WO1999008681A1

WO1999008681A1 - Inducing neurotransmitter and neuropeptide activity

Info

Publication number: WO1999008681A1
Application number: PCT/US1998/016882
Authority: WO
Inventors: William E. Shell; Mark E. Jarmel
Original assignee: Nutracorp Scientific, Inc.
Priority date: 1997-08-13
Filing date: 1998-08-13
Publication date: 1999-02-25
Also published as: AU9197598A

Abstract

A method and compositions for promoting the neural synthesis and release in an animal subject of the neurotransmitters acetylcholine, GABA, glutamate, norepinephrene, dopamine, aspartate, histamine and serotonin. To enhance release of the neurotransmitter in the subject precursors for each of these neurotransmitters may be administered concomitantly with a xanthine and with one or more precursors for another neurotransmitter selected from precursors for the neurotransmitters histamine, glutamine and aspartate. The xanthines include caffeine, theophylline and theobromine. This procedure for the promotion of synthesis and release of the neurotransmitters may be employed in the treatment of subjects having a neurotransmitter deficiency, including reduced neural tone and excessive neural activity.

Description

INDUCING NEUROTRANSMITTER AND NEUROPEPTTDE ACTIVITY

Technical Field

This invention relates generally to dietary supplements for inducing the synthesis and release of neurotransmitters. There has been increasing attention to the role neurotransmitters play in various aspects of health and disease. This has lead to an appreciation of the effects neurotransmitters have on mood, appetite, memory and addiction. Additionally, it is known that neurotransmitters play a crucial role in regulating the functions of the cardiovascular, endocrine, digestive, respiratory, reproductive, musculoskeletal, and immune systems. Numerous pharmaceutical agents have been developed which exert their effects on the body by promoting the activity of one or more neurotransmitters. However, pharmaceutical agents are known to produce unacceptable side effects. Accordingly, there is a need for an effective means for promoting the synthesis and release of specific while avoiding drug-related side effects.

Background Art

Wurtman, et al in U.S. Patent No. 4,309,445 described a composition and method using d-fenfluramine to block intermittent carbohydrate cravings. This method disclosed that d-fenfluramine and the related isomer 1-fenfluramine selectively reduces carbohydrate craving. Wurtman, et al, in U.S. Patent 4,687,763 disclosed that tryptophan can increase brain serotonin levels when given with melatonin. In this patent Wurtman, et al, disclosed that oral administration of tryptophan can increase brain serotonin and that increased brain serotonin leads to reduced carbohydrate craving. The amount of tryptophan used by Wurtman, et al, were consistently between 2 and 100 mg/ kg. of body weight per dose. These amounts are significantly above the current governmental (U..S. Food and Drug Administration) safety guidelines of less than 1.6 mg/kg per day of supplemental tryptophan, particularly if the tryptophan comes from bacterial synthesized sources.

In Wurtman, et al U.S. Patent No. 5,118,670, a composition and method for increasing brain dopamine release is described. The dose of tyrosine proposed by Wurtman is between 10 and 500 mg. per kg. body weight when concomitantly administered with a drug such as thyrotropin-releasing hormone. This method has the limitation of needing a prescription medication to produce the desired effect. Thus, physician visits are required and the potential for drug-related side effects is still present. Wurtman, et al, in U.S. Patent No. 4,673,689 disclose that tyrosine can be used to potentiate sympathomimetic agents such as phenylpropanolamine, ephedrine or pseudoephedrine. However, this patent contains no disclosure or suggestion of any usefulness or synergism for any purpose for combining tyrosine with any other agents active in the central nervous system. Further, because Wurtman et al utilize these neurotransmitter precursors in combination with sympathomimetic drugs, the risk of drug-related side effects remains.

Prior art in the field of weight management agents has focused on the release of serotonin, dopamine, and norepinephrine to produce appetite suppression in a subject. However, pharmaceutical agents that increase the release of particularly serotonin or inhibit reuptake of serotonin, are known to produce undesirable side effects.

It is known that serotonin, norepinephrine, acetylcholine, glutamate and histamine each induce release of the neuropeptide corticotrophin-releasing factor. In addition to its desirable effects on appetite, corticotrophin-releasing factor is known to act as an immunosuppressive, anti-inflammatory and anti-nociceptive agent.

The activity of various types of neurons is inhibited by the endogenous neuromodulator, adenosine. Xanthines are known to act as adenosine antagonists and thus serve to promote the release of neurotransmitters that are tonically inhibited by adenosine. Thus, xanthines act to dis-inhibit neuronal firing, resulting in increased neurotransmitter activity. Naturally occurring xanthines such as caffeine, theobromine and theophylline are found in food substances and herbs such as coffee, tea, cocoa, ephedra, mate' or guarana. Chocolate, particularly the cocoa powder, contains among other active ingredients, the xanthines theobromine and caffeine. Chocolate has been used both directly and indirectly, knowingly and unknowingly, as a mood elevator. The mechanism of chocolate's appeal has, heretofore, not been specifically defined. Most common knowledge attributes the appeal of chocolate to its taste, not to neurotransmitter effects.

Naftchi in U.S. Patent No. 4,742,054 describes utilizing xanthines as de-sensitizing agents in combination with pharmaceutical receptor agonists for promoting neural function in cases of damage to the central nervous system. Naftchi's invention has the limitation of utilizing prescription drugs with known undesirable side effects, as agonists for various receptors.

Laruelle et al U.S. Patent No. 4,472,387 describes pharmaceutical compositions for increasing cerebral serotonin production that are comprised of synthetic salts formed by combining xanthines with serotonin precursors. Laruelle's examples demonstrate that xanthines significantly increase the amount of serotonin released, compared to levels produced by administering serotonin precursors alone. The dose of 5-hydroxy tryptophan utilized by Laruelle was between 10 and 50 mg. per kg. in rats. For a 70 kg. man, the dose would range between 700 and 3,500 mg. to potentially achieve similar effects. As with tryptophan itself, these levels of 5-hydroxytryptophan may potentially cause muscle damage. Additionally, the compositions disclosed by Laruelle have the limitation of being pharmaceuticals and thus require lengthy and costly testing to comply with FDA regulations. Thus, there exists a need for a non-drug dietary supplement that utilizes the synergistic actions of xanthines and neurotransmitter precursors. This invention has the advantage of utilizing these mechanisms in the form of a dietary supplement that does not require FDA approval. Laruelle's invention has the disadvantage of comprising synthetic compositions with unknown possible adverse effects.

Histidine is a precursor for the neurotransmitter histamine. Orally administered histidine is known to increase levels of histamine in the brain. Histamine is known to promote the release of acetylcholine, serotonin, dopamine, norepinephrine, gamma- aminobutyric acid (GABA), and neuropeptides such as corticotrophin- releasing hormone. It has been reported that histamine and its precursor histidine will decrease the food intake of experimental animals (rats) when administered by intraperitoneal injection ("Manipulation of Central Nervous System Histamine, Histaminergic Receptors (HI) Affects Food Intake in Rats," Mercer et al., J. of Nutrition, 1994, Vol. 24, pp 1029-1036). However, the effectiveness of either histamine or its precursor histidine for suppression of appetite by oral administration or at dosage levels at which the known side effects could be tolerated has not been elucidated.

The report "Caffeine Potentiates the Enhancement by Choline of Striatal Acetylcholine Release" Life Sciences, Vol. 51, pp. 1597-1601, Johnson et al., 1992, Pergamon Press, is a study concerning the intraparatoneal administration of choline in vivo to determine whether the choline will increase the release of striatal ACh and whether caffeine administered therewith can amplify the effect of the choline. Choline was administered i.p. at doses of 30, 60 and 120 mg./kg, both alone and together with caffeine at a dose of 50 mg./kg. (3,500 mg. dose in man). Measurement of striatal choline at intervals after administration indicated an enhanced release of ACh for the combined administration of the choline and caffeine over choline or caffeine administered alone, at all three dosage levels of choline. Administration is by intraperoneal administration rather than oral, thus avoiding the uncertainties of passage through and absorption from the gastrointestinal tract. The doses are also massive, both of choline and caffeine, telling very little as to the practical effectiveness of the potentiation observed for choline, much less for any other precursor. For man the choline dose would be 2,100, 4,200 and 8,400 milligrams, respectively. The caffeine dose would be 3,500 milligrams in all cases, clearly an intolerable amount. While the adenosine receptor activity of caffeine is mentioned, the authors are unable to conclude what the mechanism is for the potentiation observed.

Disclosure of the Invention

The following description illustrates the manner in which the principles of the invention are applied but is not to be construed as limiting the scope of the invention. Pharmaceutical agents produce their effects by either activating or inhibiting mechanisms that are already present in the body. They therefore, attempt to emulate actions normally produced by the body's intrinsic homeostatic mechanisms. All pharmaceuticals which are foreign to the body have associated undesirable side effects since synthetic drugs imperfectly interact with the body's regulatory mechanisms. Side effects are further promoted by the non-selective distribution of drugs throughout the bloodstream. These pharmaceuticals thus may affect each organ and body system in unknown and potentially undesirable ways. This invention has the advantage of administering naturally occurring agents, namely neurotransmitter precursors, that are normally utilized by the body's intrinsic homeostatic mechanisms. These include precursors for the neurotransmitters acetylcholine, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine. By administering these precursors that the body normally utilizes to synthesize neurotransmitters, the occurrence of side effects is desirably decreased. Thus, this invention advantageously emulates effects produced by synthetic pharmaceutical agents on various mechanisms regulated ty neurotransmitters, with reduced risk of side effects.

In this invention the neurotransmitter precursors are administered for the purpose of ameliorating neurotransmitter deficiency and thereby optimizing neurotransmitter functioning. Neurotransmitter deficiency includes any condition in which the production of a neurotransmitter or its release in the is less than optimal. It may constitute a general deficiency of neurotransmitters or an imbalance of neurotransmitters caused by a relative deficiency of some. Such deficiencies may involve one or more of the neural pathways of the body, which may be in the form of a reduction in tone, as in the case of depression, or in a state of excessive activity, as in cardiac tachyarrhythmia. Neurotransmitter deficiency results in less than optimal regulation of body functions leading to a wide variety of conditions and disorders. These are the conditions and disorders that may be treated utilizing neurotransmitter precursors under this invention thereby emulating synthetic neuroactive pharmaceutical agents. Precursors for each neurotransmitter may be administered for treatment of neurotransmission deficiencies involving the neural pathways with which that neurotransmitter is associated, including reduced tone or excessive neural activity in the affected pathway.

The various precursors for the neurotransmitters acetylcholine, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine include tyrosine, phenylalanine, tryptophan, histidine, pyruvates, carnitine, acetyl-L-carnitine, glucose, choline, lecithin, glutamine, glutamic acid and aspartic acid form a class of precursors for neurotransmitters that are active in the central nervous system. It is to be understood that the precursors may also be in the form of their pharmaceutically acceptable derivitives, including their salts, hydrates, acid adducts (e.g. hydrochloric acid) and mineral chelates (e.g. salts bound to the precursor by chelation bonding).

In this invention, to increase synthesis and release of each precursor's respective neurotransmitter or transmitters, one or more of the foregoing precursors is administered in combination with one or more xanthines and in combination with one or more precursors for another neurotransmitter, selected from the neurotransmitters histamine, glutamate and /or aspartate. This is based on the discovery that xanthines will act synergistically with precursors for any of the neurotransmitters histamine, glutamate and aspartate, to promote synthesis and release of another neurotransmitter, when they are both administered together with a precursor of the other neurotransmitter. While xanthines are known to have various neural activities, their mode of operation in this invention is not yet clearly elucidated. However, their role is clearly distinct from that of the precursors for histamine, glutamate and aspartate. While Applicants do not wish to be bound by any theory, it is believed that histamine, glutamate and aspartate are each capable of promoting neural firing for other neurotransmitters (including for each other). Thus, in this invention the precursors for each of these promoter neurotransmitters promote its respective neurotransmitter, which neurotransmitter, in turn, promotes the synthesis and release of the desired other neurotransmitter, the precursor for which is administered with the precursor for the promoter neurotransmitter. The precursors of the desired neurotransmitter, administered with xanthine and with one or more of the precursors for histamine, glutamate and /or aspartate, may then be employed in the treatment of the various conditions involving neurotransmitter deficiency. Tyrosine and its precursors, e.g. phenylalanine, potentiate the production and release of dopamine and /or norepinephrine. They may be beneficial in the formulations of this invention in the treatment of disorders involving deficiencies of these neurotransmitters. In the case of norepinephrene these include conditions involving a reduction in adrenergic tone and in the case of dopamine conditions involving a reduction of dopaminergic tone.

Where it is desired to enhance synthesis of norepenephrine preferentially to dopamine, the concomitant administration of precursors for histamine and glutamate is particularly desirable, because they have the effect of suppressing the synthesis of dopamine in favor of norepinephrene in addition to further enhancing the effect synthesis and release of the norepinephrene. On the other hand, where it is desired to stimulate synthesis and release of dopamine, it is desirable to utilize a precursor for aspartate to promote neural firing, rather than precursors for histamine or glutamate, because aspartate has a lesser suppressing effect on dopamine.

Conditions such as Parkinson's disease, in which brain levels of dopamine and norepinephrine are reduced, thus involve a reduction in both adrenergic and catacholaminergic tone. Thus for this condition tyrosine and its precursors may be used in order to promote both dopaminergic and adrenergic activity.

Tyrosine-containing formulations can emulate the effects of amphetamines, phentermine, ephedrine, and other adrenergic or dopaminergic agonists. Depleted brain levels of dopamine and norepinephrine promote addictive cravings for psychostimulants. Thus, the tyrosine-containing formulations of this invention may be administered to promote the synthesis and release of dopamine and norepinephrine in the treatment of addiction to psychostimulants such as cocaine or amphetamines without utilizing a pharmaceutical foreign to the body.

Trytophan, the precursor of serotonin, may be employed in this invention in treatment of disorders in serotonergic transmission, as in the case of anxiety states, addiction, depression and impaired immune function. Tryptophan-containing formulations of this invention emulate the increases in serotonin activity produced by fenfluramine, d- fenfluramine and flouxetine. Serotonin reuptake-inhibiting drugs such as these are known to deplete serotonin. Desired effects from increasing serotonin activity may be promoted by this invention without inhibiting reuptake of serotonin.

In addition to separate use of tryptophan or tyrosine as the sole neurotransmitter precursor combined with xanthines and /or histidine, they may be used advantageously in combination. Desirably, both tryptophan and tyrosine formulations are given to a subject, but at different times, thus avoiding competition of the precursors for uptake into the brain. Administering these formulations in combination promotes increased synthesis and release of serotonin, dopamine and norepinephrine. Thus, this invention has the advantage of emulating the desirable effects of various pharmaceutical antidepressants, with reduced risk of drug-related side effects

Additionally, the combination of tryptophan and tyrosine in this invention can be used to emulate the actions of fenfluramine and phentermine used together as serotonin and dopamine agonists. Hitzig in U.S. Patent No. 5,502,080 describes concomitant administration of these same agonists for serotonin and dopamine, particularly fenfluramine and phentermine, in the treatment of a variety of disorders of the immune system. T-cell CD4+ counts can be increased in subjects infected with human immunodeficiency virus (HIV), by concomitantly administering agonists for serotonin and dopamine. They are also utilized together in the treatment of addiction to psychostimulants. However, fenfluramine and phentermine, in combination, are known to be associated with side effects such as pulmonary hypertension and mitral valve disease. Tryptophan and tyrosine may be used together in the invention to emulate desirable effects produced by these pharmaceuticals on addictive cravings, immune disorders and appetite, with reduced risk of side effects.

The precursors for norepinephrine, serotonin, acetylcholine, histamine and glutamate of this invention may all be used to enhance the secretion of corticotrophin-releasing factor and thereby beneficial effects thereof. They thus may emulate the effects of synthetic corticosteroids such as cortisone, but without the associated side effects. In accordance with this invention they may be combined together to even more effectively enhance secretion of corticotrophin-releasing factor. Thus, this invention takes advantage of agents that are naturally utilized by intrinsic neural mechanisms to promote secretion of corticotrophin-releasing factor.

The precursors for glutamate may be used advantageously with the precursors for the other neurotransmitters that promote the activity of corticotropin-releasing factor, as glutamate promotes the firing of the other neurotransmitters. Thus formulations which include either or both glutamic acid and glutamine are advantageously employed together with tyrosine, precursors for tyrosine, aspartic acid, pyruvates, carnitine, acetyl-L-carnitine, glucose, choline, lecithin, histidine and tryptophan in combinations with xanthines and /or histidine of this invention. Precursors for acetylcholine are utilized in this invention in the treatment of conditions involving reduced tone of cholinergic nerves. Formulations containing the precursors pyruvate, carnitine, acetyl-L- carnitine, glucose, choline and or lecithin in combination with xanthines and desirably also with a precursor for histamine, glutamine and /or aspartate e.g. histidine, glutamic acid, glutamine, and /or aspartic acid, emulate the effects of pharmaceuticals that enhance acetylcholine activity. Since nicotine is a potent agonist of acetylcholine-releasing neurons, this invention may advantageously be administered in the treatment of nicotine addiction. Depleted brain levels of acetylcholine promote addictive cravings for nicotine. This invention has the advantage of enhancing the synthesis and release of acetylcholine in the brain, without utilizing pharmaceuticals. Pharmaceutical agents for aiding withdrawal from nicotine such as nicotine transdermal patches and nicotine gum, have undesirable side effects. This invention has the advantage of lessening or eliminating cravings for nicotine and other symptoms of nicotine withdrawal, with reduced risk of drug-associated side effects.

Decreased levels of acetylcholine, norepinephrine, dopamine, serotonin and corticotropin-releasing factor are present in Alzheimer's disease. Brain dopamine levels are known to be decreased in Parkinson's disease. Concomitantly administering separate formulations containing choline, tyrosine, tryptophan and glutamine desirably promotes activity of acetylcholine, dopamine, norepinephrine, serotonin, glutamate and corticotropin-releasing factor. This invention may be administered in the treatment of Alzheimer's disease, senile dementia, or Parkinson's disease to desirably promote synthesis and release of depleted neurotransmitters. Thus, this invention may be advantageously administered in the treatment of certain cognitive or neurological deficits in order to enhance neural and mental functioning.

Where it is desired to stimulate GABA preferentially to glutamate, a glutamate inhibitor may administered along with the glutamate precursor and xanthine. Glutamate inhibitors include proline, either as the free acid, pharmaceuti^cally accept salts thereof and hydrates and acid adducts thereof. Pharmaceutically acceptable magnesium salts, particularly water soluble salts such as magnesium chloride, may also be employed. The latter may be advantageously administered chelated with an amino acid.

Formulations containing glutamic acid or glutamine with a glutamate inhibitor may be used to emulate the stimulating effects on GABA-activity of pharmaceuticals such as the benzodiazepines or other anxiolytics. Since GABA does not cross the blood-brain barrier, in this invention a GABA precursor, along with xanthines and /or precursors for histamine and /or aspartate, is administered to induce GABA synthesis and release in the brain.

By providing a safe and effective means for promoting activity of selected neurotransmitters, the combinations of this invention may be advantageously administered in the treatment of autonomic nervous system dysfunctions. Dysfunction of the autonomic nervous system can be involved in conditions such as cardiac arrhythmias, myocardial ischemia, hypertension, diabetes, asthma, impotence and various digestive problems. For example, unbalanced activity of the cardiac autonomic nerves promotes risk of sudden cardiac death. Pharmaceuticals currently utilized to treat autonomic dysfunctions such as beta-adrenergic receptor blocking agents, or anti-arrhythmic drugs have numerous undesirable side effects. Compositions of this invention may be advantageously administered in the treatment of autonomic nervous system dysfunctions in order to promote homeostatic neural activity. For example, formulations of this invention containing glutamine and the glutamate suppresser, proline, may be administered to modulate the excessive sympathetic neural activity involved in hypertension and certain cardiac arrhythmia. This invention thus has the advantage of promoting homeostatic functioning of the autonomic nervous system, with reduced risk of drug-associated side effects.

The precursors may be employed in this invention in pure form, e.g. exogenous material synthesized or derived from animal or vegetable protein, particularly purified extracts isolated from the amino acid residues in enzyme hydrolyzed proteins. However, a source for the precursor tryptophan particularly useful in this invention, both because it is a natural food source and because of regulatory restrictions, are naturally occurring proteins. These proteins may either be enzyme hydrolyzed prior to administration to release tryptophan, or unhydrolyzed protein may be administered along with a proteolytic enzyme that will liberate tryptophan in the gastrointestinal tract. Commercial preparations of predigested proteins typically from milk- derived protein, such as casein or whey, are available and may be administered in composition with histidine and/ or a xanthine. Where the tryptophan is to be administered in the form of a predigested protein or a protein to be enzyme hydrolyzed upon administration, it is important in this invention to administer the protein concomitantly with a carbohydrate. Concomitant administration of a carbohydrate and particularly sugar, dextrins, starch and the like, is desired in order to cause release of insulin to remove from the bloodstream the other amino acids competing with tryptophan for transport across the blood-brain barrier.

Where unhydrolyzed protein is administered together with a proteolytic enzyme, soluble proteins such as albumin, are preferred, for ease of breakdown. Whey, casein and soy are convenient protein sources. Proteolytic enzymes may include papain, chymopapain, bromelain, trypsin, and pepsin.

Xanthines constitute a class of non-selective adenosine antagonists and they include theobromine, caffeine and theophylline. They are capable of promoting release of the neurotransmitters serotonin, dopamine, norepinephrine, histamine, acetylcholine, glutamate, aspartate, and GABA. Xanthines administered in accordance with this invention, potentiate neurotransmitter synthesis and release for each of serotonin, dopamine, norepinephrine, acetylcholine, glutamate, aspartate, and GABA. Combining one or more xanthines, with one or more neurotransmitter precursors, allows the desired effects to be achieved with reduced, safe, doses of the individual agents.

The xanthines may be used in the form of their free compounds or as their salts, adducts or other derivatives, for example citrated caffeine, theophylline ethylenediamine, theophylline sodium acetate, sodium glycinate, the choline salt, the theophylline derivatives theophylline megumine and dyphylline, theobromine calcium salicylate, sodium acetate or sodium salicylate.

A particularly suitable form of xanthines for use in this invention are those that are derived from natural sources. Cocoa provides a unique combination of the xanthines theobromine and caffeine in a form that is normally easily ingested and tolerated by the subject. Cocoa powder was originally included in preliminary formulations with neurotransmitter precursors to improve flavor and because its mood enhancing effects have appealed to people for centuries. An unexpected result was that the cocoa powder significantly potentiated the effects of the neurotransmitter precursors. This potentiating effect was determined by us to be produced by the naturally occurring xanthines present in cocoa powder.

Infusions of caffeine from coffee beans and of caffeine and theophylline from tea leaves may be employed as a natural source of these xanthines, either in liquid form as coffee and tea, or in dried extract form, administered separately or, more conveniently, in composition with the neurotransmitter precursor. Caffeinated soft drinks, chocolate, guarana, ephedra, mate' and other food or herb sources may be employed.

Xanthines are employed in this invention in dosage ranges appropriate to promote release of neurotransmitters and to avoid undesired side effects. Theobromine may be administered in a dosage of from 1 mg. to 2 grams (from about .02 to 40 mg./Kg. body weight) or higher. Caffeine may be administered in a dose of from 1 to 200 mg. or higher if tolerated by the subject. Theophylline may be administered in a dose of from 1 to 200 mg. or higher if tolerated by the subject. Cocoa may be administered in a dose of 1 mg. to 10 grams (from about 0.04 to 200 mg./Kg. body weight) or higher for an appropriate dose of xanthines, with a preferred dose being 500 to 800 milligrams. Xanthine-containing beverages such as tea or coffee may be employed, with one to two cups providing an appropriate dose. Somewhat higher doses of these xanthines may be employed with some subjects without undue discomfort.

The dosage of any of the precursors for histamine, glutamine and aspartate, for use either in promoting its respective neurotransmitter for the direct benefits thereof and /or for promoting the synthesis and release of another neurotransmitter, is an amount sufficient to enhance synthesis and release of their respective neurotransmitter. The desired single dose range for these purposes for histidine and its salts, hydrates and adducts is typically from about 1 to 500 milligrams (approximately 0.02 to 10 mg./Kg. body weight of the subject) and may be up to 1,000 milligrams (20 mg./Kg. body weight of the subject), with a typical dose being 30 to 200 milligrams. The desired single dose for precursors for glutamate and aspartate when used to enhance the synthesis and release of other neurotransmitters, when administered with precursors for those neurotransmitters, is the same as for their use to enhance production of their associated neurotransmitters, glutamate and aspartate as discussed below. Namely, for precursor for either glutamate or aspartate and their salts, hydrates and adducts, an amount per dose of from about 100 to 1,000 milligrams (essentially from about 2 to 20 mg./Kg. body weight of the subject), with a typical dose of between 300 and 600 milligrams.

The dosage of each other neurotransmitter precursor is in an amount sufficient to enhance synthesis and release of its respective neurotransmitter in combined administration with histidine and /or the xanthines employed. The synergistic effect of these combinations induces increased activity of the selected neurotransmitter. Additionally, this invention induces increases in neurotransmitter activity at lower dosage levels of its respective precursor than otherwise possible. Desirably, these lower dosage levels are employed to avoid possible side effects and particularly those now limiting the use of tryptophan, including grogginess. For tryptophan and its salts, hydrates and adducts, the desired single dose range is from about 2.5 to 100 milligrams (essentially from 0.05 to 2 mg./Kg. body weight), with a typical dose of 45 milligrams. The desired dosage range of tyrosine and precursors for tyrosine, including their salts, hydrates and adducts, is from about 10 to 600 milligrams (from about 0.2 to 8 mg./Kg. body weight), with a typical dose of 500 milligrams. However, doses up to 700 milligrams and even to 1 gram or higher, e.g. up to 3 grams (60 mg. per Kg. body weight) may be administered without undue risk of side effects. For pyruvates, carnitine, acetyl-L-carnitine, glucose, choline, lecithin, including their salts, hydrates and adducts, the precursors for the neurotransmitter acetylcholine, the desired single dose range is from about 1 to 500 milligrams (from 0.02 to 7 mg. per Kg. body weight) , with a typical dose of 300 milligrams. For glucose the desired dosage is from 200 mg. to 1 gram (from about 2 to 20 mg./Kg. body weight or higher. The desired dosage range for precursors of the neurotransmitters glutamate and GABA, e.g. glutamine or glutamic acid and their salts, hydrates and adducts, is from about 100 to 1,000 milligrams (from about 2 to 20 mg./Kg. body weight), with a typical dose of between 300 and 600 milligrams.

Where proline or its salts, hydrates and adducts is administered in combination with glutamine or glutamic acid in order to maximize the production and release of GABA, the desired dosage range of proline or its derivative is from about 1 to 1,000 milligrams (from about 0.02 to 20 mg./Kg. body weight), with a typical dose of 100 to 600 milligrams. Where a magnesium salt is administered to maximize GABA, desirably a pharmaceutically acceptable, water soluble salt is employed, such as magnesium chloride or citrate, in a dose of from 25 mg. to 500 mg. (from about 0.5 to 10 mg./Kg. body weight For aspartic acid, and its salts, hydrates and adducts, the precursors for the neurotransmitter aspartate, the desired dosage range is from about 100 to 1,000 milligrams (from about 2 to 20 mg. per Kg. body weight), with a typical dose of 300 to 600 milligrams.

The dosage range for each precursor applies to combined administration of the precursor with a precursor for histamine, glutaπύne and/ or aspartate or with yet other precursors. Where hydrolyzed proteins or proteins to be hydrolyzed in the gastrointestinal tract are employed as the source of tryptophan, the proteins should be in an amount to provide the tryptophan dosage levels of this invention as discussed above. Typically, this will be in a range of between around one half of a gram and 30 gm. The amount of enzyme employed may be 30 to 50 mg. per gram of protein. Insulin producing carbohydrates are desirably administered with the protein at dosage levels of from about one half gram to 5 grams. Hydrolyzed protein sources of tryptophan may be taken separately in tablet form, utilizing commercially available predigested protein tablets, such as LLP Concentrated Predigested Protein sold by Twin Laboratories, Inc., Ronkonkoma, New York containing approximately 18 mg. of tryptophan per 1 gram tablet.

The neurotransmitter precursors and xanthines of this invention may be administered orally separately, at the same time, or for assurance of appropriate proportions and dosages as well as for convenience, they are administered together in the same composition. The dosage forms for administration separately or in the same composition may be any of the conventional forms, including capsules, capulets, chewable wafers, tablets, liquid suspensions, powders and the like. Xanthine dosages may take the form of chocolate preparations, cocoa drinks, infusions, e.g. coffee and tea and cola drinks containing caffeine.

The compositions in the form of powders or liquids may be packaged in multiple dosage quantities with instructions to the user to extract therefrom for ingestion appropriate individual dosage amounts, e.g. a teaspoonful. However, the compositions are desirably prepared in discreet units, e.g. capsules, wafers, etc., which each contain the appropriate dosage amounts of neurotransmitter precursors with xanthines and/ or histidine, for a single dose as discussed above.

The compositions may include the usual carriers, fillers, excipients, flavorings and adjuvants in addition to neurotransmitter precursors and the potentiating agents contained in cocoa. Advantageously, they may also include folic acid and vitamin B6 to enhance conversion of tryptophan to serotonin, tyrosine to dopamine and norepinephrine, and histidine to histamine respectively. The preferred amount of folic acid is 200 meg per dose with a range of 1 to 800 meg / dose. The preferred amount of vitamin B6 is 10 mg with a range of 1 to 100 mg / dose.

It is important in carrying out this invention to administer the dosages when the subject has an empty stomach, typically at least an hour after the subject has eaten. Administering the compositions on an empty stomach is important in order to avoid undesirably slow uptake of precursors across the blood-brain barrier. Uptake of administered neurotransmitter precursors would be inhibited by competition for absorption by other amino acids from the ingested food. The effects of the formulations of this invention normally should be sufficiently potent that their effects can be experienced after the first dose. Their effectiveness can be detected by a given individual using subjective questionnaires of such factors as appetite, mood, or addictive craving. Additionally, objective measures of physiologic functions that are mediated by neurotransmitters may advantageously be assessed. Examples of such objective measures are 24-hour electrocardiograms, plethysmography, oximetry, analysis of exhaled gases, or measurement of substances contained in blood, saliva, or urine. This is in contradistinction to other dietary supplements and many pharmaceuticals, that require multiple doses or indirect measures such as weight loss to assess their effectiveness.

Example 1

A formulation may prepared by blending in powder form 10 parts of caffeine with 5 parts tryptophan and 3 parts histidine. Gelatin capsules are filled with the powder blend so that each gelatin capsule contain 50 mg. of tryptophan 30 mg. histidine and 100 mg. of caffeine. A one capsule dose of this formulation is best administered on an empty stomach, at least one or two hours after eating. Alternatively, the blended powder may be prepared in the form of a chewable wafer sized to contain the same dose, by combining with the powder wheat bran, apple pectin and a sweetener. This formulation may be used in the treatment of neurotransmitter deficiencies, and particularly manifestations of reduced neurotransmitter tone, such as depression and addictions, and of excessive neurotranmitter activity such as in anxiety states.

Example 2

A formulation may prepared by blending in powder form 50 parts of cocoa with 50 parts tyrosine and 3 parts histidine. Gelatin capsules are filled with the powder blend so that each gelatin capsule contain 500 mg. of tyrosine 30 mg. histidine and 500 mg. of cocoa. This formulation is administered as in example 1. This formulation may be administered to promote increased synthesis and release of dopamine and norepinephrine in the subject for a variety of indications. This formulation may be administered to a patient suffering from drug addiction, to relieve cravings for such psychostimulants This formulation induces synthesis of neurotransmitters depleted by stress and psychostimulants such as cocaine or amphetamine. It thereby relieves the depletion of neurotransmitters that chemically promotes addiction and cravings. Additionally, this formulation may be administered to patients suffering from a depressive state. It thereby increases norepinephrine activity to ameliorate depression, emulating the pharmaceutical antidepressants amitriptyline, desipramine, doxepin, imipramine, nortryptyline, protriptyline, trimipramine, and bupropion, with reduced risk of their associated side effects.

Example 3

A formulation that contains cocoa in addition to hydrolyzed milk protein and histidine may prepared by blending in powder form 50 parts of cocoa with 200 parts of the hydrolyzed milk protein and 3 parts histidine. Gelatin capsules are filled with the powder blend so that three capsules together contain a single dose of 30 mg. histidine, 2 gm. of hydrolyzed milk protein, which provides approximately 32 mg. of tryptophan, and 500 mg. of cocoa. This formulation is administered as in example 1. This procedure advantageously emulates the increase in serotonin-activity produced by serotonin releasers such as fenfluramine or d-fenfluramine, or serotonin-specific reuptake inhibitors such as fluoxetine, sertraline, paroxetine, and venlafaxine, with reduced risk of their associated side effects

Following examples 4 and 5 illustrate the practice of the invention utilizing unhydrolyzed protein, together with a proteolytic enzyme, as the source of the neurotransmitter precursor tryptophan, both with and without concomitant application of a xanthine and/ or histidine as an additional neurotransmitter precursor. This examples advantageously emulate the increase in serotonin-activity produced by serotonin releasers such as fenfluramine or d-fenfluramine, or serotonin-specific reuptake inhibitors such as fluoxetine, sertraline, paroxetine, and venlafaxine, with reduced risk of their associated side effects.

Example 4

This example illustrates the administration of tryptophan in accordance with this invention by giving to the subject orally unhydrolyzed protein together with a proteolytic enzyme which will hydrolyze the protein when it enters the gastrointestinal tract to release the tryptophan.

Specifically, between 1 and 2 grams of whey powder, approximately 40 mg. of papain powder, 30 mg. of histidine and 40 mg. of cocoa may be administered, on an empty stomach in treament of neurotransmitter deficiencies in a subject that are responsive to serotonin.

This procedure provides an easy mode of administering tryptophan using natural food sources together with xanthine and histidine without undue grogginess.

Example 5

A formulation of cocoa with tryptophan in the form of unhydrolyzed protein together with a proteolytic enzyme to hydrolyze the protein in the G. I. tract may be prepared as follows. Whey in dry powder is blended with papain and cocoa in powder form in a proportion of 200 parts by weight of hydrolyzed protein, 4 parts papain, 3 parts histidine and 50 parts cocoa. This product is then portioned into gelatin capsules so that each contains 500 mg. cocoa, 30 mg histidine, 2 gm. of whey and 40 mg. papain. Hydrolysis of the whey in the gastrointestinal tract provides a dose of approximately 50 mg. of tryptophan. The capsules are administered as in Example 1.

Examples 6 through 11 illustrate formulations of this invention with one or more of the neurotransmitter precursors choline, pyruvate, carnitine, acetyl-L-carnitine, glutamine, glutamic acid, or aspartic acid.

Example 6

A formulation is prepared that contains a combination of precursors and specifically those for norepinephrine, dopamine, aspartate and acetylcholine, that includes xanthines and aspartic acid to promote production and release of the precursors associated neurotransmitters. A powder blend is prepared in the proportions of 50 parts of cocoa with 50 parts tyrosine, 30 parts aspartic acid, and 30 parts choline. Gelatin capsules are filled with the powder blend so that 3 gelatin capsules contain 500 mg. of tyrosine 300 mg. aspartic acid, 300 mg. of choline and 500 mg. of cocoa. This formulation is administered as in Example 1. This formulation may advantageously be administered to promote increased synthesis and release of dopamine and norepinephrine, acetylcholine and aspartate within the brain for all the conditions indicated in Example 2.

Example 7

This example illustrates the oral administration of glutamine concomitantly with proline and xanthines in accordance with this invention to promote synthesis of GABA within the brain while modulating glutamate synthesis. Alternatively, glutamic acid may be utilized as a GABA precursor, however glutamine is preferred due to its greater uptake across the blood-brain barrier. This invention has the advantage of promoting, across the blood-brain barrier, the synthesis and release of GABA within the brain. A formulation comprising glutamine 600 mg, proline 400 mg, cocoa 600 mg, sugar 500 mg. histidine 50 mg, magnesium chloride 50 mg, vitamin B6 10 mg, and folic acid 100 meg, was prepared and administered to a subject orally, on an empty stomach. The subject reported experiencing a noticeable tranquilizing effect without drowsiness or agitation. This formulation may advantageously be utilized as a non-drug anti-anxiety agent. This invention has the advantage of emulating the desired effects of benzodiazepenes or other anxiolytic pharmaceuticals, with reduced risk of drug-associated side effects or tolerance.

Example 8

This example illustrates the oral administration of choline concomitantly with tyrosine, glutamine and xanthines in accordance with this invention to promote synthesis of acetylcholine, dopamine, norepinephrine, and glutamate within the brain. This formulation may be used advantageously to relieve cravings and other symptoms associated with nicotine withdrawal. A formulation comprising choline 350 mg, glutamine 200 mg, tyrosine 200 mg, cocoa 500 mg, sugar 500 mg, vitamin B6 10 mg, and folic acid 200 meg, was prepared and administered to 4 subjects orally, on an empty stomach. Each subject had been a smoker of approximately 20 cigarettes per day for at least three years. After ingesting the formulation twice a day for 2-3 days, each subject reported experiencing an absence of their accustomed craving for nicotine and a decrease in the number of cigarettes smoked per day. This formulation desirably induces synthesis of neurotransmitters depleted by nicotine. Depletion of neurotransmitters chemically promotes addiction and cravings. Thus, this invention may advantageously be administered in order to address underlying chemical causes of addictive cravings.

Example 9

Levels of acetylcholine, norepinephrine, dopamine and corticotropin-releasing factor are decreased in Alzheimer's disease and senile dementia. A formulation is prepared and administered as in

Example 10 in order to induce synthesis and release of acetylcholine, glutamate, norepinephrine and dopamine. Additionally, a tryptophan- releasing formulation as in Examples 3 through 5 of this invention may advantageously be concomitantly administered to promote serotonin activity. An additional tyrosine-containing formulation as in Example 2 may advantageously be concomitantly administered to desirably further promote dopamine and norepinephrine activity. These tryptophan and tyrosine separate formulations are given to a subject at different times, at least 30 to 60 minutes apart, thus avoiding competition of the precursors for uptake into the brain. These treatments may be utilized in for Alzheimer's disease or senile dementia conditions in order to desirably increase brain levels of depleted neurotransmitters. These formulations may also be administered in to enhance memory and mental functioning in other conditions of cognitive deficits.

Example 10

This example illustrates the oral administration of glutamine concomitantly with xanthines in accordance with this invention to promote synthesis of glutamate within the brain. Alternatively, glutamic acid or aspartic acid may be utilized as a glutamate or aspartate precursor respectively, however glutamine is preferred due to its greater uptake across the blood-brain barrier. A formulation comprising glutamine 600 mg, cocoa 600 mg, and sugar 500 mg may be prepared and administered to a subject orally, on an empty stomach. This formulation may advantageously be used as a non-drug agent for inducing glutamate-mediated release of corticotropin-releasing factor. This invention has the advantage of promoting desirable effects on inflammation, pain and immune function by enhancing corticotropin- releasing factor activity. Additionally, it is known that brain levels of corticotropin-releasing factor are decreased in Alzheimer's disease. Thus, this invention may also be advantageously administered in the treatment of Alzheimer's disease in order to increase depleted corticotropin-releasing factor levels. These combined treatments may be employed as well in cases of central nervous system damage where promotion of neural function may be beneficial. Example 11

In treating damage to the central nervous system, xanthines and pharmaceutical neurotransmitter agonists have been advantageously administered to promote neural functioning. This example illustrates the concomitant administration of a combination of this invention's formulations in order to promote neural functioning in cases of central nervous system damage. In treating a subject who has sustained damage to the central nervous system, 2 or 3 separate formulations may advantageously be administered as in Example 9. Separate tryptophan and tyrosine formulations are given to the subject at different times, at least 30 to 60 minutes apart, thus avoiding competition of the precursors for uptake into the brain. Additionally, concomitant administration of a glutamate-releasing formulation as in Example 10, or a GABA-releasing formulation as in Example 7 may be advantageously utilized in certain types of central nervous system damage. This invention thus has the advantage of selectively inducing activity of acetylcholine, norepinephrine, dopamine, serotonin, glutamate and/ or GABA. Thus, this invention may advantageously be administered to promote neural functioning in cases of central nervous system damage.

Example 12

A formula was prepared in order to treat conditions involving deficient functioning of neural pathways utilizing acetylcholine. The formula comprised precursors for the acetyl group contained in acetylcholine in combination with choline and other nutrients that support cholinergic transmission. A powder blend was prepared in the proportions of 50 parts of cocoa with 50 parts dextrose, 25 parts acetyl-L- carnitine, 25 parts choline from bitartrate, 10 parts carnitine, 25 parts calcium pyruvate, 10 parts arginine, 5 parts histidine, 10 parts vitamin C, 5 parts pantothenic acid, 5 parts nicotinamide, 5 parts dry-form vitamin E, 2.5 parts lipoic acid, 1 part thiamine, 0.1 part vitamin B12 and 0.04 parts folic acid. Gelatin capsules were filled with the powder blend so that 5 gelatin capsules contain cocoa 500 mg., dextrose 500 mg., acetyl- L-carnitine 250 mg., choline 250 mg., carnitine 100 mg., calcium pyruvate 250 mg., arginine 100 mg., histidine 50 mg., vitamin C 100 mg., pantothenic acid 50 mg., nicotinamide 50 mg., dry-form vitamin E 50 IU, lipoic acid 25 mg., thiamine 10 mg., vitamin B12 1 mg. and folic acid 400 meg. This formulation is administered as in Example 1. This formulation may advantageously be administered to promote increased synthesis and release of acetylcholine. This formulation was administered to a 54 year old diabetic who had demonstrated reduced parasympathetic activity on 24-hour ECG. After ingesting this formula twice a day for 1 week, this individual demonstrated an increase in parasympathetic activity on follow-up 24-hour ECG. Subsequently, using transtelephonic cardiac monitoring, this individual also demonstrated a 20% reduction in resting heart rate within 30 minutes of ingesting the formulation.

Comparison Example 13

A formula was prepared comprising only precursors for acetylcholine plus histidine in the same concentrations as in Example 12. Histidine, the precursor for the neurotansmitter histamine, was included since histamine depolorizes cholinergic neurons. This formula did not contain any xanthines or other potentiating agents contained in Example 12. This formulation was prepared in order to compare the ability of acetylcholine precursors to affect parasympathetic function in the absence of xanthines. A powder blend was prepared in the proportions of 25 parts acetyl-L carnitine, 25 parts choline from bitartrate, 10 parts carnitine, 25 parts calcium pyruvate and 5 parts histidine. Gelatin capsules were filled with the powder blend so the 3 gelatin capsules contain acetyl-L-carnitine 250 mg., choline 250 mg., carnitine 100 mg., calcium pyruvate 250 mg. and histidine 50 mg. This formulation was administered as in Example 1 twice daily to the 54 year old diabetic male mentioned in Example 12. No decrease in heart rate was produced in this individual after ingestion of the formula described in this example containing no xanthines.

Example 14

A formula was prepared as in Example 13 with the sole addition of cocoa powder. A powder blend was prepared in the proportions of 50 parts cocoa, 25 parts acetyl-L carnitine, 25 parts choline from bitartrate, 10 parts carnitine, 25 parts calcium pyruvate and 5 parts histidine. Gelatin capsules were filled with the powder blend so the 4 gelatin capsules contain cocoa 500 mg., acetyl-L-carnitine 250 mg., choline 250 mg., carnitine 100 mg., calcium pyruvate 250 mg. and histidine 50 mg. This formulation was administered as in Example 1 twice daily to the 54 year old diabetic male mentioned in Examples 12 and 13. This individual experienced a 12% reduction in resting heart rate after ingesting this formulation. When compared with Example 13, this example demonstrated the synergistic effect produced by the acetylcholine precursors combined with a xanthine and a precursor for histamine (histidine) and the lack of effectiveness of administering the precursors without both xanthine and histidine.

Comparison Example 15

A formula was prepared as in Example 14 without histidine in order to test whether a xanthine combined with precursors for acetylcholine would be sufficient to produce the desired effect. A powder blend was prepared in the proportions of 50 parts of cocoa, 25 parts acetyl-L-carnitine, 25 parts choline from bitartrate, 10 parts carnitine, and 25 parts pyruvate from calcium pyruvate. Gelatin capsules were filled with the powder blend so that 4 gelatin capsules contain cocoa 500 mg., acetyl-L-carnitine 250 mg., choline 250 mg., carnitine, 100 mg. and calcium pyruvate. This formulation was administered as in Example 1 to the 54 year old diabetic male of Examples 12 through 14. No decrease in heart rate was produced in this individual after ingestion of the formula of this example, which did not contain histidine. This result demonstrates the important role in this invention of precursors for histamine, glutamine and aspartate in promoting neural firing and hence the synthesis and release of the desired neurotransmitter, acetylcholine.

As can be seen from the foregoing, the synergistic combinations of the invention allow reduced doses of the individual components, particularly of the neurotransmitter precursors, to be used to achieve the desired effects. The reduced doses decrease side effects caused by the large doses heretofore necessary to achieve the desired effects. Our invention allows appetite suppression, reduction of cravings, improvement of mood, and desirable effects on immune, neural or cognitive function, to be achieved without utilizing pharmaceuticals. Our invention allows these desired effects to be achieved at dosage levels of neurotransmitter precursors that are considered safe by regulatory authorities. Previous attempts to use certain of the components in isolation were either ineffective or required dosages which caused side effects. The decreased dose of tryptophan, for example, allows reduction of carbohydrate craving or anti-depressant effects without safety concerns associated with higher doses or causing feelings of grogginess. The reduced dose of tyrosine allows appetite suppression without the agitation and anxiety induced by amphetamines. The reduced dose of histidine reduces or eliminates potential side effects of histamine.

It is further seen that the combinations of the invention enable the use of naturally occurring substances thereby enhancing their regulatory approval and market acceptance.

Although the description above contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently preferred embodiments of this invention. Various other embodiments and ramifications are possible within it's scope.

Claims

1. A method for promoting synthesis and release of a first neurotransmitter selected from acetylchoUne, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine in an animal subject having a neurotransmitter deficiency responsive to the first neurotransmitter which comprises concomitantly administering orally to the subject at least one precursor for the first neurotransmitter, in a dose that is effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for a second neurotransmitter selected from histamine, glutamine and aspartate that is different than the first neurotransmitter, in a dose effective to enhance release of the first neurotransmitter, and a xanthine, in an amount effective to enhance release of the first neurotransmitter in the subject.

2. A method as in claim 1 and wherein the precursor for the second neurotransmitter comprises histidine or its pharmaceutically acceptable salt, hydrate or adduct.

3. A method as in claim 1 and wherein the xanthine comprises theobromine.

4. A method as in claim 3 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subject.

5. A method as in claim 1 and wherein the xanthine is in the form of cocoa.

6. A method as in claim 1 and wherein the xanthine comprises caffeine.

7. A method as in claim 1 and wherein the first neurotransmitter is acetylchoUne, the precursor for the first neurotransmitter is selected from choline, lecithin and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic acid, glutamine, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

8. A method as in claim 7 and wherein the subject exhibits a reduction in adrenergic tone.

9. A method as in claim 7 and wherein the precursor for the acetylcholine is administered in a dose of from 0.02 to 7 mg. per Kg. body weight of the subject.

10. A method as in claim 7 and wherein the precursors for the first neurotransmitter further comprises a precursor for the acetyl group of acetylcholine selected from pyruvates, carnitine acetyl-L-carnitine and their pharmaceutically acceptable salts, hydrates and adducts.

11. A method as in claim 7 and wherein the xanthine comprises theobromine.

12. A method as in claim 11 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subject.

13. A method as in claim 7 and wherein the xanthine is in the form of cocoa.

14. A method as in claim 7 and wherein the precursor for the second neurotransmitter comprises histidine or its pharmaceutically acceptable salt, hydrate or adduct.

15. A method as in claim 1 and wherein the first neurotransmitter is glutamate, the precursor for the first neurotransmitter is selected from glutamine and glutamic acid and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

16. A method as in claim 15 and wherein the precursor for glutamate is administered in a dose of from 2 to 20 mg. per Kg. body weight of the subject.

17. A method as in claim 15 and wherein the xanthine comprises theobromine.

18. A method as in claim 17 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subject.

19. A method as in claim 15 and wherein the xanthine is in the form of cocoa.

20. A method as in claim 15 and wherein the precursor for the second neurotransmitter comprises histidine administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

21. A method as in claim 1 and wherein the first neurotransmitter is GABA, the precursor for GABA is selected from glutamine and glutamic acid and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

22. A method as in claim 20 and wherein a glutamate suppresser selected from proUne, pharmaceutically acceptable salts and esters thereof and pharmaceutically acceptable water soluble magnesium salts, is concomitantly administered to the subject to maximize the synthesis and release of GABA.

23. A method as in claim 22 and wherein the glutamate suppresser comprises proline administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

24. A method as in claim 20 and wherein the precursor for the second neurotransmitter comprises histidine administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

25. A method as in claim 20 and wherein the xanthine comprises theobromine.

26. A method as in claim 1 and wherein the first neurotransmitter is norepinephrine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic acid, glutamine, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

27. A method as in claim 26 and wherein the precursor for norepinephrine is administered in a dose of from 0.2 to 8 mg. per Kg. body weight of the subject.

28. A method as in claim 26 and wherein the xanthine comprises theobromine.

29. A method as in claim 28 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subject.

30. A method as in claim 26 and wherein the xanthine is in the form of cocoa.

31. A method as in claim 26 and wherein the precursor for the second neurotransmitter comprises histidine administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

32. A method as in claim 1 and wherein the first neurotransmitter is dopamine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from aspartic acid and its pharmaceuticaUy acceptable salts, hydrates and adducts.

33. A method as in claim 32 and wherein the precursor for dopamine is administered in a dose of from 0.2 to 8 mg. per Kg. body weight of the subject.

34. A method as in claim 1 and wherein the first neurotransmitter is Wstamine, the precursor for the first neurotransmitter is selected from histidine and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamic acid, glutamate, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

35. A method as in claim 34 and wherein the precursor for the first neurotransmitter is administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

36. A method as in claim 35 and wherein the xanthine comprises theobromine.

37. A method as in claim 1 and wherein the first neurotransmitter is aspartate, the precursor for the first neurotransmitter is selected from aspartic acid and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic acid, glutamate, and their pharmaceutically acceptable salts, hydrates and adducts.

38. A method as in claim 1 and wherein the first neurotransmitter is serotonin, the precursor for the first neurotransmitter is selected from tyryptophan and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic acid, glutamate, and their pharmaceutically acceptable salts, hydrates and adducts.

39. A method as in claim 38 and wherein the precursor for serotonin is administered in a dose of from 0.05 to 2 mg. per Kg. body weight of the subject.

40. A method as in claim 38 and wherein the xanthine comprises theobromine.

41. A method as in claim 40 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subject.

42. A method as in claim 38 and wherein the xanthine is in the form of cocoa.

43. A method as in claim 38 and wherein the precursor for the second neurotransmitter comprises histidine administered in a dose of between 0.02 to 20 mg. per Kg. body weight of the subject.

44. A method as in claim 38 and wherein the tryptophan is administered in the form of enzyme hydrolyzed protein.

45. A composition for promoting synthesis and release of a first neurotransmitter selected from acetylchoUne, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine in an animal subject, in unit dosage form for oral administration, comprising at least one precursor for the first neurotransmitter in an amount effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for a second neurotransmitter selected from histamine, glutamine and aspartate that is different than the first neurotransmitter and a xanthine in an amount effective to increase neural release of the first neurotransmitter in the subject.

46. A composition as in claim 45 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

47. A composition as in claim 45 and wherein the xanthine comprises caffeine in an amount of between 1 and 200 mg. per dose.

48. A composition as in claim 45 and wherein the precursor for the second neurotransmitter comprises histidine or its pharmaceutically acceptable salt, hydrate or adduct.

49. A composition as in claim 45 and wherein the first neurotransmitter is acetylcholine, the precursor for the first neurotransmitter is selected from choline, lecithin and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic acid, glutamine, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

50. A composition as in claim 49 and wherein the precursor for the acetylcholine comprises an amount of between 1 to 500 mg per dose.

51. A composition as in claim 49 and wherein the precursors for the first neurotransmitter further comprises a precursor for the acetyl group of acetylcholine selected from pyruvates, carnitine acetyl-L-carnitine and their pharmaceutically acceptable salts, hydrates and adducts.

52. A composition as in claim 49 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

53. A composition as in claim 49 and wherein the xanthine is in the form of cocoa.

54. A composition as in claim 49 and wherein the precursors for the second neurotransmitter comprise histidine or its pharmaceutically acceptable salt, hydrate or adduct.

55. A composition as in claim 45 and wherein the first neurotransmitter is glutamate, the precursor for the first neurotransmitter is selected from glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

56. A composition as in claim 55 and wherein the precursor for the glutamine, comprises an amount of between 100 to 1,000 mg per dose.

57. A composition as in claim 55 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

58. A composition as in claim 55 and wherein the xanthine is in the form of cocoa.

59. A composition as in claim 55 and wherein the precursors for the second neurotransmitter comprise histidine or its pharmaceutically acceptable salt, hydrate or adduct.

60. A composition as in claim 45 and wherein the first neurotransmitter is GABA, the precursor for the first neurotransmitter is selected from glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts, the precursors for the second neurotransmitter are selected from histidine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts and the composition further comprises a glutamate inhibitor, selected from proUne, pharmaceutically acceptable salts and esters thereof and pharmaceutically acceptable water soluble magnesium salts.

61. A composition as in claim 60 and wherein the glutamate inhibitor is proUne in the dosage amount of between 1 and 1,000 mg.

62. A composition as in daim 60 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

63. A composition as in claim 60 and wherein the xanthine is in the form of cocoa.

64. A composition as in claim 60 and wherein the precursor for GABA, comprises an amount of between 100 to 1,000 mg per dose.

65. A composition as in claim 45 and wherein the first neurotransmitter is norepinephrine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are seleded from histidine, glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts

66. A composition as in claim 65 and wherein the precursor for norepinephrine, comprises an amount of between 10 mg. to 3 grams per dose.

67. A composition as in claim 65 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

68. A composition as in claim 65 and wherein the xanthine is in the form of cocoa.

69. A composition as in claim 65 and wherein the precursors for the second neurotransmitter comprise histidine or its pharmaceutically acceptable salt, hydrate or adduct.

70. A composition as in claim 45 and wherein the first neurotransmitter is dopamine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from aspartic add and its pharmaceuticaUy acceptable salts, hydrates and adducts.

71. A composition as in claim 45 and wherein the first neurotransmitter is aspartate, the precursor for the first neurotransmitter is selected from aspartic add and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts.

72. A composition as in claim 45 and wherein the first neurotransmitter is histamine, the precursor for the first neurotransmitter is selected from histidine and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

73. A composition as in claim 72 and wherein the xanthine comprises theobromine.

74. A composition as in claim 72 and wherein the xanthine is in the form of cocoa.

75. A composition as in claim 45 and wherein the first neurotransmitter is serotonin, the precursor for the first neurotransmitter is selected from tryptophan and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from, histidine, glutamic add, glutamine, aspartic add and their pharmaceuticaUy acceptable salts, hydrates and adducts.

76. A composition as in claim 75 and wherein the precursor for serotonin, comprises an amount of between 1 mg. to 100 mg. per dose.

77. A composition as in claim 75 and wherein the precursors for the second neurotransmitter comprise histidine or its pharmaceutically acceptable salt, hydrate or adduct.

78. A composition as in claim 75 and wherein the tryptophan is present in the form of enzyme hydrolyzed protein.

79. A method for promoting synthesis and release of the neurotransmitter acetylchoUne in an animal which comprises concomitantly administering orally to the subject at least one precursor for acetylcholine, in a dose that is effective to enhance synthesis of acetylchoUne in the subjed, at least one precursor for a second neurotransmitter selected from histamine, glutamine and aspartate, in a dose effedive to enhance release of the acetylcholine, and a xanthine, in an amount effective to enhance release of the acetylchoUne in the subject.

80. A method as in claim 79 and wherein the precursor for the acetylchoUne is administered in a dose of from 0.02 to 7 mg. per Kg. body weight of the subjed.

81. A method as in claim 79 and wherein the precursor for the second neurotransmitter comprises histidine or its pharmaceutically acceptable salt, hydrate or adduct.

82. A method as in claim 79 and wherein the xanthine comprises theobromine.

AMENDED CLAIMS

[received by the International Bureau on 25 January 1999 (25.01.99); original claims 1, 10, 32, 34, 37, 38, 45, 51, 56, 70 and 79, amended; remaining claims unchanged ( 8 pages )]

1. A method for promoting synthesis and release of a first neurotransmitter selected from acetylcholine, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine in an animal subject having a neurotransmitter deficiency responsive to the first neurotransmitter which comprises concomitantly administering orally to the subject at least one precursor for the first neurotransmitter, in a dose that is effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for a second neurotransmitter selected from histamine, glutamate and aspartate that is different than the first neurotransmitter, in a dose effective to enhance release of the first neurotransmitter, and a xanthine, in an amount effedive to enhance release of the first neurotransmitter in the subject.

3. A method as in claim 1 and wherein the xanthine comprises theobromine.

5. A method as in claim 1 and wherein the xanthine is in the form of cocoa.

6. A method as in claim 1 and wherein the xanthine comprises caffeine.

7. A method as in claim 1 and wherein the first neurotransmitter is acetylchoUne, the precursor for the first neurotransmitter is selected from choline, lecithin and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adduds.

10. A method as in claim 7 and wherein the precursors for the first neurotransmitter further comprises a precursor for the acetyl group of acetylcholine selected from pyruvates, carnitine, acetyl-L-carnitine and their pharmaceuticaUy acceptable salts, hydrates and adducts.

11. A method as in claim 7 and wherein the xanthine comprises theobromine.

12. A method as in daim 11 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subjed.

13. A method as in claim 7 and wherein the xanthine is in the form of cocoa.

15. A method as in claim 1 and wherein the first neurotransmitter is glutamate, the precursor for the first neurotransmitter is selected from glutamine and glutamic acid and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

17. A method as in claim 15 and wherein the xanthine comprises theobromine. Jo

aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

28. A method as in claim 26 and wherein the xanthine comprises theobromine.

30. A method as in claim 26 and wherein the xanthine is in the form of cocoa.

32. A method as in claim 1 and wherein the first neurotransmitter is dopamine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamine, glutamine add, aspartic acid and their pharmaceutically acceptable salts, hydrates and adducts.

34. A method as in claim 1 and wherein the first neurotransmitter is histamine, the precursor for the first neurotransmitter is selected from histidine and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

36. A method as in claim 35 and wherein the xanthine comprises theobromine.

37. A method as in claim 1 and wherein the first neurotransmitter is aspartate, the precursor for the first neurotransmitter is selected from aspartic add and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine, and their pharmaceutically acceptable salts, hydrates and adducts.

38. A method as in claim 1 and wherein the first neurotransmitter is serotonin, the precursor for the first neurotransmitter is selected from tryptophan and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine, and their pharmaceutically acceptable salts, hydrates and adducts.

40. A method as in claim 38 and wherein the xanthine comprises theobromine.

41. A method as in claim 40 and wherein the theobromine administered is in a dose of between from about 0.02 to 40 mg./Kg. body weight of the subjed.

42. A method as in claim 38 and wherein the xanthine is in the form of cocoa.

45. A composition for promoting synthesis and release of a first neurotransmitter selected from acetylchoUne, GABA, glutamate, aspartate, serotonin, norepinephrine, histamine and dopamine in an animal subject, in unit dosage form for oral administration, comprising at least one precursor for the first neurotransmitter in an amount effective to enhance synthesis of the first neurotransmitter in the subject, at least one precursor for a second neurotransmitter selected from histamine, glutamate and aspartate that is different than the first neurotransmitter and a xanthine in an amount effective to increase neural release of the first neurotransmitter in the subject.

49. A composition as in claim 45 and wherein the first neurotransmitter is acetylcholine, the precursor for the first neurotransmitter is selected from choline, lecithin and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

51. A composition as in claim 49 and wherein the precursors for the first neurotransmitter further comprises a precursor for the acetyl group of acetylcholine selected from pyruvates, carnitine, acetyl-L-carnitine and their pharmaceutically acceptable salts, hydrates and adducts.

55. A composition as in claim 45 and wherein the first neurotransmitter is glutamate, the precursor for the first neurotransmitter is selected from glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from histidine, aspartic add and their pharmaceutically acceptable salts, hydrates and adduds.

56. A composition as in claim 55 and wherein the precursor for the glutamate, comprises an amount of between 100 to 1,000 mg per dose.

60. A composition as in claim 45 and wherein the first neurotransmitter is GABA, the precursor for the first neurotransmitter is selected from glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts, the precursors for the second neurotransmitter are selected from histidine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts and the composition further comprises a glutamate inhibitor, selected from proline, pharmaceutically acceptable salts and esters thereof and pharmaceutically acceptable water soluble magnesium salts.

61. A composition as in claim 60 and wherein the glutamate inhibitor is proline in the dosage amount of between 1 and 1,000 mg.

62. A composition as in claim 60 and wherein the xanthine comprises theobromine in an amount of between 1 and 2,000 mg. per dose.

65. A composition as in claim 45 and wherein the first neurotransmitter is norepinephrine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are seleded from histidine, glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adduds

70. A composition as in claim 45 and wherein the first neurotransmitter is dopamine, the precursor for the first neurotransmitter is selected from tyrosine, phenylalanine and their pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamine, glutamic add, aspartic add and its pharmaceutically acceptable salts, hydrates and adducts.

71. A composition as in claim 45 and wherein the first neurotransmitter is aspartate, the precursor for the first neurotransmitter is selected from aspartic add and its pharmaceutically acceptable salts, hydrates and adduds and the precursors for the second neurotransmitter are selected from histidine, glutamic add, glutamine and their pharmaceutically acceptable salts, hydrates and adducts.

72. A composition as in claim 45 and wherein the first neurotransmitter is histamine, the precursor for the first neurotransmitter is selected from histidine and its pharmaceutically acceptable salts, hydrates and adducts and the precursors for the second neurotransmitter are selected from glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adduds.

75. A composition as in claim 45 and wherein the first neurotransmitter is serotonin, the precursor for the first neurotransmitter is selected from tryptophan and its pharmaceutically acceptable salts, hydrates and adduds and the precursors for the second neurotransmitter are selected from, histidine, glutamic add, glutamine, aspartic add and their pharmaceutically acceptable salts, hydrates and adducts.

79. A method for promoting synthesis and release of the neurotransmitter acetylchoUne in an animal which comprises concomitantly administering orally to the subject at least one precursor for acetylcholine, in a dose that is effective to enhance synthesis of acetylchoUne in the subject, at least one precursor for a second neurotransmitter selected from histamine, glutamate and aspartate, in a