– NADH – NADH INTRODUCTION NADH is an abbreviation for the reduced form of nicotinamide adenine dinucleotide. NADH and NAD (the oxidized form) are part of what is chemically known as a redox pair, and are also considered biologically active cofactors. These compounds participate in various oxidation and reduction reactions throughout the body. The ubiquitous NADH can reduce substrates in reactions. Metabolic pathways that require NADH include; glycolysis, gluconeogenesis, fatty acid synthesis and degradation, the hexose monophosphate pathway, and the tricarboxylic acid pathway. [1] NADH also participates in DNA repair and maintenance, and cellular immunity. [2] Nicotinamide adenine dinucleotide is synthesized from niacin (also known as vitamin B3), nicotinamide, and tryptophan. The pharmacologic and physiologic effects of NADH are diverse. NADH has demonstrated cytokine-modulating effects on peripheral blood cells. In 18 healthy donors, NADH significantly stimulated the dose-dependent release of IL-6, which is an important cytokine of particular significance to focal central nervous system inflammation. [3] This finding is related to treatment of neurodegenerative diseases like Alzheimer's and Parkinson's disease. NADH can be used in the biosynthesis of tetrahydrobiopterin (BH4), which is an essential cofactor for tyrosine hydroxylase, as well. This enzyme is the rate limiting step in the production of dopamine. Research in rat brains has shown that NADH can increase dopamine release from striatal slices. [4] Increased dopamine is important in the treatment of conditions like Parkinson's disease. NADH also has direct effects on cognitive ability in animals. One particular study in rats showed that repeated administrations of NADH improved the performance of old rats in the acquisition phase (place version) and the spatial probe of the Morris water maze when compared to vehicle-treated controls. [5] NADH Food Sources NADH formation requires niacin (vitamin B3) and tryptophan, therefore an adequate supply of this vitamin and amino acid is necessary. Good sources of niacin include unrefined grains, fortified cereals, milk, and lean meats (especially liver). Tryptophan is found in highest levels in brown rice, cottage cheese, meat, peanuts, and soy proteins. NADH itself must be taken in supplemental form to achieve the therapeutic effect. NADH Uses Currently, research supports the use of NADH primarily for three conditions: chronic fatigue syndrome, Parkinson's disease, and Alzheimer's disease. Chronic fatigue syndrome (CFS) is a complex disorder that is diagnosed by criteria defined by the Centers for Disease Control. Typically, patients have prolonged excessive fatigue, and a myriad of other symptoms such as muscle pain, headaches and sleep difficulties. In a study of 35 patients meeting the criteria for CFS, 10 milligrams per day of NADH or placebo was administered for 4 weeks. [6] After a 4 week washout period, each group received the other treatment. The results of the study showed that NADH significantly improved the symptom score when compared to placebo. As well, only minor side effects were noted on the first day of therapy with NADH. Another clinical study was conducted in patients with CFS to compare the effectiveness of NADH to standard conventional therapy. Again, 31 patients meeting CDC criteria for CFS were enrolled in this study. [7] They were randomized into two treatment groups: NADH or nutritional supplements and psychotherapy for 24 months. The results showed that for the first trimester of the study, patients in the NADH group were significantly improved compared to those receiving conventional therapy. However, following the initial trimester there were no significant differences between these groups. The authors conclude that NADH needs to be further studied with a larger sample size to determine effectiveness in the subsequent trimesters. Considering that no therapeutic regimen has proven effective for treating CFS, NADH offers a novel approach to treating this debilitating disorder. NADH has been studied in the treatment of Parkinson's disease. The theory proposed is that NADH stimulates the activation of tyrosine hydroxylase, which in turn may stimulate the synthesis of endogenous levodopa. Levodopa is typically low in Parkinson's disease. An initial clinical trial was conducted in 1989. NADH was administered either intravenously and intramuscularly to 34 participants enrolled in the open study. [8] The results showed that all patients received benefit from the treatment, with i.v. application demonstrating the most clinical benefit. More than 30% improvement in disability was noted in 62% of the patients. The best therapeutic dose was observed between 25 to 50 milligrams per day. In another clinical trial, patients with idiopathic Parkinson's disease were treated with an intravenous application form of NADH, in addition to their standard pharmaceutical therapy, over the course of seven days. [9] The results showed that NADH significantly increased bioavailability of plasma levodopa and improved Parkinsonian symptoms. A review of NADH as a treatment for Parkinson's disease questioned its application based on the lack of a supportive large scale placebo-controlled trials to support its use. [10] However, due to the low toxicity associated with NADH, its utilization in this condition should not be discounted. As mentioned, NADH has demonstrated positive effects on the cognitive ability of test animals. Studies have extrapolated this information and applied it to the treatment of Alzheimer's. An open label trial of 17 patients with dementia of Alzheimer's was conducted using NADH for 8 - 12 weeks. [11] The results showed improvements in cognitive ability. Furthermore, there were no adverse effects noted. More recently, a double-blind, placebo-controlled study was conducted to definitively determine if NADH is of benefit in persons suffering from Alzheimer's. Twenty six patients with probable Alzheimer's were randomized to receive 10 milligrams per day of stabilized oral NADH or placebo over a period of 6 months. [12] The results showed that the group given NADH had no evidence of progressive concerning cognitive deterioration and had significantly higher total scores on the MDRS (Mattis Dementia Rating Scale) compared with subjects treated with placebo. This study confirms that NADH is beneficial to patients with cognitive decline caused by Alzheimer's. Other conditions for which NADH may be beneficial include jet lag and age related hypertension and hypercholesterolemia. [13, 14] NADH Dosages Most studies use a dose of 10 milligrams daily. An enteric coated form is the most effective, avoiding potential breakdown in stomach. Intravenous and intramuscular forms are also available. The i.v. form has demonstrated superior efficacy over the i.m. form. NADH Deficiencies and Toxicities NADH Deficiency NADH deficiency has not been documented. Applications of NADH appear to be therapeutic only. NADH Toxicities NADH is generally considered a safe therapeutic substance when taken in recommended doses. The majority of studies reveal the absence of severe side effects in patients taking NADH. Adverse reactions that may be observed clinically include; mild overstimulation, anxiety, loss of appetite, odd taste, dryness, and insomnia. An animal toxicity study was conducted using a stabilized, orally absorbable form of NADH (ENADA). The animals were given dose levels of 20, 100, and 150 mg/kg for 14 days. Observed effects included a transitory change in stool formation with intermediate and high doses, and increases in adrenal, heart, kidney, liver, brain, and thyroid weights, primarily in male subjects. However, these effects were not deemed toxicologically significant. The maximum tolerated intravenous dose (MTD) of betaNADH (the reduced form of NADH) was also determined and was considered to be 500 mg/kg/day. Doses above that level reduced food consumption and body weight. [15] Another animal study involving a daily dose of 5 mg of ENADA revealed that this particular form of NADH is relatively safe. The 5mg dose in a rat corresponds to a dose of 175 mg per day in a 70 kilogram human, which is 175 times the recommended daily dosage of 1 ENADA tablet per day. The authors conclude that the recommended dose is generally regarded as safe. [16] NADH REFERENCES
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