Vitamin C

(ascorbic acid)

Chain breaking antioxidant; lowers NF-kappa B activity; reported to scavenge peroxynitrite and also help restore tetrahydrobiopterin (BH4) levels by reducing an oxidized derivative of BH4

May require high doses to be effective with the latter two mechanisms; this may be the basis of so called “megadose therapy” for vitamin C; clinical trials on CFS and MCS used high dose IV ascorbate

Magnesium

Lowers NMDA activity and may be useful in improving energy metabolism and ATP utilization

Magnesium is the agent that is most widely studied and found to be useful in the treatment of the multisystem illnesses

Fish oil (long chain omega-3 fatty acids)

Lowers iNOS induction; lowers production of inflammatory eicosonoids; important for brain function

Highly susceptible to lipid peroxidation and may, therefore be depleted; four studies reported improvements in clinical trials, 3 with CFS and one with FM

Flavonoids

Chain breaking antioxidants; some scavenge peroxynitrite, some scavenge superoxide; some reported to induce SOD; All three types are found in FlaviNox; some flavonoids may also act to help restore BH4 levels; lower NF-kappa B activity

Ginkgo extract tested in CFS; anthocyanidin flavonoids in FM; other flavonoids tested in CFS animal model

NMDA antagonists

Lower NMDA activity

Four different antagonists reported to be effective in the treatment of fibromyalgia; anecdotal reports of effectiveness for MCS

Agents that indirectly lower excitotoxicity including NMDA activity

Only clinical trials done with pregabalin for fibromyalgia, but other members of this class often used clinically

Acetyl L-carnitine/

carnitine

Helps transport fatty acids into mitochondria; may be important here not only directly for energy metabolism but also to restore the oxidized fatty acid residues that may be produced in the cardiolipin of the inner membrane

May also help lower reductive stress; two trials in CFS

Ecklonia cava extract

Polyphenolic chain breaking antioxidant; reported to help scavenge both peroxynitrite and superoxide; based on its reported properties, it may also help restore BH4 levels

Appears to stay in the body much longer than do the flavonoids, a useful property; reported to be helpful in a clinical trial study of fibromyalgia

Reductive stress relieving agents

These include S-adenosyl methionine (SAM or SAMe), trimethylglycine (betaine), carnitine and choline

SAM reported to be effective in multiple clinical trials with FM and CFS patients; betaine widely used clinically

Hydroxocobalamin form of vitamin B-12

Potent nitric oxide scavenger, lowers nitric oxide levels

Limited intestinal transport; often taken by IM injection or as a nasal spray or inhalant; clinical trial with CFS-like illnesses; widely used for treatment of CFS, FM and MCS

Folic acid

Relatively high doses will lower the partial uncoupling of the nitric oxide synthases by helping to restore tetrahydrobiopterin (BH4)

Reacts with oxidants and therefore may be depleted due to the NO/ONOO- cycle

Algal supplements

Probably act as antioxidants

Hyperbaric oxygen

May act to help restore cytochrome oxidase activity by competing with nitric oxide

My impression is that this approach needs to be used with substantial care – too high or prolonged dosage can cause damage

Trimethyl glycine (betaine), S-adenosyl methionine (SAM), choline, carnitine

Lower reductive stress; also helps with the generation of S-adenosyl methionine (SAM)

While lowering reductive stress may be the main concern, SAM generation may also be of concern; the enzyme methionine synthase is inhibited by nitric oxide and inactivated under conditions of oxidative stress, thus leading to lowered SAM and lowered methylation

Coenzyme Q10 (ubiquinone)

Important in mitochondrial function; important antioxidant, especially in mitochondrion; reported to scavenge peroxynitrite

Optimal dosage may vary considerably among different individuals; suggest taking early in day

D-ribose, RNA or inosine

Two important functions:  Provides adenosine for restoring adenine nucleotide pools after energy metabolism dysfunction; when catabolized, the purine bases generate uric acid, a peroxynitrite scavenger

Each of these may act somewhat similarly; however only D-ribose has been tested in a clinical trial and reported to be effective; each of these agents has distinct drawbacks

Vitamin B6, including pyridoxal phosphate

multiple functions, most relevant may be to stimulate glutamate decarboxylase activity, limit excitotoxicity

Niacin, including nicotinic acid and nicotinamide

Helps restore NAD/NADH pools after poly-ADP ribosylation leads to pool depletion; important for energy metabolism

Thiamine

Is depleted by oxidants; essential for two steps in pentose phosphate shunt and is needed, therefore to help provide NADPH for glutathione reductase

Riboflavin including 5’- phosphate

Depletion can limit glutathione reductase activity

Carotenoids including natural b-carotene, lycopene, lutein

Helps scavenge peroxynitrite, especially in biological membranes

Natural vitamin E, including g-tocopherol and the tocotrienols

g-tocopherol thought to have special role in scavenging NO2 radical (from peroxynitrite);  tocotrienols may have special role in protecting from excitotoxicity and/or mitochondrial oxidation

Taurine

thought to lower excitoxicity by stimulating gabaergic activity

Zinc, manganese, copper

Modest doses used; may increase superoxide dismutase activity

a-lipoic acid

Multiple antioxidant roles on reduction to dihydrolipoic acid; helps restore reduced glutathione pools

N-acetyl cysteine

Helps restore reduced glutathione pools; modest doses used to prevent or lower possible excitotoxicity

Selenium as seleno-L-methionine

Important antioxidant; a variety of organic selenium compounds are peroxynitrite scavengers; selenium levels often low in multisystem illnesses