Draft:Orthomolecular medicine

""Megavitamin therapy" was first coined in 1952 by psychiatrists Humphry Osmond and Abram Hoffer to describe the large dosages of niacin used in the treatment of schizophrenia and mescaline psychosis."

"Megavitamin therapy has become a sub-category of Orthomolecular medicine."

Theoretical orthomolecular medicine

Def. "the restoration and maintenance of health through the administration of adequate amounts of substances that are normally present in the body" is called orthomolecular medicine.

Def. a "nutrient or food believed to have curative properties" or a "food used as a drug" is called a nutraceutical.

Alkaloids

Historically, Zanthoxylum (Prickly ash) bark was used in traditional medicine.

Species identified in Nigeria contains several types of alkaloids including benzophenanthridines (nitidine, dihydronitidine, oxynitidine, fagaronine, dihydroavicine, chelerythrine, dihydrochelerythrine, methoxychelerythrine, norchelerythrine, oxychelerythrine, decarine and fagaridine), furoquinolines (dictamine, 8-methoxydictamine, skimmianine, 3-dimethylallyl-4-methoxy-2-quinolone), carbazoles (3-methoxycarbazole, glycozoline), aporphines (berberine, tembetarine, magnoflorine, M-methyl-corydine), canthinones (6-canthinone), acridones (1-hydroxy-3-methoxy-10-methylacridon-9-one, 1-hydroxy-10-methylacridon-9-one, zanthozolin), and aromatic and aliphatic amides. Hydroxy-alpha sanshool is a bioactive component of plants from the genus Zanthoxylum, including the Sichuan pepper.

Aporphines

Aporphines include berberine and tembetarine found in Prickly ash bark.

Benzophenanthridines

Benzophenanthridines incude nitidine, dihydronitidine, oxynitidine, fagaronine, dihydroavicine, chelerythrine, dihydrochelerythrine, methoxychelerythrine, norchelerythrine, oxychelerythrine, decarine and fagaridine found in Prickly ash bark.

Berberines

Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as Berberis, such as Berberis vulgaris (barberry), Berberis aristata (tree turmeric), Mahonia aquifolium (Oregon grape), Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense (Amur cork tree), Coptis chinensis (Chinese goldthread), Tinospora cordifolia, Argemone mexicana (prickly poppy), and Eschscholzia californica (Californian poppy).

Berberine is usually found in the roots, rhizomes, stems, and bark.

The safety of using berberine for any condition is not adequately defined by high-quality clinical research.

Its potential for causing adverse effects is high, including untoward interactions with prescription drugs, reducing the intended effect of established therapies. Berberine inhibits the CYP2D6 and CYP3A4 enzymes which are involved in metabolism of endogenous substances and xenobiotics, including many prescription drugs.

It is particularly unsafe for use in children. On the other hand, in May 2021, a comprehensive review article was published that highlighted the efficacy of berberine as a promising anti-oncogenic herpesvirus drug

The dried fruit of Berberis vulgaris is used in herbal medicine. The chemical constituents include isoquinolone alkaloids, especially berberine, with a full list of phytochemicals compiled.

Carbazoles

Carbazoles include 3-methoxycarbazole and glycozoline found in Prickly ash bark.

Furoquinolines

Furoquinolines include dictamine, 8-methoxydictamine, skimmianine, and 3-dimethylallyl-4-methoxy-2-quinolone found in Prickly ash bark.

Huperzine A

Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian. Huperzine A has been investigated as a treatment for neurological conditions such as Alzheimer's disease, but a meta-analysis of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution.

Huperzine A is extracted from Huperzia serrata. "Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE)." It is a reversible acetylcholinesterase inhibitor and NMDA receptor antagonist that crosses the blood-brain barrier. Acetylcholinesterase is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine and of some other choline esters that function as neurotransmitters. The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).

For some years, huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration, particularly Alzheimer's disease. A 2013 meta-analysis found that huperzine A may be efficacious in improving cognitive function, global clinical status, and activities of daily living for individuals with Alzheimer's disease. However, due to the poor size and quality of the clinical trials reviewed, huperzine A should not be recommended as a treatment for Alzheimer's disease unless further high quality studies confirm its beneficial effects.

Huperzine A is also marketed as a dietary supplement with claims made for its ability to improve memory and mental function.

Huperzine A has also been noted to help induce lucid dreaming.

Valerian alkaloids

Actinidine, chatinine, shyanthine, valerianine, and valerine

Alpha-lipoic acids

"Alpha-Lipoic Acid is a naturally occurring micronutrient, synthesized in small amounts by plants and animals (including humans), with antioxidant and potential chemopreventive activities. Alpha-lipoic acid acts as a free radical scavenger and assists in repairing oxidative damage and regenerates endogenous antioxidants, including vitamins C and E and glutathione. This agent also promotes glutathione synthesis. In addition, alpha-lipoic acid exerts metal chelating capacities and functions as a cofactor in various mitochondrial enzyme complexes involved in the decarboxylation of alpha-keto acids."

Lipoic acid (LA), also known as α-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA is made in animals normally, is essential for aerobic metabolism, and is manufactured and available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.

(R)-(+)-lipoic acid (RLA) may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulforaphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents. This stress response indirectly improves the antioxidant capacity of the cell.

Amino acids

GABA

GABA is an amino acid, as it has both a primary amine and a carboxylic acid functional group.

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.

L-ornithine

In mammalian non-hepatic tissues, the main use of the urea cycle is in arginine biosynthesis, so, as an intermediate in metabolic processes, ornithine is quite important.

L-Ornithine supplementation attenuated fatigue in subjects in a placebo-controlled study using a cycle ergometer. The results suggested that L-ornithine has an antifatigue effect in increasing the efficiency of energy consumption and promoting the excretion of ammonia.

L-tyrosine

Tyrosine is a precursor to neurotransmitters and increases plasma neurotransmitter levels (particularly dopamine and norepinephrine), but has little if any effect on mood in normal subjects. However, a number of studies have found tyrosine to be useful during conditions of stress, cold, fatigue (in mice), prolonged work and sleep deprivation, with reductions in stress hormone levels, reductions in stress-induced weight loss seen in animal trials, and improvements in cognitive and physical performance seen in human trials.

Tyrosine does not seem to have any significant effect on cognitive or physical performance in normal circumstances, but does help sustain working memory better during multitasking.

Coenzyme Q10

"Coenzyme Q10 (ubiquinone, or coQ10) is an antioxidant that is essential for mitochondrial energy production. It is manufactured in the body, but with aging the amounts are inadequate for optimum health. CoQ10 is essential for the heart muscle, and it helps lower blood pressure, improve congestive heart failure, and protect the brain in degenerative conditions such as Parkinson’s and Alzheimer’s diseases (Morisco et al 1993). Statin drugs significantly lower the production of coQ10. Typical supplemental doses of coQ10 range from 100 mg daily for prevention against high blood pressure to 400 mg for heart disease patients (Munkholm et al 1999)."

A meta-analysis of people with heart failure 30–100 mg/d of CoQ₁₀ resulted in 31% lower mortality, exercise capacity was also increased, but no significant difference was found in the endpoints of left heart ejection fraction and New York Heart Association NYHA) classification.

Generally, CoQ₁₀ is well tolerated. The most common side effects are gastrointestinal symptoms (nausea, vomiting, appetite suppression, and abdominal pain), rashes, and headaches.

While there is no established ideal dosage of CoQ₁₀, a typical daily dose is 100–200 milligrams.

The Canadian Headache Society guideline for migraine prophylaxis recommends, based on low-quality evidence, that 300 mg of CoQ₁₀ be offered as a choice for prophylaxis.

Detailed reviews on occurrence of CoQ₁₀ and dietary intake were published in 2010. Besides the endogenous synthesis within organisms, CoQ₁₀ also is supplied to the organism by various foods. Despite the scientific community's great interest in this compound, however, a very limited number of studies have been performed to determine the contents of CoQ₁₀ in dietary components. The first reports on this aspect were published in 1959, but the sensitivity and selectivity of the analytical methods at that time did not allow reliable analyses, especially for products with low concentrations. Since then, developments in analytical chemistry have enabled a more reliable determination of CoQ₁₀ concentrations in various foods:

CoQ₁₀ levels in selected foods

Food		CoQ10 concentration (mg/kg)
Beef	heart	113
	liver	39–50
	muscle	26–40
Pork	heart	12–128
	liver	23–54
	muscle	14–45
Chicken	breast	8–17
	thigh	24–25
	wing	11
Fish	sardine	5–64
	mackerel:
	– red flesh	43–67
	– white flesh	11–16
	salmon	4–8
	tuna	5
vegetable oils	soybean	54–280
	olive	4–160
	grapeseed	64–73
	sunflower	4–15
	canola	64–73
Nuts	peanut	27
	walnut	19
	sesame seed	18–23
	pistachio	20
	hazelnut	17
	almond	5–14
Vegetables	parsley	8–26
	broccoli	6–9
	cauliflower	2–7
	spinach	up to 10
	Chinese cabbage	2–5
Fruit	avocado	10
	blackcurrant	3
	grape	6–7
	strawberry	1
	orange	1–2
	grapefruit	1
	apple	1
	banana	1

Meat and fish are the richest sources of dietary CoQ₁₀; levels over 50 mg/kg may be found in beef, pork, and Chicken as food|chicken heart and liver. Dairy products are much poorer sources of CoQ₁₀ than animal tissues. Vegetable oils also are quite rich in CoQ₁₀. Within vegetables, parsley and perilla are the richest CoQ₁₀ sources, but significant differences in their CoQ₁₀ levels may be found in the literature. Broccoli, grapes, and cauliflower are modest sources of CoQ₁₀. Most fruit and berries represent a poor to very poor source of CoQ₁₀, with the exception of avocados, which have a relatively high CoQ₁₀ content.

Intake

In the developed world, the estimated daily intake of CoQ₁₀ has been determined at 3–6 mg per day, derived primarily from meat.

Cynarines

Artichoke contains the bioactive agents apigenin and luteolin.

Def. "any of many compounds that are plant metabolites, being formally derived from flavone; they have antioxidant properties, and sometimes contribute to flavor" is called a flavonoid.

Def. "any of a class of tricyclic aromatic heterocyclic ketones, especially the naturally occurring flavonoids" is called a flavone.

Apigenin (4′,5,7-trihydroxyflavone), found in many plants, is a natural product belonging to the flavone class that is the aglycone of several naturally occurring glycosides.

Apigenin is found in many fruits and vegetables, but parsley, celery, celeriac, and chamomile tea are the most common sources. Apigenin is particularly abundant in the flowers of chamomile plants, constituting 68% of total flavonoids. Dried parsley can contain about 45 mg/gram and dried chamomile flower about 3-5 mg/gram apigenin. The apigenin content of fresh parsley is reportedly 215.5 mg/100 grams, which is much higher than the next highest food source, green celery hearts providing 19.1 mg/100 grams.

Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin can function as either an antioxidant or a pro-oxidant and plants rich in luteolin have been used in Chinese traditional medicine

Luteolin is most often found in leaves, but it is also seen in rinds, barks, clover blossom, and ragweed pollen. It has also been isolated from the aromatic flowering plant, Salvia tomentosa in the mint family, Lamiaceae.

Dietary sources include celery, broccoli, artichoke, Bell pepper (green pepper), parsley, thyme, dandelion, perilla, chamomile tea, carrots, olive oil, peppermint, rosemary, navel oranges, and oregano. It can also be found in the seeds of the palm Aiphanes aculeata.

The total antioxidant capacity of artichoke flower heads is one of the highest reported for vegetables. Cynarine is a chemical constituent in Cynara. The majority of the cynarine found in artichoke is located in the pulp of the leaves, though dried leaves and stems of artichoke also contain it.

Cynarine is a hydroxycinnamic acid derivative and a biologically active chemical constituent of artichoke (Cynara cardunculus).

Enzymes

Enzymes can be classified by two main criteria: either protein primary structure (amino acid sequence) similarity (and thus evolutionary relationship) or enzymatic activity.

Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase. Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.

The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the Enzyme Commission number (EC number). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.

The top-level classification is:

• EC 1, Oxidoreductases: catalyze oxidation/reduction reactions
• EC 2, Transferases: transfer a functional group (e.g. a methyl or phosphate group)
• EC 3, Hydrolases: catalyze the hydrolysis of various bonds
• EC 4, Lyases: cleave various bonds by means other than hydrolysis and oxidation
• EC 5, Isomerases: catalyze isomerization changes within a single molecule
• EC 6, Ligases: join two molecules with covalent bonds.

These sections are subdivided by other features such as the substrate, products, and chemical mechanism. An enzyme is fully specified by four numerical designations. For example, hexokinase (EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1).

EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as Pfam.

Oxidoreductases

15-cis-phytoene desaturases (PDS, plant-type phytoene desaturases) (EC 1.3.5.5, 15-cis-phytoene:plastoquinone oxidoreductase), are enzymes involved in the carotenoid biosynthesis in plants and cyanobacteria. Phytoene desaturases are membrane-bound enzymes localized in plastids and introduce two double bonds into their colorless substrate phytoene by dehydrogenation and isomerize two additional double bonds. This reaction starts a biochemical pathway involving three further enzymes (zeta-carotene isomerase, 9,9'-Dicis-zeta-carotene desaturase) and carotene cis-trans isomerase) called the poly-cis pathway and leads to the red colored lycopene. The homologous phytoene desaturase found in bacteria and fungi (Phytoene desaturase (lycopene-forming) CrtI) converts phytoene directly to lycopene by an all-trans pathway.

Fatty acids

Three-dimensional representations of several fatty acids are shown. Saturated fatty acids have perfectly straight chain structure. Unsaturated ones are typically bent, unless they have a trans configuration. Credit: phma.

Def. any "of a class of aliphatic carboxylic acids, of general formula C_nH_2n+1COOH, that occur combined with glycerol as animal or vegetable oils and fats" is called a fatty acid.

"Only those with an even number of carbon atoms are normally found in natural fats"

Usage notes: "The above general formula applies to the saturated fatty acids. Remove 2 hydrogen atoms for an unsaturated fatty acid, and 2 hydrogen atoms for every double bond in a polyunsaturated faty acid."

Flavonoids

The raw dandelion flowers contain diverse phytochemicals, including polyphenols, such as flavonoids apigenin, isoquercitrin (a quercetin-like compound), and caffeic acid, as well as terpenoids, triterpenes, and sesquiterpenes. The roots contain a substantial amount of the prebiotic fiber inulin. Dandelion greens contain lutein.

Flavonoids (or bioflavonoids; from the Latin word flavus, meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in diets.

The tartness of cranberry juice derives from its mixed content of polyphenols, including flavonoids, proanthocyanidins, anthocyanins, phenolic acids, and ellagitannins.

Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen). This carbon structure can be abbreviated C6-C3-C6. According to the IUPAC nomenclature, they can be classified into:

• flavonoids or bioflavonoids
• isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
• neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure

Flavonoids (vitexin, casticin), iridoid glycoside (agnuside, aucubin), p-hydroxybenzoic acid, alkaloids, essential oils, fatty oils, diterpenoids and steroids have been identified in the chemical analysis of Vitex agnus-castus. They occur in the fruits and in the leaves.

Flavanones

Flavanones: hesperidin, 6-methylapigenin, and linarin occur in Valerian.

Flavonols

Def. any "of several flavonoids that have a 3-hydroxyflavone backbone" is called a flavonol.

Herbacetin is a flavonol, a type of flavonoid.

Flavonolignans

Rhodiolin, a flavonolignan, is the product of the oxidative coupling of coniferyl alcohol with the 7,8-dihydroxy grouping of herbacetin. It can be found in the rhizome of Rhodiola rosea.

Proanthocyanidins

Proanthocyanidins, including the lesser bioactive and bioavailable polymers (four or more catechins) represent a group of condensed flavan-3-ols, such as procyanidins, prodelphinidins and propelargonidins, that can be found in many plants, most notably apples, maritime pine bark and that of most other pine species, cinnamon, aronia fruit, cocoa beans, grape seed, grape skin (procyanidins and prodelphinidins). Cocoa beans contain the highest concentrations.

Proanthocyanidins also may be isolated from Quercus petraea and Quercus robur heartwood (wine barrel oaks). Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in numerous procyanidin oligomers.

Apples contain on average per serving about eight times the amount of proanthocyanidin found in wine, with some of the highest amounts found in the Red Delicious and Granny Smith varieties.

An extract of maritime pine bark called Pycnogenol bears 65-75 percent proanthocyanidins (procyanidins).

Proanthocyanidin glycosides can be isolated from cocoa liquor.

The seed testas of field beans (Vicia faba) contain proanthocyanidins that affect the digestibility in piglets and could have an inhibitory activity on enzymes. Cistus salviifolius also contains oligomeric proanthocyanidins.

Dietary source	Proanthocyanidin (mg/100g)
Fruits
Grape seeds	3532
Blueberries	332
Apples	70-141
Pears	32-42
Nuts
Hazelnuts	501
Other
Cinnamon bark	8108
Sorghum grains	3965
Baking chocolate	1636
Red wine	313

Grape seeds are rich in unsaturated fatty acids, which helps lowering levels of total cholesterol and LDL cholesterol in the blood.

Quercetin

"Quercetin is a flavonoid that helps to control allergy symptoms of rhinitis and sinusitis. It stabilizes the membranes of mast cells, reducing the release of histamine. It is also helpful in lowering the risk of cataract by inhibiting glycoprotein formation in the lens (Cornish, et al 2002). Typical doses of quercetin are 800 mg to 1200 mg daily."

Rutins

Rutin (rutoside or rutinoside) and other dietary flavonols are under preliminary clinical research for their potential biological effects, such as in reducing post-thrombotic syndrome, venous insufficiency, or endothelial dysfunction, but there was no high-quality evidence for their safe and effective uses as of 2018. As a flavonol among similar flavonoids, rutin has low bioavailability due to poor absorption, high metabolism, and rapid excretion that collectively make its potential for use as a therapeutic agent limited.

Glycosides

Herbacetin diglucoside can be isolated from flaxseed hulls.

Rhodionin is a herbacetin rhamnoside found in Rhodiola species.

Glycosides	Aglycone	Glycone	Plants	Genus species
Alcohol glycosides	Alcohol	Glycone	Common name	Genus species
Rosavin	cinnamyl alcohol	arabinose	Rhodiola	Rhodiola rosea
Salicin	salicyl alcohol	glucose	Willow	Salix
Salidrosides	tyrosol	glucose	Rhodiola	Rhodiola rosea
Anthraquinone glycosides	Anthraquinone derivative	Glycone	Common name	Genus species
Sennosides	reduced anthraquinone	glucose	Legume	Senna
Chromone glycosides	Benzo-gamma-pyrone	Glycone	Common name	Genus species
3,5,7-trihydroxylchromone-3-O-alpha-L-arabinopyranoside	chromone	arabinose	Rhododendron	Rhododendron spinuliferum
Eucryphin	chromone	rhamnoside	Eucryphia	Eucryphia cordifolia
Coumarin glycosides	coumarin	Glycone	Common name	Genus species
Aesculin	coumarin	glucose	Horse chestnut	Aesculus hippocastanum
Cyanogenic glycosides	Cyanogin	Glycone	Common name	Genus species
Amygdalin	cyanohydrin	glucose	Apricot kernels	Prunus armeniaca
Flavonoid glycosides	Flavonoid	Glycone	Common name	Genus species
Hesperidin	Hesperetin	Rutinose	Bitter Orange	Citrus aurantium
Naringin	Naringenin	Neohesperidose	Grapefruit	Citrus × paradisi
Rutin	Quercetin	Rutinose	Common rue	Ruta graveolens
Quercitrin	Quercetin	Rhamnose	American white oak	Quercus alba
Iridoid glycosides	iridoid	Glycone	Common name	Genus species
Aucubin	cyclopentan-[C]-pyran	glucose	spotted laurel	Aucuba japonica
Phenolic glycosides	Phenol	Glycone	Common name	Genus species
Arbutin	Phenol	glucose	Common Bearberry	Arctostaphylos ova-ursi
Astringin	Piceatannol	glucose	Japanese knotweed	Reynoutria japonica
Rhapontigenin	Pinosylvin	glucose	Crimson glory vine	Vitis coignetiae
Steroidal glycosides	Steroid	Glycone	Common name	Genus species
Digitonin	saraponin	glucose	foxglove	Digitalis purpurea
Steviol glycosides	Steviol	Glycone	Common name	Genus species
Steviosides	Steviol	isosteviol	candyleaf	Stevia rebaudiana
Thioglycosides	Thiod	Glycone	Common name	Genus species
Sinigrin	sulfur	glucose	Black mustard	Brassica nigra
Triterpene glycosides	Triterpene	Glycone	Common name	Genus species
Saponins	Triterpene	glucose	soapbark tree	Quillaja saponaria

Lagerstroemins

Chemical compounds that have been isolated from the extract include corosolic acid, lager-stroemin, flosin B, and reginin A.

Corosolic acid is a pentacyclic triterpene acid found in Lagerstroemia speciosa, similar in structure to ursolic acid, differing only in the fact that it has a 2-alpha-hydroxy attachment.

In Vietnam the plant's young leaves are consumed as vegetables, and its old leaves and mature fruit are used in traditional medicine for reducing glucose in blood.

Banaba plant, Lagerstroemia speciosa (giant crepe-myrtle, Queen's crepe-myrtle, banabá plant, or pride of India) is a species of Lagerstroemia native to tropical southern Asia.

Lignans

The lignans are a large group of low molecular weight polyphenols found in plants, particularly seeds, whole grains, and vegetables. The name derives from the Latin word for "wood". Lignans are precursors to phytoestrogens. They may play a role as antifeedants in the defense of seeds and plants against herbivores.

Structures of some lignans

• 
  Matairesinol, illustrating the debenzylbutyrolactone motif
• 
  Secoisolariciresinol, illustrating the 9,9'-dihydroxydibenzylbutane motif
• 
  Justicidin A, illustrating the arylnaphthalene mofif
• 
  Pinoresinol, illustrating the furanofuran motif
• 
  Steganacin, illustrating the dibenzocyclooctadienelactone motif
• 
  Podophyllotoxin, illustrating the aryltetralin motif

Lignans and lignin differ in their molecular weight, the former being small and soluble in water, the latter being high polymers that are undigestable:

1. both are polyphenolic substances derived by oxidative coupling of monolignols
2. most lignans feature a C₁₈ cores, resulting from the dimerization of C₉ precursors
3. coupling of the lignols occurs at C8
4. classes of lignans: "furofuran, furan, dibenzylbutane, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, dibenzocyclooctadiene, and dibenzylbutyrolactol."

Many lignans are metabolized by mammalian gut microflora, producing enterolignans.

Flax seeds and sesame seeds contain high levels of lignans.

The principal lignan precursor found in flaxseeds is secoisolariciresinol diglucoside.

Other foods containing lignans include cereals (rye, wheat, oat and barley), soybeans, tofu, cruciferous vegetables, such as broccoli and cabbage, and some fruits, particularly apricots and Strawberry|strawberries.

Lignans are not present in seed oil, and their contents in whole or ground seeds may vary according to geographic location, climate, and maturity of the seed crop, and the duration of seed storage.

Secoisolariciresinol and matairesinol were the first plant lignans identified in foods.

Lariciresinol and pinoresinol contribute about 75% to the total lignan intake, whereas secoisolariciresinol and matairesinol contribute only about 25%.

Foods containing lignans:

Source	Lignan amount
Flaxseeds	85.5 mg per oz (28.35 g)
Sesame seeds	11.2 mg per oz
Brassica vegetables	cup (125 ml)
Strawberries	0.2 per half cup

Magnolia

The aromatic bark contains magnolol, honokiol, 4-O-methylhonokiol, and obovatol. Magnolol and honokiol activate the nuclear receptor peroxisome proliferator-activated receptor gamma.

Magnolol is an organic compound, classified as lignan, a bioactive compound found in the bark of the Houpu magnolia (Magnolia officinalis) or in Magnolia grandiflora. The compound exists at the level of a few percent in the bark of species of magnolia, the extracts of which have been used in traditional Chinese and Japanese medicine. In addition to magnolol, related lignans occur in the extracts including honokiol, which is an isomer of magnolol.

It is known to act on the GABA_A receptors in rat cells in vitro as well as having antifungal properties. Magnolol has a number of osteoblast-stimulating and osteoclast-inhibiting activities in cell culture and has been suggested as a candidate for screening for anti-osteoporosis activity. It has anti-periodontal disease activity in a rat model. Structural analogues have been studied and found to be strong allosteric modulators of GABA_A.

Magnolol is also binding in dimeric mode to PPARγ, acting as an agonist of this nuclear receptor.

Prickly ash bark

Historically, Zanthoxylum (Prickly ash) bark was used in traditional medicine.

Plants in the genus Zanthoxylum contain the lignan sesamin.

Minerals

Main article: Remedy/Minerals

Oils

Main article: Remedy/Oils

Phenylpropanoids

4-Coumaroyl-CoA is the central biosynthetic precursor to phenylpropanoids (shown in protonated state). Credit: Leyo.{{free media}}

Phenylalanine is shown. Credit: NEUROtiker.{{free media}}

Tyrosine is shown. Credit: NEUROtiker.{{free media}}

The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of coumaric acid, which is the central intermediate in phenylpropanoid biosynthesis. From 4-coumaroyl-CoA emanates the biosynthesis of myriad natural products including lignols (precursors to lignin and lignocellulose), flavonoids, isoflavonoids, coumarins, aurones, stilbenes, catechin, and phenylpropanoids. The coumaroyl component is produced from cinnamic acid.

Phenylpropanoids are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and mediate plant-pollinator interactions as floral pigments and scent compounds.

Hydroxycinnamic acids

Cinnamic acid is diagrammed. Credit: NEUROtiker.{{free media}}

Phenylalanine is first converted to cinnamic acid by the action of the enzyme phenylalanine ammonia-lyase (PAL). Some plants, mainly monocotyledonous, use tyrosine to synthesize p-coumaric acid by the action of the bifunctional enzyme phenylalanine/tyrosine ammonia-lyase (PTAL). A series of enzymatic hydroxylations and methylations leads to coumaric acid, caffeic acid, ferulic acid, 5-hydroxyferulic acid, and sinapic acid. Conversion of these acids to their corresponding esters produces some of the volatile components of herb and flower fragrances, which serve many functions such as attracting pollinators. Ethyl cinnamate is a common example.

Cinnamic aldehydes and monolignols

Coniferyl alcohol is diagrammed. Credit: Yikrazuul.{{free media}}

Safrole is shown. Credit: Calvero.{{free media}}

Reduction of the carboxylic acid functional groups in the cinnamic acids provides the corresponding aldehydes, such as cinnamaldehyde. Further reduction provides monolignols including coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol, which vary only in their degree of methoxylation. The monolignols are monomers that are polymerized to generate various forms of lignin and suberin, which are used as a structural component of plant cell walls.

The phenylpropenes, including eugenol, chavicol, safrole and estragole, are also derived from the monolignols. These compounds are the primary constituents of various essential oils.

Coumarins and flavonoids

Umbelliferone is shown. Credit: Calvero.{{free media}}

Hydroxylation of cinnamic acid in the 4-position by trans-cinnamate 4-monooxygenase leads to p-coumaric acid]], which can be further modified into hydroxylated derivatives such as umbelliferone. Another use of p-coumaric acid via its thioester with coenzyme A, i.e. 4-coumaroyl-CoA, is the production of chalcones. This is achieved with the addition of 3 malonyl-CoA molecules and their cyclization into a second phenyl group. Chalcones are the precursors of all flavonoids, a diverse class of phytochemicals.

Stilbenoids

Trans-resveratrol is diagrammed. Credit: Fvasconcellos.{{free media}}

Stilbenoids, such as resveratrol, are hydroxylated derivatives of stilbene. They are formed through an alternative cyclization of cinnamoyl-CoA or 4-coumaroyl-CoA.

A 2018 meta-analysis found no effect of resveratrol on systolic or diastolic blood pressure; a sub-analysis revealed a 2 mmHg decrease in systolic pressure only from resveratrol doses of 300 mg per day, and only in diabetic people. A 2014 Chinese meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis found an 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg per day.

One review found limited evidence that resveratrol lowered fasting plasma glucose in people with diabetes. Two reviews indicated that resveratrol supplementation may reduce body weight and body mass index, but not fat mass or total blood cholesterol. A 2018 review found that resveratrol supplementation may reduce biomarkers of inflammation, TNF-α and C-reactive protein.

Sporopollenin

Phenylpropanoids and other natural phenols are part of the chemical composition of sporopollenin. It is related to cutin and suberin. This ill-defined substance found in pollen is unusually resistant to degradation. Analyses have revealed a mixture of biopolymers, containing mainly hydroxylated fatty acids, phenylpropanoids, phenolics and traces of carotenoids. Tracer experiments have shown that phenylalanine is a major precursor, but other carbon sources also contribute. It is likely that sporopollenin is derived from several precursors that are chemically cross-linked to form a rigid structure.

Polycyclic polyprenylated acylphloroglucinols

Hyperforin, a phytochemical constituent of the species Hypericum perforatum, known as perforate St John's-wort,, is a unique PPAP because it consists of a C8 quaternary stereocenter which was a synthetic challenge unlike other PPAP synthetic targets. The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975. A total synthesis of the non-natural hyperforin enantiomer was reported in 2010 which required approximately 50 synthetic transformations and relied heavily on basic organic reactivity. In 2010, an enantioselective total synthesis of the correct enantiomer was disclosed. The retrosynthetic analysis was inspired by hyperforin's structural symmetry and biosynthetic pathway. The synthetic route undertaken generated a prostereogenic intermediate which then established the synthetically challenging C8 stereocenter and facilitated the stereochemical outcomes for the remainder of the synthesis.

Hyperforin is unstable in the presence of light and oxygen. Frequent oxidized forms contain a C3 to C9 hemiketal/heterocyclic bridge or will form furan/pyran derivatives.

Polypeptide-p

"Polypeptide-p is a very effective hypoglycemic agent when administered subcutaneously to gerbils, langurs, and humans."

An "active principle [polypeptide-p was isolated] from fruits, seeds, and tissue culture of [bitter gourd or melon Momordica charantia] (6, 7)."

Polyphenols

Main article: Remedy/Polyphenols

Saponins

Saponins occur naturally in plants as glycosides and have foam forming properties.

"The seeds of Trigonella foenum graecum (fenugreek) have been reported to have antidiabetic and hypocholesterolaemic properties in both animal models and humans. Activity has been attributed largely to fenugreek's saponin and high fibre content, and is probably not related to its major alkaloid trigonelline. Antihyperglycaemic effects have been linked to delayed gastric emptying caused by the fibre content, and to (unidentified) components that inhibit carbohydrate digestive enzymes. Fenugreek administration may increase plasma insulin levels in vivo. Its major free amino acid, 4-hydroxyisoleucine, stimulates insulin secretion from perfused pancreas in vitro. The hypocholesterolaemic effect has been attributed to increased conversion of hepatic cholesterol to bile salts due to loss, in the faeces, of complexes of these substances with fenugreek fibre and saponins. Fenugreek treatment selectively reduces the LDL and VLDL fractions of total cholesterol, and HDL-cholesterol has also been reported to increase in alloxan-induced diabetic rats and type II diabetic individuals following treatment with fenugreek. Fenugreek administration has not been reported to cause any toxicological effects. Its regular consumption may therefore be beneficial in the management of diabetes and the prevention of atherosclerosis and coronary heart disease."

Diosgenin, a steroidal sapogenin, is reported from Smilax menispermoidea. "Other active compounds reported from various greenbrier species are Parillin (also sarsaparillin or smilacin), sarsapic acid, sarsapogenin and sarsaponin".

Aescins

The main active compound of aescin (Horse chestnut seed extract)) is β-aescin, although the mixture also contains various other components including α-aescin, protoescigenin, barringtogenol, cryptoescin and benzopyrones.

Aescin, especially pure β-aescin, may be a safe and effective treatment for short-term treatment of chronic venous insufficiency; however, more high quality randomized controlled trials are required to confirm the effectiveness. Horse chestnut extract may be as effective and well tolerated as the use of compression stockings.

Aescin induces endothelial nitric oxide synthesis by making endothelial cells more permeable to calcium ions, and also induces release of prostaglandin F_2α. Other possible mechanisms include serotonin antagonism and histamine antagonism and reduced catabolism of tissue mucopolysaccharides.

Bacopasides

Bacopasides are triterpene saponins isolated from Bacopa monnieri.

Members of this class of compounds include:

• Bacopaside I, shows antidepressant-like effects in a mouse model
• Bacopaside II
• Bacopaside III
• Bacopaside IV
• Bacopaside V
• Bacopaside VI
• Bacopaside VII
• Bacopaside VIII
• Bacopaside IX
• Bacopaside X
• Bacopaside XI, shows nootropic activity in a mouse model

Ruscosaponins

The major phytochemicals in butcher's broom are steroidal saponins. The specific saponins found in butcher's broom are ruscogenins, ruscogenen and neoruscogenin, named for the genus Ruscus. Ruscogenins function as anti-inflammatory agents and are also believed to cause constriction in veins. Currently the mode of action of ruscogenins is not well understood, but one proposed mechanism suggests that ruscogenins suppresses leukocyte migration through both protein and mRNA regulation. Neoruscogenin has been identified as a potent and high-affinity agonist of the nuclear receptor RORα (NR1F1).

Newer research has also uncovered that there are polyphenols present in butcher's broom may also be physiologically active, possibly as an antioxidant.

Silybum marianum

Def. a "mixture of flavonolignans extracted from the blessed milk thistle (Silybum marianum), used as a source of silibinin" is called a silymarin.

Silibinin (International Nonproprietary Name (INN)), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the Silybum marianum (milk thistle) seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silychristin, silidianin, and others. Silibinin itself is a mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio. The mixture exhibits a number of pharmacological effects, particularly in the fatty liver, non-alcoholic fatty liver, non-alcoholic steatohepatitis, and there is great clinical evidence for the use of silibinin as a supportive element in alcoholic and Child–Pugh grade 'A', liver cirrhosis. However, despite its several beneficial effects on the liver, silibinin and all the other compounds found in silymarin, especially silychristin seem to act as potent disruptors of the thyroid system by blocking the Monocarboxylate transporter 8 (MCT8) transporter. The long term intake of silymarin can lead to some form of thyroid disease and if taken during pregnancy, silymarin can cause the development of the Allan–Herndon–Dudley syndrome. Although this information is unfortunately still not being taken into consideration by all regulatory bodies, several studies now consider silymarin and especially silychristin to be important inhibitors of the MCT8 transporter and a potential disruptor of the thyroid hormone functions.

Silipide (trade name Siliphos, not to be confused with the water treatment compound of the same name, a glass-like polyphosphate containing sodium, calcium magnesium and silicate, formulated for the treatment of water problems), a complex of silymarin and phosphatidylcholine (lecithin), is about 10 times more bioavailable than silymarin. An earlier study had concluded Siliphos to have 4.6 fold higher bioavailability. It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself. There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect.

Silymarin, like other flavonoid]]s, has been shown to inhibit P-glycoprotein-mediated cellular efflux. It has been reported that silymarin inhibits cytochrome P450 enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded.

All of the flavonolignan compounds found in the silymarin mixture seem to block the uptake of thyroid hormones into the cells by selectively blocking the Monocarboxylate transporter 8 (MCT8) transmembrane transporter. The authors of this study noted that especially silychristin, one of the compounds of the silymarin mixture seems to be perhaps the most powerful and selective inhibitor for the (MCT8) transporter. Due to the essential role played by the thyroid hormone in human metabolism in general it is believed that the intake of silymarin can lead to thyroid disease (disruptions of the thyroid system). Because the thyroid hormones and the MCT8 as well are known to play a critical role during early and fetal development, the administration of silymarin during pregnancy is especially thought to be dangerous, potentially leading to the Allan–Herndon–Dudley syndrome, a brain development disorder that causes both moderate to severe intellectual disability and problems with speech and movement.

A phase I clinical trial in humans with prostate cancer designed to study the effects of high dose silibinin found 13 grams daily to be well tolerated in patients with advanced prostate cancer with asymptomatic liver toxicity (hyperbilirubinemia and elevation of alanine aminotransferase) being the most commonly seen adverse event.

Silymarin is also devoid of embryotoxic potential in animal models.

For approved drug preparations and parenteral applications in the treatment of Amanita mushroom poisoning, the water-soluble silibinin-C-2',3-dihyrogensuccinate disodium salt is used and in 2011, it also received Orphan Medicinal Product Designation for the prevention of recurrent hepatitis C in liver transplant recipients by the European Commission.

Silibinin is under investigation to see whether it may have a role in cancer treatment (e.g. due to its inhibition of STAT3 signalling).

Silibinin has a number of potential mechanisms that could benefit the skin: chemoprotective effects from environmental toxins, anti-inflammatory effects, protection from UV induced photocarcinogenesis, protection from sunburn, protection from Ultraviolet (UVB)-induced epidermal hyperplasia, and DNA repair for UV induced DNA damage (double strand breaks). Studies on mice demonstrate a significant protection on chronic unpredictable mild stress (CUMS) induced depressive-like behavior on mice and increased cognition in aged rats as a result of consuming silymarin.

Due to its immunomodulatory, iron chelating and antioxidant properties, this herb has the potential to be used in beta-thalassemia patients who receive regular blood transfusions and suffer from iron overload.

Silymarin can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.

The biosynthesis of silibinin A and silibinin B is composed of two major parts, taxifolin and coniferyl alcohol. Coniferyl alcohol is synthesized in milk thistle seed coat, starting with the transformation of phenylalanine into cinnamic acid mediated by phenylalanine ammonia-lyase (PAL).

St. John's wort

Chemical structure shows hypericin. Credit: Fuse809.{{free media}}

The plant contains the following:

• Flavonoids (e.g. epigallocatechin, rutin, hyperoside, isoquercetin, quercitrin, quercetin, amentoflavone, biapigenin, astilbin, myricetin, miquelianin, kaempferol, luteolin)
• Phenolic acids (e.g. chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, p-hydroxybenzoic acid, vanillic acid)
• Naphthodianthrones (e.g. hypericin, pseudohypericin, protohypericin, protopseudohypericin)
• Phloroglucinols (e.g. hyperforin, adhyperforin)
• Tannins (unspecified, proanthocyanidins reported)
• Volatile oils (e.g. 2-methyloctane, nonane, 2-methyldecane, undecane, α-pinene, β-pinene, α-terpineol, geraniol, myrcene, limonene, caryophyllene, humulene)
• Saturated fatty acids (e.g. isovaleric acid (3-methylbutanoic acid), myristic acid, palmitic acid, stearic acid)
• Alkanols (e.g. 1-tetracosanol, 1-hexacosanol)
• Vitamins & their analogues (e.g. carotenoids, choline, nicotinamide, nicotinic acid)
• Miscellaneous others (e.g. pectin, β-sitosterol, hexadecane, triacontane, kielcorin, norathyriol)

The naphthodianthrones hypericin and pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be among the numerous active constituents. It also contains essential oils composed mainly of sesquiterpenes.

Selected chemical constituents of Hypericum perforatum

• 
  Hypericin
• 
  Pseudohypericin
• 
  Adhyperforin
• 
  Hyperforin
• 
  Amentoflavone
• 
  Hyperoside
• 
  Rutin
• 
  Kaempferol
• 
  Myricetin
• 
  Quercetin
• 
  Quercitrin
• 
  Isoquercitrin
• 
  Luteolin
• 
  Catechin
• 
  Epicatechin
• 
  Epigallocatechin
• 
  Chlorogenic acid
• 
  Caffeic acid
• 
  Kielcorin
• 
  Norathyriol

Temperatures

Both energy metabolism and body temperature increases are observed in humans following extracted capsinoids [Cayenne pepper] or CH-19 Sweet administration. Animal studies also demonstrate these increases, as well as suppressed in body fat accumulation following capsinoids intake. The exact mechanisms and the relative importance of each remain under investigation, as are the effects of capsinoids on appetite and satiation.

Terpenoids

Main article: Remedy/Terpenoids

Vitamins

Main article: Remedy/Vitamins

Waxes

Main article: Remedy/Waxes

History

"The term "Orthomolecular" was first utilized by two-time Nobel Laureate Linus Pauling in 1968 to characterize the treatment of disease with nutrients that were endogenous to the human body. Orthomolecular simply means "correct molecule" which translates into "essential nutrient". Orthomolecular physicians treat disease by varying the dosages of "correct molecules" which are required but not synthesized by the human body. Doctors, adjusting diet, by eliminating junk foods, and prescribing mega dosages of essential vitamins, minerals, trace metals, amino acids, and fats can correct the chemical imbalances of disease."

See also

• Amino acids (32 kB) (6 November 2019)
• Biology (25 kB) (15 January 2020)
• Chemicals (190 kB) (18 February 2020)
• Control groups (43 kB) (24 November 2019)
• Cytokinesis (14 kB) (29 October 2019‎)
• Deoxyribonucleic acids (48 kB) (29 February 2020)
• Epigenetics (41 kB) (18 January 2020)
• Epigenomes (30 kB) (5 November 2019)
• Eukaryotes (12 kB) (5 November 2019‎)
• Evolution (41 kB) (18 January 2020)
• Genealogy (10 kB) (29 February 2020)
• Genes (42 kB) (14 March 2020)
• Genetics (23 kB) (5 November 2019‎)
• Gene transcriptions (36 kB) (5 November 2019‎)
• Genomes (29 kB) (5 November 2019)
• Genomics (16 kB) (5 November 2019‎)
• Glandular system (3 kB) (23 May 2014)
• Hair colors (12 kB) (30 November 2018)
• Heredity (13 kB) (24 December 2019)
• How-to's (3 kB) (2 July 2019)
• Human RNA (35 kB) (5 November 2019)
• Human skin pigmentation (4 kB) (16 August 2010)
• Human teeth (31 kB) (19 January 2020)
• Lamarckism (24 kB) (19 January 2020)
• Liquids (39 kB) (11 February 2020)
• Mammalogy (31 kB) (4 March 2020)
• Medicine (20 kB) (11 February 2020)
• Melanocytes (54 kB) (1 February 2020)
• Minerals
• Molecular genetics (14 kB) (5 November 2019‎)
• Neutraceuticals
• Pigmented lesions of the oromucosa (16 kB) (28 June 2016)
• Orthomolecular medicine (10 kB) (16 March 2020)
• Osteoarthritis (14 kB) (15 February 2020)
• Phosphate biochemistry (63 kB) (5 November 2019‎)
• Phosphate budgets (50 kB) (5 November 2019)
• Phosphate reactions (87 kB) (17 February 2020)
• Proof of concepts (24 kB) (19 January 2020)
• Proteins (28 kB) (18 February 2020)
• Safety (15 kB) (31 December 2019‎)
• Spaceflights (24 kB) (31 December 2019)
• Stroke management (12 kB) (4 November 2019)
• Teeth (25 kB) (9 October 2019‎)
• Terpenoids
• Two-word terms (29 kB) (7 March 2020)
• Waxes
• What is a human? (26 kB) (24 February 2020)

Further reading

• Eric Braverman (1979). "Orthomolecular Medicine and Megavitamin Therapy: Future and Philosophy". Orthomolecular Psychiatry 8 (4): 265-72. http://www.orthomolecular.org/library/jom/1979/pdf/1979-v08n04-p265.pdf. Retrieved 2014-08-20.