Nicotine Adenine Dinucleotide (NADH) for Parkinson’s Disease
Nicotine Adenine Dinucleotide (NADH) for Parkinson’s Disease
December 2000; Volume 3; 137-140
By Robert J. Nardino, MD, FACP
The coenzyme nicotine adenine dinucleotide (NADH) is essential to energy production in every living cell. Now NADH is being investigated as a therapeutic agent for several medical conditions, including for Parkinson’s disease. The basic premise for the use of NADH is that harnessing its coenzyme activity can spur the affected brain to produce more dopamine, and thereby ameliorate the symptoms of this degenerative disorder.
Pathophysiology
In patients with Parkinson’s disease, the biosynthesis of dopamine appears to be blocked at the step where tyrosine is converted to levodopa. Tyrosine hydroxylase and its coenzyme (tetrahydrobiopterin) are responsible for this step.1 NADH serves as a coenzyme in the synthesis of tetrahydrobiopterin.
Mechanism of Action
NADH supplementation may shift the equilibrium in dopamine synthesis toward more tetrahydrobiopterin, leading to an increase in endogenous dopamine production.2 (See Figure 1.) Alternatively, NADH could decrease the degradation of dopamine by its negative feedback on the activity of aldehyde dehydrogenase.3
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An attempt at using tetrahydrobiopterin to stimulate activity of tyrosine hydroxylase to treat Parkinson’s disease was unsuccessful.1 The reason for its failure was postulated to be its inability to cross the blood-brain barrier. Since tyrosine hydroxylase is an iron-containing enzyme, iron loading also was tried, but was only modestly successful.4
Clinical Studies
The clinical studies of NADH for the treatment of Parkinson’s disease are summarized in Table 1.
| Table 1-Clinical studies of NADH in the treatment of Parkinson's disease | |||||
| Study | Design | # Patients | Dose/Route | Outcome Measure | Result |
| Birkmayer5 | Open-label | 34 | 25 mg IV qd or qod for 10-14 days | Disability score* | Improvementa |
| Birkmayer7 | Open-label | 885 | 12.5 mg IV qod for 14 days; 5 mg PO qod for 14 days |
Disability score* | Improvementb |
| Dizdar8 | RCT double-blind |
9** | 25 mg IV for 4 days, then 25 mg IM at two weeks and 4 weeks |
UPDRS | No Improvementc |
| Kuhn9 | Open-label | 15 | 10 mg IV for 7 days | UPDRS (day 1 and 8) | Improvementd |
| *Disability score of Birkmayer and Neumayr RCT = Randomized controlled trial | |||||
| **5 received NADH, 4 received placebo UPDRS = Unified Parkinson's Disease Rating Scale | |||||
| asymptomatic improvement lasted from 1-7 days | |||||
| bresults shown in Figure 2 | |||||
| cabsolute decrease in UPDRS of 7.3 + 2.3 in NADH group; 5.3 + 0.8 in placebo group | |||||
| dabsolute decrease in UPDRS of 9.3 points (P = 0.025) | |||||
Birkmayer and Birkmayer first reported the use of NADH in an open-label study of 34 patients with Parkinson’s disease.5 They infused 25 mg intravenously over 30 minutes, daily or every second day, for 10 to 14 days. Dosing frequency reportedly was based on the patients’ disability scores and their improvement, but no specific guideline for this determination was provided.
Patients ranged in age from 40 to 85 years, with a disease duration ranging from eight to 20 years. Using the disability scale of Birkmayer and Neumayr, they found that 62% of the treated patients had a very good improvement (defined as a score decreasing by > 30%) and 38% had a moderate improvement (defined as a score decreasing by up to 30%). It is unclear when during the course the patients were examined, although it is noted that the "on" phase was prolonged in many patients. The authors also note that after NADH withdrawal, symptoms worsened. Finally, they found an increase in urinary homovanillic acid, a metabolite of dopamine, which was interpreted as indicating increased dopamine production.5,6
Birkmayer et al followed up this report with a report on 885 patients who had been treated with NADH.7 In this open-label, uncontrolled trial, 415 patients received 12.5 mg NADH intravenously every other day for 14 days, and 470 patients received 5 mg NADH orally every other day. It is not clear what led to a reduction in the intravenous dose from the authors’ first study, and the authors designed the oral formulation. There also is no information on patient selection or whether those who were performing the clinical assessments were blinded to the patient assignment. Their results are demonstrated in Figure 2, with improvement based on the percentage change in the Birkmayer-Neumayr disability score.
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The authors report that age and longer disease duration negatively impact response to NADH, but the data for this conclusion are not supplied. Also not provided are the data to substantiate the claim that many patients were able to decrease or eliminate their levodopa dose. Additionally, in this article they report the results of a tissue culture study in which neuroblastoma cells were incubated with NADH. Increasing concentrations of NADH led to increased dopamine production. Furthermore, it is noted that tyrosine hydroxylase activity increased in this experiment.
The only randomized, double-blind, placebo-
controlled trial of NADH for the treatment of Parkinson’s disease was published by Dizdar et al in 1994.8 Ten patients were randomized to receive an intravenous dose of 25 mg NADH or saline placebo daily for four days, followed by IM injections at two and four weeks. One patient subsequently was excluded because of sciatic pain that interfered with the disability score determination. Four of five patients receiving NADH showed improvement after the initial intravenous dosing; however, the placebo group also showed improvement in disability score, and the difference between the groups was not statistically significant. The study suffers from small sample size, and generates questions about the validity of the open-label results.
Kuhn et al published the most recent NADH study, an uncontrolled, open-label study of 15 patients with Parkinson’s disease.9 They investigated a novel intravenous preparation of NADH, using a dose of 10 mg/d for seven days, and looked at clinical response and effect on levodopa concentration. A significant reduction in the Unified Parkinson’s Disability Rating Scale was seen following NADH treatment. Levodopa maximum concentrations and area under the plasma concentration-time curve were increased. This was interpreted to mean that endogenous production of levodopa was increased, although it does not exclude the possibility of decreased or delayed metabolism of levodopa instead. Differences in study design and heterogeneity among the various dosing schedules preclude any systematic analysis of the data. It is clear that a response can be achieved, but whether it is above and beyond a placebo response remains uncertain.
Adverse Effects
No adverse effects were noted with short-term intravenous or oral use of NADH in the aforementioned studies. In a recent study of NADH inpatients with chronic fatigue syndrome, the only adverse effects reported were mild loss of appetite, heartburn, increased flatulence, and an odd taste on the first day of taking the drug. One patient reported feeling overly stimulated. None were sufficiently severe to result in discontinuation. Although NADH has been shown to decrease blood pressure in hypertensive rats, no such effect has been observed in humans.10 There are no data available concerning the use of NADH in pregnancy or lactation, and its use in these settings should be avoided.
Drug Interactions
No drug interactions with NADH have been described.
Formulation
Oral NADH is prepared in an enteric-coated formula. When exposed to the stomach’s acidic environment, it is inactivated rapidly. The oral preparation used in the Parkinson’s disease studies is acid-stable and releases the active ingredient over two to three hours.7 It is available commercially as Enada®. The manufacturer recommends taking the supplement once daily in the morning on an empty stomach, and waiting 20-30 minutes before eating or taking other medications.
Conclusion
The evidence for use of NADH in the treatment of Parkinson’s disease is contradictory. Large case series show a benefit with short-term NADH supplementation, but the only placebo-controlled trial shows no difference. This trial suffers from its small size; there was no sample size calculation performed. Therefore, data from randomized, controlled trials are lacking. The individual who discovered the enteric-coated formulation of NADH, and who has a proprietary interest, has performed the large case series. There is some controversy over the exact mechanism whereby NADH might exert its effect. Finally, there also is some discrepancy in laboratory measurement of dopamine precursors, metabolites, and synthetic enzyme function between studies.
Recommendation
At this time, the evidence for use of NADH for the treatment of Parkinson’s disease is marginal. The treatment appears to be safe for short-term use, but data on long-term safety are lacking. Patients who are interested in taking NADH should consider the enteric-coated formulation in a dosage of 5 mg/d, with monitoring of their symptoms. A four-week trial probably is sufficient to assess whether there is any benefit.
Dr. Nardino is Program Director of the Internal Medicine Residency at the Hospital of Saint Raphael in New Haven, CT, and Assistant Clinical Professor of Medicine, Yale University School of Medicine.
References
1. Nagatsu T, et al. Biopterin in human brain and urine from controls and Parkinsonian patients: Application of a new radioimmunoassay. Clin Chim Acta 1981;109:305-311.
2. Birkmayer GJ, Birkmayer W. Stimulation of endogenous L-dopa biosynthesis—a new principle for the therapy of Parkinson’s disease. The clinical effect of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotidephosphate (NADPH). Acta Neurol Scand Suppl 1989;126:183-187.
3. Swerdlow RH. Is NADH effective in the treatment of Parkinson’s disease? Drugs Aging 1998;13:263-268.
4. Birkmayer JG, Birkmayer W. Improvement of disability and akinesia of patients with Parkinson’s disease by intravenous iron substitution. Ann Clin Lab Sci 1987;17:32-35.
5. Birkmayer W, Birkmayer GJ. Nicotinamidadenindinucleotide (NADH): The new approach in the therapy of Parkinson’s disease. Ann Clin Lab Sci 1989;19:38-43.
6. Birkmayer W, et al. The clinical benefit of NADH as stimulator of endogenous L-dopa biosynthesis in parkinsonian patients. Adv Neurol 1990;53:545-549.
7. Birkmayer JG, et al. Nicotinamide adenine dinucleotide (NADH)—a new therapeutic approach to Parkinson’s disease. Comparison of oral and parenteral application. Acta Neurol Scand Suppl 1993;146:
32-35.
8. Dizdar N, et al. Treatment of Parkinson’s disease with NADH. Acta Neurol Scand 1994;90:345-347.
9. Kuhn W, et al. Parenteral application of NADH in Parkinson’s disease: Clinical improvement partially due to stimulation of endogenous levodopa biosynthesis. J Neural Transm 1996;103:1187-1193.
10. Bushehri N, et al. Oral reduced B-nicotinamide adenine dinucleotide (NADH) affects blood pressure, lipid peroxidation, and lipid profile in hypertensive rats (SHR). Geriatr Nephrol Urol 1998;8:95-100.
December 2000; Volume 3; 137-140
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