There’s an ongoing debate in health circles about nicotinic acid (commonly known as niacin). Some argue it’s beneficial, while niacinamide and nicotinamide, other forms of vitamin B3, are problematic. But let’s take a closer look. The science reveals that there is no meaningful difference between them when it comes to their effects on the body. Both can be damaging, especially at high doses.
High dose nicotinic acid yields higher amounts of N-methyl-2-pyridone-5-carboxamide (N-Me-2PY), which is a degradation of nicotinic acid. This compound is known to cause kidney problems.
“In one study, 2PY was isolated from the hemodialysis fluid of uremic patients (who were not consuming nicotinamic acid derivatives) [22], and it was suggested that the accumulation of 2PY in kidney failure might contribute directly to the signs and symptoms of uremia.” (NLM)
“The presence of 2PY in human blood serum can be an indication of poor kidney performance or chronic kidney disease.[2][3] 2PY has been identified as a product of the metabolism of caffeine and niacin.[5]”. (Wikipedia)
“ N-Me-2PY has been described as a uremic toxin because of the correlation between its abundance in blood and kidney disease states [71]”. (NLM)
It also seems as if it turns into aldehydes, among many other toxic components.
“Oxidation of circulating N-methyl-Nam by aldehyde oxidase yields N-methyl-4-pyridone3-carboxamide (N-Me-4PY) and N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) [6,67–69].”(NIH)
“NA undergoes reactions typical for carboxylic acids and forms appropriate amides, esters, thioesters, acid halides, anhydrides, and salts. NA is also reduced to aldehyde or alcohol and hydrogenated to nipecotic acid, and it can form ionic liquids.”(NIH)
This relationship is similar to vitamin A and carotenoids. Carotenoids are converted into retinoic acid in the body. While retinoic acid is even more damaging than carotenoids, we still convert them as part of the body’s attempt to process and eliminate them. Unfortunately, we can’t fully control how much retinoic acid is produced from the carotenoids we ingest. If you’d like to dive deeper into how retinoic acid causes harm, I recommend reading Grant Genereux’s books at ggenereux.blog/my-ebooks.
The same holds true for nicotinic acid and niacinamide: taking large amounts of nicotinic acid can lead to an abundance of niacinamide in the body. Some argue that niacinamide is more harmful than nicotinic acid. Whether or not that’s true, it’s worth asking: couldn’t prolonged high doses of nicotinic acid flood your system with niacinamide too?
Taking large amounts of nicotinic acid also causes the body to concentrate it in different parts of the body.
“The plasma half-life time of nicotinic acid is about 1 h, and it can be concentrated in the liver, adipose tissue, and kidneys. “Niacin excess” per se has to be divided based on the effects of excess nicotinic acid and those of nicotinamide.” (Springer)
The Methyl Group Problem
Both nicotinic acid and niacinamide consume methyl groups in the body. Why does this matter? Because methyl groups are essential for detoxification, gene regulation, reducing inflammation, and even healthy cell replication.
“Cumulative doses of nicotinic acid produced a dose-dependent increase in the plasma levels of N(1)-methylnicotinamide and hydrogen peroxide, which was associated with a decrease in liver and skeletal muscle glycogen levels.” (PubMed, 2012)
In simple terms, continued use of nicotinic acid depletes your methyl reserves. And when methyl groups run low, detoxification slows, inflammation rises, and the body struggles with basic cellular repair and maintenance.
“At the DNA level, methyl groups are vital for normal cell replication. They literally ‘turn on’ or ‘turn off’ genes. Stage II liver detoxification, protein methylation, homocysteine metabolism (which reduces inflammation), neurotransmitter synthesis, and nucleic acid synthesis all require methyl groups.” (Vedantu Chemistry)
What else do methyl groups support beyond detoxification and inflammation control? If you’ve ever noticed that methylated B vitamins seem to work better for you than other forms, there’s a reason for that.
When you’re taking high doses of nicotinic acid and find yourself needing large amounts of methylated B vitamins, it may be because of the way nicotinic acid interacts with methyl nutrients.
“The toxic effects of niacin may involve a variety of mechanisms, including methyl depletion, changes in NAD‑dependent reactions and excessive ROS generation.” (Nature)
“Methyl nutrients include folates (vitamin B9), riboflavin (vitamin B2), cobalamin (vitamin B12), pyridoxine (vitamin B6), and choline (vitamin B4), as well as methionine and betaine… The deficiency of methyl nutrients in the body can lead to disturbances in SAM synthesis, which is the primary donor of methyl groups in the DNA methylation process.”
(PubMed, 2021)
This suggests that high-dose nicotinic acid may disrupt the function of these critical B vitamins by depleting methyl groups. And because methylation processes often depend on calcium, it’s worth considering how calcium status influences your ability to use these nutrients effectively. For some, restoring calcium levels may not only support methylation, but also reduce the need for high doses of methylated B vitamins—or even prevent toxicity reactions to them.
Nicotinic Acid and Bone Health
High doses of nicotinic acid, even doses above 25mg, in my experience, can also promote bone breakdown.
“High concentrations of nicotinic acid induced cytoskeletal disassembly and promoted β-tubulin degradation in a proteasome-dependent manner. The cytoskeletal disassembly may finally contribute to the disruption of the intracellular transport process.”
(PMC, 2014)
“higher niacin intake was significantly associated with hip fractures” (ACR).
This process effectively pulls calcium from the bones, using it to balance cellular calcium levels. Some suggest “buffering” nicotinic acid with magnesium, potassium, or sodium might help. But unless you’re replenishing calcium specifically, your bones are still at risk. Worse, even if you supplement with calcium while taking nicotinic acid, that calcium may simply be consumed for cellular processes instead of strengthening your bones.
Nicotinic acid—>Niacinamide—>Methyl Depletion—>Bone Siphoning—>System-wide Ca2+ Overload
Cytosolic Calcium Overload
Nicotinic acid also plays a role in driving calcium into the cytosol of cells. While some calcium in the cytosol is necessary, too much can be highly damaging. Research indicates that nicotinic acid adenine dinucleotide phosphate (NAADP), a metabolite derived from nicotinic acid, is one of the most potent intracellular calcium (Ca²⁺) mobilizing messengers:
“An additional second messenger that can promote Ca²⁺ release into the cytosol is nicotinic acid adenine dinucleotide phosphate (NAADP), which in fact is the most potent Ca²⁺ mobilizing messenger yet identified.” (PMC, 2014)
“Nicotinic acid adenine dinucleotide phosphate (NAADP), identified as one of the most potent calcium‑mobilizing second messengers, has been studied in different eukaryotic cell types…” (MDPI)
Additionally, a study on rat astrocytes noted that:
“…bath‑applied NAADP elicited a reversible and concentration‑dependent Ca²⁺ rise in up to 90 % of astrocytes…”(Cell Calcium, 2005)
These findings demonstrate that high intracellular NAADP levels, which can stem from nicotinic acid intake, directly cause calcium to flood from internal stores into the cytosol.
Excess cytosolic calcium has been linked to inflammation and serious neurodegenerative conditions like Alzheimer’s:
“A rise in cytosolic calcium concentration triggers neurodegeneration.”
(Alzheimer’s Journal, 2023)
“Reduced mitochondrial Ca²⁺ uptake amplifies cytosolic Ca²⁺ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation.” (Nature, 2023)
This mechanism adds a crucial layer to the understanding of how excessive nicotinic acid can lead to cytosolic Ca²⁺ overload, inflammation, and disease.
The Bottom Line
Excess nicotinic acid—especially over long periods—can lead to:
- Methyl group depletion, impairing detox and increasing inflammation.
- Bone loss, as calcium is pulled to balance cellular needs.
- Cytosolic calcium overload, driving inflammation and potentially contributing to neurodegenerative diseases.
Taken together, excessive nicotinic acid, especially when consumed over long periods, can deplete calcium as it’s diverted to support various cellular processes. This calcium imbalance contributes to widespread inflammation, setting the stage for numerous health issues, including neurodegenerative diseases.
With that being said, in my opinion and from what I have personally experienced, nicotinic acid supplementation isn’t necessary. The risks seem to far outweigh any potential benefits.
However, small amounts that you find in food are actually good for you because we do need it to help with putting calcium in the cells, when needed. It is just when it is supplemented, especially in high doses and for a prolonged time, that it seems to cause a problem. When calcium is put into the cells, in a small dose, your body can actually heal as it is not over excited by too much calcium in the cells.
“…niacin deficiency leads to delayed DNA excision repair, accumulation of single and double strand breaks, impaired cell cycle arrest and apoptosis, and to an increased predisposition to cancer development.” (NIH)
It’s not so black and white; it can be both good and bad. The problem is, when you have too much of a good thing, it often backfires.