**Abstract**

Pellagra has largely been forgotten. This is unfortunate as important lessons are to be learnt about the diseases and social and economic consequences of poverty – and for the root cause of poverty (and of affluence) – that involve dietary nicotinamide and nicotinamide adenine dinucleotide (NAD) homeostasis. NAD disruption can occur not only from poor diet but from increased consumption from genotoxic, infectious and metabolic stresses. NAD deficiency is closely linked to poor physical and intellectual development, premature ageing and diseases of ageing. Acute infections, many with NAD-consuming toxins, that may differentially affect the NAD-depleted, now include COVID-19. Some Covid manifestations, such as myoclonic encephalopathy and "Long Covid," resemble pellagra clinically and biochemically as both have disturbed nicotinic and tryptophan metabolism. Symbionts that supply nicotinic acid, such as TB and some gut micro-organisms, can become dysbiotic if the diet is very deficient in milk and meat, as it is for 1–2 billion or more. High doses of nicotinamide lead to inhibition of NAD-consuming enzymes and excessive induction of nicotinamide-n-methyl transferase (NNMT) with consequent effects on the methylome: this gives a mechanism for an unrecognised hypervitaminosis-B3 with adverse effects of nicotinamide overload for consumers on a high meat diet with "fortified" foods and "high energy" drinks. Methods of measuring NAD metabolism routinely for screening the populations at risk of deficiency and in metabolically ill or infectious disease patients should be developed urgently. Successful intervention should improve human capital and prevent many aspects of poverty, reduce discrimination and even the drive to emigrate.

**Keywords:** nicotinamide, tuberculosis, meat transitions, ageing, neurodegeneration, dementia, obesity, cancer, ACE2, Covid-19, NAD, Long Covid

## **1. Introduction**

The 4 "D's" of Dementia, Dermatitis, Diarrhoea and Death are taught to medical students but the interesting history of pellagra and its wider phenotype is largely forgotten [1–4]. A characteristic blank facies and a festinating gait, fasciculation of the tongue or myoclonic encephalopathy are classic features of well-known neurological diseases that were actually first described in the pellagra epidemics. Many other close mimics of neurodegenerative and neuropsychiatric disease, including frank psychoses were seen. Pellagrins harboured dysbiotic infections and succumbed to acute infections explaining the high mortality, the gut manifestations and the high incidence of tuberculosis (TB). Pellagra was widely believed to be hereditary and certainly ran in families. Transgenerational effects created vicious cycles of ill health and poor brain development and further poverty in a manmade economic and market failure that caused a nutritional and metabolic trap.

Sufferers were exposed to considerable discrimination and "Othering", whether as poor whites or blacks, that attracted the attention of eugenicists and sterilisation programmes as their fertility was high (when short of outright starvation), yet this situation is cured by a simple dietary intervention.

### **2. History and background**

The 18thC European epidemics, as described by Gaspar Casal (1735), affected poor Mediterranean peasants on monophagic maize based polenta diets and little meat. The peasants themselves were all too aware of the condition and the relationship to lack of animal products, such as milk, meat and butter. Earlier cases must have existed, perhaps called leprosy in biblical and in earlier times (true leprosy "disappears", like TB, on a high meat diet or nicotinamide administered as an antibiotic). Central American peasants in the New World largely avoided pellagra by a cultural evolutionary approach that involved eating and growing maize with beans and cooking with alkali releasing nicotinamide – but these cultural adaptations were not transported with the plant (that compared with other cereals is low in both nicotinamide and tryptophan) in the Columbian exchange.

Casal agreed about the important role for diet and only later were genetic or infectious, from rotten maize, aetiologies favoured. The early 20th C American epidemic, that killed hundreds of thousands, predominantly affected poor blacks (and whites) working as semi-slave sharecroppers thrown in to poverty with the collapse of the cotton market and the loss of their own farms and hunting rights to plantations, eating maize, molasses (rum) and small quantities of low-quality pork. Joseph Goldberger working in the 1920's after ground-breaking epidemiological and experimental work showed once again that diet was the crucial factor [5–7]. The discovery of nicotinic acid by Elvehjem and a role for tryptophan led to the cure of patients by Spies and the prevention of others through supplementation programmes in milled bread in the 1930s-40's.

Pellagra was long believed to be degenerative in the dehumanising sense of the term. Recent research is clear that Homo sapiens evolved on a high meat diet: pellagra can therefore be seen as an atavistic example of human evolution in reverse gear. This does not downplay the role of dietary balance with plant foods and their contribution to our cooking and (agri-)culture and consciousness given their psychoactive, poisonous and medicinal properties [8–11]. Still, typical early modern and modern societies, unlike hunter-gatherers that share meat, have ruling "meat elites" that will go to almost any lengths to obtain it from wars or if necessary (in the past), human sacrifice creating their own dietary habitat and stratified classes of cognitive, creative and social capital in fragile social contracts [12–14].

Pellagrins, living in a very low meat habitat, were seen a different race having a different physiognomy that crossed colour lines even though it was an archetypal disease of poverty, rather like TB with which it is associated. Inferior cognition, antisocial and addictive behaviours led to discrimination as the "Butterfly caste." This iconic example of cultural and retaliatory "honour" wars may be a denominator common to other disadvantaged groups and their identity politics (or the drive to migrate), that can distract from the underlying economic and dietary issues that need to be faced – and resolved by (meat) redistribution [15–17]. Pellagra casts a long shadow. Some historians date many of the tensions, racial discrimination and stereotyping with insulting epithets between poor whites and blacks from these times as in "The Mind of the South" with distant echoes in segregation, incarceration and apartheid around the world, such as in South Africa (another pellagra zone), to this day [15, 18].
