Compositions and methods for modulating stress and uses thereof

Abstract

Disclosed herein are compositions and methods for treating, preventing, alleviating, regulating or improving the harmful effects of stress, stress symptoms, or chronic stress by providing compositions and carriers.The methods can include, for example, administering the therapeutically effective compound of plant extract.The compositions and methods can regulate mGlu2 and / or mGlu3 receptors.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 508,827, filed June 16, 2023, and U.S. Provisional Patent Application No. 63 / 489,625, filed March 10, 2023, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present disclosure relates to compounds and compositions for modulating stress, and methods of using them. More particularly, the present disclosure relates to compositions and methods for modulating stress by administering an effective amount of the composition and a carrier. [Background technology]

[0003] Chronic stress puts health at risk. Long-term activation of the stress response system and the resulting excessive exposure to cortisol and other stress hormones can disrupt nearly every human biological process. This can increase the body's risk for a variety of physical and mental health problems, including anxiety, depression, digestive problems, headaches, muscle tension and pain, heart disease, high blood pressure, stroke, sleep disorders, weight gain, cancer, and impaired memory and concentration. Chronic stress also suppresses the body's immune system, making recovery from illness more difficult. Furthermore, it is estimated that 60% to 80% of primary care physician visits are stress-related, yet only 3% of patients receive help with stress management.

[0004] There are three main approaches to treating chronic stress: psychotherapy, lifestyle modification, and therapeutic intervention. Psychotherapy and lifestyle modification can be effective in minimizing chronic stress and its symptoms, but both require significant time and effort. Therapeutic interventions often involve anti-anxiety and antidepressant medications, including SSRIs (selective serotonin reuptake inhibitors), CNS depressants, buspars, and beta-blockers. Unfortunately, however, most therapeutic solutions and combinations are ineffective for many patients. Furthermore, most currently approved medications require weeks to months of daily administration for maximal benefit, placing significant personal, psychosocial, and occupational burdens on affected individuals and the healthcare system.

[0005] Furthermore, most therapeutic solutions are not suitable for routine consumption for nutritional intervention or prevention. Traditional herbal remedies, including dietary supplements, are marketed as stress relief aids. Some examples include kava, passion flower, valerian, chamomile, lavender, and lemon balm. These products are unregulated, and purity of ingredients and clinical response can vary. Evidence supporting these herbal remedies is lacking.

[0006] Clearly, there remains an unmet need to develop fast-acting, safe nutritional interventions for the amelioration of stress and stress-related conditions. Summary of the Invention

[0007] Some embodiments of the present disclosure relate to an oral composition for treating, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress. The oral composition includes a therapeutically effective amount of a plant extract and one or more carriers or excipients, wherein the therapeutically effective amount of the plant extract is capable of treating, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress. In some embodiments, the plant extract is selected from the group consisting of rhubarb (Rheum officinale), Phyllanthus emblica, apple (Malus domestica), Tripterygium wilfordii, Aloe barbadensis, cacao (Theobroma cacao), quince (Chaenomeles sinensis), St. John's wort (Hypericum perforatum), Citrus unshiu, lotus (Nelumbo nucifera), Acacia luederitzii, Cassia abbreviate, Cassia fistula, mopane (Colophospermum mopane), Julbernardia globiflora, and the like. globiflora, Habranthus brachyandrus, Monactis macbridei, Arnica acaulis, Arnica montana, Daucus carota, Bauhinia manca, Botrytis cinerea, Brosimum acutifolium, Broussonetia kazinoki, Broussonetia papyrifera, Dalbergia latifolia, Dracaena cambodiana, Dragon's tree, Narcissus pseudonarcissus pseudonarcissus, Phanera guianensis, Rohdea chinensis, Soymida febrifuga, Pacific yew (Taxus brevifolia), Tupistra chinensischinensis, Abri herba, Abrus pulchellus subsp. Cantoniensis, Achyranthes bidentata, Aconitum seravschanicum, Aconitum tasiromontanum, Acori tataninowii rhizome, Acorus gramineus, Acorus tatarinowii, Actinidia chinensis planch, Adansonia grandidieri, Aframomum giganteum, Aizopsis selkiana, Albizia myriophylla, Alisma plantago-aquatica subsp. orientale, Aloe castellorum, Aloe vera, Alpiniae officinarum rhizome, Amaranthus hypochondriacus, Ampelopsis japonica, Amphorogyne spicata, Anaphalis lacteal, Anchusa azurea, Andrographis laxiflora, Andrographis neesiana, Anemarrhena asphodeloides, Aphyllocladus denticulatus, Taiwan elm (Aralia decaisneana), Artemisia annua, Artemisiaparviflora, Artemisia scoparia [synonyms: Artemisia capillaris v, Artemisia scoparia], Aspidosperma discolor, Asteris root and rhizome, Aster sedifolius, Aster tataricus, Atadinus libanoticus, Baccharis potosina, Balanophora laxiflora, Bassia muricata, Benincasa hispida, Table beet, Bistorta vulgaris, Bistorta elliptica, Bistorta officinalis officinalis, Boehmeria rhizomes and roots (Boehmeriae rhizoma et radix), Boehmeria nivea, Boehmeria platanifolia [synonyms: Boehmeria tricuspis, Boehmeria platanifolia], Bolbostemae paniculati bulbus, Bolbosthemma paniculatum, Brassica rapa, Bridelia stipularis, Canarium bengalense, Cardus tenuiflorus, Cascara sagrada, Cassia alata L., Cassia angolensis angolensis), Cassia semen, Cassia fastuosa, Cassia javanica, Cassiaobtusifolia, Cassia occidentalis, Cassia speciosa, Cassia tora L., Cassia tora, Cassia torosa L., Catalpa longissima, Caulerpa peltata, Polygonum multiflori, Sargent's houttuynia stem, Caulis sargentodoxae, Caulocystis cephalornithos, Ipecac Cephaelis ipecacuanha, Cephalotaxus griffithii, Chaiturus malviastrum marrubiastrum, Mimosa pudica (Chamaecrista mimosoides), Chamaecrista nigricans, Chamaecrista nomame, Chamaecrista pumila, Cheilanthes argentea, Quinoa (Chenopodium quinoa), Chicory (Cichorium intybus), Field thistle (Cirsium oligophyllum), Clibadium sprucei, Coreopsis tinctoria, Corydalis rhizoma, Cranfillia fluviatilis, Cratoxylum formosum, Cremastra appendiculata), Cynanchum viminale, Dalbergia hupeana, Dalbergia lanceolaria subsp. paniculata, Degenia vereviticavelebitica, Delphinium nuttallianum, Delphinium virgatum, Dendriopoterium menendezii, Dendrobium thyrsiflorum, Derris canarensis, Derris cuneifolia, Derris oblonga, Dianthi herba, Dianthus caryophyllus, Dictyopteris australis, Dillenia indica, Dioscoreae bulbiferae, Dipsacus azureus azureus, Dodonaea viscosa, Dysoxylum cumingianum, Dysoxylum muelleri, Elymus repens, Enceliopsis argophylla, Endophytic aspergillus, Epimedium koreanum, Epimedii herba, Eria mollis, Eriocaulon buergerianum, Eriocaulon sieboldianum, Erythrina lystemon, Erythrophleum ivorense, Euodia bodinieri, Euodia officinalis, Euodia ruticarpa, buckwheat (Fagopyrum esculentum), Tartary buckwheat (Fagopyrum tataricum), Polygonum multiflorum (Fallopiamultiflora), Japanese knotweed (Fallopia sachalinensis), Flacourtia jangomas, Common water laurel (Frangula alnus), Cascara saccharada (Frangula purshiana), Fridericia triplinervia (Frid ericia triplinervia, Garcinia polyantha, Gleichenia quadripartita, Glycyrrhiza uralensis, Gnaphalii affinis herba, Grangea maderaspatana, Hedera helix, Helichrysum chionosphaerum, Helichrysum plicatum, Heynea trijuga, Hoveniae dulcis semen, Hymenoxys lemmonii, Hypericum prolificum prolificum, Hypericum sampsonii, Isatdis radix, Isatis tinctoria, Jacquemontia paniculata, Juniperus formosana, Justicia secunda, Lactuca plumieri, Lettuce (Lactuca sativa), Lanaria lanata, Larix kaempferior, Lavender (Lavandula vera), Leptocereus quadricostatus, Lespedeza tomentosa, Ligularia pleurocaulis pleurocaulis), Lilium bulbus, Lilium brownii fe brown var. colchesteri wils, Lilium brownii var. viridulum [synonyms: Lilium brown,Lilium browniivar. viridulum], Lobelia berlandieri, Loranthus pentandrus, Lupinus corymbosus, Lycii cortex, Maclura tinctoria, Magnolia figo, Magnolia ovata, Mandragora autumnalis, Melicope triphylla, Mentha arvensis, Mentha canadensis, Mentha herba, Metrodorea nigra, Miliusa velutina, Mitracarpus scaber scaber, Muehlenbeckia tamnifolia, Muntingia calabura, Myrsine africana, Nekemias grossedentata, Neobalanocarpus heimii, Nepeta granatensis, Nepeta parnassica, Nuxia floribunda, Onobrychis arenaria, Oryctes monoceros, Osmanthus armatus, Passiflora sexflora sexflora), Persicaria decipiens, Persicaria hydropiper, Persicaria maculosa, Persicaria perfoliata, Persicaria salicifoliasalicifolia, Petunia integrifolia subsp. inflata, Phaseolus vulgaris, Phlogacanthus curviflorus, Photinia serratifolia, Chinese lantern plant (Physalis alkekengi), Picramia antidesma, Picramia hirsuta, Picramnia teapensis, Picramnia teapensis Tul., Picrasma quassioides, Pinalia stricta, Pisum sativum, Plantago serratifolia coronopus, Plantago lanceolata, Pleione bulbocodioides, Pleione yunnanensis, Ploiarium alternifolium, Pluchea odora, Pneumatopteris pennigera, Japanese knotweed rhizomes and roots, Polygonum cuspidatum, Polygonum hypoleucum, Polygonum multiflorum, Polygonum perfoliatum, Pseudolarix amabilis), Psorospermum glaberrimum, Psorospermum laurentii, Psorospermum tenuifoliumtenuifolium, Psychotria stachyoides, Red oak (Quercus rubra), Radix Boehmeriae, Rhubarb root and rhizome (Radix et Rhizoma Rhei), Rhubarb root and rhizome (Radix et Rhizoma Rhei Praeparata), Ravenia spectabilis, Japanese knotweed (Reynoutria japonica), Buckthorn (Rhamnus cathartica), Blackthorn (Rhamnus davurica), Rhamnus erythroxyloides, Taiwan buckthorn (Rhamnus formosana), Common water buckthorn (Rhamnus frangula) [syn: Frangula alnus], Common water buckthorn (Rhamnus frangula, Rhamnus hirtella, Rhamnus kurdica, Rhamnus nakaharae, Rhamnus nepalensis, Rhamnus pallasii, Rhamnus prinoides, Rhamnus procumbens, Rhamnus punctata, Rhamnus saxatilis, Rhamnus thymifolius, Rhamnus triquetra, Rhamnus wightii, Rheum acuminatum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi, Rheum emodi [syn: Rheum australe], Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangense, Rheum nanum, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum, Rhubarb, Rheum rhabarbarum, Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum spp., Rheum subacaule, Rheum sublanceolatum, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum wittrocki, Rheum yunnanense, Rhizoma fagopyri cymose, Rhodiola viridula viridula), Siberian purple azalea (Rhododendron dahuricum), Rosa pomifera (Rosa pomifera), Rumex abyssinicus (Rumex abyssinicus), Japanese sorrel (Rumex acetosa), Rumex acetosella, Rumex aegyptiacus, Rumex alpinusalpinus, Rumex bequaertii, Rumex chalepensis, Rumex crispus, Rumex cristatus, Rumex cyprius, Rumex dentatus, Rumex japonicus s), Rumex lanceolatus, Rumex limoniastrum, Nepal sorrel (Rumex nepalensis), Rumex patientia, Rumex pictus, Rumex pulcher, Rumex ruwenzoriensis, Rumex scutatus, Rumex simpliciflorus, Rumex spp., Rumex tuberosus, Rumex usambarensis, Rumex vesicarius vesicarius, Salvia aurea, Salvia greggii, Sargent vine (Sargentodoxa cuneata), Sargentodoxae caulis, Saururus chinensis, Schistostephium artemisiifolium, Scilla socialis, Selaginella labordei, Semen pharbitidis, Senecio behnii, Senecio bonariensis, Senecio praecox, Senecio subdentatus, Golden candle (Senna alata), Senna (Senna alexandrina), Senna angustisiliqua, Senna artemisioides, Senna auriculata, Senna corymbosa, Sennadidymobotrya, Sennae folium, Senna lindheimeriana, Senna macranthera, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna podocarpa, Senna septemtrionalis, Senna siamea, Senna sophera, Senna spectabilis, Senna tora, Simaba orinocensis, Smythea bombaiensis bombaiensis, Solanum cleistogamum, Sophorae tonkinensis radix et rhizome, Spatholobus suberectus, Sphaerella rosigena, Spinach, Stevia berlandieri, Stevia ovata, Australian myrtle, Syzygium australe, Tagetes filifolia, Tanacetum coccineum, Taraxacum kok-saghyz, Taraxacum platycarpum subsp. hondoense, Tetradium japonica ruticarpum, Teucrium yemense, Thymelaea hirsute, Tribuli fructus, Tribulus terrestris, Uvaria afzelii, Vatairea heteropteranheteropteran, Ventilago calyculata, Ventilago denticulata, Ventilago leiocarpa, Ventilago madraspatana, Verbascum thapsiforme, Vismia guianensis, Vismia guineensis, Vismia laurentii, Vismia orientalis, Vitis vinifera, Wilbrandia ebracteata, Xanthii fructus, Xerochrysum viscosum, Angelica archangelica, Cascara saccharada (Frangula purshiana), Geranium maculatum, Rumex crispus, Senecio congestus, Senna (Senna alexandrina), Aloe africana, Aloe arborescens, Aloe castellorum, Aloe ergonica, Aloe ferox, Aloe rubroviolacea, Aloe spicata, Aloe succotrina, Asphodeline tenuiol tenuior, Asphodelus aestivus, Asphodelus albus, Asphodelus fistulosus, Asphodelusramosus, Asphodelus tenuifolius, Berchemia floribunda, Bergenia hissarica, Bulbine annua, Bulbine asphodeloides, Callisia fragrans, Cassia aldabrensis, Cassia grandis, Cassia javanica, Mimosa pudica, Commiphora socotrana, Frangula alnus, Cascara sagrada purshiana, Kniphofia ensifolia, Kniphofia foliosa, Kniphofia insignis, Kniphofia isoetifolia, Kniphofia schimperi, Picramnia antidesma, Picramnia hirsute, Guava (Psidium guajava), Japanese knotweed (Reynoutria japonica), Rhamnus alaternus, Common buckthorn (Rhamnus cathartica), Blackthorn rose (Rhamnus davurica), Rheum acuminatum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi, Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangense, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum, Rheum rhabarbarum, Rheum rhaponticum, Rheum ribes, Rheum spiciforme spiciforme, Rheum subacaule, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum yunnanense, Rumex cristatus, Rumex paulsenianus, Rumex scutatus, Selaginella delicatula, Senna alata, Senna alexandrina, Senna didymobotrya, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna reticulata, Senna siamea, Senna tora, Spatholobus suberectus, Stephania dinkulaedinklagei, Xanthorrhoea australis, Chicory (Cichorium intybus), Cassia occidentalis, Morinda royoc, Galium aparine, Bryophyllum pinnatum, Anthema tinctoria ria), bell tree (Aegle marmelos), lemongrass (Cymbopogon spp.), American sea buckthorn (Wedelia trilobata), Angelica archangelica, Vitis tilifolia, Mirabilis jalapa, Japanese snowbell (Centipeda minima), Bauhinia manca, Juniperus drupacea, Forsythia suspensa, orange (Citrus sinensis), rock moss (Hylocomium splendens), safflower (Carthamus tinctorius), rosemary (Rosmarinus officinalis), rice (Oryza sativa), red clover (Trifolium pratense cv. Redman), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan wild jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), cacao (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan wild jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var.menziesii, Penstemon centranthifolius, pea (Pisum sativum), soybean (Glycine max), oat (Avena sativa), apple (Malus domestica), gardenia (Gardenia jasminoides), aloe ferox, rice (Oryza sativa), coffee plant (Coffea arabica), safflower (Carthamus tinctorius), horse gram (Macrotyloma uniflorum), eggplant (Solanum melongena), mandarin orange (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostook, eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricula-judae), orange (Citrus sinensis), cycad (Cycas revoluta), bitter melon (Momordica charantia), Brassica carinata, gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var.niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum), agaricus (Agaricus subrufescens), flax (Linum usitatissimum), peony (Paeonia lactiflora), chili pepper (Capsicum annuum), creosote bush (Larrea tridentata), mirabilis (Mirabilis jalapa), periwinkle (Catharanthus roseu), alfalfa (Medicago sativa subsp. sativa), American nightshade (Solanum americanum), coffee arabica (Coffea arabica), bitter melon (Momordica charantia), milk thistle (Silybum marianum), cacao (Theobroma cacao), aloe ferox (Aloe ferox), gardenia (Gardenia jasminoides), cashew nut (Anacardium occidentale), chili pepper (Capsicum annuum), peony (Paeonia lactiflora), clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), pepper (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), oats (Avena sativa), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), corn (Zea mays), creosote bush (Larrea tridentata), tobacco (Nicotiana tabacum), eucalyptus (Eucalyptus globulus subsp.bicostata, Malayan wild jasmine (Musa acuminata), eggplant (Solanum melongena), Phyllanthus emblica, tomato (Solanum lycopersicum), Veronica polita (Veronica polita), hollyhock (Alcea rosea), Sacha inchi (Plukenetia volubilis), green coral (Euphorbia tirucalli), long-necked jasmine (Neolamarckia cadamba), lemon (Citrus limon), periwinkle (Catharanthus roseus), morning glory (Mirabilis jalapa), Podocarpus spicatus, Japanese laurel (Tripterygium wilfordii), Japanese honeysuckle (Spatholobus suberectus), and Japanese honeysuckle (Crinum moorei, Juniperus monosperma, Oyster mushroom (Pleurotus ostreatus), Gypsophila perfoliate, Clausena excavate, Gynura procumbens, Red clover (Trifolium pratense cv. Redman), Rice (Oryza sativa), Rosemary (Rosmarinus officinalis), Lotus (Nelumbo nucifera), Safflower (Carthamus tinctorius), Satsuma mandarin (Citrus unshiu), Hylocomium splendens, Orange (Citrus sinensis), Juniperus drupacea, Forsythia suspensa), bitter melon (Momordica charantia), milk thistle (Silybum marianum), aloe ferox (Aloe ferox), clementine (Citrus clementina), barley (Hordeum vulgare cv.Seco), common mustard (Erucastrum gallicum), flax (Linum usitatissimum), giant milkweed (Asclepias syriaca), St. John's wort (Hypericum perforatum), creosote bush (Larrea tridentata), eucalyptus (Eucalyptus globulus subsp. bicostata), Phyllanthus emblica, Veronica polita, hollyhock (Alcea rosea), long-necked hollyhock (Neolamarckia cadamba), periwinkle (Catharanthus roseus), Podocarpus spicatus, Tripterygium wilfordii, Juniperus monosperma monosperma), oyster mushroom (Pleurotus ostreatus), sunflower (Gypsophila perfoliate), Clausena excavate, Gynura procumbens, red clover (Trifolium pratense cv.Redman, rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), unshu mandarin (Citrus unshiu), splendens (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia (Forsythia suspensa), or a combination thereof. In some embodiments, the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof. In some embodiments, the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the oral composition is in one of the following dosage forms: a softgel capsule, a hard capsule, a liquid, a powder, and a tablet. In some embodiments, the oral composition comprises 10% to 99% w / w of the plant extract. In some embodiments, the plant extract further comprises a preservative. In some embodiments, the plant extract further comprises a sweetener. In some embodiments, the plant extract further comprises a colorant. In some embodiments, the plant extract further comprises an additive. In some embodiments, the plant extract further contains a flavoring agent.

[0008] Some embodiments relate to methods for treating, preventing, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a composition comprising an oral composition described herein. In some embodiments, the plant extract of the oral composition is capable of activating a group II metabotropic receptor. In some embodiments, the plant extract activates mGlu2 receptors. In some embodiments, the plant extract activates mGlu3 receptors. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing plant fractions for which antagonistic / inhibitory activity was confirmed. [Figure 2] 1 is a graph showing plant fractions with confirmed agonist / activating activity. [Figure 3] 1 is a flow chart showing a standardized bioassay protocol. [Figure 4] 1 is a bar graph showing mGluR2 antagonist / NAM assay activity. [Figure 5] 1 is a bar graph showing mGluR2 antagonist / PAM assay activity. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure provides, among other things, compounds, compositions (including oral compositions), and methods of administering the compounds and compositions to modulate or ameliorate stress or stress-related symptoms or disorders. In some embodiments, the oral composition comprises a therapeutically effective amount of a compound or plant extract and one or more carriers or excipients. In some embodiments, a method for treating, preventing, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress in a subject comprises administering a composition described herein. The present disclosure also provides, among other things, oral compositions and methods for orally administering a composition to modulate one or more group II metabotropic glutamate receptors. In some embodiments, the compound, plant extract, or composition described herein is a positive allosteric modulator (PAM) of group II metabotropic glutamate receptors. In some embodiments, the compound, plant extract, or composition described herein is an antagonist of one or more group II metabotropic glutamate receptors. In some embodiments, the compound, plant extract, or composition described herein is an agonist of one or more group II metabotropic glutamate receptors.

[0011] (composition) In some aspects, the present disclosure provides compositions comprising a plant extract and a carrier. In some embodiments, the composition is an oral composition. As used herein, the term "extract" refers to a composition containing a desired compound of interest separated from other substances present in the naturally-occurring source from which the oral composition is obtained. Plant extracts can be obtained from whole plants, plant parts (e.g., vegetative organs / structures, such as leaves, stems, and tubers), roots, flowers and floral organs / structures (e.g., bracts, calyxes, petals, stamens, pistils, anthers, and ovules), seeds (including embryos, endosperm, and seed coats), fruits (mature ovaries), plant tissues (e.g., vascular tissue, ground tissue, etc.), or cells (e.g., guard cells, egg cells, etc.), as well as their progeny, cultures, or cell lines. In some embodiments, the extract is generally recognized as safe for human consumption. Thus, in certain embodiments, the extract is of edible origin. In this respect, the extract is an edible extract. Extracts may be prepared by freezing, crushing, macerating, pulverizing, and / or fermenting the material of interest, subjecting the material to solvent extraction, and separating insoluble material from soluble material. In this respect, an "extract" of the present disclosure may be, but is not limited to, a crude extract, a fraction, a subfraction, a separation, an isolation, a concentration, or a purification.

[0012] In some embodiments, a plant extract may be a crude extract. As used herein, "crude" refers to a compound or molecule that has not been completely separated from components present in the original composition. In embodiments involving fractionation or subfractionation, molecules in a crude extract may be subjected to partial separation to obtain a less crude extract that contains other substances. In contrast, the term "isolated" means that a compound or molecule is substantially enriched or purified relative to the complex cellular environment in which it naturally occurs, e.g., a crude extract. When an isolated molecule is enriched or purified, its absolute level of purity is not critical, and one of skill in the art can easily determine an appropriate level of purity depending on the intended use of the substance. In some cases, an isolated molecule may constitute part of a composition (e.g., a cruder extract containing numerous other substances) and may, for example, contain other components. In other cases, an isolated molecule may be purified to substantial homogeneity, as determined, for example, by spectroscopy, NMR, or chromatography (e.g., LC-MS).

[0013] Suitable solvents for preparing extracts include, for example, n-pentane, hexane, butane, chloroform, dichloromethane, diethyl ether, acetonitrile, water, butanol, isopropanol, ethanol, methanol, glacial acetic acid, acetone, norflurane (HFA134a), ethyl acetate, dimethyl sulfoxide, heptafluoropropane (HFA227), and subcritical or supercritical fluids such as liquid carbon dioxide or water, or any combination of these in any proportion. When using such solvents, the resulting extract typically contains nonspecific, lipid-soluble substances. These can be removed by various processes, such as "winterization," which involves cooling to a specific temperature (usually -20°C) and removing waxy impurities by filtration or centrifugation; extraction with subcritical or supercritical carbon dioxide or a nonpolar solvent (e.g., hexane); or distillation.

[0014] In some embodiments, the plant extract is selected from the group consisting of rhubarb (Rheum officinale), Phyllanthus emblica, apple (Malus domestica), Tripterygium wilfordii, Aloe barbadensis, cacao (Theobroma cacao), quince (Chaenomeles sinensis), St. John's wort (Hypericum perforatum), Citrus unshiu, lotus (Nelumbo nucifera), Acacia luederitzii, Cassia abbreviate, Cassia fistula, mopane (Colophospermum mopane), Julbernardia globiflora, and the like. globiflora, Habranthus brachyandrus, Monactis macbridei, Arnica acaulis, Arnica montana, Daucus carota, Bauhinia manca, Botrytis cinerea, Brosimum acutifolium, Broussonetia kazinoki, Broussonetia papyrifera, Dalbergia latifolia, Dracaena cambodiana, Dragon's tree, Narcissus pseudonarcissus pseudonarcissus, Phanera guianensis, Rohdea chinensis, Soymida febrifuga, Pacific yew (Taxus brevifolia), Tupistra chinensischinensis, Abri herba, Abrus pulchellus subsp. Cantoniensis, Achyranthes bidentata, Aconitum seravschanicum, Aconitum tasiromontanum, Acori tataninowii rhizome, Acorus gramineus, Acorus tatarinowii, Actinidia chinensis planch, Adansonia grandidieri, Aframomum giganteum, Aizopsis selkiana, Albizia myriophylla, Alisma plantago-aquatica subsp. orientale, Aloe castellorum, Alpiniae officinarum rhizome, Amaranthus hypochondriacus, Ampelopsis japonica, Amphorogyne spicata, Anaphalis lacteal, Anchusa azurea, Andrographis laxiflora, Andrographis neesiana, Anemarrhena asphodeloides, Aphyllocladus denticulatus, Taiwan elm (Aralia decaisneana), Artemisia annua, Artemisia parviflora, Artemisia serratascoparia [synonyms: Artemisia capillaris v, Artemisia scoparia], Aspidosperma discolor, Asteris radix et rhizome, Aster sedifolius, Aster tataricus, Atadinus libanoticus, Baccharis potosina, Balanophora laxiflora, Bassia muricata, Benincasa hispida, Table beet (Beta vulgaris vulgaris), Bistorta elliptica, Bistorta officinalis officinalis, Boehmeria rhizomes and roots (Boehmeriae rhizoma et radix), Boehmeria nivea, Boehmeria platanifolia [synonyms: Boehmeria tricuspis, Boehmeria platanifolia], Bolbostemae paniculati bulbus, Bolbosthemma paniculatum, Brassica rapa, Bridelia stipularis, Canarium bengalense, Cardus tenuiflorus, Cascara sagrada, Cassia alata L., Cassia angolensis angolensis), Cassia semen, Cassia fastuosa, Cassia javanica, Cassia obtusifolia, Cassiaoccidentalis, Cassia speciosa, Cassia tora L., Cassia tora, Cassia torosa L., Catalpa longissima, Caulerpa peltata, Polygonum multiflori, Sargent's houttuynia stem, Caulis sargentodoxae, Caulocystis cephalornithos, Ipecac Cephaelis ipecacuanha, Cephalotaxus griffithii, Chaiturus marrubiastrum, Mimosa pudica mimosoides, Chamaecrista nigricans, Chamaecrista nomame, Chamaecrista pumila, Cheilanthes argentea, Quinoa (Chenopodium quinoa), Chicory (Cichorium intybus), Field thistle (Cirsium oligophyllum), Clibadium sprucei, Coreopsis tinctoria, Corydalis rhizoma, Cranfillia fluviatilis, Cratoxylum formosum, Cremastra appendiculata, Cynanchum viminale), Dalbergia hupeana, Dalbergia lanceolaria subsp. paniculata, Degenia vereviticavelebitica, Delphinium nuttallianum, Delphinium virgatum, Dendriopoterium menendezii, Dendrobium thyrsiflorum, Derris canarensis, Derris cuneifolia, Derris oblonga, Dianthi herba, Dianthus caryophyllus, Dictyopteris australis, Dillenia indica, Dioscoreae bulbiferae, Dipsacus azureus azureus, Dodonaea viscosa, Dysoxylum cumingianum, Dysoxylum muelleri, Elymus repens, Enceliopsis argophylla, Endophytic aspergillus, Epimedium koreanum, Epimedii herba, Eria mollis, Eriocaulon buergerianum, Eriocaulon sieboldianum, Erythrina lystemon, Erythrophleum ivorense, Euodia bodinieri, Euodia officinalis, Euodia ruticarpa, buckwheat (Fagopyrum esculentum), Tartary buckwheat (Fagopyrum tataricum), Polygonum multiflorum (Fallopiamultiflora, Japanese knotweed (Fallopia sachalinensis), Flacourtia jangomas, Common water laurel (Frangula alnus), Cascara saccharada (Frangula purshiana), Fridericia triplinervia (Fridericia tripliner) via, Garcinia polyantha, Gleichenia quadripartita, Glycyrrhiza uralensis, Gnaphalii affinis herba, Grangea maderaspatana, Hedera helix, Helichrysum chionosphaerum, Helichrysum plicatum, Heynea trijuga, Hoveniae dulcis semen, Hymenoxys lemmonii, Hypericum prolificum prolificum, Hypericum sampsonii, Isatdis radix, Isatis tinctoria, Jacquemontia paniculata, Juniperus formosana, Justicia secunda, Lactuca plumieri, Lettuce (Lactuca sativa), Lanaria lanata, Larix kaempferior, Lavender (Lavandula vera), Leptocereus quadricostatus, Lespedeza tomentosa, Ligularia pleurocaulis pleurocaulis), Lilium bulbus, Lilium brownii fe brown var. colchesteri wils, Lilium brownii var. viridulum [synonyms: Lilium brown,Lilium browniivar. viridulum], Lobelia berlandieri, Loranthus pentandrus, Lupinus corymbosus, Lycii cortex, Maclura tinctoria, Magnolia figo, Magnolia ovata, Mandragora autumnalis, Melicope triphylla, Mentha arvensis, Mentha canadensis, Mentha herba, Metrodorea nigra, Miliusa velutina, Mitracarpus scaber scaber, Muehlenbeckia tamnifolia, Muntingia calabura, Myrsine africana, Nekemias grossedentata, Neobalanocarpus heimii, Nepeta granatensis, Nepeta parnassica, Nuxia floribunda, Onobrychis arenaria, Oryctes monoceros, Osmanthus armatus, Passiflora sexflora sexflora), Persicaria decipiens, Persicaria hydropiper, Persicaria maculosa, Persicaria perfoliata, Persicaria salicifoliasalicifolia, Petunia integrifolia subsp. inflata, Phaseolus vulgaris, Phlogacanthus curviflorus, Photinia serratifolia, Chinese lantern plant (Physalis alkekengi), Picramia antidesma, Picramia hirsuta, Picramnia teapensis, Picramnia teapensis Tul., Picrasma quassioides, Pinalia stricta, Pisum sativum, Plantago serratifolia coronopus, Plantago lanceolata, Pleione bulbocodioides, Pleione yunnanensis, Ploiarium alternifolium, Pluchea odora, Pneumatopteris pennigera, Japanese knotweed rhizomes and roots, Polygonum cuspidatum, Polygonum hypoleucum, Polygonum multiflorum, Polygonum perfoliatum, Pseudolarix amabilis), Psorospermum glaberrimum, Psorospermum laurentii, Psorospermum tenuifoliumtenuifolium, Psychotria stachyoides, Red oak (Quercus rubra), Radix Boehmeriae, Rhubarb root and rhizome (Radix et Rhizoma Rhei), Rhubarb root and rhizome (Radix et Rhizoma Rhei Praeparata), Ravenia spectabilis, Japanese knotweed (Reynoutria japonica), Buckthorn (Rhamnus cathartica), Blackthorn (Rhamnus davurica), Rhamnus erythroxyloides, Taiwan buckthorn (Rhamnus formosana), Common water buckthorn (Rhamnus frangula) [syn: Frangula alnus], Common water buckthorn (Rhamnus frangula, Rhamnus hirtella, Rhamnus kurdica, Rhamnus nakaharae, Rhamnus nepalensis, Rhamnus pallasii, Rhamnus prinoides, Rhamnus procumbens, Rhamnus punctata, Rhamnus saxatilis, Rhamnus thymifolius, Rhamnus triquetra, Rhamnus wightii, Rheum acuminatum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi, Rheum emodi [syn: Rheum australe], Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangense, Rheum nanum, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum, Rhubarb, Rheum rhabarbarum, Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum spp., Rheum subacaule, Rheum sublanceolatum, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum wittrocki, Rheum yunnanense, Rhizoma fagopyri cymose, Rhodiola viridula viridula), Siberian purple azalea (Rhododendron dahuricum), Rosa pomifera (Rosa pomifera), Rumex abyssinicus (Rumex abyssinicus), Japanese sorrel (Rumex acetosa), Rumex acetosella, Rumex aegyptiacus, Rumex alpinusalpinus, Rumex bequaertii, Rumex chalepensis, Rumex crispus, Rumex cristatus, Rumex cyprius, Rumex dentatus, Rumex japonicus, Rumex lanceolatus Rumex lanceolatus, Rumex limoniastrum, Nepal sorrel (Rumex nepalensis), Rumex patientia, Rumex pictus, Rumex pulcher, Rumex ruwenzoriensis, Rumex scutatus, Rumex simpliciflorus, Rumex spp., Rumex tuberosus, Rumex usambarensis, Rumex vesicarius, Salvia aurea aurea, Salvia greggii, Sargentodoxa cuneata, Sargentodoxae caulis, Saururus chinensis, Schistostephium artemisiifolium, Scilla socialis, Selaginella labordei, Semen pharbitidis, Senecio behnii, Senecio bonariensis, Senecio praecox, Senecio subdentatus, Golden candle (Senna alata), Senna alexandrina, Senna angustisiliqua, Senna artemisioides, Senna auriculata, Senna corymbosa, Sennadidymobotrya, Sennae folium, Senna lindheimeriana, Senna macranthera, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna podocarpa, Senna septemtrionalis, Senna siamea, Senna sophera, Senna spectabilis, Senna tora, Simaba orinocensis, Smythea bombaiensis bombaiensis, Solanum cleistogamum, Sophorae tonkinensis radix et rhizome, Spatholobus suberectus, Sphaerella rosigena, Spinach, Stevia berlandieri, Stevia ovata, Australian myrtle, Syzygium australe, Tagetes filifolia, Tanacetum coccineum, Taraxacum kok-saghyz, Taraxacum platycarpum subsp. hondoense, Tetradium japonica ruticarpum, Teucrium yemense, Thymelaea hirsute, Tribuli fructus, Tribulus terrestris, Uvaria afzelii, Vatairea heteropteranheteropteran, Ventilago calyculata, Ventilago denticulata, Ventilago leiocarpa, Ventilago madraspatana, Verbascum thapsiforme, Vismia guianensis, Vismia guineensis, Vismia laurentii, Vismia orientalis, Vitis vinifera, Wilbrandia ebracteata, Xanthii fructus, Xerochrysum viscosum, Angelica archangelica, Cascara saccharada (Frangula purshiana), Geranium maculatum, Rumex crispus, Senecio congestus, Senna (Senna alexandrina), Aloe africana, Aloe arborescens, Aloe castellorum, Aloe ergonica, Aloe ferox, Aloe rubroviolacea, Aloe spicata, Aloe succotrina, Asphodeline tenuiol tenuior, Asphodelus aestivus, Asphodelus albus, Asphodelus fistulosus, Asphodelusramosus, Asphodelus tenuifolius, Berchemia floribunda, Bergenia hissarica, Bulbine annua, Bulbine asphodeloides, Callisia fragrans, Cassia aldabrensis, Cassia grandis, Cassia javanica, Mimosa pudica, Commiphora socotrana, Frangula alnus, Cascara sagrada purshiana, Kniphofia ensifolia, Kniphofia foliosa, Kniphofia insignis, Kniphofia isoetifolia, Kniphofia schimperi, Picramnia antidesma, Picramnia hirsute, Guava (Psidium guajava), Japanese knotweed (Reynoutria japonica), Rhamnus alaternus, Common buckthorn (Rhamnus cathartica), Blackthorn rose (Rhamnus davurica), Rheum acuminatum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi, Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangense, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum, Rheum rhabarbarum, Rheum rhaponticum, Rheum ribes, Rheum spiciforme spiciforme, Rheum subacaule, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum yunnanense, Rumex cristatus, Rumex paulsenianus, Rumex scutatus, Selaginella delicatula, Senna alata, Senna alexandrina, Senna didymobotrya, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna reticulata, Senna siamea, Senna tora, Spatholobus suberectus, Stephania dinkulaedinklagei, Xanthorrhoea australis, Chicory (Cichorium intybus), Cassia occidentalis, Morinda royoc, Galium aparine, Bryophyllum pinnatum, Anthema tinctoria, and Aegle marmelos, lemongrass (Cymbopogon spp.), American sea cucumber (Wedelia trilobata), Angelica archangelica, Vitis tilifolia, Mirabilis jalapa, Japanese snowbell (Centipeda minima), Bauhinia manca, Juniperus drupacea, Forsythia suspensa, orange (Citrus sinensis), Hylocomium splendens, safflower (Carthamus tinctorius), rosemary (Rosmarinus officinalis), rice (Oryza sativa), red clover (Trifolium pratense cv. Redman), barley (Hordeum vulgare) vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan wild jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), cacao (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan wild jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var.menziesii, Penstemon centranthifolius, pea (Pisum sativum), soybean (Glycine max), oat (Avena sativa), apple (Malus domestica), gardenia (Gardenia jasminoides), aloe ferox, rice (Oryza sativa), coffee plant (Coffea arabica), safflower (Carthamus tinctorius), horse gram (Macrotyloma uniflorum), eggplant (Solanum melongena), mandarin orange (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostook, eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricula-judae), orange (Citrus sinensis), cycad (Cycas revoluta), bitter melon (Momordica charantia), Brassica carinata, gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var.niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum), agaricus (Agaricus subrufescens), flax (Linum usitatissimum), peony (Paeonia lactiflora), chili pepper (Capsicum annuum), creosote bush (Larrea tridentata), mirabilis (Mirabilis jalapa), periwinkle (Catharanthus roseu), alfalfa (Medicago sativa subsp. sativa), American nightshade (Solanum americanum), coffee arabica (Coffea arabica), bitter melon (Momordica charantia), milk thistle (Silybum marianum), cacao (Theobroma cacao), aloe ferox (Aloe ferox), gardenia (Gardenia jasminoides), cashew nut (Anacardium occidentale), chili pepper (Capsicum annuum), peony (Paeonia lactiflora), clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), pepper (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), oats (Avena sativa), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), corn (Zea mays), creosote bush (Larrea tridentata), tobacco (Nicotiana tabacum), eucalyptus (Eucalyptus globulus subsp.bicostata, Malayan wild jasmine (Musa acuminata), eggplant (Solanum melongena), Phyllanthus emblica, tomato (Solanum lycopersicum), Veronica polita (Veronica polita), hollyhock (Alcea rosea), Sacha inchi (Plukenetia volubilis), green coral (Euphorbia tirucalli), long-necked jasmine (Neolamarckia cadamba), lemon (Citrus limon), periwinkle (Catharanthus roseus), morning glory (Mirabilis jalapa), Podocarpus spicatus, Japanese laurel (Tripterygium wilfordii), Japanese honeysuckle (Spatholobus suberectus), and Japanese honeysuckle (Crinum moorei, Juniperus monosperma, Oyster mushroom (Pleurotus ostreatus), Gypsophila perfoliate, Clausena excavate, Gynura procumbens, Red clover (Trifolium pratense cv. Redman), Rice (Oryza sativa), Rosemary (Rosmarinus officinalis), Lotus (Nelumbo nucifera), Safflower (Carthamus tinctorius), Satsuma mandarin (Citrus unshiu), Hylocomium splendens, Orange (Citrus sinensis), Juniperus drupacea, Forsythia suspensa), bitter melon (Momordica charantia), milk thistle (Silybum marianum), aloe ferox (Aloe ferox), clementine (Citrus clementina), barley (Hordeum vulgare cv.Seco), common mustard (Erucastrum gallicum), flax (Linum usitatissimum), giant milkweed (Asclepias syriaca), St. John's wort (Hypericum perforatum), creosote bush (Larrea tridentata), eucalyptus (Eucalyptus globulus subsp. bicostata), Phyllanthus emblica, Veronica polita, hollyhock (Alcea rosea), long-necked hollyhock (Neolamarckia cadamba), periwinkle (Catharanthus roseus), Podocarpus spicatus, Tripterygium wilfordii, Juniperus monosperma monosperma), oyster mushroom (Pleurotus ostreatus), sunflower (Gypsophila perfoliate), Clausena excavate, Gynura procumbens, red clover (Trifolium pratense cv.Redman), rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), Satsuma mandarin (Citrus unshiu), splendens (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia (Forsythia suspensa), or combinations thereof. In some embodiments, the plant extract comprises a purified extract or a crude extract. In some embodiments, the extract may be obtained directly from the seed. In some embodiments, the extract may be obtained directly from the whole seed. In some embodiments, the extract may be obtained directly from the leaf. In some embodiments, the extract may be obtained directly from the pulp. In some embodiments, the extract may be obtained directly from the tuber. In some embodiments, the extract may be obtained directly from the flower. In some embodiments, the extract may be obtained directly from the root. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be powdered and then heated to a selected temperature ranging from about 30°C to about 100°C to remove the oil before proceeding to the extraction step.

[0015] In some embodiments, the plant extract comprises Rheum officinale. In some embodiments, the plant extract comprises a purified or crude extract of Rheum officinale. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature in the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0016] In some embodiments, the plant extract comprises amla (Phyllanthus emblica). In some embodiments, the plant extract comprises a purified or crude extract of amla (Phyllanthus emblica). In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0017] In some embodiments, the plant extract comprises apple (Malus domestica). In some embodiments, the plant extract comprises a refined or crude extract of apple (Malus domestica). In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0018] In some embodiments, the plant extract comprises Tripterygium wilfordii. In some embodiments, the plant extract comprises a purified or crude extract of Tripterygium wilfordii. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature in the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0019] In some embodiments, the plant extract comprises Aloe vera (Aloe barbadensis). In some embodiments, the plant extract comprises a purified or crude extract of Aloe vera (Aloe barbadensis). In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0020] In some embodiments, the plant extract comprises cocoa (Theobroma cacao). In some embodiments, the plant extract comprises a refined or crude extract of cocoa (Theobroma cacao). In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0021] In some embodiments, the plant extract comprises quince (Chaenomeles sinesis). In some embodiments, the plant extract comprises a purified or crude extract of quince (Chaenomeles sinesis). In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0022] In some embodiments, the plant extract comprises Hypericum perforatum. In some embodiments, the plant extract comprises a purified or crude extract of Hypericum perforatum. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0023] In some embodiments, the plant extract comprises Citrus unshiu. In some embodiments, the plant extract comprises a purified or crude extract of Citrus unshiu. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0024] In some embodiments, the plant extract comprises quince (Chaenomeles sinensis). In some embodiments, the plant extract comprises a purified or crude extract of quince (Chaenomeles sinensis). In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0025] In some embodiments, the plant extract comprises lotus (Nelumbo nucifera). In some embodiments, the plant extract comprises a purified or crude extract of lotus (Nelumbo nucifera). In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0026] In some embodiments, the plant extract comprises Inula helenium. In some embodiments, the plant extract comprises a purified or crude extract of Inula helenium. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature in the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0027] In some embodiments, the plant extract comprises Acacia luederitzii. In some embodiments, the plant extract comprises a purified or crude extract of Acacia luederitzii. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0028] In some embodiments, the plant extract comprises Cassia abbreviate. In some embodiments, the plant extract comprises a purified or crude extract of Cassia abbreviate. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0029] In some embodiments, the plant extract comprises Cassia fistula. In some embodiments, the plant extract comprises a purified or crude extract of Cassia fistula. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0030] In some embodiments, the plant extract comprises Colophospermum mopane. In some embodiments, the plant extract comprises a purified or crude extract of Colophospermum mopane. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature in the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0031] In some embodiments, the plant extract comprises Solidago Canadensis. In some embodiments, the plant extract comprises a purified or crude extract of Solidago Canadensis. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature in the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0032] In some embodiments, the plant extract comprises Julbernardia globiflora. In some embodiments, the plant extract comprises a purified or crude extract of Julbernardia globiflora. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0033] In some embodiments, the plant extract comprises Habranthus brachyandrus. In some embodiments, the plant extract comprises a purified or crude extract of Habranthus brachyandrus. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0034] In some embodiments, the plant extract comprises Monactis macbridei. In some embodiments, the plant extract comprises a purified or crude extract of Monactis macbridei. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0035] In some embodiments, the plant extract comprises Arnica acaulis. In some embodiments, the plant extract comprises a purified or crude extract of Arnica acaulis. In some embodiments, the extract may be derived directly from the whole seeds. In some embodiments, the extract may be derived directly from the leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from the tubers. In some embodiments, the extract may be derived directly from the flowers. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the extract may be derived directly from the roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0036] In some embodiments, the plant extract comprises Arnica montana. In some embodiments, the plant extract comprises a purified or crude extract of Arnica montana. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from the pulp. In some embodiments, the extract may be derived directly from tubers. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers, pulp, tubers, and / or roots may be ground into a powder and then heated to a selected temperature within the range of about 30° C. to about 100° C. to remove oils before proceeding to the extraction step.

[0037] In some embodiments, the oral composition comprises an extract from one or more plant sources. In some embodiments, the oral composition comprises an extract from two or more plant sources. In some embodiments, the oral composition comprises an extract from three or more plant sources.

[0038] In some embodiments, the extracts described herein include juices, infusions, and fermentation residues. These fermented plant-derived extracts, or processed fractions thereof, are utilized in ingestible compositions, such as human and animal health-promoting compositions or tonics. As used herein, "plant-derived" refers to sourcing a compound from a plant and may or may not refer to a pure extract from the plant.

[0039] In some embodiments, the compounds of the present disclosure have formula (I): [ka] or a salt thereof.

[0040] In some embodiments of the present invention, R 1 , R2 , R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, keto, optionally substituted ester, optionally substituted aryl, optionally substituted alkoxy, optionally substituted C-C alkyl, optionally substituted —O—C-C alkyl, or optionally substituted C-C cycloalkyl. In some embodiments, R 1 , R 2 and R 3 are hydroxyl groups, and R 4 is optionally substituted C1-C6 alkyl. In some embodiments, R 1 is hydrogen and R 2 and R 3 is hydroxyl and R 4 is optionally substituted O-C1-C6 alkyl. In some embodiments, R 1 and R 4 is hydrogen and R 2 and R 3 is hydroxyl. In some embodiments, R 1 is hydrogen and R 2 , R 3 and R 4 is keto. In some embodiments, R 1 is hydrogen and R 2 and R 3 is hydroxyl and R 4 is keto. In some embodiments, R 1 , R 2 and R 3 is hydroxyl and R 4 is optionally substituted C1-C6 alkyl.

[0041] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain comprising a fully saturated (i.e., no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms. (When a numerical range such as "1 to 20" appears in this specification, it refers to each integer within the range. For example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1, 2, 3, etc., up to 20 carbon atoms, but this definition also applies to "alkyl" when no numerical range is specified.) The alkyl group can be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group can be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl," etc. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0042] As used herein, "aryl" refers to an all-carbon, monocyclic or polycyclic aromatic ring system (e.g., including fused, bridged, or spiro ring systems in which two carbon rings share a chemical bond, including cases where one or more aryl rings and one or more aryl or non-aryl rings are present), having a fully delocalized pi-electron system across at least one ring. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C6 14 Aryl groups, C6-C 10 The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0043] As used herein, "halogen" or "halo" refers to any of the radioactive stable isotopes of Group 7 of the periodic table, such as chloro (Cl), fluoro (F), bromo (Br), and iodo (I) groups.

[0044] When a group is described as "optionally substituted," it means that the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituents can be selected from one or more of the indicated substituents. When no substituents are indicated, an "optionally substituted" or "substituted" group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicycle, aralkyl, heteroaralkyl, (heteroalicycle)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbohydrate, and the like. It means that each of the groups can be individually and independently substituted with one or more groups individually and independently selected from amyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, mono-substituted amino, and di-substituted amino, and protected derivatives thereof.

[0045] In some embodiments, the compound of Formula (I) is a compound that can be useful as a modulator of a metabotropic glutamate receptor. In some embodiments, the modulator can be an agonist of mGlu2. In some embodiments, the modulator can be an agonist of mGlu3. In some embodiments, the modulator can be an antagonist of mGlu2. In some embodiments, the modulator can be an antagonist of mGlu3.

[0046] In some embodiments, the compounds of formula (I), the compounds and plant extracts of the present disclosure include the compounds shown in Table A.

[0047] [Table A]

[0048] In some embodiments of the present disclosure, compositions are provided comprising a compound of Table A and a carrier. As used herein, "carrier" refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium, or zinc stearate, or stearic acid), or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be compatible with the other ingredients of the formulation and not deleterious to the subject. Examples of materials that can function as carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, and hydroxypropyl methylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) fats and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) glycols such as propylene glycol. (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffers; (21) polyesters, polycarbonates, and / or polyanhydrides; (22) lipids and / or phospholipids; and (23) other non-toxic, compatible substances used in conventional formulations.

[0049] In some embodiments, the composition comprises a substantially pure compound of Table A. In some embodiments, the composition contains less than about 5%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.5%, 0.25%, 0.1% of impurities, or a range including and / or spanning these values. As used herein, "substantially pure" refers to a state in which one or more desired active compounds are highly isolated and / or concentrated with minimal undesired impurities. In some embodiments, the compound is derived from a plant and may be concentrated in the plant source without necessarily extracting the compound completely or partially from the plant. As a non-limiting example, a plant containing a compound of Table A can be processed to separate specific parts of the plant that are enriched in the compound of Table A from other parts that have relatively low concentrations of the compound of Table A. As another non-limiting example, a plant containing a compound of Table A can be heated or crushed to make the compound of Table A within the plant more available for chemical extraction or digestion.

[0050] In some embodiments, the composition comprises about 0.1%, 0.25%, 0.50%, 0.75%, 1.0%, 1.5%, 2.5%, 5.0%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 99% of a compound of Table A, or a range comprising and / or spanning these values. In some embodiments, the composition comprises about 10% to about 90% of a compound of Table A. In some embodiments, the composition comprises about 20% to about 75% of a compound of Table A. In some embodiments, the composition comprises about 25% to about 50% of a compound of Table A. In some embodiments, the composition comprises about 15% of a compound of Table A. In some embodiments, the composition comprises about 25% of a compound of Table A. In some embodiments, the composition comprises about 50% of a compound of Table A. In some embodiments, the composition comprises about 75% of a compound of Table A. In some embodiments, the composition comprises about 90% of a compound of Table A.

[0051] In some embodiments, the composition is formulated as an oral composition. In some embodiments, the composition comprises one or more compounds of Table A and a carrier. In some embodiments, the composition comprises Compound 1 and a carrier. In some embodiments, the composition comprises Compound 2 and a carrier. In some embodiments, the composition comprises Compound 3 and a carrier. In some embodiments, the composition comprises Compound 4 and a carrier. In some embodiments, the composition comprises Compound 5 and a carrier. In some embodiments, Compound 1 is an antagonist of mGlu2. In some embodiments, Compound 1 is an antagonist of mGlu3. In some embodiments, Compound 2 is an antagonist of mGlu2. In some embodiments, Compound 2 is an antagonist of mGlu3. In some embodiments, Compound 3 is an antagonist of mGlu2. In some embodiments, Compound 3 is an antagonist of mGlu3. In some embodiments, Compound 4 is an antagonist of mGlu2. In some embodiments, Compound 4 is an antagonist of mGlu3. In some embodiments, Compound 5 is an antagonist of mGlu2. In some embodiments, Compound 5 is an antagonist of mGlu3. In some embodiments, compound 6 is an antagonist of mGlu2. In some embodiments, compound 6 is an antagonist of mGlu3. In some embodiments, compound 7 is an antagonist of mGlu2. In some embodiments, compound 7 is an antagonist of mGlu3. In some embodiments, compound 8 is an antagonist of mGlu2. In some embodiments, compound 8 is an antagonist of mGlu3. In some embodiments, compound 9 is an antagonist of mGlu2. In some embodiments, compound 9 is an antagonist of mGlu3. In some embodiments, compound 10 is an antagonist of mGlu2. In some embodiments, compound 10 is an antagonist of mGlu3. In some embodiments, compound 11 is an antagonist of mGlu2. In some embodiments, compound 11 is an antagonist of mGlu3.In some embodiments, compound 12 is an antagonist of mGlu2. In some embodiments, compound 12 is an antagonist of mGlu3. In some embodiments, compound 11 is an antagonist of mGlu3. In some embodiments, compound 13 is an antagonist of mGlu2. In some embodiments, compound 13 is an antagonist of mGlu3. In some embodiments, compound 1 is an antagonist / negative allosteric modulator. In some embodiments, compound 2 is an antagonist / negative allosteric modulator. In some embodiments, compound 3 is an antagonist / negative allosteric modulator. In some embodiments, compound 4 is an antagonist / negative allosteric modulator. In some embodiments, compound 5 is an antagonist / negative allosteric modulator. In some embodiments, compound 6 is an antagonist / negative allosteric modulator. In some embodiments, compound 7 is an antagonist / negative allosteric modulator. In some embodiments, compound 8 is an antagonist / negative allosteric modulator. In some embodiments, compound 9 is an antagonist / negative allosteric modulator. In some embodiments, compound 10 is an antagonist / negative allosteric modulator. In some embodiments, compound 11 is an antagonist / negative allosteric modulator. In some embodiments, compound 12 is an agonist / positive allosteric modulator. In some embodiments, compound 13 is an agonist / positive allosteric modulator.

[0052] In some embodiments, the oral compositions comprise salt forms of the compounds described herein. Salts of the compounds of the present disclosure are compounds that possess the desired pharmacological activity of the parent compound, and include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, and the like. The term "acid addition salts" includes (1) acid addition salts formed with organic acids such as benzoic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid, or (2) salts formed when an acidic proton in the parent compound is replaced.

[0053] In some embodiments, the oral composition comprises a pharmaceutically acceptable salt form of the compound described herein.The term "pharmaceutically acceptable salt" as used herein is a broad term and has the usual and customary meaning for those skilled in the art (not limited to any special or customized meaning), and refers, without limitation, to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound.In some embodiments, the salt is an acid addition salt of the compound.Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, such as formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form an ammonium salt, an alkali metal salt such as a lithium, sodium or potassium salt, an alkaline earth metal salt such as a calcium, magnesium or aluminum salt, a salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, amino acids such as arginine and lysine, or an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0054] When the compounds described herein have one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or stereoisomeric mixtures, including all diastereomeric and enantiomeric forms. Furthermore, when the compounds described herein have one or more double bonds, resulting in geometric isomers definable as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Stereoisomers may be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. Similarly, it is understood that all tautomers of the compounds described herein are encompassed.

[0055] It is understood that the compounds described herein can be labeled by isotopic or other means, including, but not limited to, the use of chromophores or fluorescent groups, luminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer therapeutic advantages due to greater metabolic stability, such as increased half-life in the body and reduced dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, when a hydrogen atom is explicitly depicted in a compound structure or understood to be present in the compound, the hydrogen atom, which may be present at any position in the compound, may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Therefore, reference to a compound herein encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0056] It is understood that the compounds described herein can be labeled by isotopic or other means, including, but not limited to, the use of chromophores or fluorescent groups, luminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer therapeutic advantages due to greater metabolic stability, such as increased half-life in the body and reduced dosage. Each chemical element represented in a compound structure may include any isotope of that element. For example, when a hydrogen atom is explicitly depicted in a compound structure or understood to be present in the compound, the hydrogen atom, which may be present at any position in the compound, may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), or hydrogen-3 (tritium). Therefore, reference to a compound herein encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0057] It is understood that the oral compositions, formulations, and methods described herein include the use of crystalline forms, amorphous phases, and / or pharmaceutically acceptable salts, solvates, hydrates, and conformers, as well as metabolites and active metabolites of these compounds with similar activity. Conformers refer to structures that are conformational isomers. Conformers are molecules that have the same structural formula but differ in the alignment of atoms around rotatable bonds. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent during crystallization of a compound with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). Hydrates are formed when water is the solvent, and alcohol adducts are formed when alcohol is the solvent. Furthermore, the compounds provided herein may exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. Other forms of the compounds provided in some embodiments may include amorphous, pulverized, and nanoparticulate forms.

[0058] Similarly, the compounds described herein (such as the compounds of some embodiments) include any form described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous forms, solvated forms, enantiomeric forms, tautomeric forms, etc.).

[0059] In some embodiments, the composition may further comprise a preservative. In some embodiments, the preservative may be present at about 0.01%, 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0% w / w, or a range including and / or spanning these values. In some embodiments, the preservative is not limited to the group selected from sodium benzoate, methylparaben, propylparaben, sodium nitrite, sulfur dioxide, sodium sorbate, and potassium sorbate. Other suitable preservatives include, but are not limited to, edetate (ethylenediaminetetraacetic acid salt, EDTA, eg, disodium EDTA).

[0060] In some embodiments, the composition may further comprise a sweetener. In some embodiments, the sweetener may be present at about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% w / w, or a range including and / or spanning these values. In some embodiments, the sweetener may comprise a natural sweetener. In some embodiments, the sweetener may comprise an artificial sweetener. Non-limiting examples of sweeteners include sucrose, dextrose, maltose, dextrin, dry invert sugar, fructose, high fructose corn syrup, levulose, galactose, corn syrup solids, tagatose, polyols (e.g., sorbitol, mannitol, xylitol, lactitol, erythritol, and maltitol), hydrogenated starch hydrolysates, isomalt, trehalose, and mixtures thereof.

[0061] In some embodiments, the composition may further comprise a flavoring agent. In some embodiments, the flavoring agent may be present at about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or a range including and / or spanning these values. In some embodiments, the flavoring agent may comprise a natural or artificial flavor. In certain embodiments, the flavoring agent comprises essential oils derived from plants or fruits, such as peppermint oil, spearmint oil, other mint oils, clove oil, cinnamon oil, oil of wintergreen, bay, thyme, cedar leaf, nutmeg, allspice, sage, mace, and almond. In another particular embodiment, the flavoring agent comprises a plant extract or fruit essence, such as apple, banana, watermelon, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, and mixtures thereof. In yet another particular embodiment, the flavoring agent comprises a citrus flavor, such as lemon, lime, orange, tangerine, grapefruit, citron, or kumquat extract, essence, or oil.

[0062] In some embodiments, the composition may further comprise a colorant, which may be present at about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or a range including and / or spanning these values.

[0063] In some embodiments, the composition may further comprise at least one additive. In some embodiments, the additive may be present at about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or a range including and / or spanning these values. In some embodiments, the at least one additive may be an emulsifier. In some embodiments, the additive may include one or more vitamins. In some embodiments, the additive may include one or more minerals. In some embodiments, the additive may include a stabilizer. Formulation

[0064] The composition comprising the plant extract or compound of the present disclosure can be combined with a carrier and provided in any form suitable for ingestion or administration by a subject. In this regard, the plant extract or compound is added to a consumable product as an exogenous ingredient or additive. Suitable consumable forms include, but are not limited to, dietary supplements, food ingredients or additives, medical foods, nutritional supplement compositions, or pharmaceutical compositions. In some embodiments, the plant extract or compound is provided in either liquid or powder form.

[0065] As used herein, the term "food ingredient" or "food additive" refers to an edible substance intended, directly or indirectly, to be a component of or otherwise affect the properties of any food (including substances intended for use in manufacturing, processing, packing, treating, preparing, treating, packaging, transporting, or storing food). Food products, particularly functional foods, are foods that have been fortified or supplemented with additional complementary nutrients and / or beneficial ingredients during processing. Food products according to the present disclosure may be in the form of, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, health bars, bread, cakes, cereals, candy, confectionery, soups, milk, yogurt, or fermented dairy products, cheese, fruit and vegetable juice drinks, fermented beverages, shakes, flavored waters, teas, oils, or other suitable foods. In some embodiments, the food product may be a whole food product that has been fortified with a concentration of a compound by post-harvest and food production and processing methods to a level that provides an effective amount of the compound.

[0066] Dietary supplements are products containing the compounds or extracts of the present disclosure that are taken orally and intended to supplement the diet. Nutraceuticals are food-derived products that provide additional health benefits beyond the basic nutritional value of the food. Pharmaceutical compositions are defined to include any component of a pharmaceutical product intended to affect the structure or function of the human or other animal body or to provide pharmacological activity or other direct effect for the diagnosis, treatment, mitigation, or prevention of disease. Dietary supplements, dietary supplements, and pharmaceutical compositions can often be provided in the form of tablets, coated tablets, pills, capsules, pellets, granules, softgels, gel capsules, liquids, powders, emulsions, suspensions, elixirs, syrups, or other suitable forms.

[0067] The pharmaceutical compositions disclosed herein can be prepared by known methods, such as conventional mixing, dissolving, granulating, dragee-forming, pulverizing, emulsifying, encapsulating, entrapping, or tabletting processes. Further, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical compositions disclosed herein can be provided as salts with pharmaceutically compatible counterions.

[0068] Methods of administration of the compounds, salts and / or compositions include, but are not limited to, oral, rectal, pulmonary, transdermal, aerosol, injection, infusion and parenteral administration such as intramuscular, subcutaneous, intravenous, intraosseous injection, intrathecal, direct intraventricular injection, intraperitoneal, intranasal and intraocular injection. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, may be administered orally.

[0069] In addition, compound, salt and / or composition can be administered locally rather than systemically, for example, by injecting or implanting the compound directly into the affected area, often as a depot or sustained-release preparation.Furthermore, compound can be administered in a targeted drug delivery system, for example, by encapsulating in liposomes coated with tissue-specific antibodies.Liposomes are selectively taken up by target organs.For example, to target respiratory diseases or conditions, nasal or pulmonary administration may be desirable.

[0070] Oral compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, the notice reflecting approval of the drug for human or veterinary administration. For example, the notice may be labeling approved by the U.S. Food and Drug Administration (FDA) for prescription drugs or an approved product insert. Compositions formulated with the compounds and / or salts described herein and compatible pharmaceutical excipients may also be placed in an appropriate container and labeled for treatment of a given indication.

[0071] The compounds, salts, and / or pharmaceutical compositions may be provided to the administering physician or other healthcare professional in the form of a kit. A kit is a package containing a container containing the compound in a suitable pharmaceutical composition and instructions for administering the pharmaceutical composition to a subject. The kit may optionally contain one or more additional therapeutic agents. The kit may include individual doses of the compound or pharmaceutical composition for sequential or sequential administration. The kit may optionally include one or more diagnostic tools and instructions for use. The kit may include a suitable administration device, such as a syringe, and instructions for administering the compound and other therapeutic agents. The kit may optionally include instructions for storage, reconstitution (if applicable), and administration of any or all of the therapeutic agents. The kit may include multiple containers corresponding to the number of doses to be administered to a subject.

[0072] In some embodiments, the oral compositions described herein may be administered at a dose ranging from about 0.1 to 200 mg / kg body weight. In some embodiments, the oral compositions described herein may be administered at a dose ranging from about 0.1 to 1, 0.5 to 1, 0.1 to 10, 0.5 to 10, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 1 to 200, 1 to 300, 1 to 400, 1 to 500, 1 to 600, 1 to 700, 1 to 800, 1 to 900, 1 to 1000, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 1 0-60, 10-70, 10-80, 10-90, 10-100, 10-200, 10-300, 10-400, 10-500, 10-600, 10-700, 10-800, 10-900, 10-1000, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-200, 20-300, 20-400, 20-500, 20-600, 20-700, 20-800, 20-900, 20-1000, 30-40, 30-50, 30-60, 30-70, 30-80 , 30~90, 30~100, 30~200, 30~300, 30~400, 30~500, 30~600, 30~700, 30~800, 30~900, 30~1000, 40~50, 40~60, 40~70, 40~80, 40~90, 40~100, 40~200, 40~300, 40~400, 40~500, 40~600, 40~700, 40~800, 40~900, 40~1000, 50~60, 50~70, 50~80, 50~90, 50~100, 50~200, 50~300, 50~400, 50~50 0, 50-600, 50-700, 50-800, 50-900, 60-70, 60-80, 60-90, 60-100, 60-200, 60-300, 60-400, 60-500, 60-600, 60-700, 60-800, 60-900, 60-1000, 70-80, 70-90, 70-100, 70-200, 70-300, 70-400, 70-500, 70-600, 70-700, 70-800, 70-900, 70-1000, 80-90, 80-100, 80-200, 80-300, 80-400,It may be administered at a dose of 80-500, 80-600, 80-700, 80-800, 80-900, 80-100, 90-100, 90-200, 90-300, 90-400, 90-500, 90-600, 90-700, 90-800, 90-900, 90-1000, 100-150, 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, or 100-1000 mg / kg body weight. In some embodiments, the oral compositions described herein contain at least about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, It may be administered at a dose of 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 80, 90, or 95 mg / kg body weight. In some embodiments, the oral compositions described herein are administered to an area of ​​about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, , 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m of the subject's body weight.0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, It may be administered at a dose of greater than 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg.

[0073] In some embodiments, the dose of the oral compositions described herein is about 0.1 mg to 10 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 50 mg, 0.1 mg to 75 mg, 0.1 mg to 100 mg, 0.5 mg to 10 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 50 mg, 0.5 mg to 75 mg, 0.5 mg to 100 mg, 1 mg to 10 mg, 1 mg to 2 5mg, 1mg~30mg, 1mg~50mg, 1mg~75mg, 1mg~100mg, 2mg~10mg, 2mg~25mg, 2mg~30mg, 2mg~50mg, 2mg~75mg, 2mg ~100mg, 3mg~10mg, 3mg~25mg, 3mg~30mg, 3mg~50mg, 3mg~75mg, 3mg~100mg, 4mg~100mg, 5mg~10mg, 5mg~25mg, 5mg~30mg, 5mg~50mg, 5mg~75mg, 5mg~300mg, 5mg~200mg, 7.5mg~15mg, 7.5mg~25mg, 7.5mg~30mg, 7.5mg~50m g, 7.5mg~75mg, 7.5mg~100mg, 7.5mg~200mg, 10mg~20mg, 10mg~25mg, 10mg~50mg, 10mg~75mg, 10mg~100mg, 15 mg to 30mg, 15mg to 50mg, 15mg to 100mg, 20mg to 20mg, 20mg to 100mg, 30mg to 100mg, 40mg to 100mg, 10mg to 80mg, 15mg to 80mg, 20mg to 80mg, 30mg to 80mg, 40mg to 80mg, 10mg to 60mg, 15mg to 60mg, 20mg to 60mg, 30mg to 60mg, or about 40mg to 60mg. In some embodiments, the oral compositions described herein contain between about 1 mg and 5 mg, 1 mg and 7.5 mg, 2.5 mg and 5 mg, 2.5 mg and 7.5 mg, 5 mg and 7.5 mg, 5 mg and 9 mg, 5 mg and 10 mg, 5 mg and 12 mg, 5 mg and 14 mg, 5 mg and 15 mg, 5 mg and 16 mg, 5 mg and 18 mg, 5 mg and 20 mg, 5 mg and 22 mg, 5 mg and 24 mg, 5 mg and 26 mg, 5 mg and 28 mg, 5 mg and 30 mg, 5 mg and 32 mg, 5 mg and 34 mg, 5 mg and 36 mg, 5 mg and 38 mg, 5 mg and 40 mg, 5 mg and 42 mg, 5 mg and 44 mg, 5 mg and 46 mg, 5 mg and 48 mg, 5 mg and 50 mg,5mg~52mg、5mg~54mg、5mg~56mg、5mg~58mg、5mg~60mg、7mg~7.7mg、7mg~9mg、7mg~10mg、7mg~12mg、7mg~14mg、7mg~15mg、7mg~16mg、7mg~18mg、7mg~20mg、7mg~22mg、7mg~24mg、7mg~26mg、7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg、40mg~52mg、40mg~54mg、40mg~56mg、40mg~58mg、40mg~60mg、43mg~46mg、43mg~48mg、43mg~50mg、43mg~52mg、43mg~54mg、43mg~56mg、43mg~58mg、42mg~60mg、45mg~48mg、45mg~50mg、45mg~52mg、45mg~54mg、45mg~56mg、45mg~58mg、45mg~60mg、48mg~50mg、48mg~52mg、48mg~54mg、48mg~56mg、48mg~58mg、48mg~60mg、50mg~52mg、50mg~54mg、50mg~56mg、In some embodiments, the dose of the oral compositions described herein is 0.1 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 58 mg, about 50 mg, about 60 mg, about 52 mg, about 54 mg, about 52 mg, about 56 mg, about 52 mg, about 58 mg, or about 52 mg. mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg or more, equal to or approximately the same value. In some embodiments, the dose of the oral compositions described herein is less than about 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0074] To prepare solid compositions such as tablets or capsules, the compound or extract is mixed with a carrier (e.g., conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium hydrogen phosphate, or gum) and other diluents (e.g., water) to form a solid composition. This solid composition is divided into unit dosage forms containing an effective amount of the disclosed compound. Tablets or pills containing the compound or extract can be coated or otherwise prepared to provide a dosage form with the advantage of prolonged action.

[0075] The liquid forms that the compounds or extracts of the present disclosure are incorporated into for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, flavored emulsions using edible oils, and elixirs and similar media.Suitable dispersants or suspending agents for aqueous suspensions include tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or synthetic natural gums such as gelatin.Liquid preparations for oral administration can be in the form of, for example, solution, syrup or suspension, or can be provided as a dry product that is reconstituted with water or other suitable media before use. Such liquid preparations may be prepared by conventional methods with acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid), and artificial or natural colorants and / or sweeteners.

[0076] The method for preparing the formulation or composition of the present disclosure comprises combining the compound or extract of the present disclosure with a carrier, and optionally with one or more accessory ingredients and / or active ingredients.Generally, the formulation is prepared by uniformly and intimately combining the compound or extract of the present disclosure with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.Therefore, the disclosed formulation can consist of or essentially consist of the combination of the compound or extract described herein with a suitable carrier.

[0077] When the compounds or extracts of the present disclosure are administered to humans or animals as pharmaceuticals, nutritional supplements, or dietary supplements, they can be administered per se or as a composition containing, for example, 0.1-99% of the active ingredient in combination with an acceptable carrier. In some embodiments, the compounds or extracts of the present disclosure can be administered in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% w / w, or a range including and / or spanning these values.

[0078] Food products, particularly functional foods, are foods that have been fortified or enriched to include additional complementary nutrients and / or beneficial ingredients during processing. Food products according to the present disclosure may be in the form of, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, health bars, bread, cakes, cereals, candy, confectionery, soups, milk, yogurt or fermented dairy products, cheese, juice-based and vegetable-based beverages, fermented beverages, shakes, flavored waters, teas, oils, or other suitable food products. In some embodiments, the food product is a whole food product that has been enriched by post-harvest and food production processing methods to provide an effective concentration of compounds. In some embodiments, the food product comprises one or more compounds described herein and a dietary fiber source. In some embodiments, the food product comprises one or more compounds described herein. In some embodiments, the food product is a food bar. In some embodiments, the food bar comprises from about 0.01% to about 20% (w / w) of one or more compounds described herein. In some embodiments, the food bar comprises from about 0.1% to about 10% (w / w) of one or more compounds described herein. In some embodiments, the food product is a crisp. In some embodiments, the food crisp comprises from about 0.01% to about 20% (w / w) of one or more compounds described herein. In some embodiments, the food crisp comprises from about 0.1% to about 10% (w / w) of one or more compounds described herein.

[0079] The compounds, compositions, and extracts of the present disclosure may be prepared as nutritional formulations, including foods, medicinal, or functional foods. A "medical or functional food" is defined as a food that is consumed as part of a normal diet but that has been demonstrated to provide physiological benefits and / or reduce the risk of a disease or condition, such as a chronic disease, beyond its basic nutritional function. By way of example, and without limitation, medicinal and functional foods may contain one or more of the compounds described herein, compositions described herein, extracts described herein, vitamins, minerals, herbs, botanicals, amino acids, dietary substances intended to increase dietary intake, concentrates, metabolites, ingredients, extracts, or any combination thereof. Dietary supplements may also be incorporated into foods, such as functional foods, for the purpose of promoting health or preventing disease or disorders. When administered as a pharmaceutical formulation, the compositions may be administered to patients in a variety of ways, either prophylactically or therapeutically. In some embodiments, the compositions described herein may be administered alone or in combination with other additives or pharmaceuticals, and may be combined with a physiologically acceptable carrier. The effective amount and method of administration, as well as the purpose of a particular formulation, may vary based on the individual subject, the stage of the disease or condition, and other factors apparent to one skilled in the art. In the case of pharmaceutical and nutraceutical formulations, the concentration of the subject composition (e.g., plasma concentration may be monitored) may be monitored during the course of treatment to ensure that the desired level is maintained.

[0080] In some embodiments, food products contain carbohydrates. A variety of carbohydrates, including various sugars and starches, are used in food products. Carbohydrates, including complex carbohydrates (such as whole grains and vegetables) and simple carbohydrates (such as sugars and refined grains), are important sources of energy for the body. Common carbohydrates used in food products include starch, sugars, fructose, maltodextrin, dextrose, corn syrup, oligosaccharides, cellulose, and complex carbohydrates such as inulin, which may be added to processed foods as a prebiotic fiber. According to the present disclosure, the concentration of carbohydrates may vary depending on the intended use of the product. In some embodiments, carbohydrates may comprise between about 1% and about 95% by weight of the food product. In some embodiments, carbohydrates may comprise between about 1% and about 95% by weight of the food product. In some embodiments, food products may comprise carbohydrates at about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or ranges therebetween or spanning inclusive of those values.

[0081] In some embodiments, food products may contain sugars. Sugars such as high-fructose corn syrup, sucrose, glucose syrup, dextrose, and other sweeteners are often added to enhance the flavor of processed foods. Additionally, sugar alcohols or maltodextrins may be added to reduce the calorie content of food products and / or improve the nutritional profile of the product. In some embodiments, food products may comprise one or more sugars that are slowly, incompletely, or not digested at all by humans. These sugars may include isomaltose, panose, and branched oligomers with a degree of polymerization of 4 or greater. Additional non-limiting examples of sugars include sucrose, HFCS, fructose, brown sugar (which may be either partially or fully refined), powdered sugar (also known as confectioner's sugar), high-fructose corn syrup, honey, molasses, maple syrup, agave nectar, coconut sugar, date sugar, fruit juice concentrate, maltodextrin, dextrose, glucose syrup, maple syrup, molasses, and lactose. According to the present disclosure, the sugar concentration can vary depending on the intended use of the product. In some embodiments, the sugar may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the sugar component comprises from about 2% to about 10% by weight of the composition. In some embodiments, the sugar may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or a range therebetween or spanning, inclusive of these values.

[0082] In some embodiments, the food product comprises a dietary fiber source. In some embodiments, the food product comprises about 5% to about 30% (w / w) fiber. In some embodiments, the food product comprises at least 10% fiber. In some embodiments, the food product comprises at least 15% fiber. In some embodiments, the food product comprises at least 20% fiber. In some embodiments, the food product comprises at least 30% fiber. In some embodiments, the fiber may be selected from psyllium husk, inulin, beta-glucan, acacia fiber, pectin, wheat dextrin, cellulose, fructooligosaccharides, guar gum, fruit fiber, or combinations thereof. In some embodiments, the fiber is water-soluble dietary fiber.

[0083] In some embodiments, food products may contain protein. Protein may be present in various concentrations depending on the product. Protein sources may include soy protein, soy flour, soy protein isolate, whey protein isolate, casein, gelatin, pulse protein isolate, soy protein concentrate, egg albumin or egg white, wheat protein concentrate, pulse protein concentrate, and mixtures thereof. In some embodiments, meat products such as beef jerky, sausage, and meatballs may contain protein as a primary ingredient. Protein may be present at a concentration of about 10% to about 25% of the total ingredients. Dairy products such as cheese, yogurt, and milk may contain proteins such as casein and whey as primary ingredients. Protein may be present at a concentration of about 3% to about 15% of the total ingredients. Plant-based products such as tofu, tempeh, and seitan may contain proteins derived from soybeans, peas, pulses, or wheat as primary ingredients. Protein may be present at a concentration of about 10% to about 25% of the total ingredients. In energy and protein bars, proteins such as whey and soy, or any protein disclosed herein, may be added as a protein source. Proteins may be present at a concentration of about 10% to about 25% of the total ingredients. According to the present disclosure, the protein concentration may vary depending on the intended use of the product. In some embodiments, the protein may comprise about 1% to about 95% by weight of the food product. In some embodiments, the protein may comprise about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% protein, or ranges inclusive, between, and / or spanning these values, with the high and low values ​​independently selected.

[0084] In some embodiments, the food product may include starch. In some embodiments, the food product may additionally comprise a starch component in an amount of about 5% to 45%, or about 10% to 30%, or about 15% to 25%. The starch component may include purely added flour or other particulate matter, as well as starch fractions provided by other ingredients, such as oat bran or soy protein. In some embodiments, the starch may comprise any conventionally known starch or flour component used in ready-to-eat cereals. Suitable starchy grains for application include flours obtained from primary grains such as wheat, rice, corn (maize), oats, barley, and rye, or starch fractions isolated from flours, such as corn starch, wheat starch, and rice starch, as well as various processed starches, such as pregelatinized starches and modified starches.

[0085] In some embodiments, food products may contain flour. Multiple types of flour may be used according to the present disclosure. For example, common flours used in food products include all-purpose flour (which may contain protein, like many other flours), whole wheat flour, bread flour, cake flour, pastry flour, self-rising flour, and gluten-free flour. According to the present disclosure, the concentration of flour may vary depending on the intended use of the product. For example, in baked goods such as breads, cakes, and cookies, flour is the primary ingredient and may be present at a concentration of 50% to 100% of the total dry ingredients. In soups and sauces, flour is often used as a thickener and may be present at a concentration of 1% to 5% of the total ingredients. Batters and Coatings: In deep-fried foods such as chicken and fish, flour is used as part of the batter or coating and may be present at a concentration of 20% to 50% of the total dry ingredients. In snack foods such as crackers and chips, flour may be present at a concentration of 30% to 70% of the total ingredients. In some embodiments, flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise flour at any of about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or ranges inclusive, between, and / or spanning these values, with the high and low values ​​independently selected.

[0086] In some embodiments, food products may include lipids. In some embodiments, food products may include oils. In some embodiments, food products may include one or more lipids or oils. Multiple lipids may be used according to the present disclosure. For example, common lipids include butter, margarine, vegetable oil, shortening, and lard. According to the present disclosure, the concentration of lipids may vary depending on the intended use of the product. In baked foods such as cakes, cookies, and pastries, lipids such as butter, shortening, and oils are often used to provide moisture, flavor, and texture. In some embodiments, lipids may be present at a concentration of 10% to 30% of the total ingredients. In some embodiments, lipids such as olive oil and mayonnaise are often used in sauces and dressings to provide flavor and texture. In some embodiments, lipids may be present at a concentration of 10% to 30% of the total ingredients. In fried foods such as chicken and French fries, lipids such as vegetable oil and lard are used as frying oils and may be present at a concentration of 30% to 60% of the total ingredients. In snack foods such as chips and crackers, lipids such as vegetable oils and palm oils are often used to provide flavor and texture. In some embodiments, lipids may be present at a concentration of 10% to 30% of the total ingredients. In some embodiments, lipids may comprise from about 1% to about 95% by weight of the food product. In some embodiments, lipids may comprise from about 1% to about 95% by weight of the food product. In some embodiments, lipids may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% lipid, or ranges inclusive, between, and / or spanning these values, with the high and low values ​​independently selected.

[0087] In some embodiments, food products may contain one or more additional ingredients. Optionally, food products of the present disclosure may further contain various substances designed to enhance their aesthetic or nutritional properties. These supplemental substances may include vitamin and / or mineral fortification, colorants, flavorings, sweeteners, and mixtures thereof. While the exact ingredient concentrations may vary, generally, these substances may each comprise from about 0.01% to about 5%, or from about 0.1% to 2%, by dry weight of the food product. One particularly useful substance is common table salt. In some embodiments, table salt comprises from about 0.1% to 5%, or from about 0.5% to 4.0%, of the food product.

[0088] In some embodiments, the food product is plant-derived. In some embodiments, the food product is derived from hemp husk. In some embodiments, the food product is a solid food. In some embodiments, the food product is a semi-solid food. In some embodiments, the food product is a puffed product, a bakery product, a pressed cake, a cooked product, a food bar, a cereal, a crisp, or a spread.

[0089] Dietary supplements are products containing the compounds or extracts of the present disclosure, taken orally, and intended to supplement the diet. Nutraceuticals are products derived from food and provide additional health benefits beyond the basic nutritional value of the food. Pharmaceutical compositions are defined as any component of a drug product that provides pharmacological activity or other direct effect for the purpose of diagnosing, curing, mitigating, treating, or preventing disease, or affecting the structure or function of the body in humans or other animals. Dietary supplements, nutraceuticals, and pharmaceutical compositions are often provided in capsules, tablets, coated tablets, pills, capsules, pellets, granules, softgels, gel capsules, liquids, powders, emulsions, suspensions, elixirs, syrups, or other suitable forms. In some embodiments, the compositions described herein are provided as dietary supplements. In some embodiments, the dietary supplements are provided in capsule, tablet, powder, or liquid form. In some embodiments, the compositions described herein are provided as dietary supplements. In some embodiments, the dietary supplements are provided in capsule, tablet, powder, or liquid form. In some embodiments, the compositions described herein are provided as pharmaceuticals. In some embodiments, the pharmaceutical agent is provided in capsule, tablet, powder, or liquid form.

[0090] The compounds, salts, and / or pharmaceutical compositions may be provided to the administering physician or other medical professional in the form of a kit. A kit is a package containing a container containing the compound in a suitable pharmaceutical composition and instructions for administering the pharmaceutical composition to a subject. The kit may optionally contain one or more additional therapeutic agents. The kit may contain separate individual doses of the compound or pharmaceutical composition for sequential or sequential administration. The kit may optionally contain one or more diagnostic tools and instructions for use. The kit may contain an appropriate administration device, such as a syringe, and instructions for administering the compounds and any other therapeutic agents. The kit may optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all of the included therapeutic agents. The kit may contain multiple containers corresponding to the number of times to be administered to a subject.

[0091] (Method and Use) The present disclosure provides methods and uses for treating, preventing, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress in a subject. According to such methods, an effective amount of a compound or composition of the present disclosure is provided to a subject in need thereof to treat, reduce, ameliorate, ameliorate, modulate, or ameliorate stress in the subject. As used herein, "subject" refers to an animal, preferably a mammal. In some embodiments, the subject is a veterinary animal, companion animal, livestock, laboratory animal, or zoo animal. In other embodiments, the subject is a human.

[0092] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating a stress disorder in a subject can include administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, administering a therapeutically effective amount of a compound includes oral ingestion of the compound. Oral ingestion of the compound can include ingestion of a natural product in which the compound is a naturally occurring component, a concentrated natural product, and a substantially pure composition of a compound according to the present disclosure. As used herein, "stress" or "stress disorder" encompasses mental and physical diseases and conditions recognized and understood by practitioners in the relevant medical field. Stress and / or stress disorders can manifest as a variety of symptoms, including, but not limited to, sleep disorders and anxiety. Stress disorders encompass a range of mental health conditions that can result from experiencing or witnessing a traumatic event. Examples of such disorders include post-traumatic stress disorder (PTSD), which can develop after exposure to severe trauma (e.g., combat, natural disasters, serious accidents, violent personal attacks, etc.). Acute stress disorder (ASD) is another example, with symptoms similar to PTSD, but occurring shortly after a traumatic event and typically resolving within a month. Adjustment disorders are also related and are characterized by an inability to adapt to or cope with a specific stressor, such as a significant life change, resulting in significant emotional or behavioral symptoms. Each of these disorders manifests differently in each individual, highlighting the complex impact that stress has on mental health.

[0093] As used herein, the terms "treatment," "therapy," "treating," and the like refer to affecting a subject, tissue, or cell to achieve a desired pharmacological and / or physiological effect. This effect may have a prophylactic meaning, such as complete or partial prevention or reduction in severity of a disease or associated symptoms, or a therapeutic meaning, such as partial or complete cure of a disease. Thus, "treatment" of a stress disorder includes (a) helping a subject reduce stress, (b) helping a subject maintain low stress levels, (c) alleviating or ameliorating the effects of a stress disorder, e.g., enhancing a sense of normalcy, or (d) preventing the onset of a stress disorder in a subject predisposed to or at risk for a stress disorder, so that the disorder does not develop or occur in the subject, or develops in a milder form.

[0094] An "effective amount" refers to an amount sufficient to provide an amount of drug to obtain an effect when administered to a patient. In the case of a treatment method, this effect can be treatment of a stress disorder. Thus, an "effective amount" can be a "therapeutically effective amount." A "therapeutically effective amount" refers to an amount sufficient to provide an amount of drug to treat a disease or its symptoms when administered to a subject.

[0095] In some embodiments, the present disclosure provides methods for administering a therapeutically effective amount of a composition described herein to treat, prevent, control, ameliorate, or reduce the risk of a condition requiring enhanced metabotropic glutamate receptor activity in a subject. The term "enhanced amount" refers to the amount of mGluR agonist, i.e., the amount of agonist administered that is effective to treat the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present disclosure. An enhanced amount is expected to be less than the amount required to achieve the same effect when the mGluR agonist is administered without an effective amount of a compound of the present disclosure. An enhanced amount can be readily determined by a diagnostician skilled in the art by observing prior art techniques and results obtained under similar circumstances. In determining the amount of enhancement, the diagnostician will consider several factors, including, but not limited to, the choice of mGluR agonist to be administered, including its potency and selectivity, the co-administered compositions described herein, the species of mammal, its size, age, general condition, the particular disorder involved, the involvement or severity of the disorder, the response of the individual patient, the route of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of other concomitant medications, and other relevant circumstances, regarding the dosage of the mGluR agonist to be administered in combination with the compositions described herein.

[0096] In some embodiments, the compositions described herein can be administered as positive allosteric modulators of Group II metabotropic glutamate receptors. In some embodiments, the compositions described herein can be administered as agonists of Group II metabotropic glutamate receptors. In some embodiments, the compositions described herein can be administered as antagonists of Group II metabotropic glutamate receptors.

[0097] In some embodiments, the present disclosure provides methods for treating, preventing, controlling, ameliorating, or alleviating neurological or psychiatric disorders associated with glutamate dysfunction. In some embodiments, the neurological or psychiatric disorders associated with glutamate dysfunction include brain damage after cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, stress, cardiac arrest, hypoglycemic neurological damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive impairment, idiopathic and drug-induced Parkinson's disease, disorders associated with muscle spasms and dystonia (including tremors), epilepsy, convulsions, migraines (including migraine headaches), urinary incontinence, disorders associated with substance tolerance, and substance abuse. Includes one or more of the following conditions or diseases: withdrawal-related disorders (including opioids, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics and other substances), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), mood disorders (including depression, mania, and bipolar disorder), trigeminal neuralgia, hearing loss, tinnitus, age-related macular degeneration, vomiting, cerebral edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention-deficit / hyperactivity disorder, and conduct disorder.

[0098] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating a mood disorder in a subject can include administering an effective amount of a compound or composition described herein. In some embodiments, administering a therapeutically effective amount of a compound includes oral ingestion of the compound. As used herein, the term "mood disorder" encompasses mental and physical diseases and conditions recognized and understood by physicians in the relevant medical fields. Mood disorders can include one or more of a wide range of psychological and physiological symptoms that can significantly affect an individual's emotional state and daily functioning. For example, symptoms of mood disorders can manifest as prolonged sadness or depression, loss of interest in previously enjoyed activities, significant changes in appetite or weight, sleep disturbances, fatigue, feelings of worthlessness or excessive guilt, and, in severe cases, thoughts of death or suicide. Mood disorders can lead to difficulties maintaining interpersonal relationships, performing work duties, and participating in social activities. The compounds of the present disclosure can provide natural compounds that are safe and effective in reducing anxiety. In some embodiments, the compounds of the present disclosure can be more or less effective depending on the severity or type of mood disorder.

[0099] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating a sleep disorder in a subject may include administering an effective amount of a compound or composition described herein. In some embodiments, administering a therapeutically effective amount of a compound includes oral ingestion of the compound. Oral ingestion of a compound may include ingestion of a natural product in which the compound is a naturally occurring component, a concentrated natural product, and a substantially pure composition of a compound according to the present disclosure. As used herein, the term "sleep disorder" encompasses mental and physical diseases and conditions recognized and understood by practitioners in the relevant medical field. Treatment of a sleep disorder may include addressing one or more of a wide range of symptoms that can affect quality of life and overall health. Individuals suffering from sleep disorders may experience difficulty falling asleep (insomnia), frequent awakenings during the night, difficulty falling asleep again after early morning awakenings, or non-restorative sleep, which means not feeling refreshed upon awakening. Other symptoms include excessive daytime sleepiness, difficulty concentrating, mood changes such as increased irritability or anxiety, and impaired performance at work or school. In more severe cases, sleep disorders may also manifest as sleep disorders such as sleep apnea syndrome, characterized by abnormal breathing patterns, or restless legs syndrome, which causes discomfort and the urge to move legs when falling asleep.The compounds of the present disclosure can provide natural compounds that are safe and effective in protecting sleep and circadian rhythms.In some embodiments, the compounds of the present disclosure may be more or less effective depending on the severity or type of sleep disorder.In some embodiments, the compounds of the present disclosure can treat sleep disorders independently of the cause of stress.

[0100] In some embodiments, the compositions of the present disclosure are also useful in methods for the prevention, treatment, control, amelioration, or reduction of risk of diseases, disorders, and conditions in combination with other agents, including mGluR agonists. In some embodiments, the present disclosure provides methods for administering a therapeutically effective amount of a composition described herein to a subject in need thereof to treat, prevent, control, or alleviate a disease or condition associated with the mGlu2 receptor. In some embodiments, the present disclosure provides methods for administering a therapeutically effective amount of a composition described herein to a subject in need thereof to treat, prevent, control, or alleviate a disease or condition associated with the mGlu3 receptor.

[0101] In some embodiments, the present disclosure provides a method for treating anxiety in a subject, comprising administering an effective amount of a composition described herein. In some embodiments, the anxiety is generalized anxiety disorder. In some embodiments, the anxiety disorder is due to a general medical condition. In some embodiments, the anxiety is due to substance-induced anxiety disorder. As used herein, the term "anxiety" includes treatment of anxiety disorders and related disorders described in DSM-IV. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems exist for neurological and psychiatric disorders, particularly anxiety, and that these systems evolve with advances in medical science. Thus, the term "anxiety" is intended to encompass similar disorders described in other diagnostic materials. In some embodiments, the subject's anxiety is improved by about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25.0%, 50.0%, 75.0%, or a range including / spanning these values. In some embodiments, methods and uses for treating, preventing, reducing, modulating, or ameliorating anxiety in a subject can include administering an effective amount of a compound or composition described herein. In some embodiments, administering a therapeutically effective amount of a compound includes oral ingestion of the compound. Oral ingestion of the compound can include ingestion of a natural product in which the compound is a naturally occurring component, a concentrated natural product, or a substantially pure composition of a compound in accordance with the present disclosure.

[0102] In another embodiment, the present disclosure provides a method for treating anxiety, comprising administering to a patient in need thereof an effective amount of a compound or composition described herein. In some embodiments, anxiety-related conditions include, but are not limited to, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and anxiety disorder not otherwise specified.

[0103] In some embodiments, the present disclosure provides a method for treating stress-induced depression, comprising administering an effective amount of a composition described herein. Currently, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) (2022, American Psychiatric Association, Washington, DC) provides diagnostic tools, including depression and related disorders. Depressive disorders include, for example, single or recurrent major depressive disorder, dysthymia, depressive neurosis and neurotic depression, melancholic depression, including anorexia, weight loss, insomnia and early morning awakening, and psychomotor slowing, atypical depression (reactive depression), including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety, and phobias, seasonal affective disorder, bipolar disorder, or manic depression (e.g., bipolar I disorder, bipolar II disorder, cyclothymic disorder). As used herein, "depression" includes treatment of depressive disorders and related disorders described in DSM-IV. In some embodiments, the subject's stress-induced depression is improved by about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25.0%, 50.0%, 75.0%, or a range including / spanning these values.

[0104] In some embodiments, the present disclosure provides a method for treating schizophrenia in a subject, comprising administering an effective amount of a composition described herein. According to the Merck Manual (2006-2007), schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized thinking and behavior, flat affect (limited emotional range), cognitive impairment (impaired reasoning and problem-solving skills), and occupational and social dysfunction. In some embodiments, the subject's schizophrenia is improved by about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25.0%, 50.0%, 75.0%, or a range including and / or spanning these values.

[0105] In some embodiments, the disclosure provides a method of treating panic disorder in a subject, comprising administering an effective amount of a composition described herein. In some embodiments, the panic disorder is associated with agoraphobia. In some embodiments, the panic disorder is not associated with agoraphobia. In some embodiments, the subject's panic disorder is improved by about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25.0%, 50.0%, 75.0%, or a range including and / or spanning these values.

[0106] In some embodiments, the present disclosure provides a method of treating post-traumatic stress disorder (PTSD) in a subject, comprising administering an effective amount of a composition described herein. In some embodiments, the subject's PTSD is improved by about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25.0%, 50.0%, 75.0%, or a range including and / or spanning these values.

[0107] The methods described herein may further include identifying a patient having a disease or condition described herein. In some embodiments, the methods further include identifying a subject having a condition requiring enhanced metabotropic glutamate receptor activity. In some embodiments, the methods further include identifying a subject having a neurological or psychiatric disorder associated with glutamate dysfunction. In some embodiments, the methods further include identifying a subject having a disease or disorder associated with the mGlu2 receptor. In some embodiments, the methods further include identifying a subject having a disease or disorder associated with the mGlu3 receptor. In some embodiments, the methods further include identifying a subject having generalized anxiety disorder. In some embodiments, the methods further include identifying a subject having depression. In some embodiments, the methods further include identifying a subject having schizophrenia. In some embodiments, the methods further include identifying a subject having a panic disorder. In some embodiments, the methods further include identifying a subject having post-traumatic stress disorder (PTSD). In some embodiments, identifying the subject includes obtaining a sample from the patient. In some embodiments, identifying the subject includes isolating a sample from the subject. In some embodiments, isolating a sample from the subject includes isolating DNA from the subject. In some embodiments, the method further comprises determining whether the patient has a disease or condition.

[0108] In some embodiments, methods and uses are provided for modulating metabotropic glutamate receptors. In some embodiments, the methods and uses include providing one or more compounds of Table A or compositions comprising one or more compounds of Table A. In some embodiments, the modulation of metabotropic glutamate receptors includes Group II. In some embodiments, the metabotropic glutamate receptor includes one or more compounds that can act as antagonists of metabotropic glutamate receptor 2 and / or metabotropic glutamate receptor 3. In some embodiments, the metabotropic glutamate receptor includes one or more compounds that can act as agonists of metabotropic glutamate receptor 2 and / or metabotropic glutamate receptor 3.

[0109] In some embodiments, the methods and uses of the present disclosure include supporting a healthy stress response. In some embodiments, the methods and uses include providing one or more compounds of Table A or a composition described herein. In some embodiments, the compositions described herein are formulated for oral use. In some embodiments, the compositions are in a dosage form comprising one of a softgel capsule, a hard capsule, a gummy bear, a functional beverage, a functional food, a liquid, a powder, or a tablet. In some embodiments, the compositions comprise 1.0% to 99% w / w of a plant extract described herein. In some embodiments, the compositions further comprise a carrier, a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof. In some embodiments, the compositions are formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, an oral composition for use in a medicament for supporting a healthy stress response or a condition thereof comprises one or more compounds of Table A. In some embodiments, the use of a composition for supporting a healthy stress response in a subject is characterized in that the composition comprises one or more compounds of Table A.

[0110] In some embodiments, the methods and uses of the present disclosure include supporting glutamate homeostasis. In some embodiments, the methods and uses include providing one or more compounds of Table A or a composition described herein. In some embodiments, the compositions described herein are formulated for oral use. In some embodiments, the compositions are in a dosage form comprising one of a softgel capsule, a hard capsule, a gummy bear, a functional beverage, a functional food, a liquid, a powder, or a tablet. In some embodiments, the compositions comprise 1.0% to 99% w / w of a plant extract described herein. In some embodiments, the compositions further comprise a carrier, a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof. In some embodiments, the compositions are formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, an oral composition for use in a medicament for supporting glutamate homeostasis or a condition thereof comprises one or more compounds of Table A. In some embodiments, the use of a composition for supporting glutamate homeostasis in a subject is characterized in that the composition comprises one or more compounds of Table A.

[0111] In some embodiments, the methods and uses of the present disclosure involve stress management. In some embodiments, the methods and uses involve providing one or more compounds of Table A or a composition described herein. In some embodiments, the compositions described herein are formulated for oral use. In some embodiments, the compositions are in a dosage form comprising one of a softgel capsule, a hard capsule, a gummy bear, a functional beverage, a functional food, a liquid, a powder, or a tablet. In some embodiments, the compositions comprise 1.0% to 99% w / w of a plant extract described herein. In some embodiments, the compositions further comprise a carrier, a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof. In some embodiments, the compositions are formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, an oral composition for use in stress management or as a medicament for treating a condition comprises one or more compounds of Table A. In some embodiments, the use of a composition for stress management in a subject is characterized in that the composition comprises one or more compounds of Table A.

[0112] In some embodiments, the methods and uses of the present disclosure include providing mood support. In some embodiments, the methods and uses include providing one or more compounds of Table A or a composition described herein. In some embodiments, the compositions described herein are formulated for oral use. In some embodiments, the compositions are in the form of one of a softgel capsule, a hard capsule, a gummy bear, a functional beverage, a functional food, a liquid, a powder, or a tablet. In some embodiments, the compositions comprise 1.0% to 99% w / w of a plant extract described herein. In some embodiments, the compositions further comprise a carrier, a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof. In some embodiments, the compositions are formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, an oral composition for use in a medicament for mood support or improvement of a condition comprises one or more compounds of Table A. In some embodiments, the use of the composition for mood support in a subject is characterized in that the composition comprises one or more compounds of Table A.

[0113] Accordingly, some aspects described herein relate to the following numbered alternatives:

[0114] 1. An oral composition for treating, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress, comprising a therapeutically effective amount of a plant extract and one or more carriers or excipients, wherein the therapeutically effective amount of the plant extract is capable of treating, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress.

[0115] 2. The oral composition of alternative 1, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0116] 3. The oral composition of alternative 1 or 2, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition.

[0117] 4. The oral composition of any one of alternatives 1 to 3, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0118] 5. The oral composition of any one of alternatives 1 to 4, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0119] 6. The oral composition of any one of alternatives 1 to 5, wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring agent, or a combination thereof.

[0120] 7. A method comprising administering a therapeutically effective amount of a composition comprising an oral composition described in any one of alternatives 1 to 6 in a subject in need of treating, preventing, reducing, modulating, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress.

[0121] 8. The method of alternative 7, wherein the plant extract of the oral composition is capable of activating a group II metabotropic receptor.

[0122] 9. The method of alternative 7 or 8, wherein the plant extract activates mGlu2 receptors.

[0123] 10. The method of alternative 7 or 8, wherein the plant extract activates mGlu3 receptors.

[0124] 11. An oral composition comprising a plant extract that is an mGlu2 or mGlu3 receptor antagonist and one or more carriers or excipients.

[0125] 12. The oral composition of alternative 11, wherein the plant extract is selected from the group selected from Rheum officinale, Phyllanthus emblica, Theobroma cacao, or combinations thereof.

[0126] 13. The oral composition of alternatives 11 or 12, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0127] 14. The oral composition of any one of alternatives 11 to 13, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition.

[0128] 15. The oral composition of any one of alternatives 11 to 14, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0129] 16. The oral composition of any one of alternatives 11 to 15, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0130] 17. The oral composition of any one of alternatives 11 to 16, wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring agent, or a combination thereof.

[0131] 18. An oral composition comprising a plant extract that is an mGlu2 or mGlu3 receptor agonist or positive allosteric modulator and one or more carriers or excipients.

[0132] 19. The oral composition of alternative 18, wherein the plant extract is selected from the group consisting of Tripterygium wilfordii, Phyllanthus emblica, Hypericum perforatum, Aloe barbadensis, Hypericum perforatum, or combinations thereof.

[0133] 20. The oral composition of alternatives 18 or 19, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0134] 21. The oral composition of any one of alternatives 18 to 20, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition or a pharmaceutical composition.

[0135] 22. The oral composition described in any one of alternatives 18 to 21, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0136] 23. The oral composition of any one of alternatives 18 to 22, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0137] 24. The oral composition of any one of alternatives 18 to 23, wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring agent, or a combination thereof.

[0138] 25. A method for modulating a disease or condition associated with mGlu2 / 3, comprising administering to a subject in need thereof a therapeutically effective amount of an oral composition described in any one of alternatives 18 to 24.

[0139] 26. An oral composition for inhibiting mGlu2 or mGlu3, comprising: rhubarb (Rheum officinale), rhubarb (Rheum officinale), cocoa (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Chinese quince (Chaenomeles sinensis), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan mountain rhubarb (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), Penstemon centranthifolius, pea (Pisum sativum), Aloe africana (Aloe africana), soybean (Glycine max), oat (Avena sativa), apple (Malus domestica), gardenia (Gardenia jasminoides), Aloe ferox, rice (Oryza sativa), Arabica coffee (Coffea arabica), safflower (Carthamus tinctorius), horsegram (Macrotyloma uniflorum), eggplant (Solanum melongena), aloe vera, Satsuma mandarin (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostook), eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv.Redman, Cat's claw (Uncaria tomentosa), Wood ear mushroom (Auricularia auricula-judae), Orange (Citrus sinensis), Cycad (Cycas revoluta), Bitter melon (Momordica charantia), Brassica carinata, Gaillardia pulchella, Lotus (Nelumbo nucifera), Black radish (Raphanus sativus var. niger), Maca (Lepidium meyenii), Corn (Zea mays), Tobacco (Nicotiana tabacum), Agaricus (Agaricus subrufescens), Flax (Linum usitatissimum), Peony (Paeonia lactiflora), Chili pepper (Capsicum annuum), Creosote bush (Larrea tridentata), Mirabilis (Mirabilis An oral composition comprising a plant extract selected from the group consisting of: Catharanthus roseus, Catharanthus jalapa, Catharanthus roseus, or a combination thereof, and one or more carriers or excipients.

[0140] 27. The oral composition of alternative 26, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0141] 28. The oral composition of alternatives 26 or 27, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition or a pharmaceutical composition.

[0142] 29. The oral composition described in any one of alternatives 26 to 28, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0143] 30. The oral composition of any one of alternatives 26 to 29, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0144] 31. The oral composition of any one of alternatives 26 to 30, wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring agent, or a combination thereof.

[0145] 32. A method for treating or modulating a disease or condition associated with mGlu2 or mGlu3, comprising administering to a subject in need thereof a therapeutically effective amount of an oral composition described in any one of alternatives 26 to 31.

[0146] 33. An oral composition for activating mGlu2 or mGlu3, comprising bitter melon (Momordica charantia), aloe vera (Aloe vera), milk thistle (Silybum marianum), aloe ferox (Aloe ferox), rhubarb (Rheum officinale), Chinese quince (Chaenomeles sinensis), clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), Chinese pepper (Erucastrum gallicum), flax (Linum usitatissimum), giant milkweed (Asclepias syriaca), St. John's wort (Hypericum perforatum), creosote bush (Larrea tridentata), eucalyptus (Eucalyptus globulus subsp. bicostata), Phyllanthus emblica (Phyllanthus annuus), or any of the following: emblica, Veronica polita, Hollyhock (Alcea rosea), Long-necked hollyhock (Neolamarckia cadamba), Catharanthus roseus, Podocarpus spicatus, Tripterygium wilfordii, Aloe africana, Juniperus monosperma, Oyster mushroom (Pleurotus ostreatus), Gypsophila perfoliate, Clausena excavate, Gynura procumbens, Red clover (Trifolium pratense cv.An oral composition comprising a plant extract selected from the group consisting of (Redman), rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), Satsuma mandarin (Citrus unshiu), splendens (Hylocomium splendens), orange (Citrus sinensis), forsythia (Forsythia suspensa), or combinations thereof, and one or more carriers or excipients.

[0147] 34. The oral composition of alternative 33, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0148] 35. The oral composition of alternatives 33 or 34, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition or a pharmaceutical composition.

[0149] 36. The oral composition described in any one of alternatives 33 to 35, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0150] 37. The oral composition of any one of alternatives 33 to 36, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0151] 38. The oral composition of any one of alternatives 33 to 37, wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring agent, or a combination thereof.

[0152] 39. A method for treating or modulating a disease or condition associated with mGlu2 or mGlu3, comprising administering to a subject in need thereof a therapeutically effective amount of an oral composition described in any one of alternatives 33 to 38.

[0153] 40. An oral composition having enhanced binding affinity and increased activity, comprising: alfalfa (Medicago sativa subsp. sativa), nightshade (Solanum americanum), coffee arabica (Coffea arabica), bitter melon (Momordica charantia), aloe vera (Aloe vera), milk thistle (Silybum marianum), cacao (Theobroma cacao), aloe ferox (Aloe ferox), gardenia (Gardenia jasminoides), cashew nut (Anacardium occidentale), chili pepper (Capsicum annuum), peony (Paeonia lactiflora), rhubarb (Rheum officinale), quince (Chaenomeles sinensis), clementine (Citrus clementina), barley (Hordeum vulgare), or a combination thereof. cv. Seco), common mustard (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), oats (Avena sativa), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), corn (Zea mays), creosote bush (Larrea tridentata), tobacco (Nicotiana tabacum), eucalyptus (Eucalyptus globulus subsp.bicostata, Malayan wild jasmine (Musa acuminata), eggplant (Solanum melongena), Phyllanthus emblica, tomato (Solanum lycopersicum), Veronica polita (Veronica polita), hollyhock (Alcea rosea), Sacha inchi (Plukenetia volubilis), green coral (Euphorbia tirucalli), long-necked jasmine (Neolamarckia cadamba), lemon (Citrus limon), periwinkle (Catharanthus roseus), Mirabilis jalapa, Podocarpus spicatus, Tripterygium wilfordii, Honeysuckle (Spatholobus suberectus), Aloe africana (Aloe africana, Crinum moorei, Juniperus monosperma, Pleurotus ostreatus, Gypsophila perfoliate, Clausena excavate, Gynura procumbens, Trifolium pratense cv. Redman, Rice (Oryza sativa), Rosemary (Rosmarinus officinalis), Lotus (Nelumbo nucifera), Safflower (Carthamus tinctorius), Citrus unshiu, Hylocomium splendens, Citrus sinensis, Juniperus dulcearia 1. An oral composition comprising a plant extract selected from the group consisting of Forsythia suspensa, Forsythia drupacea, or a combination thereof, and one or more carriers or excipients.

[0154] 41. The oral composition of alternative 40, wherein the plant extract comprises a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof.

[0155] 42. The oral composition of alternatives 40 or 41, wherein the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition.

[0156] 43. The oral composition of any one of alternatives 40 to 42, wherein the oral composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a liquid, a powder, and a tablet.

[0157] 44. The oral composition of any one of alternatives 40 to 43, wherein the oral composition comprises 10% to 99% w / w of the plant extract.

[0158] 45. An oral composition described in any one of alternatives Error! Reference source not found. to Error! Reference source not found., wherein the plant extract further comprises a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof.

[0159] 46. ​​A method for treating or modulating a disease or condition associated with mGlu2 or mGlu3, comprising administering to a subject in need thereof a therapeutically effective amount of an oral composition described in any one of alternatives 40-45.

[0160] 47. A method for treating, preventing, reducing, modulating, or ameliorating anxiety in a subject, comprising providing to the subject a composition comprising a compound selected from an mGlu2 receptor antagonist, an mGlu3 antagonist, or a combination thereof, and a carrier.

[0161] 48. A method for treating, preventing, reducing, modulating, or ameliorating anxiety in a subject, comprising providing to the subject a composition comprising a compound selected from (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or combinations thereof, and a carrier.

[0162] 49. A method for treating, preventing, reducing, modulating, or ameliorating the adverse effects of emotional stress on sleep in a subject, comprising providing to the subject a composition comprising a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or combinations thereof, and a carrier.

[0163] 50. A method for treating, preventing, reducing, modulating, or ameliorating the adverse effects of emotional stress on sleep in a subject, comprising providing to the subject a composition comprising a compound selected from an mGlu2 receptor antagonist, an mGlu3 antagonist, or a combination thereof, and a carrier.

[0164] 51. A method for treating, preventing, reducing, modulating, or ameliorating adverse effects of physiological rhythms in a subject, comprising providing to the subject a composition comprising a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or combinations thereof, and a carrier.

[0165] 52. A method for treating, preventing, reducing, regulating, or ameliorating adverse effects of physiological rhythms in a subject, comprising providing to the subject a composition comprising a compound selected from an mGlu2 receptor antagonist, an mGlu3 antagonist, or a combination thereof, and a carrier.

[0166] 53. A method for treating, preventing, reducing, modulating, or ameliorating adverse mood effects in a subject, comprising providing to the subject a composition comprising a compound selected from (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or combinations thereof, and a carrier.

[0167] 54. A method for treating, preventing, reducing, modulating, or ameliorating adverse mood effects in a subject, comprising providing to the subject a composition comprising a compound selected from an mGlu2 receptor antagonist, an mGlu3 antagonist, or a combination thereof, and a carrier.

[0168] 55. A method for treating, preventing, reducing, modulating, or ameliorating a sleep disorder in a subject, comprising providing to the subject a composition comprising a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or combinations thereof, and a carrier.

[0169] 56. An oral composition comprising a compound selected from the group consisting of (2S)-2α-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol, giburtinidol, frangula-emodin, aloe-emodin, (3aR,4aR,7aR,8R,9aR)-4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydroazuleno[6,5-b]furan-4-yl methacrylate, or a combination thereof, and a carrier, for use in a medicament for the treatment of stress, anxiety, sleep disorders, or these conditions. [Example]

[0170] The following examples provide protocols and methods for verifying and demonstrating the activity of compounds of the present disclosure in treating or ameliorating one or more of the conditions described herein. In some examples, experiments may demonstrate or evaluate whether one or more compounds of the present disclosure reduce the adverse effects of emotional stress on sleep, physiological rhythms, and mood. One or more compounds of the present disclosure may be administered to a subject by oral ingestion, such as in the form of a nutritional supplement. In some embodiments, methods and procedures according to the following examples may be performed on rodents, such as mice or rats. Where applicable, experiments to test the effectiveness of oral supplements in reducing the effects of stress on rodents may be designed and conducted under the supervision of an Animal Care and Use Committee (ACUC). Such committees may assist in ensuring that research protocols involving animals are conducted in accordance with ethical standards and minimize animal discomfort, distress, and pain. Depending on the compound being investigated, rigorous in vivo preclinical testing should be conducted prior to clinical trials. Such in vivo preclinical testing may include a validated rat model of emotional stress using in vivo biotelemetry tools and infrared video homecage monitoring, as described below. [Example]

[0171] Plant material was extracted using a Dionex™ Accelerated Solvent Extractor 350. Four 100 mL stainless steel ASE extraction cells were filled with 25 g of ground plant tissue. The preset temperature was 60°C, and static extraction was performed for a total of 12 extraction cycles. The solvents used for extraction were 95% ethanol, ethyl acetate, and hexane. The solvent was removed, and the 95% ethanol extract was subjected to a bioassay-guided fractionation protocol. Briefly, the extract was loaded dry onto a C18 spherical flash column. Elution was performed using a mobile phase consisting of water + 0.1% formic acid (A) and CH3CN + 0.1% formic acid (B), with a gradient from 1% to 3% B over 3 min, increasing to 100% B over 22 min, and then maintaining 100% B for 7 min, at a flow rate of 30 mL / min. Fractions with high activity were pooled and the pooled sample was further purified by bioassay-guided fractionation using a Kinetex reverse-phase C18 preparative column to yield gibrutinidol. [Example]

[0172] This is a prophetic example. In this example, the extraction method of Example 1 is applied to the plant tissues of Table 1.

[0173] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23

[0174] The amount of gibrutinidol or other compounds of interest described herein in a particular extract (% of the extract, w / w) is measured. Quantification of the compound is performed by normalizing the results to the weight of the extract. The results of these analyses are determined. [Example]

[0175] Oral compositions are routinely provided that utilize a caplet formulation comprising gibrutinidol from an extract of Cassia abbreviate and a carrier.

[0176] Dosage: As an oral composition, take one capsule orally once daily with one 8 ounce glass of water. [Example]

[0177] In this example, plant fractions were isolated and tested to confirm antagonistic or inhibitory activity.

[0178] Plant material was extracted using a Dionex™ Accelerated Solvent Extractor™ ("ASE") 350. One 25 mL stainless steel ASE extraction cell was filled with 5 g of freeze-dried, pulverized plant tissue. The preset temperature was 60°C, and static extraction was performed for each cell for a total of five extraction cycles: two times 95% ethanol (AX), one time 1:1 95% ethanol:ethyl acetate (BX), one time ethyl acetate (CX), and one time hexane (DX). A 3 mL aliquot was taken from each of the extracts (AX, BX, CX, and DX) and dried in a vacuum concentrator (HT12 3i Series, SP Scientific). Additionally, one 3 mL aliquot of the AX extract was treated with 0.5 g of poly(vinyl polypyrrolidone), or PVP, resin to create an additional sample (AP). The resin was filtered using a centrifugal filter unit (PVDF, 0.45 μm), and the remaining supernatant was dried in a vacuum concentrator. To generate fractions X0–X6, the AX, BX, CX, and DX extracts were combined, adsorbed onto Celite, and placed on a solid-loading cartridge for fractionation by C18 spherical flash chromatography on a Combi Flash (Teledyne). Fractionation was performed at a flow rate of 18 mL / min using water + 0.1% formic acid (A) and CH3CN + 0.1% formic acid (B) as mobile phases. Two-minute fractions were collected for each isosolvent step (increasing polarity: 10, 20, 40, 60, 80, and 100% B correspond to X0, X1, X2, X3, X4, and X5, respectively), followed by an additional 4-minute collection of 100% B, resulting in fraction X6.

[0179] Samples were assayed for agonist, positive allosteric modulator (PAM), and antagonist / negative allosteric modulator (NAM) activity at mGluR2 and mGluR3. Primary assays for mGluR2 and mGluR3 activity were performed using the cAMP HitHunter® assay, designed and supplied by DiscoverX. The mGluR2 assay was performed using the CHO-K1 GRM2 Gi cell line, and the mGluR3 assay was performed using the CHO-K1 GRM3 Gi cell line. The assay protocol was adjusted to assess the directionality of activity, and the same protocol was used for both mGluR2 and mGluR3 assays. For agonist activity, assays were performed without the addition of endogenous agonist to measure the effect on receptor activity. For PAM activity, assays were performed with the addition of the known control agonist LY354740 at 10 nM. Finally, for antagonist / NAM activity, the same known control agonist was added at 50 nM. The assay screening cannot distinguish between antagonist and NAM activity; both require the addition of an agonist. Activity at the target receptor was confirmed by Western blot analysis of ERK phosphorylation (pERK), a downstream component of the signaling cascade. The assay conditions were adjusted using the same differentiation strategy as above, along with various concentrations of the target agonist, for samples that showed activity in the primary assay. Agonist and PAM activity increased pERK, while antagonist / NAM activity decreased pERK.

[0180] To address potential viability issues related to assay performance and future in vivo toxicity, samples that demonstrated mGluR2 and mGluR3 activity were also measured for cellular metabolic health, viability, and live / dead analysis (a measure of cell death). Viability was measured using the CyQUANT™ XTT assay kit provided by ThermoFisher, while live / dead assays were measured using the HCS Live / Dead Green kit provided by Invitrogen.

[0181] The results of this study are shown in Tables 2-6 and Figures 1-2.

[0182] [Table 2]

[0183] [Table 3]

[0184] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9]

[0185] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0186] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Example]

[0187] This example describes in vitro data in a standardized bioassay protocol for the disclosed compounds.

[0188] A standardized bioassay protocol was performed as shown in Figure 3. The standardized bioassay protocol used an assay buffer of HBSS with 1% HEPES. Cells were cultured overnight at 10,000 cells / well in 20 μl of seeding reagent. Experimental controls included an L-glutamate agonist (AC156212500), an LY354740 agonist (Fisher part #: 32-465-0), an LY341495 antagonist (Fisher part #: 12-095-0), a BINA PAM (Fisher part #: 40-485-0), and a (decoglurant) NAM (Fisher part #: 50-203-0742).

[0189] The results are shown in Table 7 and Figures 4 and 5. Figure 4 shows that mGlu2 activity higher than the control (red dotted line at 100%) suggests an mGlu2 negative allosteric modulator or antagonist. Assays were performed at 20 μM. Figure 5 shows that mGlu2 activity lower than the control (100%) suggests an mGlu2 positive allosteric modulator or agonist. Assays were performed at 100 μM.

[0190] [Table 7] [Example]

[0191] This example describes a study protocol to test the tolerability and efficacy of a novel plant-derived supplement for sleep disorders and anxiety.

[0192] (Background and Objectives)

[0193] Emotional and physical stressors disrupt sleep and physiological rhythms, increasing the risk of developing mood disorders.In light of recent evidence that repeated or chronic use of prescription or over-the-counter sedative-hypnotic drugs has adverse effects on brain health, there is a need to discover new natural compounds that are safe and effective in reducing emotional stress and protecting sleep and circadian rhythms.The main purpose of this example is to test the hypothesis that oral intake of a dietary supplement according to one embodiment of the present disclosure reduces the adverse effects of emotional stress on sleep, physiological rhythms and mood.

[0194] (Primary Objective - Experiment 1: Maximum Tolerated Dose (MTD) Test)

[0195] The tolerability of two candidate compounds of the present disclosure will be tested. Compounds will be administered using an oral dosing method. Rats will receive compounds once daily for four days. Dose will be determined based on the pharmacological profile. Additional dependent measures will be established based on published MTD guidelines. Body weight and food consumption will be measured daily. Rats will be euthanized at the end of the study, and tissues will be dissected, observed, weighed, and cryopreserved for future toxicity-related analyses. Behavioral changes, including sickness behavior, will be recorded by continuous infrared video home cage monitoring. The results of this study will help identify the MTD for each compound evaluated in the efficacy "Stress and Biotelemetry" study described below.

[0196] (Experimental Design)

[0197] 2 x 2 (male, female) x 4-7 doses + vehicle: 16-28 groups, estimated number of rats: 160-280 depending on MTD range. Rats will be orally dosed with vehicle (Vehicle) or one of the disclosed compounds for 5 days immediately after the onset of the inactivity / sleep cycle (0900). Due to the workload of this project, multiple balanced cohorts will be tested with staggered start times. Study duration: 18 days (14 days of room acclimation, 4 cohorts of 4-day oral vehicle and compound treatments, approximately 20 weeks).

[0198] (Experiment 2: Efficacy Test: Stress and Biotelemetry)

[0199] Using the rat chronic emotional stress CCF model described below, oral administration of compounds of the present disclosure will be tested daily to measure the adverse effects of emotional stress on sleep, physiological rhythms, and anxiety. The maximum tolerated dose (MTD) of compounds of the present disclosure will be tested based on the above MTD study. Chronic conditioned fear (CCF) is a validated model of persistent emotional stress that has previously been reported to produce a series of adaptive failures, including sleep disturbances, flattened physiological rhythms, and anxiety-like behaviors. Dependent measures will be collected using in vivo biotelemetry and infrared Synology home cage monitoring. Rats will be randomly assigned to a group exposed to the chronic conditioned fear protocol (CCF) or a group that will remain in their home cage and serve as a non-stressed control.

[0200] All rats will be surgically implanted with HD-SO2 transmitters for biotelemetry, allowing for measurements of locomotor activity (LA), heart rate (HR), core body temperature (CBT), electromyography (EMG) of the dorsal neck muscles, and electroencephalography (EEG). In this project, rats will be fitted with telemetry equipment to measure LA, CBT, EMG, and EEG. After postoperative recovery, continuous biotelemetry measurements will be performed before CCF (24-hours per day for 3 days, home cage recording), during CCF (20-minute sessions, 2CF sessions per day for 21 days, conditioned fear chamber), and after CCF (24-hours per day for 7 days, home cage recording). Because sex differences in conditioned fear have been reported, both male and female rats will be tested in this project.

[0201] (Secondary purpose)

[0202] These studies will also examine the potential behavioral and physiology effects of oral administration of the disclosed compounds in the absence of stress. Maximum tolerated dose studies will include home cage monitoring to assess the effects of compounds on home cage behavior. Stress and biotelemetry studies will also include a non-stressed control group, thereby clarifying the effects of repeated oral administration of compounds on sleep, in vivo physiology, and behavior.

[0203] (Foundations and feasibility of experimental approaches)

[0204] Conditioned fear (CF): CF is produced by placing rats in a fear conditioning chamber and administering three 2-second, 1.5 mA foot shocks to condition a specific environment. A single pairing of the foot shock with the chamber in the fear conditioning chamber, without any additional foot shocks, conditions the rat to fear the chamber. This is called "conditioned fear (CF)." Rodents express fear by exhibiting a "freeze" behavior, remaining motionless except for movements required for breathing. CF also produces typical characteristics of an in vivo stress response, including increases in heart rate, blood pressure, and core temperature.

[0205] Chronic Conditioned Fear (CCF): The CCF model is designed to examine the mental and physical effects of sustained emotional stress. In the CCF model, rats are exposed to a conditioning chamber for 20 minutes, twice daily, at random times during the sleep cycle. Multiple exposures to the chamber in the absence of footshocks abolish fear behavior. If freezing time during the 20-minute test falls below 50%, a single "reminder" footshock (2 seconds, 1.5 mA) restores fear behavior and stress responses. Typically, simply one or two "reminder" footshocks are sufficient to maintain fear behavior and stress responses for 14 days (twice daily). The Fleshner Stress Physiology Laboratory, an expert in this technique, has reported that conditioned fear induces in vivo stress responses, including increases in heart rate (HR), mean arterial pressure (MAP), and core body temperature (CBT), and that chronic conditioned fear produces sleep disturbances, flattened circadian rhythms, and anxiety-like behaviors. In humans, repeated exposure to psychological stressors such as fear increases HR, CBT, and anxiety, enhancing the translational utility of this model.

[0206] Home cage behavior patterns suggestive of anxiety: Stressor exposure results in changes in home cage behavior patterns suggestive of increased anxiety and depression. A 24-hour video recording of home cage behavior is acquired using an infrared camera. Behavior is analyzed before, during, and after stressor exposure. Changes in anxiety and depression are captured by Behavioral Observation Research Interactive Software (BORIS) analysis of home cage behavior rather than open field, forced swim test, or radial arm maze tasks, because these tests themselves have been shown to disrupt sleep, flatten circadian rhythms, and be affected by the presence of an observer.

[0207] (method)

[0208] Biotelemetry (DSI™)-in vivo stress response, circadian rhythms, and sleep-EEG: Sleep (REM and NREM sleep) was measured using EMG and EEG data and analyzed with Neuroscore™ software. Circadian rhythm flattening was captured using LA, EEG, and CBT data and scored using the ClockLab program version 6.1.02 (Actimetrics Software™, Wilmette, IL, USA).

[0209] Infrared Synology Homecage Monitoring: Due to video equipment limitations and time constraints, rats in the tolerance test were videotaped in their home cages using the system described, but not in the stress and biotelemetry tests. This non-invasive method does not disturb the animals. Axis Model #M3104 infrared cameras were placed near the rats' home cages, allowing 24-hour lateral video recording of homecage behavior. These cameras provide excellent visibility of animals during the light and dark phases and do not emit light, so they do not disrupt circadian rhythms of sleep or physiological rhythms. Video recordings were acquired using Synology Surveillance Station. Homecage video recordings were scored using Behavioral Observation Research Interactive Software (BORIS) (Friard and Gamba, 2016). This software allows for simultaneous scoring of multiple behaviors. Snapshot analysis: Home cage behavior was scored 1 hour before and 1 hour after lights out and expressed as a percentage of control (total time of specific activity in control animals (vehicle, HCC) / total time of specific activity in emotional stress-exposed rats). This period captures activity motivated by the light / dark change. It is well established that rats are highly active spontaneously for 1 hour after lights out, and feeding and drinking occur almost exclusively during the dark phase (active phase). The following details the behaviors to be scored (duration, frequency) based on the Stanford Ethogram definition. Inactive behavior: "Absence of movement" and includes periods when the animal is "quiet and alert" and "quiet and not alert, suggesting a sleep state." Overall activity: "All behaviors in which movement is present." Total duration (and frequency) is scored. Active behavior is further classified into two subcategories: "maintenance behavior" or "general activity." Maintenance behaviors: Behaviors that function to maintain the animal's physiological homeostasis, comfort, and appearance, including drinking, feeding, grooming (self-grooming), and nest-building. General activities: Other behaviors that involve movement that do not fall under maintenance behaviors, including exploratory behaviors, affiliative interactions (allo-grooming, wrestling / play), aggressive interactions, and other behaviors.

[0210] Expected Results: Based on previous results, we expect that CCF-exposed rats will have disrupted sleep / wake behavior, sleep architecture, circadian LA, CBT, and EEG rhythms. Strengths of this experimental approach include the use of an emotional stressor (conditioned fear (CF)), rigorous and reproducible outcomes in the chronic conditioned fear (CCF) model, automated measurements of behavior, physiology, and sleep, real-time, continuous, and non-contact measurements of fear behavior and in vivo stress physiology, and an ethological approach (24-hour video recording of home-cage behavior and BORIS analysis) to determine the emotional and behavioral effects of stressor exposure.

[0211] With respect to the use of plural and singular terms herein, those skilled in the art will understand that conversion from plural to singular and vice versa may be possible depending on the context and application. For clarity, various singular / plural combinations may be expressly set forth herein.

[0212] Those skilled in the art will understand that the terms used in this specification generally, and in particular in the accompanying alternatives (e.g., the body of the alternatives), are generally intended as "open" terms (e.g., "including" should be interpreted as "including but not limited to," "having" should be interpreted as "having at least," "including" should be interpreted as "including but not limited to," etc.). Furthermore, those skilled in the art will understand that if a specific number of listed alternatives to be introduced is intended, that intention will be explicitly stated in the alternative, and that no such intention exists otherwise. For example, to aid in understanding, the following accompanying alternatives may include the introductory phrases "at least one" and "one or more." However, the use of such phrases should not be interpreted as meaning that the introduction of an alternative description with an indefinite article such as "a" or "an" is limited to embodiments in which the alternative includes only one such description (even when the same alternative includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an," "a" and / or "an" should be interpreted as "at least one" or "one or more"); similarly, the introduction of an alternative description with a definite article. Furthermore, even when a specific number of alternative descriptions introduced is explicitly recited, those skilled in the art will recognize that the description should be interpreted as at least the recited number (e.g., a mere recitation of "two descriptions" means at least two, i.e., two or more, unless otherwise qualified). Furthermore, when expressions such as "at least one of A, B, and C" are used, they are intended in the sense that would be generally understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems including only A, only B, only C, A and B, A and C, B and C, and / or all of A, B, and C, etc.).

[0213] When phrases such as "at least one of A, B, or C" are used, they are intended to have the meaning generally understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems including only A, only B, only C, A and B, A and C, B and C, and / or all of A, B, and C). Additionally, any disjunctive phrases or phrases presenting two or more options in descriptions, alternatives, or drawings should be understood to contemplate the possibility of including either, both, or both. For example, the phrase "A or B" should be understood to include the possibilities of "A" or "B" or "A and B."

[0214] Furthermore, when features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure also describes any individual member or subgroup member of the Markush group.

[0215] As one of ordinary skill in the art will understand, for all purposes, including within the scope of the description, all ranges disclosed herein encompass any and all subranges and combinations thereof. It can be readily recognized that any described range can be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, upper third, etc. Additionally, terms such as "up to," "at least," "greater than," "less than," etc., refer to ranges that are inclusive of the recited values ​​and that are divisible into subranges as described above. Furthermore, as one of ordinary skill in the art will understand, a range includes each individual component. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items.

Claims

1. one or more compounds capable of modulating metabotropic glutamate receptors; A stress supplement composition comprising:

2. The one or more compounds are 【Chemistry 1】 A compound of formula (I), or a salt thereof, R １ , R ２ , R ３ and R ４ are each independently hydrogen, deuterium, hydroxyl, halogen, keto, optionally substituted ester, optionally substituted aryl, optionally substituted alkoxy, optionally substituted C １ -C ６ Alkyl, optionally substituted —O—C １ -C ６ Alkyl or optionally substituted C ３ -C ６ The composition of claim 1 wherein the alkyl is selected from cycloalkyl.

3. R １ The composition of claim 2 , wherein is hydrogen or hydroxyl.

4. R ２ The composition of claim 2 , wherein is hydroxyl or keto.

5. R ３ The composition of claim 2 , wherein is hydroxyl or keto.

6. R ４ is hydrogen, hydroxyl, keto, optionally substituted O—C １ -C ６ Alkyl or optionally substituted C １ -C ６ The composition of claim 2 wherein the alkyl is alkyl.

7. The one or more compounds are 【Chemistry 2】 or a combination thereof.

8. The composition of claim 1 , wherein the metabotropic glutamate receptor is a group II receptor.

9. 10. The composition of claim 1, wherein the one or more compounds are derived from a plant extract.

10. The plant extracts include those of rhubarb (Rheum officinale), Phyllanthus emblica, apple (Malus domestica), Tripterygium wilfordii, aloe barbadensis, cacao (Theobroma cacao), Chinese quince (Chaenomeles sinensis), St. John's wort (Hypericum perforatum), Citrus unshiu, lotus (Nelumbo nucifera), and acacia luderitzii. luederitzii), Cassia abbreviate, Cassia fistula, mopane (Colophospermum mopane), Julbernardia globiflora, Habranthus brachyandrus, Monactis macbridei, Arnica acaulis, Arnica montana, Daucus carota, Bauhinia mancha manca), Botrytis cinerea, Brosimum acutifolium, Broussonetia kazinoki, Broussonetia papyrifera, Dalbergia latifolia, Dracaena cambodiana, Dracaena draco, Narcissus pseudonarcissus, Phanera guianensis, Rohdea chinensis chinensis), Soymida febrifuga, Pacific yew (Taxus brevifolia), Tupistra chinensischinensis), Abri herba, Abrus pulchellus subsp. Cantoniensis, Achyranthes bidentata, Aconitum seraphschanicum, Aconitum tashiromontanum, Acorus tataninowii rhizome, Acorus gramineus, Acorus tatarinowii, Actinidia chinensis planch), Adansonia grandidieri, Aframomum giganteum, Aizopsis selkiana, Albizia myriophylla, Alisma plantago-aquatica subsp. orientale, Aloe castellorum, Aloe vera, Alpiniae officinarum rhizome, Amaranthus hypochondriacus, Ampelopsis japonica, Amphorgyne spicata, Anaphalis lacteal, Anchusa azurea, Andrographis laxiflora, Andrographis neesiana, Anemarrhena asphodeloides, Aphyllocladus denticulatus, and Aralia aralia. decaisneana), Artemisia annua, Artemisiaparviflora), Artemisia scoparia [synonyms: Artemisia capillaris v, Artemisia scoparia], Aspidosperma discolor, Asteris root and rhizome, Aster sedifolius, Aster tataricus, Atadinus libanoticus, Baccharis potosina, Balanophora laxiflora laxiflora), Bassia muricata, wax gourd (Benincasa hispida), table beet (Beta vulgaris vulgaris), Bistorta elliptica, Bistorta officinalis, ramie rhizomes and roots (Boehmeriae rhizoma et radix), ramie (Boehmeria nivea), Boehmeria platanifolia [synonyms: Boehmeria tricuspis, Boehmeria platanifolia], Bolbostenma paniculati bulbus, Bolbostenma paniculatum, Brassica rapa, Bridelia stipularis, Canarium bengalense, Carduus tenuiflorus, Cascara sagrada, Cassia alata L., Cassia angolensis, Cassiae semen), Cassia fastuosa, Java senna (Cassiajavanica), Cassia obtusifolia, Cassia occidentalis, Cassia speciosa, Cassia tora L., Cassia tora, Cassia torosa L., Catalpa longissima, Caulerpa peltata, Caulerpa polygoni multiflori, Caulerpa sargentii stems Sargentodoxae, Caulocystis cephalornithos, Ipecac (Cephaelis ipecacuanha), Cephalotaxus griffithii, Chaiturus marrubiastrum, Mimosa mimosoides, Chamaecrista nigricans, Chamaecrista nomame, Chamaecrista pumila pumila), Cheilanthes argentea, quinoa (Chenopodium quinoa), chicory (Cichorium intybus), field thistle (Cirsium oligophyllum), Clibadium sprucei, coreopsis tinctoria, Corydalis rhizoma, Cranifilia fluviatilis, Cratoxylum formosum, and Cremastra appendiculata), Cynanchum viminale, Dalbergia hupeana, Dalbergia lanceolaria subsp. paniculata, Dalbergia lanceolaria subsp.paniculata), Degenia velebitica, Delphinium nuttallianum, Delphinium virgatum, Dendriopoterium menendezii, Dendrobium thyrsiflorum, Derris canarensis, Derris cuneifolia, Derris oblonga, Dianthi herba, carnation (Dianthus caryophyllus, Dictyopteris australis, Dillenia indica, Dioscoreae bulbiferae, Dipsacus azureus, Dodonaea viscosa, Dysoxylum cumingianum, Dysoxylum muelleri, Elymus repens, Enceliopsis argophila argophila), Endophytic aspergillus, Epimedium koreanum, Epimrdii herba, Eria mollis, Eriocaulon buergerianum, Eriocaulon sieboldianum, Erythrina lysistemon, Erythrophleum ivorance, Euodia bodinieri, Euodia officinalis), Euodia ruticarpa, Fagopyrum esculentum, Tartary buckwheattataricum, Fallopia multiflora, Fallopia sachalinensis, Flacourtia jangomas, Frangula alnus, Frangula purshiana, Fridericia triplinervia triplinervia, Garcinia polyantha, Gleichenia quadripartita, Glycyrrhiza uralensis, Gnaphalii affinis herba, Grangea maderaspatana, Hedera helix, Helichrysum chionosphaerum, Helichrysum plicatum, Heynea trijuga trijuga), Hoveniae dulcis semen, Hymenoxys lemmonii, Hypericum prolificum, Hypericum sampsonii, Isatdis radix, Isatis tinctoria, Jacquemontia paniculata, Taiwan juniperus, Justicia secunda, Lactuca plumieri), lettuce (Lactuca sativa), Ranaria lanata, larch (Larix kaempferior), lavender (Lavandula vera), Leptocereus quadricostatus, bush clover (Lespedeza tomentosa), Ligularia pleurocaulis, white jasmine (Lilii bulbus), and Lilium brownii f.e. brown var. colchesteri. wils), Lilium brownii var. viridulum [synonyms: Lilium brown, Lilium browniivar. viridulum], Lobelia berlandieri, Loranthus pentandrus, Lupinus corymbosus, Lycii cortex, Maclura tinctoria, Magnolia figo, Magnolia ovata, Mandragora autumnalis, Melicope triphylla, Mentha arvensis, Japanese mint, Mentha canadensis, Mentha herba, Metrodorea nigra, Miliusa velutina, Mitracarpus scaber, Muehlenbeckia tamnifolia, Muntingia calabura, Myrsine africana, Nekemias grossedentata, Neobalanocarpus heimii heimii), Nepeta granatensis, Nepeta parnassica, Nuxia floribunda, Onobrychis arenaria, Oryctes monoceros, Osmanthus armatus, Passiflora sexflora, Persicaria decipiens, Persicaria hydropiper, Persicaria maculosa), Ishimikawa (Persicaria perfoliata), Persicaria salicifolia (Persicariasalicifolia, Petunia integrifolia subsp. inflata, Phaseolus vulgaris, Phlogacanthus curviflorus, Photinia serratifolia, Physalis alkekengi, Picramia antidesma, Picramia hirsuta, Picramia tiapensis teapensis, Picramnia teapensis Tul., Picrasma quassioides, Pinalia stricta, Pisum sativum, Plantago coronapus, Plantago lanceolata, Pleione bulbocodioides, Pleione yunnanensis, Ploiarium alternifolium alternifolium), Pluchea odora, Pneumathopteris pennigera, Japanese knotweed rhizomes and roots (Polygoni cuspidatii rhizoma et radix), Japanese knotweed (Polygonum cuspidatum), Polygonum hypoleucum, Polygonum multiflorum, Polygonum perfoliatum, Pseudolarix amabilis), Psorospermum glaberrimum, Psorospermum laurentii, Psorospermum tenuifoliumtenuifolium), Psychotria stachyoides, Red oak (Quercus rubra), Radix boehmeriae, Rhubarb roots and rhizomes (Radix et Rhizoma Rhei), Rhubarb roots and rhizomes (Radix et Rhizoma Rhei Praeparata), Ravenia spectabilis, Japanese knotweed (Reynoutria japonica), Buckthorn (Rhamnus cathartica), Black rose (Rhamnus davurica), Rhamnus erythroxyloides, Taiwan buckthorn (Rhamnus formosana), Rhamnus frangula [synonym: Frangula alnus], Rhamnus frangula, Rhamnus hirtella, Rhamnus kurdica, Nakahara buckthorn (Rhamnus nakaharae), Rhamnus nepalensis, Rhamnus parasii pallasii, Rhamnus prinoides, Rhamnus procumbens, Rhamnus punctata, Rhamnus saxatilis, Rhamnus thymifolius, Rhamnus triquetra, Rhamnus wightii, Rheum acuminatum, Rheum alexandrae, Rheum altaicum altaicum), Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi), Rheum emodi [synonym: Rheum australe], Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangens, Rheum nanum, Rheum nobile, Rheum palmatum, Rheum pumilium pumilum, Rheum racemiferum, Rheum reticulatum, Rhubarb (Rheum rhabarbarum), Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum spp., Rheum subacaule, Rheum sublanceolatum, Rheum tanguticum, Rheum tataricum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum wittrocki, Rheum yunnanense, Rhizoma fagopyri cymose, Rhodiola viridula, Rhododendron dahuricum, Rosa pomifera, Rumex abyssinicus abyssinicus), sorrel (Rumex acetosa), red sorrel (Rumex acetosella), Rumex aegyptiacus, Rumex alpinus sorrel (Rumexalpinus), Rumex bequaertii, Rumex chalepensis, Rumex crispus, Rumex cristatus, Rumex cyprius, Rumex dentatus, Rumex japonicus, Rumex Rumex lanceolatus, Rumex limoniastrum, Nepal sorrel (Rumex nepalensis), Rumex patientia, Rumex pictus, Rumex pulcher, Rumex ruwenzoriensis, Rumex scutatus, Rumex simpliciflorus, Rumex spp., Rumex tuberosus tuberosus, Rumex usambarensis, Rumex vesicarius, Salvia aurea, Salvia greggii, Sargentodoxa cuneata, Sargentodoxae caulis, Saururus chinensis, Schistostephium artemisiifolium, Scilla socialis socialis), Selaginella labordei, Senecio pharbitis, Senecio behnii, Senecio bonariensis, Senecio praecox, Senecio subdentatus, Golden Candle, Senna alexandrina, Senna angustisiliqua, Senna artemisioides, Senna auriculata auriculata), Senna corymbosa, Sennadidymobotrya, Senna folium, Senna lindheimeriana, Senna macranthera, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna podocarpa, Senna septemtrionalis, Senna siamea, Senna sophera, Senna spectabilis spectabilis, Senna tora, Simaba orinocensis, Smythea bombaiensis, Solanum cleistogamum, Sophorae tonkinensis radix et rhizome, Mitsukato (Spatholobus suberectus), Sphaerella rosigena, Spinach (Spinacia oleracea), Stevia berlandieri berlandieri, Stevia ovata, Australian myrtle (Syzygium australe), Tagetes filifolia, Tanacetum coccineum, Taraxacum kok-saghyz, Chinese dandelion (Taraxacum platycarpum subsp. hondoense), Tetradium ruticarpum, Teucrium yemense, Thymelaea hirsute hirsute), Tribulus fructus, Tribulus terrestris, Uvaria afzelii, Vatairea heteropteransheteropteran, Ventilago calyculata, Ventilago denticulata, Ventilago leiocarpa, Ventilago madraspatana, Verbascum thapsiforme, Vismia guianensis, Vismia guineensis, Vismia laurentii, Vismia orientalis orientalis, European grape (Vitis vinifera), Wilbrandia ebractea, Xanthi fructus, Strawberry (Xerochrysum viscosum), Angelica archangelica, Cascara saccharina (Frangula purshiana), Geranium maculatum, Rumex crispus, Senecio congestus, Senna alexandrina, Aloe africana africana), Aloe arborescens, Aloe castellorum, Aloe ergonica, Aloe ferox, Aloe rubroviolacea, Aloe spicata, Aloe succotrina, Asphodeline tenuior, Asphodelus aestivus, Asphodelus albus, Asphodelus serrulata fistulosus), Asphodelusramosus, Asphodelus tenuifolius, Berchemia floribunda, Bergenia hissarica, Bulbine annua, Bulbine asphodeloides, Callisia fragrans, Cassia aldabrensis, Cassia grandis, Cassia javanica, Mimosa pudica, Chamaecrista mimosoides, Commiphora socotrana, Frangula alnus, Frangula purshiana, Kniphofia ensifolia, Kniphofia foliosa, Kniphofia insignis, Kniphofia isoetifolia, Kniphofia schimperi, Picramia antidesma antidesma, Picramia hirsute, Guava (Psidium guajava), Japanese knotweed (Reynoutria japonica), Rhamnus alaternus, Buckthorn (Rhamnus cathartica), Black rose (Rhamnus davurica), Rheum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum rhubarb compactum), Rheum coreanum, Rheum delavaidelavayi, Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangens, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum reticulatum, Rhubarb (Rheum rhabarbarum), Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum subacaule, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum unnanens yunnanense, Rumex cristatus, Rumex paulsenianus, Rumex scutatus, Selaginella delicatula, Golden Candle (Senna alata), Senna (Senna alexandrina), Senna didymobotrya, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna reticulata, Senna tagliatelle, siamea), Senna tora, Spatholobus suberectus, Stephania dinkulagueidinklagei), Xanthorrhoea australis, chicory (Cichorium intybus), Cassia occidentalis, Morinda royoc, Galium aparine, Bryophyllum pinnatum, Anthema tinctoria, Aegle marmelos, Cymbopogon spp., Wedelia trilobata, Angelica archangelica, Vitis tilifolia, Mirabilis jalapa, Centipeda minima, Bauhinia manca, Juniperus drupacea, Forsythia suspensa, Citrus sinensis, Hylocomium splendens), safflower (Carthamus tinctorius), rosemary (Rosmarinus officinalis), rice (Oryza sativa), red clover (Trifolium pratense cv. Redman), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan mountain jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), cacao (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana, Malayan mountain jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), Penstemon centranthifolius, pea (Pisum sativum), soybean (Glycine max), oat (Avena sativa), apple (Malus domestica), gardenia (Gardenia jasminoides), aloe ferox, rice (Oryza sativa), sativa), Arabica coffee plant (Coffea arabica), safflower (Carthamus tinctorius), horsegram (Macrotylomauniflorum), eggplant (Solanum melongena), Satsuma mandarin (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostalk), eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricularia-judae), orange (Citrus sinensis), cycad (Cycas revoluta), bitter melon (Momordica charantia), Brassica carinata, gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var. niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum, Agaricus (Agaricus subbrufescens), Flax (Linum usitatissimum), Peony (Paeonia lactiflora), Capsicum (Capsicum annuum), Creosote bush (Larrea tridentata), Mirabilis (Mirabilis jalapa), Catharanthus roseus, Alfalfa (Medicago sativa subsp. sativa), Nightshade (Solanum americanum), Arabica coffee (Coffea arabica), Bitter melon (Momordica charantia), milk thistle (Silybum marianum), cacao (Theobroma cacao), aloe ferox, gardeniajasminoides), cashew nuts (Anacardium occidentale), chili peppers (Capsicum annuum), peony (Paeonia lactiflora), clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), peppers (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), oats (Avena sativa), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), corn (Zea mays), creosote bush (Larrea tridentata), tobacco (Nicotiana tabacum), eucalyptus (Eucalyptus globulus subsp. bicostata), Malayan wild jasmine (Musa acuminata), eggplant (Solanum melongena), Phyllanthus emblica, tomato (Solanum lycopersicum), Veronica polita, hollyhock (Alcea rosea), sacha inchi (Plukenetia volubilis), green coral (Euphorbia tirucalli), Neolamarckia cadamba, Citrus limon, Catharanthus roseus, Mirabilis jalapa, Podocarpus spicatus, Tripterygium wilfordii, Spatholobus suberectus, Crinum moorei, Juniperus monosperma, Pleurotus oyster mushroom ostreatus), Gypsophila perfoliate, Clausena excavata, Gynura procumbensprocumbens), red clover (Trifolium pratense cv. Redman), rice (Oryza sativa), rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), safflower (Carthamus tinctorius), Satsuma mandarin (Citrus unshiu), rock moss (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia (Forsythia suspensa), bitter melon (Momordica charantia), milk thistle (Silybum marianum), aloe ferox, clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), peppercorn (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), St. John's wort (Hypericum perforatum), creosote bush (Larrea tridentata), eucalyptus (Eucalyptus globulus subsp. bicostata), Phyllanthus emblica, Veronica polita, Alcea rosea, Neolamarckia cadamba, Catharanthus roseus, Podocarpus spicatus, Tripterygium wilfordii, Juniperus monosperma, Pleurotus ostreatus, Gypsophila perfoliate), Clausena excavate, Gynura procumbens, red clover (Trifolium pratense cv.Redman), rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), Satsuma mandarin (Citrus unshiu), rock moss (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia (Forsythia suspensa), 10. The composition of claim 9, wherein the plant extract is selected from the group consisting of:

11. The plant extracts include those of rhubarb (Rheum officinale), cocoa (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Chinese quince (Chaenomeles sinensis), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan mountain jasmine (Musa acuminata), Douglas fir (Pseudotsuga menziesii var. menziesii), Penstemon centranthifolius, pea (Pisum sativum), Aloe africana (Aloe africana), soybean (Glycine max) max), oats (Avena sativa), apples (Malus domestica), gardenias (Gardenia jasminoides), aloe ferox (Aloe ferox), rice (Oryza sativa), coffee arabica (Coffea arabica), safflower (Carthamus tinctorius), horse gram (Macrotyloma uniflorum), eggplant (Solanum melongena), aloe vera (Aloe vera), Satsuma mandarins (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostalk), eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricula-judae), orange (Citrus sinensis), cycad (Cycas revoluta) revoluta), Momordica charantia, Brassica catarinacarinata), gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var. niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum), agaricus (Agaricus subbrufescens), flax (Linum usitatissimum), peony (Paeonia lactiflora), chili pepper (Capsicum annuum), creosote bush (Larrea tridentata), and Mirabilis 11. The composition of claim 10, wherein the extract is a plant extract selected from the group consisting of: periwinkle (Catharanthus roseus), jalapenos (Catharanthus roseus), or a combination thereof.

12. 11. The composition of claim 10, wherein the plant extract is selected from the group consisting of Rheum officinale, Phyllanthus emblica, Theobroma cacao, or a combination thereof.

13. 11. The composition of claim 10, wherein the plant extract is selected from Tripterygium wilfordii, Phyllanthus emblica, Hypericum performum, Aloe barbadensis, Hypericum performum, or combinations thereof.

14. The one or more compounds from the plant extract are 【Transformation 3】 The composition of claim 10, wherein the composition is selected from:

15. 10. The composition of claim 1, wherein the composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition.

16. 10. The composition of claim 1, wherein the composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a gummy, a functional drink, a functional food, a liquid, a powder, and a tablet.

17. 11. The composition of claim 10, wherein the composition comprises 1.0% to 99% w / w of the plant extract.

18. The composition of claim 1 , wherein the composition further comprises a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof.

19. The one or more compounds are 【Chemistry 4】 The composition of claim 7, wherein

20. The one or more compounds are 【Transformation 5】 The composition of claim 7, wherein

21. The one or more compounds are 【Transformation 6】 The composition of claim 7, wherein

22. 1. A method for treating, reducing, preventing, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress in a subject, said method comprising: providing to a subject a composition comprising one or more compounds capable of modulating metabotropic glutamate receptors and a carrier; The composition is provided in an amount sufficient to treat, reduce, prevent or ameliorate stress, symptoms of stress or harmful effects of stress.

23. The one or more compounds have the formula (I): 【Transformation 7】 or a salt thereof, R １ , R ２ , R ３ and R ４ are each independently hydrogen, deuterium, hydroxyl, halogen, keto, optionally substituted ester, optionally substituted aryl, optionally substituted alkoxy, optionally substituted C １ -C ６ Alkyl, optionally substituted —O—C １ -C ６ Alkyl or optionally substituted C ３ -C ６ 23. The method of claim 22, wherein the alkyl is selected from cycloalkyl.

24. R １ is hydrogen or hydroxyl.

25. R ２ is hydroxyl or keto.

26. R ３ is hydroxyl or keto.

27. R ４ is hydrogen, hydroxyl, keto, optionally substituted O—C １ -C ６ Alkyl or optionally substituted C １ -C ６ 24. The method of claim 23, wherein the alkyl is alkyl.

28. The compound is 【Transformation 8】 23. The method of claim 22, wherein the

29. 23. The method of claim 22, wherein providing the composition supports a healthy stress response in the subject.

30. 23. The method of claim 22, wherein providing the composition supports glutamate homeostasis in the subject.

31. 23. The method of claim 22, wherein the step of providing the composition provides stress management for the subject.

32. 23. The method of claim 22, wherein the step of providing the composition provides mood support to the subject.

33. 31. The method of claim 30, wherein the compound is a Glu2 agonist and a positive allosteric modulator, or an mGlu3 agonist and a positive allosteric modulator.

34. 31. The method of claim 30, wherein the compound is an mGlu2 antagonist and a negative allosteric modulator, or an mGlu3 antagonist and a negative allosteric modulator.

35. 23. The method of claim 22, wherein the one or more compounds are derived from a plant extract.

36. The plant extracts include those of rhubarb (Rheum officinale), Phyllanthus emblica, apple (Malus domestica), Tripterygium wilfordii, aloe barbadensis, cacao (Theobroma cacao), Chinese quince (Chaenomeles sinensis), St. John's wort (Hypericum perforatum), Citrus unshiu, lotus (Nelumbo nucifera), and acacia luderitzii. luederitzii), Cassia abbreviate, Cassia fistula, mopane (Colophospermum mopane), Julbernardia globiflora, Habranthus brachyandrus, Monactis macbridei, Arnica acaulis, Arnica montana, Daucus carota, Bauhinia mancha manca), Botrytis cinerea, Brosimum acutifolium, Broussonetia kazinoki, Broussonetia papyrifera, Dalbergia latifolia, Dracaena cambodiana, Dracaena draco, Narcissus pseudonarcissus, Phanera guianensis, Rohdea chinensis chinensis), Soymida febrifuga, Pacific yew (Taxus brevifolia), Tupistra chinensischinensis), Abri herba, Abrus pulchellus subsp. Cantoniensis, Achyranthes bidentata, Aconitum seraphschanicum, Aconitum tashiromontanum, Acorus tataninowii rhizome, Acorus gramineus, Acorus tatarinowii, Actinidia chinensis planch), Adansonia grandidieri, Aframomum giganteum, Aizopsis selkiana, Albizia myriophylla, Alisma plantago-aquatica subsp. orientale, Aloe castellorum, Aloe vera, Alpiniae officinarum rhizome, Amaranthus hypochondriacus, Ampelopsis japonica, Amphorgyne spicata, Anaphalis lacteal, Anchusa azurea, Andrographis laxiflora, Andrographis neesiana, Anemarrhena asphodeloides, Aphyllocladus denticulatus, and Aralia aralia. decaisneana), Artemisia annua, Artemisiaparviflora), Artemisia scoparia [synonyms: Artemisia capillaris v, Artemisia scoparia], Aspidosperma discolor, Asteris root and rhizome, Aster sedifolius, Aster tataricus, Atadinus libanoticus, Baccharis potosina, Balanophora laxiflora laxiflora), Bassia muricata, wax gourd (Benincasa hispida), table beet (Beta vulgaris vulgaris), Bistorta elliptica, Bistorta officinalis, ramie rhizomes and roots (Boehmeriae rhizoma et radix), ramie (Boehmeria nivea), Boehmeria platanifolia [synonyms: Boehmeria tricuspis, Boehmeria platanifolia], Bolbostenma paniculati bulbus, Bolbostenma paniculatum, Brassica rapa, Bridelia stipularis, Canarium bengalense, Carduus tenuiflorus, Cascara sagrada, Cassia alata L., Cassia angolensis, Cassiae semen), Cassia fastuosa, Java senna (Cassiajavanica), Cassia obtusifolia, Cassia occidentalis, Cassia speciosa, Cassia tora L., Cassia tora, Cassia torosa L., Catalpa longissima, Caulerpa peltata, Caulerpa polygoni multiflori, Caulerpa sargentii stems Sargentodoxae, Caulocystis cephalornithos, Ipecac (Cephaelis ipecacuanha), Cephalotaxus griffithii, Chaiturus marrubiastrum, Mimosa mimosoides, Chamaecrista nigricans, Chamaecrista nomame, Chamaecrista pumila pumila), Cheilanthes argentea, quinoa (Chenopodium quinoa), chicory (Cichorium intybus), field thistle (Cirsium oligophyllum), Clibadium sprucei, coreopsis tinctoria, Corydalis rhizoma, Cranifilia fluviatilis, Cratoxylum formosum, and Cremastra appendiculata), Cynanchum viminale, Dalbergia hupeana, Dalbergia lanceolaria subsp. paniculata, Dalbergia lanceolaria subsp.paniculata), Degenia velebitica, Delphinium nuttallianum, Delphinium virgatum, Dendriopoterium menendezii, Dendrobium thyrsiflorum, Derris canarensis, Derris cuneifolia, Derris oblonga, Dianthi herba, carnation (Dianthus caryophyllus, Dictyopteris australis, Dillenia indica, Dioscoreae bulbiferae, Dipsacus azureus, Dodonaea viscosa, Dysoxylum cumingianum, Dysoxylum muelleri, Elymus repens, Enceliopsis argophila argophila), Endophytic aspergillus, Epimedium koreanum, Epimrdii herba, Eria mollis, Eriocaulon buergerianum, Eriocaulon sieboldianum, Erythrina lysistemon, Erythrophleum ivorance, Euodia bodinieri, Euodia officinalis), Euodia ruticarpa, Fagopyrum esculentum, Tartary buckwheattataricum, Fallopia multiflora, Fallopia sachalinensis, Flacourtia jangomas, Frangula alnus, Frangula purshiana, Fridericia triplinervia triplinervia, Garcinia polyantha, Gleichenia quadripartita, Glycyrrhiza uralensis, Gnaphalii affinis herba, Grangea maderaspatana, Hedera helix, Helichrysum chionosphaerum, Helichrysum plicatum, Heynea trijuga trijuga), Hoveniae dulcis semen, Hymenoxys lemmonii, Hypericum prolificum, Hypericum sampsonii, Isatdis radix, Isatis tinctoria, Jacquemontia paniculata, Taiwan juniperus, Justicia secunda, Lactuca plumieri), lettuce (Lactuca sativa), Ranaria lanata, larch (Larix kaempferior), lavender (Lavandula vera), Leptocereus quadricostatus, bush clover (Lespedeza tomentosa), Ligularia pleurocaulis, white jasmine (Lilii bulbus), and Lilium brownii f.e. brown var. colchesteri. wils), Lilium brownii var. viridulum [synonyms: Lilium brown, Lilium browniivar. viridulum], Lobelia berlandieri, Loranthus pentandrus, Lupinus corymbosus, Lycii cortex, Maclura tinctoria, Magnolia figo, Magnolia ovata, Mandragora autumnalis, Melicope triphylla, Mentha arvensis, Japanese mint, Mentha canadensis, Mentha herba, Metrodorea nigra, Miliusa velutina, Mitracarpus scaber, Muehlenbeckia tamnifolia, Muntingia calabura, Myrsine africana, Nekemias grossedentata, Neobalanocarpus heimii heimii), Nepeta granatensis, Nepeta parnassica, Nuxia floribunda, Onobrychis arenaria, Oryctes monoceros, Osmanthus armatus, Passiflora sexflora, Persicaria decipiens, Persicaria hydropiper, Persicaria maculosa), Ishimikawa (Persicaria perfoliata), Persicaria salicifolia (Persicariasalicifolia, Petunia integrifolia subsp. inflata, Phaseolus vulgaris, Phlogacanthus curviflorus, Photinia serratifolia, Physalis alkekengi, Picramia antidesma, Picramia hirsuta, Picramia tiapensis teapensis, Picramnia teapensis Tul., Picrasma quassioides, Pinalia stricta, Pisum sativum, Plantago coronapus, Plantago lanceolata, Pleione bulbocodioides, Pleione yunnanensis, Ploiarium alternifolium alternifolium), Pluchea odora, Pneumathopteris pennigera, Japanese knotweed rhizomes and roots (Polygoni cuspidatii rhizoma et radix), Japanese knotweed (Polygonum cuspidatum), Polygonum hypoleucum, Polygonum multiflorum, Polygonum perfoliatum, Pseudolarix amabilis), Psorospermum glaberrimum, Psorospermum laurentii, Psorospermum tenuifoliumtenuifolium), Psychotria stachyoides, Red oak (Quercus rubra), Radix boehmeriae, Rhubarb roots and rhizomes (Radix et Rhizoma Rhei), Rhubarb roots and rhizomes (Radix et Rhizoma Rhei Praeparata), Ravenia spectabilis, Japanese knotweed (Reynoutria japonica), Buckthorn (Rhamnus cathartica), Black rose (Rhamnus davurica), Rhamnus erythroxyloides, Taiwan buckthorn (Rhamnus formosana), Rhamnus frangula [synonym: Frangula alnus], Rhamnus frangula, Rhamnus hirtella, Rhamnus kurdica, Nakahara buckthorn (Rhamnus nakaharae), Rhamnus nepalensis, Rhamnus parasii pallasii, Rhamnus prinoides, Rhamnus procumbens, Rhamnus punctata, Rhamnus saxatilis, Rhamnus thymifolius, Rhamnus triquetra, Rhamnus wightii, Rheum acuminatum, Rheum alexandrae, Rheum altaicum altaicum), Rheum australe, Rheum compactum, Rheum coreanum, Rheum delavaidelavayi), Rheum emodi [synonym: Rheum australe], Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangens, Rheum nanum, Rheum nobile, Rheum palmatum, Rheum pumilium pumilum, Rheum racemiferum, Rheum reticulatum, Rhubarb (Rheum rhabarbarum), Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum spp., Rheum subacaule, Rheum sublanceolatum, Rheum tanguticum, Rheum tataricum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum wittrocki, Rheum yunnanense, Rhizoma fagopyri cymose, Rhodiola viridula, Rhododendron dahuricum, Rosa pomifera, Rumex abyssinicus abyssinicus), sorrel (Rumex acetosa), red sorrel (Rumex acetosella), Rumex aegyptiacus, Rumex alpinus sorrel (Rumexalpinus), Rumex bequaertii, Rumex chalepensis, Rumex crispus, Rumex cristatus, Rumex cyprius, Rumex dentatus, Rumex japonicus, Rumex Rumex lanceolatus, Rumex limoniastrum, Nepal sorrel (Rumex nepalensis), Rumex patientia, Rumex pictus, Rumex pulcher, Rumex ruwenzoriensis, Rumex scutatus, Rumex simpliciflorus, Rumex spp., Rumex tuberosus tuberosus, Rumex usambarensis, Rumex vesicarius, Salvia aurea, Salvia greggii, Sargentodoxa cuneata, Sargentodoxae caulis, Saururus chinensis, Schistostephium artemisiifolium, Scilla socialis socialis), Selaginella labordei, Senecio pharbitis, Senecio behnii, Senecio bonariensis, Senecio praecox, Senecio subdentatus, Golden Candle, Senna alexandrina, Senna angustisiliqua, Senna artemisioides, Senna auriculata auriculata), Senna corymbosa, Sennadidymobotrya, Senna folium, Senna lindheimeriana, Senna macranthera, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna podocarpa, Senna septemtrionalis, Senna siamea, Senna sophera, Senna spectabilis spectabilis, Senna tora, Simaba orinocensis, Smythea bombaiensis, Solanum cleistogamum, Sophorae tonkinensis radix et rhizome, Mitsukato (Spatholobus suberectus), Sphaerella rosigena, Spinach (Spinacia oleracea), Stevia berlandieri berlandieri, Stevia ovata, Australian myrtle (Syzygium australe), Tagetes filifolia, Tanacetum coccineum, Taraxacum kok-saghyz, Chinese dandelion (Taraxacum platycarpum subsp. hondoense), Tetradium ruticarpum, Teucrium yemense, Thymelaea hirsute hirsute), Tribulus fructus, Tribulus terrestris, Uvaria afzelii, Vatairea heteropteransheteropteran, Ventilago calyculata, Ventilago denticulata, Ventilago leiocarpa, Ventilago madraspatana, Verbascum thapsiforme, Vismia guianensis, Vismia guineensis, Vismia laurentii, Vismia orientalis orientalis, European grape (Vitis vinifera), Wilbrandia ebractea, Xanthi fructus, Strawberry (Xerochrysum viscosum), Angelica archangelica, Cascara saccharina (Frangula purshiana), Geranium maculatum, Rumex crispus, Senecio congestus, Senna alexandrina, Aloe africana africana), Aloe arborescens, Aloe castellorum, Aloe ergonica, Aloe ferox, Aloe rubroviolacea, Aloe spicata, Aloe succotrina, Asphodeline tenuior, Asphodelus aestivus, Asphodelus albus, Asphodelus serrulata fistulosus), Asphodelusramosus, Asphodelus tenuifolius, Berchemia floribunda, Bergenia hissarica, Bulbine annua, Bulbine asphodeloides, Callisia fragrans, Cassia aldabrensis, Cassia grandis, Cassia javanica, Mimosa pudica, Chamaecrista mimosoides, Commiphora socotrana, Frangula alnus, Frangula purshiana, Kniphofia ensifolia, Kniphofia foliosa, Kniphofia insignis, Kniphofia isoetifolia, Kniphofia schimperi, Picramia antidesma antidesma, Picramia hirsute, Guava (Psidium guajava), Japanese knotweed (Reynoutria japonica), Rhamnus alaternus, Buckthorn (Rhamnus cathartica), Black rose (Rhamnus davurica), Rheum acuminatum, Rheum alexandrae, Rheum altaicum, Rheum australe, Rheum rhubarb compactum), Rheum coreanum, Rheum delavaidelavayi, Rheum franzenbachii, Rheum hotaoense, Rheum inopinatum, Rheum kialense, Rheum likiangens, Rheum nobile, Rheum palmatum, Rheum pumilum, Rheum racemiferum, Rheum reticulatum reticulatum, Rhubarb (Rheum rhabarbarum), Rheum rhaponticum, Rheum ribes, Rheum spiciforme, Rheum subacaule, Rheum tanguticum, Rheum tataricum, Rheum undulatum, Rheum uninerve, Rheum wittrockii, Rheum unnanens yunnanense, Rumex cristatus, Rumex paulsenianus, Rumex scutatus, Selaginella delicatula, Golden Candle (Senna alata), Senna (Senna alexandrina), Senna didymobotrya, Senna obtusifolia, Senna occidentalis, Senna petersiana, Senna reticulata, Senna tagliatelle, siamea), Senna tora, Spatholobus suberectus, Stephania dinkulagueidinklagei), Xanthorrhoea australis, chicory (Cichorium intybus), Cassia occidentalis, Morinda royoc, Galium aparine, Bryophyllum pinnatum, Anthema tinctoria, Aegle marmelos, Cymbopogon spp., Wedelia trilobata, Angelica archangelica, Vitis tilifolia, Mirabilis jalapa, Centipeda minima, Bauhinia manca, Juniperus drupacea, Forsythia suspensa, Citrus sinensis, Hylocomium splendens), safflower (Carthamus tinctorius), rosemary (Rosmarinus officinalis), rice (Oryza sativa), red clover (Trifolium pratense cv. Redman), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan mountain jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), cacao (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Nepenthes hookeriana, Malayan mountain jasmine (Musa acuminata), Douglas-fir (Pseudotsuga menziesii var. menziesii), Penstemon centranthifolius, pea (Pisum sativum), soybean (Glycine max), oat (Avena sativa), apple (Malus domestica), gardenia (Gardenia jasminoides), aloe ferox, rice (Oryza sativa), sativa), Arabica coffee plant (Coffea arabica), safflower (Carthamus tinctorius), horsegram (Macrotylomauniflorum), eggplant (Solanum melongena), Satsuma mandarin (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostalk), eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricularia-judae), orange (Citrus sinensis), cycad (Cycas revoluta), bitter melon (Momordica charantia), Brassica carinata, gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var. niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum, Agaricus (Agaricus subbrufescens), Flax (Linum usitatissimum), Peony (Paeonia lactiflora), Capsicum (Capsicum annuum), Creosote bush (Larrea tridentata), Mirabilis (Mirabilis jalapa), Catharanthus roseus, Alfalfa (Medicago sativa subsp. sativa), Nightshade (Solanum americanum), Arabica coffee (Coffea arabica), Bitter melon (Momordica charantia), milk thistle (Silybum marianum), cacao (Theobroma cacao), aloe ferox, gardeniajasminoides), cashew nuts (Anacardium occidentale), chili peppers (Capsicum annuum), peony (Paeonia lactiflora), clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), peppers (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), oats (Avena sativa), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), corn (Zea mays), creosote bush (Larrea tridentata), tobacco (Nicotiana tabacum), eucalyptus (Eucalyptus globulus subsp. bicostata), Malayan wild jasmine (Musa acuminata), eggplant (Solanum melongena), Phyllanthus emblica, tomato (Solanum lycopersicum), Veronica polita, hollyhock (Alcea rosea), sacha inchi (Plukenetia volubilis), green coral (Euphorbia tirucalli), Neolamarckia cadamba, Citrus limon, Catharanthus roseus, Mirabilis jalapa, Podocarpus spicatus, Tripterygium wilfordii, Spatholobus suberectus, Crinum moorei, Juniperus monosperma, Pleurotus oyster mushroom ostreatus), Gypsophila perfoliate, Clausena excavata, Gynura procumbensprocumbens), red clover (Trifolium pratense cv. Redman), rice (Oryza sativa), rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), safflower (Carthamus tinctorius), Satsuma mandarin (Citrus unshiu), rock moss (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia (Forsythia suspensa), bitter melon (Momordica charantia), milk thistle (Silybum marianum), aloe ferox, clementine (Citrus clementina), barley (Hordeum vulgare cv. Seco), peppercorn (Erucastrum gallicum), flax (Linum usitatissimum), milkweed (Asclepias syriaca), St. John's wort (Hypericum perforatum), creosote bush (Larrea tridentata), eucalyptus (Eucalyptus globulus subsp. bicostata), Phyllanthus emblica, Veronica polita, Alcea rosea, Neolamarckia cadamba, Catharanthus roseus, Podocarpus spicatus, Tripterygium wilfordii, Juniperus monosperma, Pleurotus ostreatus, Gypsophila perfoliate), Clausena excavate, Gynura procumbens, red clover (Trifolium pratense cv.

36. The method of claim 35, wherein the plant is selected from the group consisting of: rosemary (Rosmarinus officinalis), lotus (Nelumbo nucifera), unshu mandarin (Citrus unshiu), splendens (Hylocomium splendens), orange (Citrus sinensis), Juniperus drupacea, forsythia suspensa, or a combination thereof.

37. The plant extracts include those of rhubarb (Rheum officinale), cocoa (Theobroma cacao), barley (Hordeum vulgare cv. Seco), Chinese quince (Chaenomeles sinensis), Nepenthes hookeriana (Nepenthes x hookeriana), Malayan mountain jasmine (Musa acuminata), Douglas fir (Pseudotsuga menziesii var. menziesii), Penstemon centranthifolius, pea (Pisum sativum), Aloe africana (Aloe africana), soybean (Glycine max) max), oats (Avena sativa), apples (Malus domestica), gardenias (Gardenia jasminoides), aloe ferox (Aloe ferox), rice (Oryza sativa), coffee arabica (Coffea arabica), safflower (Carthamus tinctorius), horse gram (Macrotyloma uniflorum), eggplant (Solanum melongena), aloe vera (Aloe vera), Satsuma mandarins (Citrus unshiu), St. John's wort (Hypericum perforatum), turmeric (Curcuma longa), nipa palm (Nypa fruticans), rye (Secale cereale cv. Aroostalk), eye (Persicaria tinctoria), hemp (Cannabis sativa), tomato (Solanum lycopersicum), clementine (Citrus clementina), red clover (Trifolium pratense cv. Redman), cat's claw (Uncaria tomentosa), wood ear mushroom (Auricularia auricula-judae), orange (Citrus sinensis), cycad (Cycas revoluta) revoluta), Momordica charantia, Brassica catarinacarinata), gaillardia (Gaillardia pulchella), lotus (Nelumbo nucifera), black radish (Raphanus sativus var. niger), maca (Lepidium meyenii), corn (Zea mays), tobacco (Nicotiana tabacum), agaricus (Agaricus subbrufescens), flax (Linum usitatissimum), peony (Paeonia lactiflora), chili pepper (Capsicum annuum), creosote bush (Larrea tridentata), and Mirabilis jalapenos), Catharanthus roseus, or a combination thereof.

38. 36. The method of claim 35, wherein the plant extract is selected from the group consisting of Rheum officinale, Phyllanthus emblica, Theobroma cacao, or a combination thereof.

39. 36. The method of claim 35, wherein the botanical extract is selected from the group consisting of Tripterygium wilfordii, Phyllanthus emblica, Hypericum performum, Aloe barbadensis, Hypericum performum, or combinations thereof.

40. The one or more compounds from the plant extract are 【Chemistry 9】 36. The method of claim 35, wherein the compound is selected from the group consisting of:

41. 23. The method of claim 22, wherein the composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition.

42. 23. The method of claim 22, wherein the composition is in a dosage form configured as one of a soft gel capsule, a hard capsule, a gummy, a functional drink, a functional food, a liquid, a powder, or a tablet.

43. 36. The method of claim 35, wherein the composition comprises 1.0% to 99% w / w of the plant extract.

44. 23. The method of claim 22, wherein the composition further comprises a preservative, a sweetener, a colorant, an additive, a flavoring, or a combination thereof.

45. 1. A method for treating, preventing, reducing, modulating, or ameliorating anxiety in a subject, said method comprising: providing to the subject a composition comprising one or more compounds capable of modulating metabotropic glutamate receptors and a carrier; the composition is provided in an amount sufficient to treat, reduce, prevent, or ameliorate anxiety in the subject; The one or more compounds are 【Chemistry 10】 or a combination thereof.

46. 1. A method of treating, preventing, reducing, modulating, or ameliorating the adverse effects of emotional stress on sleep in a subject, said method comprising: providing to a subject a composition comprising one or more compounds capable of modulating metabotropic glutamate receptors and a carrier; the composition is provided in an amount sufficient to treat, reduce, prevent, or ameliorate anxiety in a subject; The one or more compounds are 【Chemistry 11】 or a combination thereof.

47. 1. A method of treating, preventing, reducing, modulating, or ameliorating adverse effects of physiological rhythms in a subject, said method comprising: providing to a subject a composition comprising one or more compounds capable of modulating metabotropic glutamate receptors and a carrier; the composition is provided in an amount sufficient to treat, reduce, prevent, or ameliorate anxiety in a subject; The one or more compounds are 【Chemistry 12】 or a combination thereof.

48. 1. A method of treating, preventing, reducing, modulating, or ameliorating adverse mood effects in a subject, said method comprising: providing to a subject a composition comprising one or more compounds capable of modulating metabotropic glutamate receptors and a carrier; the composition is provided in an amount sufficient to treat, reduce, prevent, or ameliorate anxiety in a subject; The one or more compounds are 【Chemistry 13】 or a combination thereof. 【Request Item 49】 【Chemistry 14】 10. An oral composition for use in medicine for the treatment of stress, anxiety, sleep disorders, or conditions thereof, comprising a compound selected from the group consisting of:

50. 1. Use of a composition for treating, reducing, preventing, or ameliorating stress, symptoms of stress, or the harmful effects of chronic stress in a subject, said composition comprising: 【Chemistry 15】 or combinations thereof.

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