The biochemical link between NAD+ and cellular energy metabolism is real and well-documented. However, leaping from the statement that „NAD+ participates in energy production” to claiming that „taking an NAD+ supplement will make you feel more energetic” requires several assumptions that current human research data does not fully support. In this article, we explain the underlying mechanism, distinguish between NAD+ and NADH, and discuss what has actually been measured in human studies regarding energy and physical performance.
Does NAD+ directly increase energy, or is that too much of a simplification?
The short answer is that NAD+ is essential for cellular energy production, but claiming that it „boosts energy” is an oversimplification of a much more complex metabolic process. Such simplification can create expectations that go beyond what has been demonstrated in human clinical trials.
NAD+ does not produce energy directly in the way that caffeine causes a stimulating effect or carbohydrates provide calories that can be used to produce energy. Instead, NAD+ acts as an electron carrier essential in biochemical reactions related to the conversion of nutrients into ATP, or adenosine triphosphate, which is the main form of usable energy inside cells [1].
When NAD+ availability is reduced, certain metabolic processes dependent on it can be disrupted, which helps to explain why a drop in NAD+ levels has been linked to changes in energy metabolism in various research models [1,2]. However, the mere fact that NAD+ is essential for these reactions to take place does not automatically mean that increasing the level of NAD+ or its precursors above a person's baseline will result in a noticeable increase in subjectively perceived energy. This is a separate question requiring direct clinical evidence.
Actual mechanism: the role of NAD+ in ATP production
The role of NAD+ in energy metabolism is easier to understand when the process is broken down into its main biochemical stages.
The breakdown of nutrients begins, among other things, during glycolysis and the citric acid cycle. During these reactions, enzymes strip electrons from molecules derived from carbohydrates and fats. NAD+ accepts these electrons and is converted into its reduced form, NADH [1].
NADH then transports these electrons to the mitochondrial electron transport chain. In complex I, electrons derived from NADH enter the chain and pass through a series of protein complexes. The energy released during this flow is used to pump protons across the inner mitochondrial membrane [1].
The resulting proton gradient provides the energy needed by ATP synthase to produce ATP. ATP is then used throughout the body in energy-requiring processes such as muscle contraction, nerve conduction, ion transport, biosynthesis and the proper maintenance of cellular functions.
After the transfer of electrons, NADH is reconverted into NAD+. The regenerated NAD+ can then participate in the next cycle of nutrient metabolism and electron transport [1].
This process occurs continuously throughout the entire body and with very high intensity. Studies analysing NAD+ synthesis and turnover have shown that NAD+ metabolism varies significantly between tissues, which reflects differences in metabolic demand and cellular functions [3]. For this reason, a single blood measurement of NAD+ does not necessarily reflect the full picture of NAD+-dependent energy metabolism in specific tissues, such as skeletal muscle, the liver, the heart or the brain.
NAD+ and NADH: which form is more closely associated with usable energy?
The difference between NAD+ and NADH is significant, because both forms perform related, yet distinct biochemical functions.
NADH is the reduced form of the molecule and transports high-energy electrons to the mitochondrial electron transport chain, where they contribute to the production of ATP. NAD+ is the oxidised form and acts as an electron acceptor, which is converted into NADH during the metabolism of nutrients [1].
In this narrow biochemical sense, NADH is more directly involved in supplying electrons to the mitochondria at any given moment. However, this does not mean that NADH is inherently more important than NAD+, nor that it should be treated as the preferred form for boosting energy.
NAD+ availability determines whether cells can continue to accept electrons during glycolysis and other metabolic pathways. If there is too little available NAD+, these reactions can slow down because a smaller amount of oxidised NAD+ is available to be converted into NADH. Both forms therefore function as part of the same continuous redox cycle.
NAD+ also has important biological functions that NADH does not perform in the same way. It is required as a substrate by sirtuins and PARP enzymes, which are involved in, among other things, gene regulation, the cellular stress response, and DNA repair [1,2].
Their relationship is therefore complementary rather than competitive. NADH carries electrons used directly in ATP production, whereas NAD+ is required both for the regeneration of NADH and for supporting several distinct signalling and enzymatic pathways.
This distinction also helps to explain why most clinical trials concerning oral NAD+ precursors have focused on increasing overall NAD+ availability, rather than treating NADH as an independently superior energy-boosting form.
What do users report, and what do studies measure?
The difference between subjective reports and objectively measured clinical outcomes is particularly important in the discussion about NAD+ and energy.
Improvements in functional outcomes were reported in some clinical trials. In a randomised, placebo-controlled, dose-ranging study involving 80 healthy middle-aged and older adults, participants received 300 mg, 600 mg, or 900 mg of NMN daily for 60 days. Those taking the higher doses achieved better results in the 6-minute walk test [4].
The 6-minute walk test is an objective measure of physical fitness and functional capacity. Although the result may be related to metabolic functioning, it should not be interpreted as direct evidence that participants experienced a subjective „energy boost”. The study evaluated walking fitness, not a standardised, self-assessed level of energy or fatigue.
Other research has yielded different results. In one study, older men took nicotinamide riboside for 21 days. The intervention significantly increased the level of NAD+-related metabolites in skeletal muscle, but did not significantly improve handgrip strength, relative strength, maximal respiratory capacity, mitochondrial content or other direct parameters of skeletal muscle mitochondrial bioenergetics [5].
This represents an important contrast. Increasing the level of NAD+-associated metabolites in muscles did not automatically lead to a measurable improvement in muscle strength or the energy-producing capacity of mitochondria in this study.
Subjective energy levels are much less researched. Most studies on NAD+ precursors have not used standardised measurements of fatigue, vitality, or perceived energy as primary endpoints. Instead, they have focused on biomarkers, physical fitness tests, metabolic parameters, cardiovascular outcomes, or disease-specific endpoints.
Therefore, widely repeated claims that NAD+ supplementation reliably produces a noticeable increase in daily energy levels are not well supported by controlled clinical trials. There are individual reports of greater energy, but it is difficult to separate these from the placebo effect, changes in sleep, physical activity, diet, caffeine intake, stress, or other simultaneously changing factors.
The related question concerns heart rate. NAD+ is not classified as a typical stimulant and does not work through the same mechanisms as caffeine or other stimulating substances.
However, a retrospective review of real-world intravenous NAD+ use showed more cardiac-related symptoms, including palpitations, compared with intravenous nicotinamide riboside administered under the same clinical conditions [6]. This result relates specifically to intravenous administration and should not be generalised to oral NAD+ precursors. It is also an observation regarding tolerability, rather than proof that NAD+ increases energy through a stimulant action.
Realistic expectations regarding the „energy boost”
The role of NAD+ in cellular energy metabolism is well established. NAD+ is essential for key reactions involved in converting nutrients into ATP and maintaining normal mitochondrial and cellular metabolism.
It remains less certain whether increasing NAD+ through supplementation leads to a consistent and noticeable increase in subjectively perceived energy in humans.
Human studies provide relatively strong evidence that several NAD+ precursors can increase the levels of circulating or tissue-related metabolites associated with NAD+ [3,4,5]. However, changes in biomarkers should not be interpreted as evidence that an individual will feel more energetic.
Some studies have noted improvements in objective measures of physical performance, such as the 6-minute walk test [4]. Other studies assessing related outcomes, including muscle strength and mitochondrial bioenergetics, showed no significant improvement despite a clear increase in NAD+-related metabolites [5].
Current research therefore does not confirm a predictable or universal, subjectively felt „boost of energy” as a clinical effect of NAD+ precursor supplementation.
A more precise interpretation is that NAD+ supports the fundamental metabolic pathways involved in cellular energy production. Increasing the availability of NAD+ can affect biomarkers associated with NAD+, but this is not equivalent to the immediate action of a stimulant or a quickly appearing sensation of increased energy.
Claims that a specific NAD+ product will reliably make someone feel more energetic should therefore be treated with caution, unless they are supported by controlled human studies using validated measures of fatigue, vitality or subjectively perceived energy.
Limitations of current evidence
- Most published human studies on NAD+ precursors have not used standardised, validated scales of fatigue, vitality, or subjectively perceived energy as primary endpoints. This limits the ability to determine whether supplementation consistently alters how energetic people feel [4,5].
- Functional outcomes related to physical fitness and energy metabolism were mixed across studies. Some reported improvements in walking performance, while others found no significant changes in strength or skeletal muscle mitochondrial bioenergetics [4,5].
- The link between increases in NAD+ biomarkers in the blood or tissues and subjectively perceived energy has not been directly and systematically established in clinical trials involving humans.
- A measurable increase in NAD+ or NAD+-related metabolites does not automatically mean an improvement in ATP production, exercise performance, reduced fatigue or an increase in everyday energy levels.
- The findings regarding heart-related symptoms originate from a single retrospective real-world study of intravenous NAD+ and should not be generalised to oral supplementation with NAD+ precursors [6].
- The biochemical necessity of NAD+ in energy metabolism does not prove that increasing NAD+ levels above physiological values will improve energy-related outcomes in every individual.
- The results of mechanistic, cellular or animal studies must not be presented as confirmed energetic benefits in humans without direct clinical evidence.
Disclaimer
The article is purely educational in nature and summarises scientific research. It does not constitute medical advice, a diagnosis, therapeutic recommendations, or a recommendation to use NAD+, NAD+ precursors, supplements, injections, or intravenous therapies.
NAD+ and its precursors should not be presented as FDA- or EMA-approved treatments for fatigue, low energy levels or any disease, unless referring to a specific approved medicinal product and indication.
The evidence discussed here includes well-established biochemistry, biomarker research, functional clinical outcomes, and real-world evidence observations. Changes in NAD+ concentration or related metabolic pathways should not be interpreted as evidence of a clinically significant increase in energy.
Persistent fatigue can have many causes, including sleep disorders, anaemia, endocrine disorders, cardiovascular diseases, infections, side effects of medications, nutritional deficiencies and mental health issues. Individuals experiencing persistent or unexplained fatigue, or symptoms such as palpitations, should seek a proper medical evaluation rather than relying solely on supplementation. Before starting any new supplement or therapy, you should consult a qualified healthcare professional, particularly during pregnancy or breastfeeding, when managing a chronic condition such as cardiovascular disease, or while taking prescription medications.
References
[1] Yoshino, J., Baur, J. A., & Imai, S. (2018). NAD+ intermediates: The biology and therapeutic potential of NMN and NR. *Cell Metabolism*, 27(3), 513–528. https://doi.org/10.1016/j.cmet.2017.11.002
[2] Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. *Nature Reviews Molecular Cell Biology*, 22(2), 119–141. https://doi.org/10.1038/s41580-020-00313-x
[3] Berven, H., Svensen, M., Eikeland, H., Tvedten, N., Sheard, E. V., Amdahl Af Geijerstam, S., Søgnen, M., McCann, A., Arnsten, L., Årseth, O., Skjeie, V., Hjellbrekke, A., Skeie, G.-O., Torres Cleuren, Y. N., Nido, G. S., Haugarvoll, K., Riemer, F., Tzoulis, C., & Dölle, C. (2026). The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation. *iScience*, 29(3), 114764. https://doi.org/10.1016/j.isci.2026.114764
[4] Yi, L., Maier, A. B., Tao, R., Lin, Z., Vaidya, A., Pendse, S., Thasma, S., Andhalkar, N., Avhad, G., & Kumbhar, V. (2022). The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: A randomised, multicentre, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. *GeroScience*, 45, 29–43. https://doi.org/10.1007/s11357-022-00705-1
[5] Elhassan, Y. S., Kluckova, K., Fletcher, R. S., Schmidt, M. S., Garten, A., Doig, C. L., Cartwright, D. M., Oakey, L., Burley, C. V., Jenkinson, N., Wilson, M., Lucas, S. J. E., Akerman, I., Seabright, A., Lai, Y., Tennant, D. A., Nightingale, P., Wallis, G. A., Manolopoulos, K. N., Brenner, C., Philp, A., & Lavery, G. G. (2019). Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. *Cell Reports*, 28(7), 1717–1728.e6. https://doi.org/10.1016/j.celrep.2019.07.043
[6] Reyna, K., Heinzen, G., Patel, N., Ritter, M., Siojo, A., Legere, H., & Pojednic, R. (2026). Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): A retrospective tolerability pilot study in a real-world setting. *Frontiers in Aging*, 7, 1652582. https://doi.org/10.3389/fragi.2026.1652582