve the palatability and acceptability of the pharmaceutical composition by giving it a sweet taste. The sweetener may be any sweetening agent conventionally known in the art for use in pharmaceutical compositions.

[0039] The pharmaceutical compositions described herein can comprise additional excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, or flavoring agent. Compositions may be formulated for selected coated and uncoated tablets, hard and soft gelatin or HMPC capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet, and chewing gums.IV. Methods of Treating Narcolepsy

[0040] Provided herein are methods of treating narcolepsy in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract, as described above.

[0041] Narcolepsy is a chronic neurological condition which is characterized by a decreased ability to regulate sleep-wake cycles. Symptoms often include excessive daytime sleepiness, brief involuntary sleep episodes, inability to stay awake for prolonged periods of time, andcataplexy. Narcolepsy is classified into two major types. A diagnosis of type 1 narcolepsy is characterized by the subject having either low levels of hypocretin as a brain hormone or reporting cataplexy, also known as sudden muscle weakness. A diagnosis of type 2 narcolepsy is characterized by the subject exhibiting symptoms of narcolepsy without cataplexy. In some embodiments, the subject is being treated for narcolepsy being type 1 or type 2 narcolepsy. In further embodiments, the subject is treated for daytime somnolence. Daytime somnolence is characterized by excessive sleepiness during waking hours. Conditions such as narcolepsy and idiopathic hypersomnia are thought to influence the hormones responsible for promoting wakefulness, causing sleepiness during the day. Sleep disorders such as obstructive sleep apnea (OSA), restless legs syndrome, and periodic limb movement disorder are known for causing fragmented sleep. Similarly, people with circadian rhythm disorders experience a disconnect between their inner body clock and the times when they need to be awake.

[0042] In some embodiments, the subject being treated for narcolepsy can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0043] The pharmaceutical composition can be administered for the treatment of narcolepsy alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for narcolepsy with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or gamma-hydroxybutyrate.

[0044] Examples of stimulants suitable for the treatment of narcolepsy include, but are not limited to, modafinil, armodafinil, solriamfetol, pitolisant, 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 and norepinephrine reuptake inhibitors suitable for the treatment of narcolepsy include, but are not limited to, desvenlafaxine, duloxetine, venlafaxine, venlafaxine XR, milnacipran, and levomilnacipran.

[0047] Examples of tricyclic antidepressant suitable for the treatment of 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 zoplicone.

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

[0050] In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate.

[0051] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the whole coca leaf extract is from about 1 g to about 500 g of whole coca leaf equivalents. That is, the administered extract comprises alkaloid concentrations equivalent to about 1 g to about 500 g of the dry leaves. The daily dose of the whole coca leaf extract can comprise any dose in a range derived from the listed exemplary values. The daily dose of the whole coca leaf extract can be, for example, from about 1 g to 400 g of leaf equivalents, about 1 g to about 300 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 100 g of leaf equivalents, about 1 g to about90 g of leaf equivalents, about 1 g to about 70 g of leaf equivalents, about 1 g to about 50 g of leaf equivalents, about 1 g to about 30 g of leaf equivalents, about 1 g to about 15 g of leaf equivalents, about 10 g to about 500 g of leaf equivalents, about 10 g to about 400 g of leaf equivalents, about 10 g to about 300 g of leaf equivalents, about 10 g to about 200 g of leaf equivalents, about 10 g to about 100 g of leaf equivalents, about 10 g to about 80 g of leaf equivalents, about 10 g to about 60 g of leaf equivalents, about 10 g to about 40 g of leaf equivalents, about 20 g to about 500 g of leaf equivalents, about 20 g to about 300 g of leaf equivalents, about 20 g to about 100 g of leaf equivalents, about 20 g to about 70 g of leaf equivalents, about 20 g to about 50 g of leaf equivalents, about 100 g to about 500 g of leaf equivalents, about 100 to about 300 g of leaf equivalents, about 40 g to about 100 g of leaf equivalents, about 40 g to about 80 g of leaf equivalents, about 40 g to about 60 g of leaf equivalents, about 50 g to about 100 g of leaf equivalents, or about 50 g to about 80 g of leaf equivalents.

[0052] In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0053] In some embodiments, treating narcolepsy in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for narcolepsy, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0054] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased synaptic activity in areas of the brain. Theseabnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., narcolepsy. Although the exact cause of narcolepsy is unknown, without wishing to be bound by theory, it is believed to be a clinical syndrome of hypothalamic disorder. In some embodiments, administration of the pharmaceutical composition causes increased activation in the perifomical hypothalamus region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy -D-glucose (FDG).

[0055] In certain embodiments, the subject being treated for narcolepsy with the pharmaceutical composition as described herein has been previously or is currently being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

[0056] In some embodiments, the subject being treated for narcolepsy with the pharmaceutical composition as described herein has been previously or is currently being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0057] In some embodiments, the subject being treated for narcolepsy is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.V. Methods of Treating Attention Deficit Hyperactivity Disorder

[0058] Provided herein are methods of treating attention deficit hyperactivity (ADHD) in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract, as described above.

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

[0060] Also provided herein are methods of ameliorating cognitive impairment associated with attention deficit hyperactivity (ADHD) in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract, as described above.

[0061] Cognition is the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses. It encompasses all aspects of intellectual functions, such as perception, attention, memory, judgment, problem solving, and comprehension and production of language. Cognitive skills relate to the ability to perform executive functions such as reasoning, planning, language, and social interactions. “Cognitive impairment” is an inclusive term used to describe the impairment of any such aspects or intellectual functions associated with cognition, including executive function. A patient with cognitive impairment may have trouble with memory, concentration, planning, or making decisions that affect daily life. Cognitive impairment and treatment of cognitive impairment can be assessed by standard assessment scales, such as, for example, tests for assessing intelligence and / or cognitive function, standard ADHD assessment scales and executive function scales.

[0062] Examples of cognitive impairments associated with ADHD which may be ameliorated by administration of a pharmaceutical composition comprising a whole coca leaf extract as described herein include, but are not limited to, attention deficits, working memory deficits, executive function deficits, delayed reaction time, logical reasoning deficits, problem solving deficits, planning deficits, and information consolidation problems.

[0063] In some embodiments, the cognitive impairment being treated by administration of an effective amount of a pharmaceutical composition comprising a whole coca leaf extract as described herein is executive function deficit. The treatment of executive function deficit can comprise 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, leading to dose escalation. Stimulants, while effective, carry significant risks, including dependency, cardiovascular side effects, and other long-term health concerns. When the pharmaceutical composition is administered in combination with a stimulant, administration of the pharmaceutical composition may prevent the need for stimulant dose escalation or a reduction in the effective dose of the stimulant.

[0064] In some embodiments, the subject being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

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

[0066] Examples of stimulants suitable for the treatment of ADHD or cognitive impairment associated with ADHD include, but are not limited to, methylphenidate, dexmethylphenidate, amphetamines, serdexmethylphenidate, and lisdexamfetamine, or a combination thereof.

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

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

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

[0070] In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

[0071] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the whole coca leaf extract is from about 1 g to about 500 g of whole coca leaf equivalents. That is, the administered extract comprises alkaloid concentrations equivalent to about 1 g to about 500 g of the dry leaves. The daily dose of the whole coca leaf extract can comprise any dose in a range derived from the listed exemplary values. The daily dose of the whole coca leaf extract can be, for example, from about 1 g to 400 g of leaf equivalents, about 1 g to about 300 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 100 g of leaf equivalents, about 1 g to about 90 g of leaf equivalents, about 1 g to about 70 g of leaf equivalents, about 1 g to about 50 g of leaf equivalents, about 1 g to about 30 g of leaf equivalents, about 1 g to about 15 g of leaf equivalents, about 10 g to about 500 g of leaf equivalents, about 10 g to about 400 g of leaf equivalents, about 10 g to about 300 g of leaf equivalents, about 10 g to about 200 g of leaf equivalents, about 10 g to about 100 g of leaf equivalents, about 10 g to about 80 g of leaf equivalents, about 10 g to about 60 g of leaf equivalents, about 10 g to about 40 g of leaf equivalents, about 20 g to about 500 g of leaf equivalents, about 20 g to about 300 g of leaf equivalents, about 20 g to about 100 g of leaf equivalents, about 20 g to about 70 g of leafequivalents, about 20 g to about 50 g of leaf equivalents, about 100 g to about 500 g of leaf equivalents, about 100 to about 300 g of leaf equivalents, about 40 g to about 100 g of leaf equivalents, about 40 g to about 80 g of leaf equivalents, about 40 g to about 60 g of leaf equivalents, about 50 g to about 100 g of leaf equivalents, or about 50 g to about 80 g of leaf equivalents.

[0072] In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0073] In some embodiments, treating attention deficit hyperactivity disorder or cognitive impairment associated with ADHD in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for attention deficit hyperactivity disorder, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0074] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., attention deficit hyperactivity disorder. Although the exact cause of attention deficit hyperactivity disorder is unknown, without wishing to be bound by theory, studies have found that attention deficit hyperactivity disorder is associated with weaker function and structure of the prefrontal cortex circuits in the brain. In some embodiments, administration of the pharmaceutical composition causes increased activation in the prefrontal cortex region ofthe subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro- deoxy-D-glucose (FDG).

[0075] In certain embodiments, the subject being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD with the pharmaceutical composition as described herein has been previously or is currently being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

[0076] In some embodiments, the subject being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD with the pharmaceutical composition as described herein has been previously or is currently being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0077] In some embodiments, the subject being treated for attention deficit hyperactivity disorder or cognitive impairment associated with ADHD is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.VI. Methods of Treating Depression

[0078] Provided herein are methods of treating depression in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract, as described above.

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

[0080] In some embodiments, the subject being treated for depression can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0081] The pharmaceutical composition can be administered for the treatment of depression alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for depression with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

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

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

[0084] Examples of norepinephrine and specific serogonerics suitable for the treatment of depression include, but are not limited to, aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline / teciptiline.

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

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

[0087] Examples of monoamine oxidase inhibitors suitable for the treatment of depression include, but are not limited to, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, pirlindole, rasagiline, selegiline, and safinamide.

[0088] In some embodiments, the pharmaceutical composition is co-administered with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

[0089] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the whole coca leaf extract is from about 1 g to about 500 g of whole coca leaf equivalents. That is, the administered extract comprises alkaloid concentrations equivalent to about 1 g to about 500 g of the dry leaves. The daily dose of the whole coca leaf extract can comprise any dose in a range derived from the listed exemplary values. The daily dose of the whole coca leaf extract can be, for example, from about 1 g to 400 g of leaf equivalents, about 1 g to about 300 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 100 g of leaf equivalents, about 1 g to about 90 g of leaf equivalents, about 1 g to about 70 g of leaf equivalents, about 1 g to about 50 g of leaf equivalents, about 1 g to about 30 g of leaf equivalents, about 1 g to about 15 g of leaf equivalents, about 10 g to about 500 g of leaf equivalents, about 10 g to about 400 g of leaf equivalents, about 10 g to about 300 g of leaf equivalents, about 10 g to about 200 g of leaf equivalents, about 10 g to about 100 g of leaf equivalents, about 10 g to about 80 g of leafequivalents, about 10 g to about 60 g of leaf equivalents, about 10 g to about 40 g of leaf equivalents, about 20 g to about 500 g of leaf equivalents, about 20 g to about 300 g of leaf equivalents, about 20 g to about 100 g of leaf equivalents, about 20 g to about 70 g of leaf equivalents, about 20 g to about 50 g of leaf equivalents, about 100 g to about 500 g of leaf equivalents, about 100 to about 300 g of leaf equivalents, about 40 g to about 100 g of leaf equivalents, about 40 g to about 80 g of leaf equivalents, about 40 g to about 60 g of leaf equivalents, about 50 g to about 100 g of leaf equivalents, or about 50 g to about 80 g of leaf equivalents

[0090] In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0091] In some embodiments, treating depression in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for depression, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0092] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., depression. Although the exact cause of depression is unknown, without wishing 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 seem to be correlated with the disorder. In some embodiments, administration of thepharmaceutical composition causes increased activation at least one of: the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens amygdala regions of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG) during treatment comprising administration of the pharmaceutical composition.

[0093] In certain embodiments, the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

[0094] In some embodiments, the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0095] In some embodiments, the subject being treated for depression is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.VII. Methods of Treating an Anxiety Disorder

[0096] Provided herein are methods of treating an anxiety disorder in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract, as described above.

[0097] Anxiety disorders are characterized by intense, excessive, and persistent worry. Often, anxiety disorders involve repeated episodes of intense anxiety and fear or terror that reacha peak within minutes. These episodes are also known as panic attacks. Symptoms of anxiety disorders include increased heart rate, having a sense of impending danger, panic, or doom, feeling nervous, hyperventilation, sleep issues, and gastrointestional problems. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, and medication-induced anxiety disorder. In some embodiments, the subject is being treated for an anxiety disorder being generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, specific phobias, post-traumatic stress disorder (PTSD), separation anxiety, or medication-induced anxiety disorder.

[0098] In some embodiments, the subject being treated for an anxiety disorder can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a human.

[0099] The pharmaceutical composition can be administered for the treatment of an anxiety disorder alone or in combination with other drugs and / or pharmaceutical compositions. In some embodiments, the pharmaceutical composition is administered alone. In some embodiments, the subject is being treated for narcolepsy with the pharmaceutical composition and at least one other drug. In various embodiments, the subject is being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor.

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

[0101] Examples of serotonin norepinephrine reuptake inhibitors suitable for the treatment of an anxiety disorder include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine.

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

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

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

[0105] Examples of monoamine oxidase inhibitors suitable for the treatment of an anxiety disorder include, but are not limited to, isocarboxazid, hydracarbazine, phenelzine, tranylcypromine, bifemelane, methylthioninium chloride, moclobemide, pirlindole, rasagiline, selegiline, and safinamide.

[0106] In some embodiments, the subject is administered a daily dose of the pharmaceutical composition. In various embodiments, the daily dose of the pharmaceutical composition is such that the daily dose of the whole coca leaf extract is from about 1 g to about 500 g of whole coca leaf equivalents. That is, the administered extract comprises alkaloid concentrations equivalent to about 1 g to about 500 g of the dry leaves. The daily dose of the whole coca leaf extract can comprise any dose in a range derived from the listed exemplary values. The daily dose of the whole coca leaf extract can be, for example, from about 1 g to 400 g of leaf equivalents, about 1 g to about 300 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 200 g of leaf equivalents, about 1 g to about 100 g of leaf equivalents, about 1 g to about 90 g of leaf equivalents, about 1 g to about 70 g of leaf equivalents, about 1 g to about 50 g of leaf equivalents, about 1 g to about 30 g of leaf equivalents, about 1 g to about 15 g of leaf equivalents, about 10 g to about 500 g of leaf equivalents, about 10 g to about 400 g of leaf equivalents, about 10 g to about 300 g of leaf equivalents, about 10 g to about 200 g of leaf equivalents, about 10 g to about 100 g of leaf equivalents, about 10 g to about 80 g of leafequivalents, about 10 g to about 60 g of leaf equivalents, about 10 g to about 40 g of leaf equivalents, about 20 g to about 500 g of leaf equivalents, about 20 g to about 300 g of leaf equivalents, about 20 g to about 100 g of leaf equivalents, about 20 g to about 70 g of leaf equivalents, about 20 g to about 50 g of leaf equivalents, about 100 g to about 500 g of leaf equivalents, about 100 to about 300 g of leaf equivalents, about 40 g to about 100 g of leaf equivalents, about 40 g to about 80 g of leaf equivalents, about 40 g to about 60 g of leaf equivalents, about 50 g to about 100 g of leaf equivalents, or about 50 g to about 80 g of leaf equivalents

[0107] In some embodiments, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day or as needed. In a further embodiment, the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times a day. In a yet further embodiment, the pharmaceutical composition is administered as needed.

[0108] In some embodiments, treating an anxiety disorder in a subject comprises administering the pharmaceutical composition during a time period of medication transition. The pharmaceutical composition as described herein can be administered as a treatment when the subject is transitioning from a drug to different drug, from a drug to no longer receiving treatment for an anxiety disorder, or from a drug to a drug comprising the pharmaceutical composition as described herein.

[0109] FDG-PET, or Positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG), is a medical imaging technique that allows clinicians to observe and quantify metabolic activity in various tissues, including the brain. FDG is a radioactive glucose analog and is injected into the body. FDG is taken up by cells similarly to glucose, resulting in the emission of gamma rays that can be detected by a PET scanner. FDG-PET can be used to identify abnormally reduced or increased synaptic activity in areas of the brain. These abnormalities in metabolic activity have been found to be associated with certain neuropsychiatric disorders, e.g., anxiety disorders. Although the exact causes of anxiety disorders are unknown, without wishing to be bound by theory, studies have shown that the amygdala and the hypothalamus regions of the brain likely play key roles in stress responses, and by extension, anxiety. In some embodiments, administration of the pharmaceutical compositioncauses increased activation in at least one of: the amygdala and hypothalamus regions of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG) during treatment comprising administration of the pharmaceutical composition.

[0110] In certain embodiments, the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.[0U1] In some embodiments, the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

[0112] In some embodiments, the subject being treated for an anxiety disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments. In a further embodiment, the subject does not tolerate existing or standard treatments due to adverse effects.VIII. Methods of Producing Pharmaceutical Compositions

[0113] Provided herein are methods of producing pharmaceutical compositions comprising an effective amount of a whole coca leaf extract.

[0114] In one embodiment, the method comprises the steps of: a. exposing leaves of a plant from the family Erythroxylaceae, 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 concentrate of the liquid phase is further powderized to form the whole coca leaf extract.

[0116] In some embodiments, the method further comprises exposing the first solid phase to the solvent to form a second liquid phase and a second solid phase and combining the first liquid phase and the second liquid phase to form a pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

[0117] In some embodiments, the solvent is selected from a C1-C4 alcohol, a ketone, water, or a combination thereof. Examples of suitable first solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropyl alcohol, / / -butanol, isobutanol, scc-butanol, / c / 7-butyl alcohol, acetone, methyl ethyl ketone, or water. The first solvent can comprise any pH. In some embodiments, the first solvent is controlled to a specific pH with one or more acids selected from the group consisting of acetic acid, adipic acid, ascorbic acid, phosphoric acid, ammonium aluminum sulphate, ammonium citrate dibasic, ammonium citrate monobasic, calcium citrate, calcium fumarate, calcium gluconate, calcium phosphate dibasic, calcium phosphate, hydrochloric acid, sulphuric acid monobasic, calcium phosphate tribasic, citric acid, fumaric acid, gluconic acid, magnesium fumarate, malic acid, phosphoric acid, potassium acid tartrate, potassium citrate, potassium fumarate, sodium citrate, sodium fumarate, sodium gluconate, sodium lactate, sodium potassium hexametaphosphate, sodium potassium tartrate, sodium potassium tripolyphosphate, sodium pyrophosphate tetrabasic, sodium tripolyphosphate and tartaric acid. 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, calcium phosphate dibasic, calcium phosphate monobasic, magnesium carbonate, potassium aluminum sulphate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, potassium phosphate dibasic, potassium pyrophosphate tetrabasic, potassium phosphate tribasic, potassium tripolyphosphate, sodium acetate, sodium acid pyrophosphate, sodium aluminum phosphate, sodium aluminum sulphate,sodium bicarbonate, sodium bisulphate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, sodium phosphate dibasic, sodium phosphate monobasic and sodium phosphate tribasic.

[0118] In some embodiments, the method comprises a. exposing the second solid phase to the 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 the pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

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

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

[0121] In some embodiments, the concentrate of the liquid phase is a slurry. The slurry can comprise a mixture of denser solids being 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 resolubilized mixture, wherein the second solvent is different to the solvent to which the leaves were exposed. Examples of suitable second solvents include, but are not limited to, methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol, isobutanol, sec-butanol, tertbutyl alcohol, acetone, methyl ethyl ketone, or water. The second solvent can comprise any pH. In some embodiments, the second solvent is controlled to a specific pH between 1-14. In some embodiments, the second solvent is controlled to a specific pH between 1-14 with one or more acids selected from the group consisting of acetic acid, adipic acid, ascorbic acid, phosphoric acid, ammonium aluminum sulphate, ammonium citrate dibasic, ammonium citrate monobasic, calcium citrate, calcium fumarate, calcium gluconate, calcium phosphate dibasic, calciumphosphate, hydrochloric acid, sulphuric acid monobasic, calcium phosphate tribasic, citric acid, fumaric acid, gluconic acid, magnesium fumarate, malic acid, phosphoric acid, potassium acid tartrate, potassium citrate, potassium fumarate, sodium citrate, sodium fumarate, sodium gluconate, sodium lactate, sodium potassium hexametaphosphate, sodium potassium tartrate, sodium potassium tripolyphosphate, sodium pyrophosphate tetrabasic, sodium tripolyphosphate and tartaric acid. 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, calcium phosphate dibasic, calcium phosphate monobasic, magnesium carbonate, potassium aluminum sulphate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, potassium phosphate dibasic, potassium pyrophosphate tetrabasic, potassium phosphate tribasic, potassium tripolyphosphate, sodium acetate, sodium acid pyrophosphate, sodium aluminum phosphate, sodium aluminum sulphate, sodium bicarbonate, sodium bisulphate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, sodium phosphate dibasic, sodium phosphate monobasic and sodium phosphate tribasic.

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

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

[0125] The concentrate of the liquid phase can be mixed with a pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include, but are not limited to, one or more of a diluting agent, abinding agent, a lubricating agent, a disintegrating agent, coloring agent, or a flavoring agent. In certain embodiments, the concentrate of the liquid phase is mixed with an alkalizing agent. As described above, alkalizing agents may promote release ofthe alkaloids from the leaves or convert them to active or absorbable forms. In the stomach, the high pH provided by the alkalizing agent may facilitate gastric absorption or inhibit gastric breakdown of the active compounds. Examples of suitable alkalizing agents to be 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 can be, for example, 7.5, 8, 9, 10, 11, 12, 13, or more. In further embodiments, the pH of the alkalizing agent can be any pH in a range derived from any two of the above listed exemplary values. For example, the pH of the alkalizing agent can be in a range of from about 7 to about 8, from about 7 to about 10, from about 7 to about 13, from about 7 to about 14, from about 8 to about 11, from about 8 to about 13, from about 9 to about 12, from about 9 to about 14, from about 10 to about 12, from about 10 to about 13, or from about 10 to about 14. In some embodiments, the pH of the alkalizing agent is from about 10 to about 13.

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

[0127] In some embodiments, the concentrate of the liquid phase is dried to using a drying technology. The drying technology further removes or evaporates excess solvent. Examples of suitable drying technologies include spray drying, belt drying, or freeze drying.IX. ExamplesExample 1 - Whole Coca Leaf Extraction

[0128] Dried whole coca leaves are first exposed to a solvent in order to extract or dissolve components of the coca leaf, including tropane alkaloids, pyrrolidinealkaloids, essential oils, and flavonoids. Next, the undissolved portion of the biomass is filtered from the solvent. The undissolved portion of the solvent is then re-extracted using the same solvent and filtering process. This extraction process can be repeated sequentially up to five times. The solvent from each extraction step is then combined into a pooled extract. The solvent is evaporated to dryness or a concentrated slurry. The slurry or dry extract can then be re-suspended into a different or similar solvent, followed by filtering. Next, the re-suspended extract is exposed to a resin such as a gel resin, a non-ionic macroporous resin, or an ion-exchange resin. The resin is then washed,and extraction fractions are eluted, which are then combined to produce a concentrate of the liquid phase. The concentrate of the liquid phase is combined with an alkalizing agent and pharmaceutically acceptable excipients. A drying technology such as spray drying, belt drying, or freeze drying is utilized to evaporate the solvent from the mixture. Lastly, the dry extract is powderized.Example 2 - Effect of Effect of Whole Coca Leaf Extract on Brain Parameters related to Narcolepsy as measured by FDG-PET

[0129] A pharmaceutical composition comprising whole coca leaf extract will be tested using positron emission tomography (PET) in mice to evaluate brain metabolism in vivo as an index of synaptic activity and communication of brain regions (connectivity) of interest for narcolepsy. Previous studies have found that narcolepsy is associated with weaker function and structure of the perifomical hypothalamus in the brain.

[0130] Fluorodeoxyglucose (FDG), a radioactive glucose analog, will be administered to mice, and PET brain scans will be performed prior to and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. It is expected to observe increased metabolic activity in the perifomical hypothalamus area of the brain in PET scans performed after administration as compared to PET scans performed prior to administration.Example 3 - A Study of the Safety and Effectiveness of Pharmaceutical Compositions Comprising Whole Coca Leaf Extract for the treatment of Narcolepsy

[0131] This study evaluates the efficacy, safety, and tolerability of pharmaceutical compositions comprising whole coca leaf extract in adults with narcolepsy.

[0132] Protocol:

[0133] Patients to be treated with whole coca leaf extract will be randomly assigned to the treatment arm or the control. Patients in the treatment arm will take a solid oral dosage form of whole coca leaf extract from 1 to 6 times a day (at about 1 g to about 500 g of leaf equivalents). Patients on the control arm will not receive whole coca leaf extract at any time on this study.

[0134] Eligibility Criteria:

[0135] Patients eligible for the study much be as follows: Willing and able to provide written informed consent; man or woman >18 years of age; have a diagnosis of narcolepsy within the past 5 years; have a negative pregnancy test at time of informed consent for women of childbearing potential; participants may be receiving current pharmacological treatment for narcolepsy or no current pharmacological treatment for narcolepsy; participants may be receiving current pharmacological treatment for narcolepsy and self-report as having no response to treatment or a significant side effect profile. Patients not eligible for the study include women who are breastfeeding; those who have a current comorbid sleep disorder such as sleep apnea syndrome or periodic limb movement disorder, patients with neurodegenerative diseases or cerebrovascular diseases, or patients who ingest caffeine of in an amount that is more than 5 cups of tea or three cups of coffee or 8 cans of soda per day.

[0136] Effectiveness Variables:

[0137] Primary outcome measures: Epworth Sleepiness Scale (ESS) [Time Frame: 14 days]. Range 0 to 24, low score indicates good outcome.

[0138] Patient Global Impression of Change (PGI-C) [Time Frame: 14 days], PGI-C is a scale completed by the participants starting from screening to last visit (all the visits).Example 4 - Effect of Whole Coca Leaf Extract on Brain Parameters related to Attention Deficit Hyperactivity Disorder (ADHD) measured by FDG-PET

[0139] A pharmaceutical composition comprising whole coca leaf extract will be tested using positron emission tomography (PET) in mice to evaluate brain metabolism in vivo as an index of synaptic activity and communication of brain regions (connectivity) of interest for ADHD. Previous studies have found attention deficit hyperactivity disorder is associated with weaker function and structure of the prefrontal cortex circuits in the brain, specifically abnormalities in the frontostriatal network. Additionally, PET has identified multiple hypometabolic brain areas, such as the frontal and cingulate cortices, suggesting a consistent synaptic dysfunction in individuals presenting with ADHD.

[0140] Fluorodeoxyglucose (FDG), a radioactive glucose analog, will be administered to mice, and PET brain scans will be performed prior to and after administration of thepharmaceutical composition. Both regional and connectivity analyses will be performed. It is expected to observe increased metabolic activity in the prefrontal cortex area of the brain in PET scans performed after administration as compared to PET scans performed prior to administration.Example 5: A Study of the Safety and Effectiveness of Pharmaceutical Compositions Comprising Whole Coca Leaf Extract for the treatment of ADHD

[0141] This study evaluates the efficacy, safety, and tolerability of pharmaceutical compositions comprising whole coca leaf extract in adults and children with attention deficit hyperactivity disorder (ADHD).

[0142] Protocol:

[0143] Patients to be treated with whole coca leaf extract will be randomly assigned to the treatment arm or the control. Patients in the treatment arm will take a solid oral dosage form of whole coca leaf extract from 1 to 6 times a day (at about 1 g to about 500 g of leaf equivalents). Patients on the control arm will not receive whole coca leaf extract at any time on this study.

[0144] Eligibility Criteria:

[0145] Patients eligible for the study much be as follows: Willing and able to provide written informed consent; male or female >18 years of age or male or female between the ages of 5 and 18 with signed and dated parental or legal guardian consent form; must meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for ADHD (including predominantly inattentive presentation, hyperactive presentation, or combined presentation) as confirmed by the Adult ADHD Clinical Diagnostic Scale (ACDS) Version 1.2.; have a negative pregnancy test at time of informed consent for women of childbearing potential; participants may be receiving current pharmacological treatment for ADHD or no current pharmacological treatment for ADHD; participants may be receiving current pharmacological treatment for ADHD and self-report as having no response to treatment or a significant side effect profile. Patients not eligible for the study include women who are breastfeeding; those who have a current comorbid psychiatric disorder that either could be expected to require treatment with medications prohibited in this trial, or to confound efficacy or safety assessments.Examples include, but are not limited to, psychotic disorder, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, a current major depressive episode, or posttraumatic stress disorder; or those who have a known history or presence of structural cardiac abnormalities.

[0146] Effectiveness Variables:

[0147] Primary outcome measures: Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS) [Time Frame: 8 weeks, assessment once a week]. The Adult Investigator Symptom Rating Scale (AISRS) is an 18-item clinician rating scale to evaluate individual ADHD symptoms on a scale of 0 (none) to 3 (severe). The total sum ranges from 0 (no ADHD symptoms) to 54 (extremely severe ADHD symptoms). Negative change from Baseline indicates improvement.Example 6 - Effect of Whole Coca Leaf Extract on Brain Parameters related to Depression as measured by FDG-PET

[0148] A pharmaceutical composition comprising whole coca leaf extract will be tested using positron emission tomography (PET) in mice to evaluate brain metabolism in vivo as an index of synaptic activity and communication of brain regions (connectivity) of interest for depression. Previous studies have found depression to be associated with weaker function and structure of the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens amygdala regions circuits in the brain.

[0149] Fluorodeoxyglucose (FDG), a radioactive glucose analog, will be administered to mice, and PET brain scans will be performed prior to and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. It is expected to observe increased metabolic activity in the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens amygdala regions of the brain in PET scans performed after administration as compared to PET scans performed prior to administration.Example 7: A Study of the Safety and Effectiveness of Pharmaceutical Compositions Comprising Whole Coca Leaf Extract for the treatment of Depression

[0150] This study evaluates the efficacy, safety, and tolerability of pharmaceutical compositions comprising whole coca leaf extract in adults with depression.

[0151] Protocol:

[0152] Patients to be treated with whole coca leaf extract will be randomly assigned to the treatment arm or the control. Patients in the treatment arm will take a solid oral dosage form of whole coca leaf extract from 1 to 6 times a day (at about 1 g to about 500 g of leaf equivalents). Patients on the control arm will not receive whole coca leaf extract at any time on this study.

[0153] Eligibility Criteria:

[0154] Patients eligible for one study may be as follows: Willing and able to provide written informed consent; man or woman >18 years of age; must meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for current depressive disorder; have a negative pregnancy test at time of informed consent for women of childbearing potential; participants may be receiving current pharmacological treatment for depression or no current pharmacological treatment for depression; participants may be receiving current pharmacological treatment for depression and self-report as having no response to treatment or a significant side effect profile. Patients not eligible for the study include women who are breastfeeding; those who have a history of schizophrenia or other psychotic disorder, and patients with suicidal ideation.

[0155] Effectiveness Variables:

[0156] Primary Outcome Measures: Change in Montgomery-Asberg Depression Rating Scale Score [Time Frame: 24 hours, 2 weeks, 4 weeks, and 8 weeks]. The Montgomery-Asberg Depression Rating Scale (MADARS) is a 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors for each item. These individual item scores are added together to form a total score, which can range between 0 and 60 points, higher score indicating poorer health outcomes. The MADRS provides a measure of the overall level of depression..Example 8 - Effect of Whole Coca Leaf Extract on Brain Parameters related to Anxiety Disorders as measured by FDG-PET

[0157] A pharmaceutical composition comprising whole coca leaf extract will be tested using positron emission tomography (PET) in mice to evaluate brain metabolism in vivo as an index of synaptic activity and communication of brain regions (connectivity) of interest for anxiety disorders. Previous studies have found depression to be associated with weaker function and structure of the amygdala and hypothalamus regions in the brain.

[0158] Fluorodeoxyglucose (FDG), a radioactive glucose analog, will be administered to mice, and PET brain scans will be performed prior to and after administration of the pharmaceutical composition. Both regional and connectivity analyses will be performed. It is expected to observe increased metabolic activity in the amygdala and hypothalamus regions of the brain in PET scans performed after administration as compared to PET scans performed prior to administration.Example 9: A Study of the Safety and Effectiveness of Pharmaceutical Compositions Comprising Whole Coca Leaf Extract for the treatment of Anxiety Disorders

[0159] This study evaluates the efficacy, safety, and tolerability of pharmaceutical compositions comprising whole coca leaf extract in adults with anxiety disorders.

[0160] Protocol:

[0161] Patients to be treated with whole coca leaf extract will be randomly assigned to the treatment arm or the control. Patients in the treatment arm will take a solid oral dosage form of whole coca leaf extract from 1 to 6 times a day (at about 1 to about 500 g of leaf equivalents). Patients on the control arm will not receive whole coca leaf extract at any time on this study and will receive a placebo tablet that looks identical to the pharmaceutical composition comprising whole coca leaf extract.

[0162] Eligibility Criteria:

[0163] Patients eligible for the study much be as follows: Willing and able to provide written informed consent; man or woman >18 years of age; must meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) one of the following primary axisI disorders according to the Diagnostic and Statistical Manual of Mental Disorders (DSM): 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; have a negative pregnancy test at time of informed consent for women of childbearing potential; participants may be receiving current pharmacological treatment for an anxiety disorder or no current pharmacological treatment for an anxiety disorder; participants may be receiving current pharmacological treatment for an anxiety disorder and self-report as having no response to treatment or a significant side effect profile. Patients not eligible for the study include women who are breastfeeding; patients with medical relative contraindications involve conditions that impede thorough exposure, e.g. cardiovascular diseases or autoimmune diseases, and patients with current or past schizophrenia, psychosis or bipolar disorder.

[0164] Effectiveness Variables:

[0165] Primary outcome measures: Change From Baseline in the Hamilton Rating Scale for Anxiety (HAM-A) Total Score [Time Frame: 8 weeks],

[0166] All publications, patents, and patent applications cited herein are hereby incorporated herein by reference in their entirety.

Claims

Attorney Docket No. 38321.000 IP 1What is claimed is:

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

2. The method according to claim 1, wherein the whole coca leaf extract comprises cocaine in an amount of no more than about 80 % by weight of the extract.

3. The method according to claims 1 or 2, wherein the whole coca leaf extract comprises methylecgonine cinnamate.

4. The method according to any of claims 1-3, wherein 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.

5. The method according to any of claims 1-4, 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 of claims 1-6, 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 from about 10 to about 13.

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

11. The method according to any of claims 1-10, wherein the whole coca leaf extract further comprises at least one of benzoyl ecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

12. The method according to any one of claims 1-11, wherein methyl ecgonine cinnamate is present as a c / .s-isomer, a / ra / zs-iso er, or a combination thereof.

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

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

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

16. The method according to any of claims 1-15, wherein the subject experiences daytime somnolence.

17. The method according to any of claims 1-16, 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 of claims 1-18, wherein the subject is being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate.

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

21. The method according to any of claims 1-20, wherein an administered daily dose of the whole coca leaf extract to the subject is from about 1 g leaf equivalents to about 500 g leaf equivalents of the whole leaf extract.

22. The method according to any of claims 1-21, wherein the pharmaceutical composition is administered 1, 2, 3, 4, 5, or 6 times per day or as needed.

23. The method according to any of claims 1-22, wherein the administration of the pharmaceutical composition causes increased activation in the perifornical hypothalamus region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro- deoxy-D-glucose (FDG).

24. The method according to any one of claims 1-23, wherein treating narcolepsy in a subject comprises administering the pharmaceutical composition during a time period of medication transition.

25. A method of treating attention deficit hyperactive disorder in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising whole coca leaf extract.

26. The method according to claim 25, wherein the whole coca leaf extract comprises cocaine in an amount of no more than about 80 % by weight of the extract.

27. The method according to claim 25 or 26, wherein the whole coca leaf extract comprises methylecgonine cinnamate.

28. The method according to any of claims 25-27, wherein 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.

29. The method according to any of claims 25-28, 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 of claims 25-30, 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 from about 10 to about 13.

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

35. The method according to any of claims 25-34, wherein the whole coca leaf extract further comprises at least one of benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

36. The method according to any one of claims 25-35, wherein methylecgonine cinnamate is present as a cv.s-isomer, a / ra / / .s-isomer, or a combination thereof.

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

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

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

40. The method according to any of claims 25-39, 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 of claims 25-41, wherein the subject is being treated for an attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

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

44. The method according to claim 42 or 43, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, 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 viloxazine.

47. The method according to any of claims 25-46, wherein an administered daily dose of the whole coca leaf extract to the subject is from about 1 g leaf equivalents to about 500 g leaf equivalents of the whole leaf extract.

48. The method according to any of claims 25-47, wherein the administration of the pharmaceutical composition causes increased activation in the frontal cortex region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG).

49. The method according to any of claims 25-48, wherein treating ADHD in a subject comprises administering the pharmaceutical composition during a time period of medication transition.

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

51. The method according to claim 50, wherein the whole coca leaf extract comprises cocaine in an amount of no more than about 10 % by weight of the extract.

52. The method according to claim 50 or 51, wherein the whole coca leaf extract comprises methylecgonine cinnamate.

53. The method according to any of claims 50-52, wherein 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.

54. The method according to any of claims 50-53, 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 of claims 50-55, 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 from about 10 to about 13.

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

60. The method according to any of claims 50-59, wherein the whole coca leaf extract further comprises at least one of benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

61. The method according to any one of claims 50-60 wherein methylecgonine cinnamate is present as a cv.s-isomer, a / ra / / .s-isomer, or a combination thereof.

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

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

64. The method according to any of claims 50-63, wherein the subject is being treated for depression with at least one antidepressant drug selected from a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a noradrenaline and specificserotonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, a monoamine oxidase inhibitor, or a combination thereof.

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

66. The method according to any of claims 50-65, 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 of claims 50-67, wherein an administered daily dose of the whole coca leaf extract to the subject is from about 1 g leaf equivalents to about 500 g leaf equivalents of the whole leaf extract.

69. The method according to any of claims 50-68, wherein administration of the pharmaceutical composition causes increased activation at least one of: the hippocampus, prefrontal cortex, cingulate cortex, and nucleus accumbens amygdala regions of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG) during treatment comprising administration of the pharmaceutical composition.

70. The method according to any of claims 50-69, wherein treating depression in a subject comprises administering the pharmaceutical composition during a time period of medication transition.

71. A method of treating an anxiety disorder in a subject comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising whole coca leaf extract.

72. The method according to claim 71, wherein the whole coca leaf extract comprises cocaine in an amount of no more than about 10 % by weight of the extract.

73. The method according to claim 71 or 72, wherein the whole coca leaf extract comprises methylecgonine cinnamate.

74. The pharmaceutical composition according to any of claims 71-73, wherein 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.

75. The pharmaceutical composition according to any of claims 71-74, wherein the pharmaceutical composition 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. The pharmaceutical composition according to any of claims 71-76, 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 ranges from about 10 to about 13.

80. The pharmaceutical composition according to any of claims 71-79, wherein the pharmaceutical composition comprises a weight percent of from about 30 % to about 100 % of the whole coca leaf extract.

81. The pharmaceutical composition according to any of claims 71-80, wherein the whole coca leaf extract further comprises at least one of benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

82. The pharmaceutical composition according to any one of claims claim 71-81, wherein methylecgonine cinnamate is present as a cz -isomer, a Zzzzz / .s-isomer, or a combination thereof.

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

84. The pharmaceutical composition according to any of claims 71-83, wherein the whole coca leaf extract further comprises at least one essential oil.

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

86. The method according to any of claims 71-85, 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 of claims 71-87, wherein the subject is being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor.

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

90. The method according to any of claims 71-89, wherein an administered daily dose of the whole coca leaf extract to the subject is from about 1 g leaf equivalents to about 500 g leaf equivalents of the whole leaf extract.

91. The method according to any of claims 71-90, wherein the administration of the pharmaceutical composition causes increased activation in at least one of the amygdala and hypothalamus regions of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D-glucose (FDG) during treatment comprising administration of the pharmaceutical composition.

92. The method according to any of claims 71-91, wherein treating anxiety in a subject comprises administering the pharmaceutical composition during a time period of medication transition.

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

94. A whole coca leaf extract produced by a method comprising the steps of: a. exposing leaves of a plant from the family Erylhroxylaceae, 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; c. evaporating the solvent from the first liquid phase to form a concentrate of the liquid phase.

95. The method of claim 94, further comprising powderizing the concentrate to form the whole coca leaf extract.

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

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

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

99. The method according to any of claims 94-98, further comprising adjusting the pH of the liquid phase or the 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, calcium phosphate dibasic, calcium phosphate monobasic, magnesium carbonate, potassium aluminum sulphate, potassiumbicarbonate, potassium carbonate, potassium hydroxide, potassium lactate, potassium phosphate dibasic, potassium pyrophosphate tetrabasic, potassium phosphate tribasic, potassium tripolyphosphate, sodium acetate, sodium acid pyrophosphate, sodium aluminum phosphate, sodium aluminum sulphate, sodium bicarbonate, sodium bisulphate, sodium carbonate, sodium hexametaphosphate, sodium hydroxide, sodium lactate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate tribasic, or any combination thereof.

100. The method according to claim 94, comprising a. exposing the second solid phase to the 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 the pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.101 . The method according to claim 100, comprising: a. exposing the third solid phase to the solvent to form a fourth liquid phase and a fourth solid phase; and b. combining the fourth liquid phase and the first liquid phase, the second liquid phase, and the third liquid phase to form the pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

102. The method according to claim 101, comprising: a. exposing the fourth solid phase to the solvent to form a fifth liquid phase and a fifth solid phase; andb. combining the fifth liquid phase and the first liquid phase, the second liquid phase, the third liquid phase, and the fourth liquid phase to form the pooled liquid phase and evaporating the solvent to produce the concentrate of the liquid phase.

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

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

105. The method according to claim 104, wherein two immiscible layers are formed when the concentrate is exposed to the second solvent, the method comprising 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 1-14.

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

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

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

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

111. The method according to any of claims 94-110, wherein the concentrate of the liquid phase is dried with a drying technology.

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

113. The method according to any of claims 1-24, wherein the subject being treated for narcolepsy with the pharmaceutical composition as described herein has been previously or is currently being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

114. The method according to any of claims 1-24, wherein the subject being treated for narcolepsy with the pharmaceutical composition as described herein has been previously or is currently being treated for narcolepsy with at least one drug selected from a stimulant, a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a benzodiazepine receptor agonist, or a gamma-hydroxybutyrate and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

115. The method according to any of claims 1-24, wherein the subject being treated for narcolepsy is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments.

116. The method according to claim 115, wherein the subject does not tolerate existing or standard treatments due to adverse effects.

117. The method according to any of claims 25-49, wherein the subject being treated for attention deficit hyperactivity disorder with the pharmaceutical composition as describedherein has been previously or is currently being treated for attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

118. The method according to any of claims 25-49, wherein the subject being treated for attention deficit hyperactivity disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

119. The method according to any of claims 25-49, wherein the subject being treated for attention deficit hyperactivity disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments.

120. The method according to claim 119, wherein the subject does not tolerate existing or standard treatments due to adverse effects.

121. The method according to any of claims 50-70, wherein the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specific serogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

122. The method according to any of claims 50-70, wherein the subject being treated for depression with the pharmaceutical composition as described herein has been previously or is currently being treated for depression with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a norepinephrine and specificserogonergic antidepressant, a tricyclic antidepressant, a serotonin antagonist and reuptake inhibitor, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

123. The method according to any of claims 50-70, wherein the subject being treated for depression is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments.

124. The method according to claim 123, wherein the subject does not tolerate existing or standard treatments due to adverse effects.

125. The method according to any of claims 71-92, wherein the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

126. The method according to any of claims 71-92, wherein the subject being treated for an anxiety disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for an anxiety disorder with at least one drug selected from a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a tricylic antidepressant, a benzodiazepine, a beta-blocker, buspirone, or a monoamine oxidase inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

127. The method according to any of claims 71-92, wherein the subject being treated for an anxiety disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments.

128. The method according to claim 127, wherein the subject does not tolerate existing or standard treatments due to adverse effects.

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

130. A method of ameliorating cognitive impairment associated with ADHD in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a whole coca leaf extract.

131. The method of claim 130, wherein the cognitive impairment is selected from attention deficits, working memory deficits, executive function deficits, delayed reaction time, logical reasoning deficits, problem solving deficits, planning deficits, and / or information consolidation problems.

132. The method according to claim 130 or 131, wherein the whole coca leaf extract comprises cocaine in an amount of no more than about 80 % by weight of the extract.

133. The method according to any of claims 130-132, wherein the whole coca leaf extract comprises methylecgonine cinnamate.

134. The method according to any of claims 130-133, wherein 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.

135. The method according to any of claims 130-134, 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 of claims 130-136, 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 from about 10 to about 13.

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

141. The method according to any of claims 130-140, wherein the whole coca leaf extract further comprises at least one of benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, or hygrine.

142. The method according to any one of claims 130-141, wherein methylecgonine cinnamate is present as a cv.s-isomer, a zra / / .s-isomer, or a combination thereof.

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

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

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

146. The method according to any of claims 130-145, 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 of claims 130-147, wherein the subject is being ameliorated for a cognitive impairment associated with attention deficit hyperactive disorder with at least one drug selected from: a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor.

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

150. The method according to claim 148 or 149, wherein the stimulant is dexmethylphenidate, methylphenidate, dextroamphetamine, amphetamine, serdexmethylphenidate, 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 viloxazine.

153. The method according to any of claims 130-152, wherein an administered daily dose of the whole coca leaf extract to the subject is from about 1 g leaf equivalents to about 500 g leaf equivalents of the whole leaf extract.

154. The method according to any of claims 130-153, wherein the administration of the pharmaceutical composition causes increased activation in the frontal cortex region of the subject’s brain, as measured by positron emission tomography (PET) with [18F]-fluoro-deoxy-D- glucose (FDG).

155. The method according to any of claims 130-154, wherein ameliorating a cognitive impairment associated with ADHD in a subject comprises administering the pharmaceutical composition during a time period of medication transition.

156. The method according to any of claims 130-155, wherein the subject being treated for cognitive impairment associated with attention deficit hyperactivity disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for cognitive impairment associated with attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing an adverse reaction to the at least one drug.

157. The method according to any of claims 130-156, wherein the subject being treated for cognitive impairment associated with attention deficit hyperactivity disorder with the pharmaceutical composition as described herein has been previously or is currently being treated for cognitive impairment associated with attention deficit hyperactivity disorder with at least one drug selected from a stimulant, an alpha-adrenergic agonist, or a norepinephrine reuptake inhibitor and has been identified as a subject that has experienced or is experiencing treatment resistance to the at least one drug.

158. The method according to any of claims 130-157, wherein the subject being treated for cognitive impairment associated with attention deficit hyperactivity disorder is refractory to existing or standard treatments and / or does not tolerate existing or standard treatments.

159. The method according to claim 158, wherein the subject does not tolerate existing or standard treatments due to adverse effects.