The NAD+ Deficiency Hypothesis

Dr. Ade Wentzel, an anaesthesiologist, initially worked at outbreak of the pandemic in developing CPAP ventilation techniques for intensive care patients with acute severe Covid-19. He worked with Robert Miller to develop a new mask and a ventilation device all whilst designing a 3000 bed factory hospital conversion. During this Miller claimed - “I can explain why people are dying….LOW NAD+” Together they came up with the NAD+ Deficiency hypothesis.

The NAD+ hypothesis in acute Covid-19

NAD+ is a very important housekeeping molecule in our cells. It is key in the production of adenosine triphosphate (ATP) and is crucial for energy production. See figure below - How cells make energy.

One of the important things NAD+ does is enable sirtuin activation . Sirtuins are a family of seven NAD+ dependent signalling proteins that are involved in metabolic and cellular regulation.

In Covid-19 infections sirtuins perform two crucial functions:

  1. Combatting the virus - sirtuins are used by the body to attack both DNA and RNA viruses. Covid-19 is a RNA based virus

  2. Controlling inflammation - sirtuins are a crucial component of the body’s mechanism to control inflammation and prevent cytokine storms

During the activation of sirtuins NAD+ is consumed and zinc is bound to the activating sirtuin.

If either NAD+ or zinc is in short supply activation will be impacted. This can be seen in naturally in

increasing age but is accelerated in those who are obese, have hyperinsulinaemia or high levels of oxidative stress. The team wrote the paper COVID-19: NAD+ deficiency may predispose the aged, obese and type2 diabetics to mortality through its effect on SIRT1 activity in the Medical Hypothesis journal.

The high risk groups identified as the most vulnerable to Covid-19 have low levels of NAD+. Those include:

  • Those over age 65+

  • Those with obesity

  • Those with type2 diabetes

  • Those with hypertension

  • Those with conditions that have high levels of oxidative stress - cardiovascular disease, cancer, rheumatoid arthritis, asthma, Alzheimer's, Parkinson's, chronic inflammation disorders.

The high risk groups were subsequently identified by Doherty et al in their paper in the BMJ Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol

The theory is that COVID19 causes NAD+ depletion. Those people in the above groups plus, some people with vitamin deficiencies, existing NAD+ depletion or genetic deficits in energy metabolism have long term NAD+ depletion. Our bodies when under attack from the Covid-19 try to make up for low NAD+ by feeding in tryptophan, which is the precursor for serotonin, causing low serotonin.

Biochemical mechanism of suspected COVID19 mechanism and druggable targets, modified from the Oxidative Stress-induced Niacin Sink OSINS model of Taylor et al.

Low serotonin leads to neurological effects, and also affects the gut microbiome (please see importance of this in my previous blog) and our bodies' homeostasis or self regulation.

Mast cells activation locally to release serotonin instead, leading to histamine release and mast cell activation issues.

Low energy production effects highly active tissues such as the heart and brain.

We can boost our NAD+ levels to try to prevent contracting Covid-19 in the first place.

The NAD+ Deficiency Hypothesis in Long Covid

We now know that Covid-19 depletes NAD+ .There is another condition that is caused by NAD+ depletion. It causes a serious condition called Pellagra. This is a nicotinic acid ( niacin, B3) deficiency and causes symptoms of dermatitis, diarrhoea, fatigue, apathy, raised temperature, loss of smell, loss of taste, loss of hair, skin lesions, mouth ulcers, aggression , insomnia, weakness, mental confusion, ataxia, paralysis of extremities, peripheral neuritis, oedema, nutritional deficiency cardiomyopathy, multi-organ failure, dementia and death. It was because of the closely related symptoms between pellagra and Long Covid which led to Dr. Ade Wentzel and his team to study the NAD+ hypothesis further. Dr Wentzel is a fellow sufferer these are his words in a recent interview:

Managing long haul covid patient is really a huge challenge. Firstly you have to deal with the severe distress that the patient finds themselves in. In many cases patients are disappointed by the medical profession. This thrown on top of a low serotonin level makes the patient feel like they are about to die, with nobody to turn to and often angry, ratty and desperately seeking answers for a set of symptoms that are often intermittent, changing and bizarre in presentation. While this is all happening, they may be fatigued, have poor effort tolerance, fast heart rates, lack of smell and taste and hair that is falling out, often to be told its just anxiety. It is not only frightening from a patient perspective, but also as a care giver. To manage it needs a huge amount of empathy and understanding of the underlying pathological process”

The team recommend Flushing Niacin (please refer to my previous blog for more information on this). They have many anecdotal evidence that 100 mg Niacin daily is benefitting Long Covid patients. This is further supported by an informal survey of over 200 long covid sufferers, showed a high correlation between niacin intake and improvement in in a recent video by a Patient Advocate Gez Medinger.

As with the acute Covid -19 infection NAD+ deficiency depletion could explain:

  • why cognitive dysfunction (brain fog) occurs - in some cases the frontal cortex of the brain shows electrical slowing with no damage to the brain matter or viral invasion. It is because the frontal cortex is a highly energy dependant organ

  • Why keen runners and other sport athletes/ enthusiasts seem to have long covid issues disproportionately.

  • Why long covid damage seems to evolve and present in all organ systems, specifically the nervous system

  • why secondary infections are so common. There is disruption of gut-immune axis allowing secondary infections to occur or allowing some infections to reactivate in the body - for example - herpes, shingles, Epstein-Barr

  • why children have less adverse events - they have naturally high NAD+ reservoirs.

  • Why certain countries who supplement their bread with nicotinic acid have drastically lower death rates than expected

Unfortunately NAD+ is difficult to measure and hence tryptophan is measured as an indicator but currently this will only be undertaken in the UK as part of research.

The NAD+ Deficiency Hypothesis team recommend the following ( please consult your GP first):

  1. Nicotinic acid aka Niacin (not nicotinamide or other forms) — 100mg

  2. Vitamin C aka Ascorbic Acid — 1500mg

  3. Vitamin D — 3000iu

  4. Zinc — 15mg - activates SIRT1, a Sirtuin, and has antiviral properties

  5. Selenium — 50mcg

  6. Quercetin — 500mg - Increases NAD+

I have written a IG post/ blog about all of these supplements apart from Zinc. Selenium is covered briefly in Post Covid hair loss.

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