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Joseph Goldberger investigated pellagra as a disease of inadequate nutrition when an infectious explanation was widely accepted. His work helped shift the question from which organism transmitted the disease to what was missing from the diet. He established a dietary explanation without isolating the specific protective nutrient; vitamin B3 was identified as the missing component later. ^[ref]

With G. A. Wheeler, Goldberger reported a 1915 experiment in which a restricted diet produced pellagra in at least six of eleven prisoners who completed the study. Their report compared the experimental group with other prisoners, considered differences in work and hygiene, and concluded that the restricted diet caused the disease.^[ref]

The scientific lesson is to separate association, intervention and identification of a mechanism. Observing that a disease clusters among people eating similar foods suggests a hypothesis. Changing the diet tests that hypothesis more directly. Identifying the missing vitamin is a further chemical step, requiring evidence beyond the original feeding comparison.

Nicotinamide, ${\mathrm{C}}_6{\mathrm{H}}_6{\mathrm{N}}_2\mathrm{O}$, is the amide of nicotinic acid, with a pyridine ring bearing a carboxamide group. It is one form of vitamin B3 and supplies the nicotinamide unit of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.^[ref]

These coenzymes connect its structure to metabolism: the nicotinamide ring participates in reversible electron transfer between oxidized and reduced forms. Incorporation into a coenzyme is different from the free nicotinamide molecule itself carrying out every associated reaction.^[ref]

Nicotinic acid, ${\mathrm{C}}_6{\mathrm{H}}_5\mathrm{N}{\mathrm{O}}_2$, is pyridine-3-carboxylic acid: a pyridine ring bearing a carboxyl group at position 3. It is one form included under vitamin B3, and can contribute to production of the coenzymes nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.^[ref][ref]

The related nicotinamide has a carboxamide group in place of the acid group. Their related names reflect related structures, while the different functional groups make them distinct chemical compounds. “Niacin” can be used broadly for the vitamin family, so an experiment reporting a particular chemical form should specify which molecule was used.

Pellagra is a disease caused by severe vitamin B3 deficiency. Its manifestations can include sun-sensitive dermatitis, diarrhea and neurological changes, including dementia. These familiar “three Ds” summarize possible effects; they are not a requirement that every affected person show all three. Vitamin B3 supplies precursors of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, so adequate dietary energy alone does not guarantee adequate support for metabolism.^[ref]

In 1915, Joseph Goldberger and G. A. Wheeler tested a restricted, cereal-heavy diet at a Mississippi prison farm. At least six of eleven remaining volunteers developed signs judged to be pellagra within five months; none were observed among the comparison prisoners. The reported menu supplied about 2,952 calories per man per day, making the contrast between calories and dietary composition especially revealing. Prisoners were offered pardons for participation; allocation was not described as randomized.^[ref]

The experiment supported a dietary cause under its conditions. It did not identify the missing molecule chemically: demonstrating that a restricted diet produces a disease and identifying the specific vitamin are different experimental achievements.

Vitamin B3 is the nutritional category including nicotinic acid and nicotinamide, compounds the body can use to make nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. These coenzymes participate in metabolism, including transfer of reducing equivalents between reactions. Adequate dietary supply supports a reusable biochemical system rather than providing the bulk of the body's fuel.^[ref]

For example, an oxidized coenzyme can accept reducing equivalents in one reaction and transfer them in another. The coenzyme is regenerated during the cycle, so its importance is not measured by how much of it is burned for energy. Humans can also derive niacin equivalents from tryptophan; severe inadequacy is associated with pellagra.^[ref]