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Orthomolecular Medicine News Service, March 9, 2024

 By W. Todd Penberthy, Stephen McConnel, Robert G. Smith, Thomas Levy, Michael Passwater, and Richard Cheng

OMNS (Mar 9, 2024) Approximately 100 years ago, the niacin deficiency disease pellagra, was at its peak in the southern United States of America. Over 120,000 people would die between 1900 to 1920 due to a deficiency of the yet to be discovered niacin molecule. [1]

Then, in the 1940s after the discovery of niacin, the government made it a law that flour and rice had to be fortified to prevent pellagra, deaths, mental health issues, and overcrowding in insane asylums. [2]

This ultimately has saved countless lives ever since the mandatory fortification of niacin, and one also wonders whether it may have played a bigger role in creating a more peaceful world, no longer engaged in World Wars. [3]

Pellagra was by far the worst nutritional disaster in the history of the US, and this history speaks volumes to the sensitivity of the human body machine to niacin deficiency.

Nobody disputes that niacin fortification was one of the biggest advances in the US history of public health and this niacin fortification continues to rescue countless people even today in 2024 from excessive consumption of processed food.

So why is there now news questioning whether niacin fortification may suddenly be causing cardiovascular disease? [4,5]

Well, it gets your attention so you can watch inserted advertisements, but it started from a just published study from Stanley Hazen’s group at Cleveland Clinic. [6]

The study involves the measurement of plasma metabolites that correlate with major adverse cardiovascular events (MACE).

They identified two excreted metabolites (2PY and 4PY) as associated with MACE. Like most metabolites, they are excreted by the body for a reason.

These two plasma metabolites are produced after NAD is broken down (nicotinamide adenine dinucleotide; Vitamin B3 is taken to make NAD). This is shown in their manuscript.

However, the authors chose to label 2PY and 4PY as “niacin-associated” metabolites when in in fact these are “NAD-associated” metabolites. 2PY and 4PY are breakdown products of NAD, not niacin at all! This is clearly shown directly in figure 1 and in the last figure of their own manuscript.

Until the publication by the Cleveland Clinic, these metabolites, 2PY and 4PY, had never been associated with negative MACE or any negative outcomes. Nephrology journals have attempted to determine if these could be true uremic toxins.

However, Niacin was shown in a VA analysis of over 3.2 million, across an eight-year period, to actually reduce mortality by 11%. [7] This had an incredibly valid, P value, and analysis of all the nephrology journals related to niacin, shows a clear benefit.

Niacin has anti-protein and uric properties, improves GFR, and some studies have shown improvements in parathyroid status and FGF 23. [8] In fact, these metabolites appear to be associated with improvements in production, fibrosis, and inflammation. This contradicts what the authors claim in the Cleveland Clinic publication.

The Cleveland Clinic study did make interesting basic research observations suggesting that 2PY/4PY may have atherogenic properties. [6] However, this is an active area of research. Just last year a study evaluated 2PY in kidney disease models and actually concluded the opposite, stating that “NAD+ metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in chronic kidney disease.” [9] Note, that these authors referred to 2PY as a “NAD+ metabolites,” which is a much more accurate description than “niacin-metabolites.”

Previously, there was a lot of focus on 2PY and 4PY in the nephrology community, given that high-dose nicotinamide was being used with great clinical success for the treatment of clinical kidney disease. [10] In these studies, it was observed that 2PY is a potent inhibitor of PARP1, which effectively helps prevent excessive depletion of NAD.

Niacin is different from the other NAD precursors (nicotinamide, NMN, nicotinamide riboside)

In fact, niacin is distinctly different from the other NAD precursors, such as nicotinamide, tryptophan, NMN, and nicotinamide riboside).

Niacin is distinguished as the only NAD precursor that consistently corrects dyslipidemia, favorably adjusting cholesterol, triglycerides, VLDL, LDL, ApoB, and Lp(a) levels in an unparalleled manner, and it has repeatedly reduced cardiovascular disease events in randomized clinical trials. [7]

Much of the uniqueness of niacin is due to the fact that it activates a separate and distinct pathway that none of the other NAD precursors activate. This is the GPR109 receptor-mediated flush-associated pathway. [11,12]

The researchers in this latest NAD-metabolite publication even took their erroneous association one grandiose step further by suggesting that an increase in niacin fortification initiated in ~1974 is what likely led to increases in MACE.

The suggestion that niacin may cause cardiovascular disease is the final straw in a string of errors, and this mistake could have potentially deadly consequences for patients.

There was no experimental niacin supplementation performed or any measures of NAD levels within the MACE population of the study. In other words, the study did not establish a direct connection with niacin at all.

Furthermore, the researchers found an association between the worst quartile of MACE patients and soluble VCAM1, which is known to be associated with atherogenesis and inflammation. They also found that the normally excreted metabolite 2PY can cause an increase in VCAM1. As a result, they concluded that niacin may be increasing VCAM1.

However, the complete opposite is true for niacin and VCAM1. It has been known for over a decade that niacin dramatically reduces VCAM1 and this has been shown in 6 independent studies. [13-18] This in direct contradiction with Dr. Hazen’s conclusions. Again, niacin administration was not even tested in this study.

Additionally, niacin decreases LpPLA2, MPO, hsCRP, ADMA, etc. An FDA indication statement: “Niacin can be used in combination with a bile acid binding agent to slow progression or regress atherosclerosis in patients with a history of CAD and hyperlipidemia.”

Plain old niacin (immediate-release niacin) is predominantly excreted through the kidneys, so these two metabolites under scrutiny do not stay in the bloodstream for any significant amount of time. Properly dosed, these metabolites are not present in the circulation for more than three or four hours a day. The authors failed to establish causality, which is the primary message here. They are putting patients at risk and confusing doctors who still use niacin.

I (SM) question whether the authors have any substantial clinical experience with niacin. I highly doubt it. If most of their day is spent doing procedures in the clinic, it is very unlikely that they have devoted any time to niacin therapy or any complex metabolic management that can be considered preventative.

Furthermore, opinions are just that, opinions. The people who have valid opinions have been using niacin for years, such as Dr. William Castelli, Dr. John Guyton, Dr. Capuzzi, and the list goes on. These are actual niacin experts. Why have they not been questioned? Why has the major media ignored any counterpoint to the Cleveland Clinic position?

Plain old grocery store available niacin still has the best outcomes for cardiovascular disease, even after nearly 90 niacin-inclusive trials attempting to improve.

The historical fact is that high-dose (≥500mg) niacin therapy has been proven to correct dyslipidemia and reduce cardiovascular disease in many independent randomized clinical trials since 1955. [7]

When niacin is assessed on its own in clinical trials, the results are that it clearly reduces the risk for strokes, acute coronary syndrome (any sudden reduced blood flow to the heart) and the likelihood for revascularization procedures, niacin clearly provides tremendous benefits in the context of cardiovascular disease. [19]

After more than 87 clinical trials using niacin, The Coronary Drug Project (CDP; 1975-) remains perhaps the only study that has ever evaluated the use of plain old grocery store-available immediate release niacin on its own compared to a placebo. [19-21]

The Coronary Drug Project (CDP; 1975-) used plain old grocery store available immediate release niacin (3g/d) daily for 5-6 years (Niacin, n=616 v Clofibrate, n=637 v placebo, n=1,587). [7]

Population was individuals with a prior myocardial infarction
11% reduction in total mortality at 15y, even after cessation of treatment at 6y
27% reduction in subsequent myocardial infarctions
25% reduction in cerebrovascular events (strokes)

This long-term benefit is remarkable and may be in part due to long-term epigenetic mechanisms of action involving niacin-NAD-Sirtuin pathways.

Most studies since the CDP have evaluated treatment groups that have either used modified forms of niacin (extended release, sustained release, other) or combinations (niacin with statins/laropiprant/other). Most of these studies compared these alternative niacin forms/combinations to statins.

In the HATS trial, niacin plus simvastatin reduced major clinical events (death, myocardial infarction, stroke or revascularization) by 90% compared to placebo (P = 0.03). [22]

For more rigorous and comprehensive explanations of niacin trials (mechanisms & meta-analysis), please see the amazing video presentations by biomedical scientist/statistician Nicolas Verhoeven, which dispel many of the misinterpretation/misinformation about niacin and clearly present in great detail the undeniable remarkably positive proven benefits of niacin in cardiovascular disease. [23-25]

You may wonder, how can there be 87 niacin-inclusive clinical trials and counting. This is because niacin remains the gold standard of cardiovascular disease dyslipidemia research.

Still plain old immediate release niacin persists as the best form of niacin, producing unbeaten positive outcomes in clinical trials with the Coronary Drug Project in spite of numerous attempts to control the flush response.

The Many Forms of Niacin: Failed Attempts to Improve

Many attempts have been made to reduce the flush by developing timed-release forms of niacin, such as extended-release niacin (ER-niacin/Niaspan) or sustained-release niacin (SR-niacin), or by adding pharmaceuticals that can inhibit the flush. These approaches did reduce the flush, but did they improve outcomes compared to common immediate-release niacin (IR-niacin)? Or could it be that the flush is actually beneficial?

While these approaches did reduce the flush response, the outcomes were never as positive as plain old IR-niacin in the CDP study (1g, 3x/d). Moreover, their safety profiles were not as good as IR-niacin. [26]

In fact, the real concerns with niacin come from its inability to be removed from the body, rather than from the flush itself. The flush may be shocking to someone who is not familiar with it, and individuals should never be given niacin without being warned about what to expect. However, with the awareness of what to expect comes comfort and unparalleled good health.

It is very clear that the flush response is desirable and has therapeutic benefits. When a flush inhibitor (laropiprant) was combined with niacin in an attempt to increase compliance in niacin-naive patients in the HPS-THRIVE trials (n>25,000), it actually prevented the positive outcome. Any basic scientist understands that this is clear evidence that the flush is desirable.

Laropiprant is a medication that was withdrawn worldwide based on recommendations from the European regulator. Despite this, niacin was still conveniently blamed. More details on this 2014 controversy tarnishing the reputation of niacin are described in my (WTP) previous OMNS piece. [8]

Other examples of the flush being therapeutic include dimethyl fumarate (Tecfidera), which is one of the most popular oral therapeutics for treating multiple sclerosis, and beta alanine, which is clinically proven to increase muscle performance. Both work by activating the same flush pathway (GPR109A activation) as niacin. However, neither of these are NAD precursors, and so dimethyl fumarate is likely inferior and Tecfidera is more expensive, while beta alanine is a precursor to vitamin B5, so it has additional benefits that have yet to be fully characterized and understood.

The data on immediate-release (standard grocery store) niacin remains an unparalleled success in the history of cardiovascular disease trial outcomes. [7,27,28]

There is no question about the benefits of plain immediate-release niacin (IRN). While extended-release niacin (ERN/Niaspan) from 1955-1998 may have drawbacks, it is therapeutically beneficial. Sustained-release niacin (SR) clearly has potential hepatic toxicity. Frankly, nearly any molecule would be toxic if it was released for more than 12-20 hours during the day, compared to the time frame of less than an hour for IRN-niacin.

Niacin vs Statins

Simple inexpensive immediate release niacin works on its own demonstrably reducing carotid intima thickness, while statins have repeatedly failed to achieve this endpoint. [7]

Niacin raises HDL more than any pharmaceutical, while lowering triglycerides, excessive cholesterol, LDL, Lp(a), ApoB, and VLDL. Statins do not achieve any of these endpoints as well and statins in fact raise Lp(a), which is actually a bad thing as Lp(a) happens to be one of the most important lipid markers of all.

Statins are well known to increase the risk for myopathy by depleting coenzyme Q (an essential part of mitochondrial respiration) [29], to increase the risk for diabetes [30], and to cause memory loss in some individuals. [31]

Statins increase Lp(a) by as much as 30% to raise the risk of major cardiovascular events (MACE) [32,33]. Statin patients with statin elevated Lp(a) is known to increase progression of calcific aortic stenosis. [34] Multiple studies have proven no benefit for statins for this indication. Niacin lowers Lp(a) to reduce MACE risk and are known to reduce carotid intimal calcifications (CIMT), while have failed to demonstrate benefits for CIMT.

Statins are known to increase the risk for new onset diabetes and the FDA has put this on their warning labels. [35,36] Statins increase the risk for hemorrhagic stroke [37],

By contrast 1g per day ER-niacin high dose niacin is actually proven to increase muscle strength [38], to reduce the most common cause of death among diabetics (heart disease; [39]), and to prevent dementia [40].

Statin clinical research has also been plagued by statistical deception as investigators make use of relative risks instead of absolute risks to make results appear more impressive and likely than they truly are. [41]

Immediate release inexpensive niacin has been used at high doses for over 70 years to correct dyslipidemia without any serious safety concerns. It costs pennies a day and continues to remain unbeaten in this regard. [26]

The Niacin Discoveries March on…

Shortly after the discovery of high dose niacin therapy for correcting elevated cholesterol in 1955, Dr. Abram Hoffer evaluated the use of high dose niacin to address schizophrenia. [42,43] He had previously been involved in determining how much niacin should be used for fortifications to Native American reservations in western Canada. After being put in charge of a mental asylum in Saskatchewan, he explored the use of high doses for schizophrenic patients. Ultimately, over several decades he would treat thousands of schizophrenic patients with great success and his legacy lives on with well-informed practicing integrative psychiatrists. [43,44]

Given the ongoing daily mass shootings in America, one wonders if we should honestly be increasing our fortification of niacin.

Niacin is the only B vitamin known to reverse chronic kidney disease by stages. [8]

We are still discovering many new uses for niacin. Four years ago it was discovered that “Niacin Cures Mitochondrial Myopathy” in a Finnish study as described a Cell Metabolism publication. [38]

One of us (WTP) personally knows of an individual that eliminated 8 years of trigeminal neuralgia after taking high dose niacin for 2 weeks. This condition is commonly called “the suicide disease” for its horrific pain. Niacin can be amazing for all things neurological.

This has now been proven in literally hundreds of basic research publications. [45,46] In this regard, basic research tends to always be 10 years ahead of what is known in clinical research due to the ethical and financial limitations of clinical research. Since the return on investment is the driving force behind most clinical research, clinical research is mostly limited to evaluating patentable xenobiotic molecules. Immediate-release niacin is not a patentable/profitable naturally occurring molecule.

Niacin is currently being evaluated in clinical trials for glioblastoma and under consideration for addressing demyelinating diseases by Dr. V. Wee Yong, Professor and Canada Research Chair of Neuroimmunology at the Hotchkiss Brain Institute and the Departments of Clinical Neurosciences and Oncology at The University of Calgary. [47,48]

His unbiased screening for small molecules led to the discovery and experimental proof that niacin is clearly extremely useful in the contexts of both cancer and demyelinating disease. With over 320 peer-reviewed publications and counting, his research is now being translated into clinical trials for the evaluation of niacin for treating glioblastoma.

Niacin has been repeatedly proven to reduce fatty liver in many studies and it is currently in clinical trials for treating Non-Alcoholic Fatty Liver Disease. [16,38,49] This stands in contrast to the common misconception that niacin exerts liver toxicity, which was a problem observed only with the previously patented sustained-release form of niacin, but not the immediate release form of niacin that is commonly available in most grocery stores.

High-dose niacin is linked to increased longevity and improved health, improved metabolic homeostasis, and antioxidant defense. [50-53]

How does niacin do so much?

Well for starters the NAD that is made from niacin is required for over 400 gene functions, which is a far greater number of genetic functions than any other vitamin. [54] Accordingly, high-dose niacin can restore good health by restoring gene function for many individuals.

Secondly, there is the flush pathway, which inherently exerts dramatic physiological effects even in the skin and brain capillaries. When combined, the benefits of niacin are too numerous to categorize and amazingly, it is completely safe. [26,55]

Again, the “niacin-associated” metabolites, 2PY and 4PY, are in fact NAD-associated excreted metabolites and they are not niacin-associated metabolites since they are not breakdown products of niacin.

Yes NAD, the hottest supplement in the past 10 years. This is shown right in their figures within the manuscript. Hardly any scientist is respecting the conclusion of their study, but unfortunately the story line is getting out.

Metabolomics technology without an appreciation of history and thorough thought, has no practical value or far worse in this case, when the conclusion is wrong. Tragically for patients, the media has taken this and ran with it, generating much misinformation disparaging a fortification that clearly saves countless lives as shown in figure 1 and despite high doses of niacin continually proven in RCTs to reduce cardiovascular disease. Every dyslipidemia cardiovascular disease scientist knows niacin remains the gold standard in their basic research for positive outcomes.

Meanwhile, Physician’s Weekly reports on the latest JAMA publication describing lower all-cause mortality in patients with higher dietary niacin intake. [56,57] This is not even patients that are taking supplements, but at least this study considered the documented niacin intake within the population of patients with NAFLD. The latest study could not even consider the niacin intake for the MACE patients.

Getting benefits from niacin can be very individualized.

Some individuals are quite sensitive to the flush from niacin, while others do not experience the flush at all. The niacin flush is always completely safe, but it can be shocking for those uninformed. Many learn to love the flush, myself (WTP) included. I know of one individual with multiple sclerosis (MS) who struggles to get a more pronounced flush response because he walks best when he experiences the flush. Moreover, clinical trials have now proven that high doses of niacin (750-1000mg) increase muscle strength, which is expected to be beneficial in the treatment of MS. [38]

There have been instances where physicians have told patients to take niacin, but did not inform them of the flush, causing panic when they experienced flushing, resulting in spiked blood pressure and falls. [58] It is important to get to know the flush on your own, starting with just 50-100mg and gradually increasing the dosage to as much as 2g at a time, typically.

One of us (RZC) includes high dose niacin (500-2,000 mg daily) as part of his integrative protocol for many chronic diseases especially for atherosclerotic cardiovascular disease, autoimmune diseases, and cancer for hundreds if not thousands of patients. He has seen significant improvement and even reversal of these diseases.

Clearly the parent molecule, nicotinic acid/niacin, has virtually, no deleterious effects. Like any medication, there are contraindications. However, it has been found to not cause diabetes or exacerbate insulin resistance, with the caveat that it needs to be dosed properly as it was before the introduction of niacin.

Taking niacin during a fasting state, as a single bolus once a day, can pose problems. These problems are all reversed when niacin is taken at mealtime. This also enables divided doses, which are easier to administer, and simplify and facilitate compliance for the patient. Smaller doses at mealtime, enable 2, 3, or 4 doses a day. The FDA still maintains an indication for the original niacin, up to 6 g per day. Very few providers are aware of this today, as most of the success of niacin was between 1955 and 1998.

It is common to build up a tolerance to higher doses of niacin. A lack of flush response is generally considered a sign of poor health. Schizophrenics on average do not flush as much or at all in response to niacin, but they often recover their ability to flush simultaneously with recovery from schizophrenia. This has led to theories about fatty acid deficiencies in schizophrenia. [59,60] In any case, niacin is completely safe and has been used by informed physicians for over 70 years and counting. [55]

In general, our suggestion is to strive for experiencing one, two, or three flushes a day with immediate release niacin (not timed, not sustained, not extended release).

This involves personal titration typically starting with 100mg for a first-time user to get to know how you respond. The range is typically 500mg-2g as an endpoint, with 500mg being the most common historically.

I (WTP) have personally taken over 1g daily for 20 years, with as much as 2g taken 3x a day more recently and always have a perfect lipid profile.

The higher doses exert a greater activity in correcting lipodystrophy and an increasing variety of yet-to-be discovered indications. [61]

It is always best to not only do niacin monotherapy but rather to always include absorbable magnesium/minerals (never the oxide form), vitamin D, zinc, and more orthomolecular or integrative basic treatments such as 500mg thiamine and 50mg vitamin B6 (pyridoxyl-5-phosphate), bowel tolerance vitamin C when indicated, etc…

Finally, sometimes elimination is the most important thing of all to solve a health issue. Eliminations may involve allergens, excessive sugar, excessive alcohol, drugs, or other toxins.

In closing, do not be scared by curious fleeting news stories. Instead, learn from history and never forget it.

Niacin is not going anywhere. It is required for life itself and higher doses are clearly safe and long-since proven to prevent cardiovascular disease just for starters.”

References

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2. Park, Y.K.; Sempos, C.T.; Barton, C.N.; Vanderveen, J.E.; Yetley, E.A. Effectiveness of Food Fortification in the United States: The Case of Pellagra. Am J Public Health 2000, 90, 727-738, doi:10.2105/ajph.90.5.727. https://pubmed.ncbi.nlm.nih.gov/10800421

3. Penberthy, W. Todd Niacin Rescues Cannibalistic Hamsters The Historical Significance of 1940s Mandatory Niacin Enrichment 2017. http://orthomolecular.org/resources/omns/v13n09.shtml

4. Cleveland Clinic-Led Study Discovers Link between High Levels of Niacin – a Common B Vitamin – and Heart Disease – Cleveland Clinic Newsroom Available online: https://newsroom.clevelandclinic.org/2024/02/19/cleveland-clinic-led-study-discovers-link-between-high-levels-of-niacin-a-common-b-vitamin-and-heart-disease/ (accessed on 21 February 2024).

5. High Levels of Niacin May Increase Heart Disease Risk: What to Know about the B Vitamin Available online: https://www.nbcnews.com/health/heart-health/high-levels-niacin-may-increase-heart-disease-risk-know-b-vitamin-rcna139249 (accessed on 21 February 2024).

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19. D’Andrea, E.; Hey, S.P.; Ramirez, C.L.; Kesselheim, A.S. Assessment of the Role of Niacin in Managing Cardiovascular Disease Outcomes: A Systematic Review and Meta-Analysis. JAMA Netw Open 2019, 2, e192224, doi:10.1001/jamanetworkopen.2019.2224. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2730481

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21. Garg, A.; Sharma, A.; Krishnamoorthy, P.; Garg, J.; Virmani, D.; Sharma, T.; Stefanini, G.; Kostis, J.B.; Mukherjee, D.; Sikorskaya, E. Role of Niacin in Current Clinical Practice: A Systematic Review. Am J Med 2017, 130, 173-187, doi:10.1016/j.amjmed.2016.07.038. https://www.amjmed.com/article/S0002-9343(16)31058-0/fulltext

22. Vittone, F.; Chait, A.; Morse, J.S.; Fish, B.; Brown, B.G.; Zhao, X.-Q. Niacin plus Simvastatin Reduces Coronary Stenosis Progression Among Patients with Metabolic Syndrome Despite a Modest Increase in Insulin Resistance: A Subgroup Analysis of the HDL-Atherosclerosis Treatment Study (HATS). J Clin Lipidol 2007, 1, 203-210, doi:10.1016/j.jacl.2007.05.003. https://pubmed.ncbi.nlm.nih.gov/18591993/

23. Massive New Study Shows Niacin and NAD+ Cause Heart Disease?? Is This True?; 2024; https://youtu.be/xInw3F2AVTg?si=-khShvyzbhLHXezN

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