Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment
Abstract
1. Introduction
2. Briefs on Biochemistry Associated with Mechanisms Underlying NAM’s Positive Effects
3. Potential Toxicity and Adverse Effects of High Doses of NAM
3.1. Possible Genotoxicity and Carcinogenicity: Inconclusive Effects of NAM
3.2. Inhibition of Sirtuin Activity: An Effect that May Not Be Important In Vivo
3.3. High NAD+/NADH Ratio: Concerns Regarding Energy Metabolism
3.4. High-Level NAD+: Effect on Protein Translation
3.5. High-Level NAM Methylation: Potential Effects of Altered Methyl Pool
3.6. High-Level NAM Methylation: Potential Adverse Effects of Altered Methyl Pool
3.6.1. Insulin Resistance and Metabolic Syndrome
3.6.2. Parkinson’s Disease
3.6.3. Cardiac Diseases
3.6.4. Liver Toxicity
3.7. Potential Positive Effects of metNAM: Contradiction to the Proposed Adverse Effects
3.8. N-Methyl-2-Pyridone-5-Carboxamide: A Potential Uremic Toxin
4. Concluding Remarks and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Effects | Examples of Effects | References |
---|---|---|
Protection against ATP depletion | [2] | |
Decreased AD pathology and cognitive decline | [10] | |
Improved sensory and motor neurological behavior | [3] | |
Increased recovery from bilateral frontal brain injury | [4] | |
Neuroprotection | Prevention/delay of ischemic stroke in stroke-prone hypertensive rats | [5] |
Reduced lateral geniculate nucleus neuronal death | [6] | |
Attenuated hippocampal neuronal death after global ischemia | [7] | |
Improved motor deficits associated with Huntington’s disease phenotype | [8] | |
Increased NAD+ level and mitochondrial function | [9] | |
Amelioration of depression and psychological disorders | Amelioration of depression | [28] |
Increased social interaction | [11] | |
Anti-inflammation | Attenuated neutrophil recruitment in carrageenan-induced pleurisy or in lesions of autoimmune disease | [12,13] |
Reduced arthritis activity | [14] | |
Protection against vision and hearing loss | Attenuated retinal pigment cell death and age-related macular degeneration in animals | [29] |
Reduced incidence of optic nerve degeneration and glaucoma | [30,31] | |
Immune modulation | Improved mouse survival after lethal Staphylococcus enterotoxin B challenge | [32] |
Skin protection/anti- skin disorders/cosmetic effects | Downregulation of the expression of inflammatory cytokines and protection against UV light | [33] |
Anti-fibrosis | Attenuated development of pulmonary fibrosis | [34,35] |
Anti-metastasis and adjuvant cancer therapy | Decreased growth and progression of bladder tumors | [36,37] |
Photo-protection and reduced incidence of skin cancers | [15] | |
Anti-HIV and -AIDS | Decreased provirus integration | [16] |
Decreased viral RNA expression | [17] |
Affected Organs and Conditions 2 | Observed Effects | Dose and Duration | References |
---|---|---|---|
Beneficial effects | |||
Joints | Reduced itching in uremic patients | 550 mg twice a day (4 weeks) | [38] |
pancreatic β-cell | β-cell function preserved and improved | 25 mg/kg daily intake (4 weeks) | [18,39] |
Reduced the rate of diabetes incidence | 500 mg twice per day (2.5 years) | [19] | |
No effect on the incidence of being diabetes-free | 1200 mg daily intake (5 years) | [20] | |
Ineffective in prevention or delaying clinical onset of diabetes | 1.2 g daily intake (3 years) | [21] | |
Skin | Reduced acne lesions and severity | 4% gel applied twice daily (8 weeks) | [26] |
Attenuated immunosuppression with alterations in metabolism and apoptosis | 5% lotion applied before UV exposure | [40] | |
Psychology | Improvements against depression | 0.5–1.5 g daily intake (3 weeks) | [22] |
Relief from anxiety | A dose of 2 ug 3 h prior to test | [23] | |
Kidney | Lowered serum concentrations of phosphorus, parathyroid hormone, and LDL, and increased serum HDL | 500 mg/day (with and increment every 2 weeks) (12 weeks) | [41] |
Skin cancers non-melanoma | Reduced incidence of various types of skin cancers and actinic keratoses | 500 mg twice daily (4 months) | [42] |
Adverse Effects | |||
Minor effects | Frontal dull headaches, nausea, headache, dizziness | 1–18 g immediate | [43,44] |
Pancreatic β-cell/plasma | Decreased insulin sensitivity, increased oxidative stress (H2O2) | 2 g daily (2 weeks) | [45,46] |
Liver | Parenchymal-cell injury, portal fibrosis and cholestasis, liver injury | 3, 9 g daily (10 days) | [47] |
Lymphocytes, platelets | Uremic toxicity-related cancer and thrombocytopenia | 1300, 1500 mg daily (24 weeks) | [48] |
Kidney/platelets | Decreased serum phosphorus and thrombocytopenia | 0.52–2 g daily (3–6 months) | [49,50] |
Subjects | Examples of Effects | Dose | Duration | Ref. |
---|---|---|---|---|
Death of mouse embryonic stem cells | 20 mM | 3–4 days | [95] | |
Tumorigenicity. DNA damage, and sister chromatid exchanges | 1–10 mM 10 mM | 3 h 40 h | [100,101] | |
Cells | 25 mM | 48 h | [102] | |
Decreased SIRT1 activity. Increased intracellular ROS, spindle defects, and mitochondria dysfunction | 5 mM | 6, 12, 24 h | [106] | |
Blocked mitochondria-related transcription. Worsened motor disturbance in Huntington’s disease model | 0.5, 1 mM | 96 h | [9] | |
Mice and Rats | Oxidative DNA damage in hepatic and renal tissues. Impaired glucose tolerance and insulin sensitivity | 1 or 4 g/kg, d.w. | 8 weeks | [94] |
Increased lethality | 4.5 g/kg, d.w., 2.5 g/kg, i.p. | 40 days | [44] | |
Occurrence of pancreatic islet cell tumor | 350 mg/kg, i.p. | 226 days | [107] | |
Increased incidence of kidney tumors | 350 mg/kg, i.p. | until die | [108] | |
Decreased growth rate | 1, 2 %, d.w. 1, 2 %, d.w. | 24 days 20 days | [109,110] | |
Growth inhibition, methyl deficiency, reduced tissue choline level, and increased hepatic lipids | 6, 20, 60 mg/100 g bw, i.p. | 2, 5 weeks | [111] | |
Amelioration of acetaminophen-induced biochemical changes but occurrence of hepatotoxicity in healthy animals | 500 mg/kg, i.p. | 1.5 h | [112] | |
Development of hepatic steatosis and fibrosis | 1%, d.w. | 6 weeks, 7 months | [113] | |
Neurodegeneration of dopaminergic neurons Behavioral deficits and structural brain changes | 500 mg/kg, i.p. | 28 days | [114] | |
Blocked mitochondrial-related transcription, worsened motor phenotype | 250mg/kg/day, s.c. | 28 days | [9] |
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Hwang, E.S.; Song, S.B. Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules 2020, 10, 687. https://doi.org/10.3390/biom10050687
Hwang ES, Song SB. Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules. 2020; 10(5):687. https://doi.org/10.3390/biom10050687
Chicago/Turabian StyleHwang, Eun Seong, and Seon Beom Song. 2020. "Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment" Biomolecules 10, no. 5: 687. https://doi.org/10.3390/biom10050687
APA StyleHwang, E. S., & Song, S. B. (2020). Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Biomolecules, 10(5), 687. https://doi.org/10.3390/biom10050687