Please find below answers to some of the questions raised by the recent publication "Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy” by the Suomalainen-Wartiovaara Lab. The original work is published on the Cell Metabolism electronically on May 7, 2020.
The original article:
Eija Pirinen, Mari Auranen, Nahid A. Khan, Virginia Brilhante, Niina Urho, Alberto Pessia, Antti Hakkarainen, Juho Kuula, Ulla Heinonen, Mark S. Schmidt, Kimmo Haimilahti, Päivi Piirilä, Nina Lundbom, Marja-Riitta Taskinen, Charles Brenner, Vidya Velagapudi, Kirsi H. Pietiläinen, Anu Suomalainen: Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metabolism, epub before print May 07, 2020.
Link to the original publication: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X
Answers by Academy Professor, Professor of Clinical Molecular Medicine, Chief Physician Anu Suomalainen-Wartiovaara, M.D., Ph.D.
Why niacin was used in this trial? What about the other forms of B3-vitamin?
B3-vitamin is found in multiple forms, which all function as precursors of metabolite NAD+. However, they increase NAD+ levels via different pathways (picture attached from the publication Pirinen et al. Cell Metabolism, 2020). Due to these differences, their efficiency in increasing NAD+ amount in a specific tissue may depend on the enzymes present in the tissue in question.
Niacin (nicotinic acid)
We decided to use niacin in this study, because it has been used as medication for patients with high blood lipids for decades, and its adverse effects are well known. The recommended daily dietary amount of niacin (FinRavinto 2017) is 14 (women) and 18 (men) mg for healthy individual. In Finland the average daily dietary intake of niacin is clearly higher than the recommended amount, and is considered adequate to maintain health. Main sources of niacin are grains, meat, dairy products and eggs. Multivitamin tablets typically contain the recommended daily amount of niacin.
Niacin as medication
I would like to emphasize that the high niacin dosage (750-1000 mg daily), such as those we used in our mitochondrial disease study, or that have been used as treatment for high blood lipids, is medical therapy to treat specific diseases. Such doses have side effects, and a risk of overdose, even liver damage. High doses of niacin should not be used by healthy individuals or subjects with diseases without a diagnosis. The treatment must be initiated by physician and requires regular follow-ups. Quick increases in dosage as well as sudden stop of medication can have severe effects on the symptoms of the disease. Therefore, high dosage of niacin must be considered as medical treatment, and used only if there is evidence that therapeutic benefits for the patient can be expected. Currently, such evidence exists for treatment of mitochondrial myopathy. Our study is so far the first study using high doses B3-vitamins for treating mitochondrial muscle disease and it focuses on this disease because of known low levels of NAD+ in this disease.
Adverse effects of niacin
Use of high dosage of niacin causes adverse effects to nearly all individuals. Those include flushing, redness of face and sometimes of the body soon after intake of the medication, itching or tingling of the body and the limbs, and increase in blood glucose levels. Furthermore, some patients may show anemia during niacin treatment, and liver functions must be followed. Extended-release form of the vitamin can reduce the adverse effects, but currently it is not available in Europe. Niacin is quite stable as a compound. Niacin products often include both nicotinamide and niacin. In this study we used slow-release niacin product.
NAM also functions as precursor of NAD+. It is known in high dosage to inhibit certain cellular nutrient sensor enzymes (sirtuins, “substrate-level inhibition”), whereas for niacin and NR this kind of inhibition has not been shown. It has not been studied whether NAM has similar effects as niacin in increasing NAD+ levels in the treatment of mitochondrial diseases. In our patient trial we did not use NAM, because there is not enough information of the optimal dosage or effects in the human body.
Nicotinamide riboside (NR)
NR is the newest described form of B3-vitamin that was originally found from milk. It does not seem cause similar adverse effects (flushing and tingling of skin) as niacin. Profound studies of NR’s functions and adverse effects on human are currently ongoing, and its function in mitochondrial diseases and metabolic diseases are being studied. Effects and safety of long-term use of NR are remaining to be studied in large cohorts. As a compound NR is less stable as niacin. In our patient trial we did not use NR, because in our opinion more information is required for its optimal dosage and effects in the human body.