NAD+: The Science of Cellular Energy, Brain Function, Aging, and Supplementation

What Is NAD+ and Why Does It Matter?

Every second of every day, trillions of cells in our bodies are working to keep us alive.

Our hearts beat, our muscles contract, our brains process information, and our cells continually maintain and repair themselves. All of these activities require energy.

One of the most important molecules involved in this process is NAD+, short for nicotinamide adenine dinucleotide.

NAD+ is not a newly invented supplement. It is a naturally occurring molecule that is essential to normal human biology.

Interest in NAD+ has increased because researchers are learning more about its relationship to mitochondrial function, cellular energy, aging, and the brain - and asking whether increasing NAD+ availability might have useful clinical effects.

NAD+, Mitochondria, and ATP

Inside nearly every cell are structures called mitochondria.

Think of mitochondria as microscopic power plants. They help convert energy from the food we eat into ATP (adenosine triphosphate), the form of energy our cells can actually use.

Your muscles need ATP to contract. Your heart needs ATP to beat. Your brain needs ATP to maintain electrical activity and transmit signals.

NAD+ plays an essential role in making this possible.

As nutrients are metabolized, NAD+ accepts high-energy electrons and becomes NADH. NADH then carries those electrons to the mitochondrial electron transport chain.

The electron transport chain uses this energy to pump hydrogen ions, or protons, across the inner mitochondrial membrane. This creates an energy reserve somewhat like water building up behind a dam.

Those protons then flow through a remarkable molecular machine called ATP synthase, which uses the stored energy to manufacture ATP.

In simplified terms:
Food → NAD+ / NADH → Electron Transport Chain → Proton Gradient → ATP After NADH delivers its electrons, NAD+ can be regenerated and used again.

This is fundamental human biochemistry.[1]

It is important, however, not to oversimplify this into “more NAD+ always means more ATP.” ATP production also depends on oxygen, nutrients, healthy mitochondria, cellular energy requirements, and many other factors.

How Much NAD+ Is in the Human Body?

One scientific review has estimated that the average human body contains approximately 3 grams of NAD+ at any given time.[2]

That is an estimate rather than a direct measurement of every NAD+ molecule in the body, but it illustrates something remarkable: a relatively small pool of NAD+ participates in an enormous amount of metabolism.

How is that possible?
The body continually recycles NAD+.

During energy metabolism, NAD+ becomes NADH and can subsequently be converted back into NAD+.

NAD+ is also consumed by enzymes involved in cellular signaling, stress responses, and DNA repair. The body can recover components of these molecules and manufacture NAD+ again through pathways including the NAD+ salvage pathway.[2,3]

Our NAD+ pool is therefore not static.

NAD+ is continually being used, regenerated, broken down, and rebuilt.

This raises an interesting question about supplementation.

If the body contains only a few grams of NAD+ and continually recycles it, could periodically providing additional NAD+ influence the body's available NAD+ pool?

It is a reasonable hypothesis, but it has not yet been proven.

For example, administering a cumulative gram of NAD+ over a month does not necessarily add one gram to the body's NAD+ stores. Some may be metabolized or excreted, while some metabolites may subsequently contribute to intracellular NAD+ synthesis.

Whether repeated supplementation meaningfully increases total-body NAD+ over time remains an important unanswered question.

What Happens to NAD+ as We Age?

Researchers have demonstrated age-related changes in NAD+ metabolism, including reductions in NAD+ within certain human tissues.

The brain is particularly interesting.

Using advanced magnetic resonance spectroscopy, researchers can measure NAD+ in the living human brain. Human studies have demonstrated age-associated changes and reductions in cerebral NAD+.[4,5]

This does not mean that every person's NAD+ falls by the same percentage as they age.

Different tissues behave differently, and blood NAD+ measurements do not necessarily tell us what is happening inside the brain, skeletal muscle, or other organs.

The most accurate conclusion is:

NAD+ metabolism changes with aging, and some human tissues - including the brain - show age-associated reductions in NAD+.

That leads to an obvious scientific question:

If NAD+ becomes less available in certain tissues with age, could restoring NAD+ availability help preserve cellular function?

We do not yet know the answer.

What About Oral NAD+ Precursors?

Most oral NAD+ research has focused on substances the body can use to manufacture NAD+, particularly:

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
Human studies demonstrate that oral precursors can increase measured NAD+ concentrations.

In one randomized human trial, NR produced dose-dependent increases in whole-blood NAD+ after two weeks of approximately:

22%, 51%, and 142%, depending upon the dose administered.[6] Those are real biochemical changes.

However, an increase in whole-blood NAD+ does not necessarily mean an identical increase occurred inside the brain, muscles, or mitochondria.

And increasing a laboratory measurement does not automatically prove improved energy, cognition, athletic performance, or longevity.

What Happens When NAD+ Is Given Intravenously?

This is particularly interesting because human pharmacokinetic data actually exist.

In a 2019 pilot study, researchers administered NAD+ intravenously to eight healthy participants over six hours and compared their results with three participants receiving saline.[7]

The investigators repeatedly measured NAD+ and its metabolites in plasma and urine.

Plasma NAD+ Increased 398%

At the end of the six-hour infusion, plasma NAD+ was 398% above baseline.[7]

NAD+ remained elevated at the study's final measurement, which occurred two hours after the infusion ended.

The researchers did not continue measuring beyond that point, so the study cannot tell us exactly how long the elevation lasted.

But it demonstrated something important:

Intravenous NAD+ can produce a very large increase in circulating plasma NAD+.

There was another intriguing observation.

During approximately the first two hours of administration, NAD+ was continuously entering the bloodstream, yet plasma NAD+ did not initially increase significantly.

Where was it going?
The study cannot completely answer that question.

The investigators found changes in several NAD+ metabolites, suggesting rapid metabolism and removal from the circulation. They did not directly measure how much NAD+ entered individual organs or tissues.

Therefore, we cannot say that the “missing” NAD+ necessarily entered cells or the brain. But clearly, the body was doing something with it.

Why the Brain Is Especially Interesting

The adult human brain weighs only about 3 pounds (approximately 1.4 kilograms) and represents roughly 2% of total body weight.

Yet it receives approximately 15-20% of resting cardiac output and consumes approximately 20% of the body's oxygen at rest.[8]

That tells us something important.
The brain is extraordinarily metabolically active.

Neurons continually maintain electrical gradients, transmit signals, release neurotransmitters, and restore themselves after firing.

All of this requires ATP.
And NAD+ participates directly in the mitochondrial machinery responsible for ATP production.

The brain's large blood supply also means that circulating substances are repeatedly presented to the cerebral circulation.

But there is an important limitation.

Does NAD+ Cross the Blood-Brain Barrier?

The brain is protected by the blood-brain barrier (BBB).
The BBB carefully regulates what leaves the bloodstream and enters brain tissue.

Therefore, the fact that the brain receives a disproportionately large amount of blood does not mean that the same proportion of every substance circulating in that blood enters the brain.

For NAD+ specifically, meaningful passage of intact intravenously administered NAD+ across the human blood-brain barrier has not been established.

NAD+ can also be metabolized outside cells into other molecules that may subsequently participate in NAD+ metabolism.

So we cannot accurately say:
“IV NAD+ goes directly into the brain.” We simply do not know that.

Can We Increase NAD+ Inside the Human Brain?

This is where the story gets particularly interesting.
Researchers now have technology capable of measuring NAD+ inside the living human brain.

In a 2024 study, investigators measured cerebral NAD+ before and after healthy volunteers received oral nicotinamide riboside.[9]

They demonstrated an acute increase in measured cerebral NAD+.

This does not prove that intact NR simply crossed into the brain unchanged, and it does not establish that IV or SQ NAD+ produces the same effect.

But it establishes an important principle:

The human brain's NAD+ pool can be experimentally changed.

That raises an important unanswered question:

Could other methods of increasing systemic NAD+ availability also influence cerebral NAD+ metabolism?

That remains to be determined.

What Does an IV NAD+ Infusion Feel Like?

Clinical experience adds another interesting piece to the story.

In my experience both administering NAD+ infusions and personally receiving them, a characteristic group of sensations occurs when the infusion runs too quickly.

These may include:

• Warmth
• Chest pressure or tightness
• An anxious or uneasy sensation
• A temporary feeling of breathlessness

In the IV NAD+ infusions I have administered or received, these symptoms have been the rate-limiting factor determining how quickly the infusion can run.

When they occur, slowing or stopping the infusion has generally allowed them to dissipate.

Published reports also describe chest pressure, increased heart rate, gastrointestinal symptoms, and other uncomfortable sensations during NAD+ infusions.[10]

Exactly why this happens remains unknown.

Rapid changes in extracellular NAD+ concentrations, NAD+ metabolites, vascular signaling, autonomic responses, or some combination of these factors could potentially contribute.

These mechanisms have not been established in humans.

Importantly, chest pressure or shortness of breath should never simply be dismissed as proof that NAD+ is “working.” New or significant symptoms require stopping administration and appropriate clinical assessment.

What Do People Feel After an NAD+ Infusion?

Some people report increased energy, mental clarity, or focus following IV NAD+. Others notice little or nothing.

In my personal experience, I have noticed increased mental clarity and energy following IV NAD+ administration.

That observation is interesting given NAD+'s central role in energy metabolism, but personal experience cannot establish the mechanism.

We cannot conclude from feeling more energetic that NAD+ necessarily entered the brain and increased neuronal ATP production.

That would require direct experimental evidence.

But the observation raises a legitimate research question.

We know NAD+ participates in ATP production.

We know IV NAD+ can dramatically increase plasma NAD+.

We know the brain is extraordinarily metabolically active.

We know cerebral NAD+ can be experimentally increased.

And some people report noticeable subjective effects following NAD+ administration.

Whether these observations are mechanistically connected is an important question - not yet a proven conclusion.

What About Subcutaneous NAD+?

Subcutaneous administration - or SQ NAD+ - means injecting NAD+ into the fatty tissue beneath the skin rather than directly into a vein.

This has an obvious practical attraction.

IV NAD+ can take considerable time because the uncomfortable sensations associated with rapid administration may determine how quickly the infusion can run.

SQ administration does not require maintaining an IV infusion.

What I Have Observed With SQ NAD+

Interestingly, I have experienced and observed some of the same characteristic sensations with SQ NAD+ that occur during IV administration.

These include:

• Warmth
• An anxious or uneasy sensation
• A temporary feeling of breathlessness, sometimes

In my own experience and among patients I have treated, these sensations have tended to become particularly noticeable with SQ doses in the 75-100 mg range.

That is an observation from clinical experience - not a scientifically established dose threshold.

Published research has not established that everyone will experience these symptoms at these doses.

The similarity between the sensations associated with IV and SQ administration nevertheless raises an interesting question:

Could these sensations reflect systemic exposure to NAD+, its metabolites, or a physiologic response triggered when exposure reaches a certain level?

We do not yet know.
That is a hypothesis that could be tested.

And because chest discomfort or breathlessness can have causes unrelated to NAD+, significant symptoms require appropriate medical assessment rather than simply being assumed to be an expected reaction.

Could SQ NAD+ Be a Practical Middle Ground?

This brings us to the reason SQ NAD+ is scientifically and practically interesting.
IV NAD+ has demonstrated the ability to produce a substantial increase in plasma NAD+.

But IV administration requires venous access, clinical resources, and potentially considerable time because the infusion rate may be limited by uncomfortable symptoms.

Oral precursors are substantially easier to use and clearly alter NAD+ metabolism, but their effects depend on absorption and conversion through metabolic pathways.

SQ administration offers a third possibility.

It is easier and faster to administer than a prolonged IV infusion while still delivering NAD+ systemically.

This makes SQ NAD+ an interesting potential compromise between convenience, cost, time, and systemic administration.

But “interesting” and “proven” are different things.

We currently lack adequate human pharmacokinetic studies showing precisely how much a given SQ dose increases plasma NAD+, how long that increase lasts, how SQ exposure compares with IV administration, or whether SQ NAD+ increases intracellular or cerebral NAD+.

Those studies need to be done.

What About Daily or Every-Other-Day SQ NAD+?

NAD+ is continuously synthesized, consumed, recycled, and redistributed. That raises another reasonable hypothesis:

Could smaller, repeated SQ exposures maintain NAD+ availability differently from occasional large IV exposures?

Daily or every-other-day SQ administration is attractive from a practical standpoint because it could provide repeated systemic exposure without requiring frequent prolonged IV infusions.

But this remains an investigational strategy.

We do not yet have controlled human evidence demonstrating that daily or every-other-day SQ NAD+ improves energy, cognition, athletic performance, mitochondrial ATP production, or longevity.

Likewise, although the body may contain only a few grams of NAD+ at any moment, we cannot assume that administering a cumulative gram of NAD+ per month permanently adds a gram to the body's NAD+ pool.

The body is much more dynamic than that.

Some administered NAD+ will be metabolized. Some metabolites may be recycled. Some will be eliminated.

Whether repeated supplementation ultimately increases tissue NAD+ stores - and by how much - is precisely the type of question that future research should answer.

What About Safety?

NAD+ occurs naturally in the human body, but that does not mean that injecting additional NAD+ is automatically risk-free.

Injectable NAD+ introduces considerations involving sterility, formulation quality, injection reactions, infusion-related symptoms, and the uncertainty surrounding repeated long-term administration.

The FDA has reported adverse events associated with compounded injectable NAD+ products and has raised concerns regarding ingredients used in some sterile compounded NAD+ preparations.[11]

Compounded NAD+ products are not FDA-approved treatments for anti-aging, fatigue, cognitive enhancement, or general wellness.

Long-term controlled safety data for repeated injectable NAD+ are also limited. Those uncertainties need to be weighed alongside any potential benefits.

Putting It All Together

Here is what we can reasonably say today:
NAD+ is essential to mitochondrial energy metabolism.

NADH delivers electrons to the mitochondrial electron transport chain, helping create the proton gradient used to manufacture ATP.

NAD+ also participates in cellular signaling, stress responses, and DNA repair.

Human cerebral NAD+ changes with aging.

Oral NAD+ precursors can substantially increase measured whole-blood NAD+.

IV NAD+ has been demonstrated to increase plasma NAD+ by 398% above baseline during a six-hour infusion.

Human cerebral NAD+ can be experimentally increased.
Some people report increased mental clarity or energy following NAD+ administration.

And clinical experience suggests that both IV and SQ NAD+ can produce noticeable, transient physiologic sensations.

What we cannot yet say is that injecting NAD+ has been proven to increase brain ATP production, improve cognition, reverse aging, increase longevity, or treat fatigue.

Those connections remain hypotheses.

The Question Worth Asking

Instead of beginning with the conclusion that NAD+ supplementation either “works” or “doesn't work,” consider what the existing evidence actually tells us.

NAD+ is central to cellular energy metabolism.

The brain is one of the most metabolically demanding organs in the human body.

Cerebral NAD+ changes with age.

Systemic interventions can change measured NAD+ concentrations.

IV NAD+ can produce a large increase in plasma NAD+.

Cerebral NAD+ itself can be experimentally increased.

And some individuals report noticeable changes in energy and mental clarity following NAD+ administration.

That leaves us with a fascinating unanswered question:

Can increasing systemic NAD+ availability meaningfully influence cellular energy metabolism, brain function, or how we feel?

There is enough evidence to justify asking the question.
There is not yet enough evidence to claim that we know the answer.

Final Thoughts

NAD+ is not a miracle molecule.
But neither is it simply another wellness trend.
It is one of the fundamental molecules involved in cellular metabolism and energy production.

The underlying biochemistry is established.
The ability to manipulate NAD+ metabolism in humans is established.

What remains uncertain is how best to do it - and whether increasing NAD+ translates into meaningful improvements in human health.

IV administration has demonstrated substantial increases in circulating NAD+, but it can be time-consuming and uncomfortable when administered too rapidly.

SQ administration offers a potentially more convenient approach and deserves further investigation, particularly as a method of providing smaller, repeated systemic exposures.

For now, the scientifically responsible position is neither to dismiss NAD+ supplementation nor to promise benefits that have not been demonstrated.

It is to recognize the compelling biology, acknowledge what patients and clinicians observe, clearly distinguish those observations from proven outcomes, and continue asking the questions that rigorous human research still needs to answer.

The science of NAD+ is established. The clinical value of supplementing it is still being determined.

References

1. Stein LR, Imai S. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab. 2012;23:420-428.

2. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: The in vivo evidence. Cell Metab. 2018;27:529-547.

3. Migaud ME, Ziegler M, Baur JA. Regulation of and challenges in targeting NAD+ metabolism. Nat Rev Mol Cell Biol. 2024;25:822-840.

4. Zhu XH, et al. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci USA. 2015;112:2876-2881.

5. Bagga P, et al. Single-Voxel 1H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+) in humans at 7T using a 32-channel volume coil. Magn Reson Med. 2020;83:806-814.

6. Conze DB, et al. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep. 2019;9:9772.

7. Grant R, et al. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD+. Front Aging Neurosci. 2019;11:257.

8. Willie CK, et al. Regulation of cerebral blood flow in humans: Physiology and clinical implications of autoregulation. Physiol Rev. 2022;102:1263-1289.

9. Nanga RPR, et al. Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo. Magn Reson Med. 2024;92:2284-2293.

10. Reyna K, et al. Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): A retrospective tolerability pilot study in a real-world setting. Front Aging. 2026.

11. U.S. Food and Drug Administration. FDA Reminds Compounders to Use Ingredients Suitable for Sterile Compounding.

12. Gallagher C, Emmanuel OO. NAD+ supplementation for anti-aging and wellness: A PRISMA-guided systematic review of preclinical and clinical evidence. Ageing Res Rev. 2026;116:103057.

Important Note

This article is for educational purposes and discusses both published research and clearly identified clinical observations. NAD+ injections are not FDA-approved treatments for anti-aging, cognitive enhancement, fatigue, or general wellness. The optimal dose, route, frequency, long-term safety, and clinical effectiveness of injectable NAD+ have not been established.