WO2000033831A1 - Combinations of st. john's wort and fatty acids - Google Patents

Abstract

This invention provides therapeutic compositions for the treatment or prevention of mental disturbances such as depressive states and for regulating the level of certain neurotransmitters and thereby improving the function of the central nervous system and cognitive function in humans and other animals. The therapeutic compositions comprise an extract of St. John's Wort, preferably one comprising approximately 2 % or more hyperforin, combined with one or more fatty acids, preferably polyunsaturated fatty acids and most preferably omega-3 fatty acids, whether naturally, synthetically, or semi-synthetically derived. The invention also provides a method of administering these compositions to humans or animals in need thereof.

Description

COMBINATIONS OF ST. JOHN'S WORT AND FATTY ACIDS

In connection with this application, priority is claimed to the following provisional application: ST. JOHN'S WORT EXTRACT (CONTAINING 5% HYPERFORIN) IN SUSPENSION OF OMEGA-3 POLYUNSATURATED FATTY ACIDS, U.S. Serial No. 60/111,619, filed December 8, 1998.

Field of the Invention

The present invention relates to the field of neurohormonal, cognitive and antidepressive therapy. More particularly, the invention pertains to combinations of an extract of St. John's Wort and fatty acids, particularly polyunsaturated fatty acids ("PUFAs"), whether naturally, synthetically, or semi-synthetically derived, for use in such therapy and for use in stabilizing moods. These ingredients have been shown to have anti-depressant properties and to lack significant side-effects. Background of the Invention

In the mammalian nervous system, nerve impulses are carried across synapses by chemical mediators called neurotransmitters. These compounds are synthesized and stored in the neuron itself, and released intυ he synaptic cleft. After binding to the post- synaptic neuron, the neurotransmitter is rapidly destroyed or removed, thus terminating its effect. By controlling the synthesis, storage, release, and destruction of neurotransmitters, the body is normally able to control nervous system function. Conversely, derangements in neurotransmitter function cause abnormalities in the functioning of the nervous system. Defective neurotransmission can result from problems with axonal transport, neuronal membrane permeability, lack of precursor substances, or with biosynthesis, release, or inactivation of neurotransmitters. The causes of such derangements of normal neural physiology are as yet incompletely understood. Guyton, A. and Hall, J., Textbook of Medical Physiology, 9^th ed., WB Saunders, pp. 565- 82 (1996). It is becoming increasingly clear, however, that the manipulation of neuronal processes can serve as a tool for controlling nervous system function.

Disturbances of mood are increasingly common in western civilization. Although these disturbances have previously been regarded as a sign of "weakness," science is now aware that these disorders are indeed caused by imbalances in the functions of neurons and the neurotransmitters that they synthesize. At present, several classes of pharmaceuticals are used to treat depression. Serotonin is sometimes called the "feelgood" neurotransmitter: levels of serotonin correlate closely with mood. Increasing serotonin levels in the synaptic cleft results in mood elevation. The selective serotonin reuptake inhibitor pharmaceuticals ("SSRIs") slow down the process by which serotonin is inactivated (FIG. 1), and thereby increase the level of serotonin within the synaptic cleft. The monoamine oxidase inhibitors ("MOA inhibitors") inhibit one of the two steps in the enzymatic catabolism of serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) (FIG. 1). Several forms of depression and other CNS diseases (e.g., Parkinson's disease) have been associated with low levels of these neurotransmitters. This inhibition results in an increased level of these neurotransmitters within the synaptic cleft.

Although the SSRIs and the MOA inhibitors have proved of great benefit in the treatment of mental disturbances, both have side effects that preclude their use by some individuals. Side effects commonly seen include anxiety, insomnia, allergic reactions [fluoxetine HC1 (tradename, "Prozac®")], and autonomic nervous system disorders including impotence, somnolence, diarrhea, and nausea [sertraline HC1 (tradename, "Zoloft®")]. Physicians Desk Reference, Medical Economics Co., Inc., Montvale, N.J., , pp. 924-28, 2443-48 (1999). St. John's Wort has been used historically to treat depression. More recently, numerous scientific studies have shown its efficacy is dependent on its hyperforin content. When administered alone, St. John's Wort extract has only a mild to moderate effect on depression, crosses the blood-brain barrier poorly, and has variable effects dependent on hyperforin content. In separate lines of research, fatty acids, particularly omega-3 fatty acids, have been shown to have anti-depressant properties by virtue of their effects on lipid cell membranes and enhancement of serotonergic channels. Fatty acids serve several important biological functions. They are structural components of cell membranes, are used for storage and transport of metabolic fuel, and act as cell-surface components for cell recognition. As such, they modulate transfer of numerous other chemicals into the brain and movement across synaptic membranes. (Leninger, A., Biochemistry, Worth Pub., p. 279 (1978)). Research has demonstrated low levels of omega-3 fractions of fatty acids in depressed patients. (Mais, M., et al., "Fatty Acid Composition in Major Depression, " J. Affect. Disord., Vol 38, pp. 35-46 (Apr. 25, 1996)). Rrecent studies have shown that polyunsaturated fatty acids ("PUFAs") carry neurotransmitters across the blood-brain barrier. The most active PUFA studied was decosahexanoic acid ("DHA"). Shashoua, V., Hesse, G., "N-Docosahexaenocyl, 3-Hydroxtyramine, a Dopaminergic Compound that Penetrates the Blood-Brain Barrier..., " Life Sci., Vol. 58, No. 16, pp. 1347-57 (1996). Patients given supplements of omega-3 fatty acids showed improvement in depression and mood liability scores while on the supplement, with no adverse side affects. Stoll, A. et al., "Omega-3 Fatty Acids fn Bipolar Disorder" Arch. Gen. Psychiatry, Vol. 56, pp. 407-12 (1999).

There exists a need in the art for a composition that will significantly enhance the beneficial effects of St. John's Wort on the nervous system of man and animals.

Enhancing the beneficial effects of St. John's Wort will have the added benefit of permitting a decrease in dose and thereby in any associated adverse side effects. Summary of the Invention

It is a primary object of the invention to provide therapeutic and prophylactic compositions that will increase levels of dopamine and serotonin in those individuals suffering from a deficiency of these neurotransmitters, and also improve neuronal cell membrane fluidity, thus enhancing receptor/ligand binding.

It is a further object of the present invention to provide such compositions which result in a low incidence of adverse side effects. It is a still further object of the present invention to provide a method of regulating and/or improving the levels and function of certain neurotransmitters by administering the compositions of the present invention to humans or other animals in need thereof.

The present invention provides novel compositions and methods for regulating the level of certain neurotransmitters and thereby improving the function of the central nervous system in humans or other animals in need thereof. The compositions of the invention comprise an extract of St. John's Wort and one or more fatty acids, preferably one or more polyunsaturated fatty acids. In a preferred embodiment, the St. John's Wort component has a hyperforin content of approximately 2% or greater. In another preferred embodiment, at least one of the polyunsaturated fatty acids is an omega-3 fatty acid. St. John's Wort (Hypericum perforatum) ("SJW") is an herbaceous plant native to Europe and North America. The plant contains several pharmacologically active compounds including hyperforin. The exact mechanism of action of SJW is not clear, but infusions of the herb have been documented to inhibit catechol-o-methyl-transferase ("COMT"), and monoamine oxidase ("MAO") types A and B. These enzymes normally catabolize the catecholamines, including dopamine, serotonin, epinephrine, and norepinephrine. Blocking COMT and MAO A and B results in increased levels of serotonin and other catecholamines. St. John's Wort and hyperforin fraction extracts of this herb inhibit MAO and COMT, therefore slowing the rate of breakdown of serotonin, the "feel good" neurotransmitter. This action is advantageous in almost all neurologic conditions because elevation of mood and reduction of perceived stress have beneficial effects on all body systems. In particular, St. John's Wort is indicated in affective disorders, such as depressive states. Its mechanism is similar to that of commonly prescribed MAO-inhibiting pharmaceuticals. Additionally, SJW blocks the re-uptake of serotonin in the synaptic cleft, thus prolonging its effect. In this effect, SJW appears to duplicate the effects of SSRIs. Additionally, SJW may also affect the metabolism of other neurotransmitters such as dopamine, GAB A A and GABAB. Numerous studies have documented the positive effect of SJW extracts on CNS function. Wincor, M. and Gutierrez, M., St. John 's Wort and the Treatment of Depressions, Pharmacist, p. 88 (August 1997); Cicero, L., et al., Can Depression Patients Be Treated with Worts?, Drug

Topics, p. 24 (September 1997); Tyler, V., The Honest Herbal, HaWorth Press, Inc., New York, p. 275 (1993); Raffa, R., Screen of Receptor and Uptake-Site Activity ofHypericin Component of St. John 's Wort Reveals Sigma Receptor Binding, Life Sci. Vol. 62 No.16, pp. PL265-70 (1998); Cott, J., In Vitro Receptor Binding and Enzyme Inhibition by Hypericum Perforatum Extract, Pharmacopsychiatry, Vol. 30 No. 2, pp. 108-12 (1997); Duke, J., et al., Western Herbal Medicine: Traditional Materia Medica, Complementary and Alternative Veterinary Medicine, Schoen, A., Wynn, S., eds., Mosby, St. Louis, Mo., pp. 329, 357 (1998). It was previously believed that hypericin was the key active ingredient in St. John's Wort extract. Recent research, however, has shown that hyperforin is the key active ingredient and has elucidated the function and importance of hyperforin content in alleviating symptoms of depression. Hyperforin has been shown to be the major active ingredient which inhibits the reuptake of serotonin, dopamine and norepinephrine. (Muller, W., et al.," Pharmacopsychiatry, Vol. 31, pp. 16-21 (June 1998). Hyperforin has biochemical actions similar to conventional antidepressants such as tricyclics and selective serotonin reuptake inhibitors. The amount of reuptake inhibition is correlated with the hyperforin content. In the Muller study cited above, the amount of reuptake inhibition affected all three systems with similar potency, a phenomenon not reported for any other known antidepressant drugs. Hyperforin, in a dose-related fashion, inhibits the synaptosomal uptake of GAB A as well, making it a unique "broad-band" reuptake inhibitor.

The role of hyperforin has been further elucidated by Laakmann, et al., "St. John's Wort in Mild to Moderate Depression: The Relevance of Hyperforin for the Clinical Efficacy, " Pharmacopsychiatry Vol 31, pp. 54-59 (June 1998). This randomized human clinical trial showed that therapeutic effects of St. John's Wort depended on hyperforin content. Patients receiving extracts of 5% hyperforin (the highest dose tested) had the greatest reduction in depression scale ratings. No adverse reactions occurred which did not also occur in the placebo group. Hyperforin has thus been shown in biochemical and clinical trials to be both effective and safe.

In a preferred embodiment, the St. John's Wort extract of the present invention contains hyperforin in quantities of approximately 2% or greater (e.g., standardized extract LI 160 or WS 5572). Most preferably, a total of 100 mg or greater of St. John's

Wort extract having a hyperforin content of 2% or greater should be given per dose two to three times daily to adult human patients. Other dose ranges are set forth below.

Long-chain fatty acids serve a number of functions in the body. One such function is regulation of cell membrane permeability. Depressed patients have been shown to have low levels of PUFAs in cell membranes. Administration of an omega-3 fatty acid, such as docosahexaenoic acid ("DHA"), can increase membrane fluidity. Several studies have documented increased permeability of neurotransmitters through membranes with supplements of omega-3 fatty acids. In addition, as discussed in the Background of the Invention, polyunsaturated fatty acids such as DHA have been shown to act as "carriers" for many molecules including neurotransmitters. PUFAs act not only as carriers across the blood-brain barrier but have preferential deposition into the cortex and hippocamus. Heron, D., et al., "Lipid Fluidity Markedly Modulates the Binding of Serotonin to Mouse Brain Membranes, " Proc. Natl. Acad. Sci USA, Vol. 77, pp. 7463- 719 (1980). Thus, PUFAs bound to neurotransmitters preferentially deposit these substances in the areas of the brain where they can be most beneficial. Omega-3 fatty acids also suppress the formation of superoxides. SJW is degraded by superoxide anions in human plasma. Increasing omega-3 fatty acids would therefore be expected to prolong the half-life of St. John's Wort. Chen, L., et al., "Reduction in Human eutrophil

-1- Superoxide Anion Generation by N-3 Polyunsaturated Fatty Acids, " Thromb. Res., Vol. 7694, pp. 317-22 (Nov. 15, 1994).

The preferred fatty acid class is polyunsaturated fatty acids with carbon chain lengths of 12-24. These include lauric acid (C12:0), myriatic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:2), stearic acid (C18:0), oleic acid (C18:l), vacconic acid

(C18: l-7), linolenic acid (C18:2-6), alpha linolenic acid (C18:3-3), eleostearic acid (C18:3-5), beta-linolenic acid (C18:3-6), gondoic acid (C18:4-3, C20:l), dihomo-y- linolenic acid (C20:3-6), arachidonic acid (C20:4-3, C20:4-6), eicosapentainoic acid (C20:5-3), docosenoic acid (C22;l), docosatetraenoic acid (C22:4-l), docosapentaenoic acid (C22:5-6), docosahexacnoic acid (C22:6-3) and nervonic acid (C24:l-9).

Highly preferred PUFAs are those with carbon chain lengths between 18 and 24, with the most preferred fatty acid being docosahexaenoic acid (sometimes spelled docosahexanoic acid or DHA) with a carbon chain length of 22.

These preferred fatty acids will be included in compositions of the present invention as distillates or part of their synthetic, plant or animal source. They may be included in the compositions of the present invention either individually or in mixtures with themselves or other fatty acids. In a preferred embodiment the PUFAs will be a commercially available product derived from animal or plant sources. Most preferably these fatty acids are derived from or contained in fish oils, flaxseed oil, dinoflagellates or algae. For an adult human, the preferred daily dose would contain at least 100 mg of a

PUFA, most preferentially of the major essential fatty acid docosahexaenoic acid. The preferred administration would be a twice or three times a day dose (i.e., 500 mg of fish oil containing 10% DHA given twice daily). It is expected that the combinations of the present invention will work synergistically because they have different, but complementary, mechanisms of action. In the brain, SJW alleviates depression by maintaining higher levels of the neurotransmitters dopamine, seratonin and norepinepherine at the synaptic site. The beneficial effects of such an increase would be multiplied if membrane fluidity were also increased, thereby facilitating interactions between the neurotransmitter and the receptor neuron. By increasing transport of neurotransmitters across the blood/brain barrier, fatty acids enhance the effect of SJW. Fatty acids also preferentially increase the levels of these neurotransmitters in the cortex and hippocampus, which are areas of the brain in which SJW is l iown to be the most active. Changes in electroencepholographic patterns consistent with a relaxant affect and improved cognitive function have been shown to predominantly affect the cerebral cortex in humans. Schulz, H., Jobert, M., "Effects of Hypericum Extracts on the Sleep EEG In Older Volunteers, " J. Geriatr. Psychiatry Neurol., Vol. 7 (Supp. 1) pp. S39-43 (1994) and Johnson, D., et al, "Effects of Hypericum Extract LI 160 Compared with Maprotiline on Resting EEG and Evoked

Potentials in 24 Volunteers, " J. Geriatr. Psychiatry Neurol. Vol. 7 (Supp. 1) pp. S44-46 (1994).

Somatodendritic autoreceptors are prevalent in the hippocampus and striatum and are known to be important pathways for the regulation of moods. Neuropharmacology studies have shown St. John's Wort extract to be particularly influential in these areas.

Bennett, D., et al., "Neuropharmacology of St. John 's Wort (Hypericum), " Annals of Pharmacotherapy, Vol. 32, pp. 1201-07 (Nov. 1998) and Dinpfel, W., et al., "Effects of a Methanolic Extract and a Hyperforin-enriched CO₂ Extract of St. John's Wort (Hypericum perforatum) on Intracerebral Field Potentials in the Freely Moving Rat, " Pharmacopsych. Supp., Vol. 31, pp. 30-35 (June 1998). Further, by suppressing the formation of superoxides which degrade S W, fatty acids prolong the half-life and thereby increase the levels of SJW. The claimed compositions thus not only combine the individual anti-depressant effects of the St. John's Wort extract and fatty acids, but allow for improved anti-depressant effects of St. John's Wort by extending its half-life and by increasing the bioavailability of neurotransmitters through fatty acids' effects on lipid membranes in the brain.

Such synergy also enables the reduction of dosage levels for each compound. This reduction in dose correspondingly would reduce the potential for adverse side effects. The compounds included in the composition of the present invention have wide margins of safety and low incidences of side effects in any case, although overdoses of St. John's Wort have caused cases of photosensitization in humans and animals. At therapeutic levels, however, the incidence of side effects associated with these compounds is very low and certainly less than that of the prior art pharmaceuticals discussed above, such as the SSRIs. By combining compounds and therefore lowering necessary doses, the risk of side effects is even further reduced.

The compositions of the present invention can be administered by a variety of routes including, but not limited to: orally, intranasally, transdermally, sublingually, intravenously, intramuscularly, rectally, and subcutaneously. The preferred method contemplated for administration would be a capsule form (particularly liquid-filled capsules or gelcaps) administered three times a day. Preferred daily doses for each of the compounds are as follows: Hypeforin (Doses based on 100% pure hyperforin extract) Total dose range: 0.25 - 2000 mg Preferred small animal dose range: 0.25 - 50 mg Preferred human dose range: 2.5 - 250 mg Preferred large animal dose range: 2.5 - 2000 mg

For a St. John's Wort extract containing 50% hyperforin, these dose ranges would be doubled (e.g., the total dose range would be 0.5 - 4000 mg, the preferred small animal dose would be 0.5 - 100 mg, etc.) For a standard St. John's Wort Extract containing 5% hyperforin, the dose ranges would be as follows:

Total dose range: 5 mg - 40 g

Preferred small animal dose range: 5 - 1000 mg

Preferred human dose range: 50 - 5000 mg

Preferred large animal dose range: 50 mg - 40 g Doses of St. John's Wort extract containing 2% hyperforin would be correspondingly greater:

Total dose range: 12.5 mg - 100 g

Preferred small animal dose range: 12.5 - 2500 mg

Preferred human dose range: 125 - 12500 mg Preferred large animal dose range: 125 mg - 100 g

Fatty acids (example: DHA) (Doses are based on 100% pure DHA) Total dose range: 2.5 - 2500 mg Preferred small animal dose range: 2.5 - 250 mg Preferred human dose range: 5 - 2000 mg

Preferred large animal dose range: 250 - 2500 mg

In keeping with accepted pharmaceutical practices and with techniques well known in the art, other ingredients may also be added as excipients, dispersing agents, diluents, suspension agents, preservatives, antioxidants, humectants, releasing agents, flavoring agents, etc. Solely by way of example, and without limiting in any respect the disclosure of the invention, the compositions of the present invention can include: diluents or excipients, such as calcium carbonate, lactose, gelatins, alginates, including sodium alginate, micro crystalline cellulose, and carboxymethylcellulose; suspensions or dispersing agents, such as liquid paraffin, vegetable oil, propylene glycol, lecithin, and polyethylene glycol; sustained release agents, such as glycerol monostearate and glycerol distearate; and preservatives or antioxidants, such as ascorbic acid, sodium benzoate, citric acid, Coenzyme Q10, tocopherols, such as dl-alpha-tocopherol acetate and d-alpha- tocopherol, n-propyl p-hydroxybenzoate and antioxidant/flavoring oils, including but not limited to rosemary and sage. A person of ordinary skill in the art will understand that other suitable substances may be used in the compositions of the present invention as well.

The composition of the present invention may be made by a number of standard extraction and mixing methods, as will be understood by a person of ordinary skill in the art. In a preferred embodiment, lipophillic extracts of St. John's Wort would be combined with omega-3 fatty acid oils using a common mixing apparatus, such as a standard blender. Alternatively, St. John's Wort extract could be combined with omega-3 fatty acids during the extraction process using an omega-3 impregnated silica gel to perform the extraction and following a standard extraction method. Although a number of methods may be used in making the compositions of the present invention, a the following standardized extraction method is provided by way of example:

1. Extraction of deep frozen blossoms of Hypericum perforatum. L. plant material (-20 degrees Celsius) with n-hexane by means of an Ultra Turrax;

Separation of lipophilic substances on a silica gel column; 3. Purification of the relevant fraction by preparative high performance liquid chromatography (HPLC);

4. Evaporation of the mobile place under reduced pressure;

5. Removal of the remaining water by freeze-drying; and

6. Storage of resultant hypericum, at -20 degrees Celsius under nitrogen.

Results from this process produce an extract having 99.9% pure hyperforin. Orth, H., et al., "Isolation, Purity Analysis and Stability of Hyperforin as a Standard Material from Hypericum Perforatum L., " J. Pharm. Pharmacol., Col. 51, No. 2, pp. 193-200 (Feb. 1999). The purified hyperforin product is unstable in the presence of oxygen and heat and is therefore difficult to manufacture and store. In an alternative preparation, step 2 of the method disclosed above would be modified such that the silica gel column would be impregnated with a polyunsaturated fatty acid (or combination of PUFAs) and removed with the relevant (lipophilic) fraction using combined data for HPLC separation. A second alternative preparation would use commercially available hydrophilic extracts of hyperforin in a suspension of PUFAs. The compositions of the present invention will be more clearly perceived and better understood from the following specific examples which are intended to provide examples of the preferred embodiments and do not limit the present invention. Moreover, as stated above, the preferred components described in these examples may be replaced by or supplemented with the any of the components of the compositions of the invention described above. EXAMPLE 1 A 37 year old white male is seen in his doctor's office for symptoms of clinical depression. He is experiencing problems with low moods, lack of concentration, inability to enjoy events he previously found fun, as well as poor sleep patterns and lack of appetite.

He describes his poor moods as being related to fears over losing his job and poor relations with his wife. He is tried on Prozac® and later Zoloft®. Both drugs fail to improve his symptoms. His depression worsens while on these medicines due to side effects of nausea and sexual dysfunction. The patient is placed on a combination of St. John's Wort extract and omega-3 fatty acids. The St. John's Wort extract is given at a twice daily dose of 300 mg of a 5% hyperforin extract and is combined with 200 mg of a 90% pure cis-DH A product obtained from menhaden fish oil. His sexual function improved and his nausea resolved. He noticed improvement in his symptoms of depression and within four weeks. No side effects were experienced.

EXAMPLE 2 A veterinarian diagnoses socially inappropriate elimination in a two year old female cat that is urinating on the beds and couches of its owner's home. The urination pattern begins after the cat is cared for by a housesitter who stays in the cat owner's house with the sitter's dog. Socially inappropriate elimination is caused by mental conflict and anxiety and has been associated with decreased serotonin levels. The animal is given a daily dose of the following: 25 mg of St. John's Wort extract containing 5% hyperforin and 100 mg of 10% DHA fish oil extract. The cat takes the composition willingly due to the fish oil taste. After two weeks, the inappropriately low levels of serotonin are corrected, the anxiety is improved and the inappropriate urination stops.

Many modifications may be made without departing from the basic spirit of the present invention. Accordingly, it will be appreciated by those skilled in the art that within the scope of the appended claims, the invention may be practiced other than has been specifically described herein. Hence, the attached claims are intended to cover the invention embodied in the claims and substantial equivalents thereto.

Claims

I claim:

1. A composition comprising John's Wort (Hypericum perforatum) extract and one or more fatty acids.

2. The composition of Claim 1 in which one of the fatty acids is a polyunsaturated fatty acid.

3. The composition of Claim 1 in which one of the fatty acids is selected from the group consisting of polyunsaturated fatty acids having carbon chains comprising from 12 to 24 carbons.

4. The composition of Claim 1 in which one of the fatty acids is an omega-3 fatty acid.

5. The composition of Claim 2 in which the fatty acid is selected from the group consisting of arachidonic acid, docosahexaenoic acid, nervonic acid and eicosapentanoic acid.

6. The composition of Claim 1 in which the daily dose of fatty acids for humans or animals ranges from 2.5 milligrams to 2500 milligrams.

7. The composition of Claim 1 in which the St. John's Wort extract contains at least approximately 2% hyperforin by percent of weight.

8. The composition of Claim 7 in which the daily dose of St. John's Wort extract for humans or animals ranges from 12.5 milligrams to 100 grams.

9. The composition of Claim 7 in which the daily dose of hypeforin for humans or animals ranges from 0.25 milligrams to 2000 milligrams.

10. A method comprising the step of administering the composition of Claim 1 to a human or other animal.

1 1. A method of regulating the neurotransmitters of a human or other animal comprising the step of administering therapeutically or prophylactically effective amounts of the composition of Claim 1.

12. A method of normalizing or improving the function of the central nervous system of a human or other animal comprising the step of administering a therapeutically or prophylactically effective amount of the composition of Claim 1.

13. The method of Claim 10 in which the composition is administered orally, intranasally, transdermally, sublingually, intravenously, intramuscularly, rectally, or subcutaneously.

14. The method of Claim 11 in which the composition is administered orally, intranasally, transdermally, sublingually, intravenously, intramuscularly, rectally, or subcutaneously.

15. The method of Claim 12 in which the composition is administered orally, intranasally, transdermally, sublingually, intravenously, intramuscularly, rectally, or subcutaneously.