NAD+ and Fatigue: Understanding the Connection

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme found in all living cells, playing a critical role in energy production, cellular repair, and metabolic processes. As a key component in mitochondrial ATP synthesis and redox reactions, NAD+ is often associated with improved energy levels and reduced fatigue, particularly in aging populations or those with chronic conditions (Conze et al., 2019). However, some individuals report fatigue as a side effect of NAD+ supplementation or therapy, raising questions about its relationship with energy dynamics. This article synthesizes current scientific evidence, clinical insights, and anecdotal reports to explore whether NAD+ can cause fatigue, why it might occur, and some methods our clinic uses to mitigate this rare side effect of NAD+ IVs.

NAD IVs in Scottsdale, AZ: Neuregen offers a range of therapeutic IV therapies including NAD+ IVs

The Role of NAD+ in Energy Metabolism

NAD+ facilitates energy production by acting as an electron carrier in metabolic pathways, such as glycolysis and the citric acid cycle, ultimately supporting ATP generation in mitochondria (Verdin, 2015). It also activates sirtuins, proteins involved in cellular repair, stress resistance, and longevity, which can enhance energy efficiency (Imai & Guarente, 2014). Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), or nicotinamide (NAM), aims to boost NAD+ levels, which naturally decline with age or in conditions like chronic fatigue syndrome (CFS) or mitochondrial dysfunction (Braidy et al., 2019).

Studies consistently show that NAD+ supplementation can reduce fatigue and improve physical performance. For example, a randomized controlled trial found that NR supplementation (1,000 mg/day for 6 weeks) improved endurance and reduced perceived fatigue in older adults (Conze et al., 2019). Similarly, NADH supplementation combined with coenzyme Q10 significantly decreased fatigue intensity in CFS patients, improving quality of life (Castro-Marrero et al., 2015). These findings suggest NAD+ typically counteracts fatigue by enhancing cellular energy production.

Can NAD+ Cause Fatigue?

Despite its energy-boosting potential, some individuals experience fatigue as a side effect of NAD+ supplementation or intravenous (IV) therapy. This paradoxical effect is not common but can arise from several mechanisms, supported by scientific literature and anecdotal reports.

1. Side Effects of Supplementation

High doses of NAD+ precursors like NR, NMN, or NAM can cause mild side effects, including fatigue, nausea, headaches, and gastrointestinal discomfort (Trammell et al., 2016). A 2024 systematic review of NAD+ supplementation trials reported fatigue as a rare side effect, particularly in studies involving CFS, Parkinson’s disease, or high-dose protocols (Pinto et al., 2024). These effects are often dose-dependent and transient, resolving within days. For instance, oral NR doses above 1,000 mg/day or NAM doses exceeding 2 grams/day may disrupt energy metabolism, potentially leading to fatigue (Knip et al., 2000).

2. IV NAD+ Therapy

IV NAD+ therapy, which delivers high concentrations directly into the bloodstream, is increasingly popular for energy enhancement. However, some patients report temporary fatigue during or after infusions- usually lasting 1–2 days when it occurs. This may result from rapid NAD+ repletion overwhelming metabolic pathways or from infusion-related factors like dehydration or fast drip rates. Slowing infusion rates and ensuring hydration can mitigate this, as noted by our clinical providers.

3. Individual Variability

Individual responses to NAD+ vary widely, influenced by health status, genetics, or metabolic imbalances. For example, some people describe fatigue even after low-dose NAD+ IV therapy, usually suggesting heightened sensitivity. We have found that starting with lower doses and titrating slowly to higher doses tends reduce side effects in similar cases. Underlying conditions like CFS or mitochondrial dysfunction may amplify fatigue until other imbalances are addressed (Braidy et al., 2019).

4. Methylation and Metabolic Disruptions

NAD+ precursors, particularly NAM, consume methyl groups during metabolism, which can strain methylation pathways in individuals with genetic variants like MTHFR mutations (Anderson et al., 2019). Methylation deficits may lead to fatigue, brain fog, or other symptoms unless supported with methyl donors like folate or vitamin B12. Additionally, high-dose NAD+ supplementation might temporarily disrupt cellular energy balance by overactivating sirtuins or altering redox homeostasis, potentially causing a “crash” or fatigue in sensitive individuals (Knip et al., 2000).

5. Adjustment Period

Some users report fatigue during the initial phase of NAD+ therapy, possibly due to the body adjusting to elevated NAD+ levels. Some speculate that this could reflect metabolic fluctuations or a withdrawal-like effect as NAD+ pools are replenished. This aligns with clinical observations that side effects often subside after 1–2 weeks of consistent use (Pinto et al., 2024).

Some of the methods Neuregen uses to mitigate Fatigue from NAD+ Supplementation

To reduce the risk of fatigue when using NAD+ precursors or IV therapy, we sometimes use the following strategies, depending on the individual client:

• “Starting Low and Going Slow”: We often begin with low doses and gradually increase to assess individual tolerance (Trammell et al., 2016).

• Optimizing IV Delivery: For IV therapy, we often use slower infusion rates, encouraging clients to stay hydrated, and eat a light meal beforehand.

• Supporting Methylation: We sometimes supplement with methyl donors like folate, B12, or betaine if methylation issues are suspected (Anderson et al., 2019).

• We Monitor Underlying Conditions: We try to address mitochondrial dysfunction, nutrient deficiencies, or chronic conditions – we are not “an IV shop” but rather an integrative medical clinic, which means that our healthcare providers develop a clinical relationship with our clients before starting NAD+ therapy (Braidy et al., 2019).

• Encouraging Adjustment Time: We urge our clients to expect mild side effects like fatigue to resolve within days to weeks as the body adapts (Pinto et al., 2024).

Conclusion

NAD+ is a powerful coenzyme that typically enhances energy production and reduces fatigue, as evidenced by studies on aging and chronic conditions (Conze et al., 2019; Castro-Marrero et al., 2015). However, fatigue can occur as a rare, transient side effect of NAD+ supplementation or IV therapy, particularly with high doses, rapid infusions, or in individuals with metabolic sensitivities. Factors like methylation deficits, underlying health conditions, or adjustment periods may contribute. By starting with low doses, supporting methylation, and optimizing therapy protocols, fatigue can be minimized while maximizing NAD+’s benefits. Neuregen: Precision NAD+ IV Therapy in Scottsdale, AZ

For those seeking a precision NAD+ IV infusion protocol in Scottsdale, AZ, Neuregen offers exceptional medical support as an integrative medical clinic, not just an IV shop. Unlike standard IV therapy providers, Neuregen combines NAD+ therapy with a holistic approach to address a range of conditions, including cognitive impairment, neuroinflammation, neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Cognitive decline), addiction, mental health disorders (e.g., depression, anxiety, PTSD), concussion, postural orthostatic tachycardia syndrome (POTS), dysautonomia, migraines, and chronic pain. Their expert team, led by professionals trained in integrative psychiatry and neurorehabilitation, customizes NAD+ protocols to individual needs, ensuring safe and effective administration in a spa-like, patient-centric environment.

References

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Braidy, N., Berg, J., Clement, J., Khorshidi, F., Poljak, A., Jayasena, T., Grant, R., & Sachdev, P. (2019). Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: Rationale, biochemistry, pharmacokinetics, and outcomes. Antioxidants & Redox Signaling, 30(2), 251–294. https://doi.org/10.1089/ars.2017.7269

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Conze, D., Brenner, C., & Kruger, C. L. (2019). 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. Scientific Reports, 9(1), 9772. https://doi.org/10.1038/s41598-019-46120-z

Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology, 24(8), 464–471. https://doi.org/10.1016/j.tcb.2014.04.002

Knip, M., Douek, I. F., Moore, W. P., Gillmor, H. A., McLean, A. E., Bingley, P. J., & Gale, E. A. (2000). Safety of high-dose nicotinamide: A review. Diabetologia, 43(11), 1337–1345. https://doi.org/10.1007/s001250051536

Pinto, S. I., Mendes, F., & Caldeira, L. (2024). NAD+ supplementation: A systematic review of clinical trials in humans. Frontiers in Aging, 5, 1342357. https://doi.org/10.3389/fragi.2024.1342357

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Verdin, E. (2015). NAD+ in aging, metabolism, and neurodegeneration. Science, 350(6265), 1208–1213. https://doi.org/10.1126/science.aac4854