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Pellagra and niacin: how NAD+ precursors were discovered
Prepared by: Research Desk
Prepared by: Research Desk. Sources are linked for verification.
Modern discussion of NMN, NR and "NAD+ precursors" rests on a much older story. In the early twentieth century, pellagra was a serious problem in the American South [1], and historians have called it a plague [4][5]. Working out its cause took competing theories, field investigations and long arguments about poverty and prejudice [1][3]. The disease was eventually understood as a deficiency of a vitamin, niacin, which cells use to make NAD+ [6][8]. This explainer traces that history and shows where it connects to modern NAD+ biochemistry. It is a history of science, not a guide to any product.
Why pellagra matters to NAD+ research
Vitamin B3 (nicotinic acid, also called niacin) is used to make the NAD+ family of coenzymes. These coenzymes take part in cellular energy metabolism and defence systems. A deficiency of vitamin B3 causes pellagra, a systemic disease that leads to dermatitis, diarrhoea, dementia and possibly death, depending on how severe it is and how long it lasts [8].
A 2005 review describes pellagra as a cellular deficiency of niacin. It can result from too little nicotinic acid in the diet, or too little of its precursor, the essential amino acid tryptophan [7]. That framing matters. It means the body has more than one route to the same coenzyme, which is the core idea behind "precursors". The tryptophan route is covered in our explainer on de novo NAD+ synthesis from tryptophan. For the wider map of how precursors converge on NAD+, see the NAD+ guide.
The disease: the "3 D syndrome"
Reviews describe pellagra by a cluster of signs often called the "3 D syndrome": dermatitis, diarrhoea and dementia [7]. The skin changes are distinctive: bilaterally symmetrical redness at sun-exposed sites, beginning as erythema and progressing to an exudative eruption on the backs of the hands, face, neck and chest, with itching and burning [7].
A 2021 review groups the manifestations as dermatitis with marked photosensitivity, gastrointestinal symptoms and neuropsychiatric problems [6]. It notes that recognition rests mainly on how the disease presents, with laboratory tests playing a secondary role [6].
Before Goldberger: competing hypotheses, 1907 to 1914
Pellagra's conquest is usually credited to one man, but a 2015 historical paper argues that the groundwork came earlier [1]. Between 1907 and 1914, a loose coalition of asylum superintendents, practitioners, local health officials and others built the first English-language expertise in the disease. They sifted through competing explanations and narrowed them to two [1]:
An insect-borne infection hypothesis, championed by the European investigator Louis Westerna Sambon.
The "vitamine hypothesis", proposed by Casimir Funk in early 1912 and set out later that year by Fleming Mant Sandwith and Rupert Blue, both members of the American Clinical and Climatological Association.
The infection idea fitted its era, when many diseases were being traced to microbes and insect carriers. The dietary idea was newer and less familiar.
Goldberger and the dietary explanation
Joseph Goldberger of the US Public Health Service went south in 1914. Within 4 months he concluded that the cause was inadequate diet [1]. He spent the rest of his life researching pellagra. Before his death from cancer in 1929, he found that brewer's yeast could prevent the disease at nominal cost [1].
Later accounts describe Goldberger as both a public health champion and an investigator of pellagra [2]. His conclusion was not welcome everywhere. The same 2015 paper notes that some people resisted his "inconvenient truth" that the root cause was southern poverty [1]. One historical article frames his work directly in terms of pellagra and prejudice [3]. The story is often told as a case study in how social and economic assumptions can slow the acceptance of a scientific finding.
From brewer's yeast to a named vitamin
Goldberger showed that something in certain foods, including brewer's yeast, could prevent pellagra [1]. Pinning down the specific factor came later: a 2021 review notes that the root cause of the disease was established in the mid-twentieth century [6]. Pellagra is now described as a disease caused by niacin deficiency or a disruption of niacin metabolism [6].
Niacin then had a second scientific life. A 2019 editorial links pellagra, Goldberger and niacin to the beginning of lipid research, and describes niacin as the first lipid-altering drug [9]. One small molecule therefore sits at the centre of a nutrition story and a pharmacology story.
Why pellagra still occurs
Pellagra has not disappeared. Cases are rare in Europe and North America. In some developing countries, however, it is still frequent and is the most common clinical feature of nutritional deficiency in adults [7].
Reviews list several routes to deficiency beyond diet. These include chronic alcohol misuse, gastrointestinal malabsorption and certain medications, among them isoniazid, pyrazinamide, 5-fluorouracil, 6-mercaptopurine, hydantoins, phenobarbital and chloramphenicol [7]. The 2021 review also names immunosuppressive and anti-tuberculosis drugs [6]. It adds that the detailed processes behind the symptoms have not yet been fully explained and involve molecular, metabolic and immunological abnormalities [6]. The review describes management as causal and based on administering niacinamide [6].
From vitamin to coenzyme: the line to NMN and NR
Because niacin is used to synthesise NAD+ [8], the pellagra story is also a story about a coenzyme. Nicotinic acid, nicotinamide and tryptophan all feed into NAD+. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are further entry points studied much more recently. Cells also recycle nicotinamide back into NAD+, as explained in the NAD+ salvage pathway.
Modern human studies pose a different question from the one the pellagra investigators faced. Goldberger's era asked what happens when intake is inadequate. Current trials ask what happens to NAD+ measurements when people who are not deficient take a precursor. A 2018 human trial reported that chronic NR supplementation was well tolerated and raised NAD+ in healthy middle-aged and older adults [10]. A 2026 human study compared three NAD+ precursors, looking at circulating NAD and microbial metabolism [11].
These measurements do not show that raising NAD+ above adequate levels changes health outcomes. The pellagra history shows that a deficiency of the vitamin causes disease; it does not show that extra precursor does anything further. For how the newer precursors compare, see NMN vs NR in human research. For how they are classified under U.S. rules, see the regulatory status of NMN, NR and IV NAD+.
Further reading: choosing a history-of-science book
Books on this subject vary widely in quality. Some neutral ways to compare them:
Sourcing. Look for endnotes that cite archival records, Public Health Service reports and the original papers, not just secondary retellings.
Scope. Some titles focus on Goldberger's life. Others cover the 1907 to 1914 period, the vitamin hypothesis and the later biochemistry. Match the scope to the question being researched.
Balance. The strongest accounts place the social context, including poverty and the resistance to dietary explanations, alongside the laboratory work.
Edition and date. Newer editions or recent histories may include scholarship that revisits the pre-Goldberger investigators.
Format and price. Check whether print, ebook and audio versions exist, compare prices across formats, and look at library availability.
For titles on the coenzyme's modern biology, our evidence-graded reading list rates books by how closely they stick to published data. Affiliate arrangements and how pages are researched are explained on our about page.
Frequently asked questions
What causes pellagra?
Pellagra results from a cellular deficiency of niacin [7]. This can come from too little nicotinic acid or tryptophan in the diet. It can also come from chronic alcohol misuse, malabsorption or certain medications [6][7].
Who discovered the cause of pellagra?
Joseph Goldberger concluded in 1914 that inadequate diet was the cause [1]. Earlier investigators had already put forward the "vitamine hypothesis" in 1912 [1]. A 2021 review notes that the root cause was established in the mid-twentieth century, and pellagra is now described as a disease of niacin deficiency [6].
How is pellagra connected to NAD+?
Vitamin B3 is used to make the NAD+ family of coenzymes [8]. This is why niacin, nicotinamide and tryptophan are described as NAD+ precursors.
Does pellagra history show that NMN or NR supplements do anything?
No. The history concerns deficiency disease. Trials of NR and NMN measure NAD+ in people who are not deficient, and those measurements are a separate question [10][11].
Related on this site
NAD+ explained: biochemistry, precursors, testing and human evidence
De novo NAD+ synthesis: how cells build NAD+ from tryptophan
NAD+ books: an evidence-graded reading list on sirtuins and aging
Last updated: 26 October 2026.
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