The biochemical connection between NAD+ and cellular energy metabolism is real and well-documented. However, moving from the statement that „NAD+ participates in energy production” to the claim 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: NAD+ is essential for cellular energy production, but stating 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 caffeine causes a stimulating effect or how 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 primary form of usable energy inside cells [1].
When NAD+ availability is reduced, certain metabolic processes dependent on it can be disrupted, which helps explain why a decline 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 does not automatically mean that increasing the level of NAD+ or its precursors above an individual's baseline will result in a noticeable increase in subjectively felt 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 organism in energy-requiring processes, such as muscle contraction, nerve conduction, ion transport, biosynthesis, and the proper maintenance of cellular functions.
After donating its electrons, NADH is converted back into NAD+. The regenerated NAD+ can then participate in the next cycle of nutrient metabolism and electron transport [1].
This process occurs constantly throughout the entire organism and with very high intensity. Studies analyzing the synthesis and turnover of NAD+ have shown that NAD+ metabolism varies significantly among tissues, reflecting differences in metabolic demand and cellular functions [3]. For this reason, a single measurement of NAD+ in the blood does not necessarily reflect the full picture of NAD+-dependent energy metabolism in specific tissues, such as skeletal muscle, liver, heart, or brain.
NAD+ or NADH: which form is more related to 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 carries high-energy electrons to the mitochondrial electron transport chain, where they contribute to ATP production. NAD+ is the oxidized 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. This does not mean, however, that NADH is inherently more important than NAD+ or that it should be treated as the preferred form for boosting energy.
NAD+ availability determines whether cells can continue accepting electrons during glycolysis and other metabolic pathways. If there is too little available NAD+, these reactions may slow down because a smaller amount of oxidized NAD+ is available to be converted into NADH. Both forms thus 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, cellular stress response, and DNA repair [1,2].
Therefore, the relationship between them is complementary rather than competitive. NADH transfers electrons directly used in ATP production, whereas NAD+ is needed both for the regeneration of NADH and to support several distinct signaling and enzymatic pathways.
This distinction also helps explain why most clinical studies on 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 of NAD+ and energy.
Improvements in functional outcomes have been reported in some clinical trials. In a randomized, placebo-controlled, dose-response trial 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 performance, not standardized, self-assessed levels of energy or fatigue.
Other studies have yielded different results. In one of them, 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, maximum respiratory capacity, mitochondrial content, or other direct parameters of skeletal muscle mitochondrial bioenergetics [5].
This represents an important contrast. Increasing the level of NAD+-related metabolites in muscles did not automatically lead to a measurable improvement in muscle strength or the mitochondrial capacity to produce energy in this study.
Subjective energy levels are much less studied. Most studies on NAD+ precursors have not used standardized measurements of fatigue, vitality, or perceived energy as primary endpoints. Instead, they have focused on biomarkers, physical performance 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 them 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 heart palpitations, compared to intravenous nicotinamide riboside administered under the same clinical conditions [6]. This result applies specifically to intravenous administration and should not be generalized to oral NAD+ precursors. This is also an observation regarding tolerability, not evidence that NAD+ increases energy through a stimulant effect.
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 proper 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 metabolites related to NAD+ [3,4,5]. However, biomarker changes should not be interpreted as evidence that an individual will feel more energetic.
Some studies have reported improvements in objective measures of physical performance, such as the 6-minute walk test [4]. Other studies evaluating 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 perceived „energy boost” as a clinical effect of NAD+ precursor supplementation.
A more precise interpretation is that NAD+ supports fundamental metabolic pathways involved in cellular energy production. Increasing NAD+ availability can affect NAD+-related biomarkers, but this is not equivalent to the immediate effect of a stimulant or a rapidly emerging feeling of having more 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 standardized, 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 inconsistent across studies. Some reported improvements in walking performance, while others found no significant changes in strength or skeletal muscle mitochondrial bioenergetics [4,5].
- The relationship between increases in blood or tissue NAD+ biomarkers 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 improved ATP production, exercise performance, reduced fatigue, or increased daily energy levels.
- Data on heart-related symptoms come from a single retrospective real-world study of intravenous NAD+ and should not be generalized to oral supplementation with NAD+ precursors [6].
- The biochemical necessity of NAD+ presence in energy metabolism does not prove that increasing NAD+ levels above physiological values will improve energy-related performance in every individual.
- Results from mechanistic, cellular, or animal studies should not be presented as confirmed health benefits in humans without direct clinical evidence.
Disclaimer
The article is for educational purposes only and summarizes scientific research. It does not constitute medical advice, 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, or any disease, unless referring to a specific approved medicinal product and indication.
The evidence discussed here includes well-established biochemistry, biomarker studies, functional clinical outcomes, and observations from real-world studies. 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, anemia, 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 an appropriate medical evaluation rather than relying solely on supplementation. Before starting any new supplement or therapy, you should consult with a qualified healthcare professional, especially during pregnancy or breastfeeding, when treating a chronic illness, including cardiovascular disease, or while taking prescription medications simultaneously.
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 randomized, multicenter, 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