The evidence for energy.
NAD+ and MOTS-c: what has been studied in people, what only in animals, and what that means before you begin.
Studies on this page
11 fetched
each read from its source
An energy protocol here is built on NAD+, with MOTS-c added where the answers support it. This page sets out what has been studied for both, and the two of them sit at opposite ends of the evidence range on this site.
NAD+ has a real body of randomised human trials, almost all of them of oral precursors rather than the injected form. MOTS-c has striking animal work and, in humans, observation rather than treatment. Both distinctions matter and both are made plainly below.
NAD+
NAD+ is a coenzyme every cell uses to turn fuel into usable energy. Levels fall with age, and the whole field rests on the idea that putting them back does something useful. The compound is given here as an injection; most of the published human evidence is about oral precursors, nicotinamide riboside and nicotinamide mononucleotide, which the body converts.
That distinction is the single most important thing on this page and it is marked in the table: the trial column says which form was studied.
What has been studied.
| Study | Who | n | How long |
|---|---|---|---|
| Am J Cardiovasc Drugs 20261RCT, intravenous | Adults with heart failure from ischaemic cardiomyopathy | 180 | 7 days |
| The only fetched randomised trial of intravenous NAD+, in a hospital population with a reduced ejection fraction, not in healthy adults. | |||
| Nat Commun 20242RCT, oral precursor | People with peripheral artery disease | 90 | 6 months |
| Six-minute walking distance improved by about 18 metres against placebo, and by about 31 metres among those who took at least three quarters of the pills. | |||
| J Clin Endocrinol Metab 20233RCT, oral precursor | Overweight or obese adults aged 45 and over | 30 | 28 days |
| Blood NAD+ rose substantially; body weight, diastolic blood pressure and total cholesterol fell against placebo over four weeks. | |||
| Geroscience 20234RCT, oral precursor | Healthy middle-aged adults, four arms | 80 | 60 days |
| Blood NAD rose with dose. The secondary measures included a six-minute walk and an insulin resistance index. | |||
| Science 20215RCT, oral precursor | Postmenopausal women with prediabetes who were overweight or obese | 25 | 10 weeks |
| Insulin-stimulated glucose disposal and muscle insulin signalling rose on the precursor and did not change on placebo. | |||
| Front Aging Neurosci 20196pilot, intravenous | Healthy men | pilot cohort | A single 6-hour infusion |
| The only fetched human study of NAD+ given by infusion. No change in plasma NAD+ or its metabolites appeared until after two hours, and extra excretion was detected at six hours. | |||
| Nat Commun 20187RCT, oral precursor | Healthy middle-aged and older adults | 30 | 2 by 6 weeks, crossover |
| The oral precursor was tolerated and raised NAD+ in blood; the authors describe blood pressure and arterial stiffness as worth testing next rather than as shown. | |||
What it is approved for.
- None found on any page fetched for this build. The oral precursors are sold as supplements, which is not an approval.
What has not been studied.
- The injected and infused form has almost no randomised evidence in healthy people. The only fetched human infusion study was a pilot that measured what happened to the molecule rather than what happened to the person, and it found no change in plasma NAD+ until after two hours.
- The only fetched randomised trial of intravenous NAD+ was in adults with heart failure from ischaemic cardiomyopathy, over seven days, alongside standard therapy. That is a hospital population and a hospital question.
- Nothing published on the injected form for energy, fatigue, or the afternoon slump, which is what people take it for.
- No trial in a Filipino population, and nothing beyond six months in any population.
Side effects, and who stopped.
The oral precursor trials report tolerability consistently: adverse events similar to placebo in the four-week trial, described as well tolerated in the six-week crossover. The infused form has no comparable dataset in healthy people.
WHAT THIS MEANS FOR YOU
What is well shown is that oral precursors raise NAD+ in blood and were tolerated, with some measured effects on insulin sensitivity, walking distance and blood pressure in specific populations. What is not shown is that the injected form does any of that in a healthy adult. If your reason for taking it is the afternoon, no fetched trial has measured that.
MOTS-c
MOTS-c is a sixteen-amino-acid peptide encoded inside mitochondrial DNA rather than in the cell nucleus, discovered in 2015. In mice it improves insulin sensitivity and physical performance, including when treatment starts late in life.
In humans it has been measured, not given. That is the whole state of the evidence and it is stated here rather than implied.
What has been studied.
| Study | Who | n | How long |
|---|---|---|---|
| Nat Commun 20218preclinical | Young, middle-aged and old mice | n/a | Late-life treatment three times a week |
| Physical performance improved at every age tested, and treatment started late in life increased physical capacity. | |||
| J Appl Physiol (1985) 20219RCT, observational in humans | Healthy adults doing endurance or resistance exercise | 30 | Single exercise sessions |
| Exercise raised circulating MOTS-c in people. This is the human evidence: the body makes more of it when you train, not that injecting it does anything. | |||
| Aging (Albany NY) 202010observational | Healthy men aged 18 to 81 | 3 age groups | Cross-sectional |
| Circulating MOTS-c fell with age while muscle expression was higher in older men, and levels tracked muscle quality in the older group. | |||
| Cell Metab 201511preclinical | Mice, and cell work | n/a | n/a |
| The paper that identified the peptide. In mice it prevented insulin resistance from age and from a high-fat diet, and prevented diet-induced obesity. | |||
What it is approved for.
- None found on any page fetched for this build.
What has not been studied.
- No trial has administered MOTS-c to a human being in any fetched publication. Not for performance, not for metabolism, not for anything.
- The human papers are observational: exercise raises circulating levels, and levels fall with age while muscle expression rises.
- There is therefore no human safety data at any dose or duration.
Side effects, and who stopped.
No human safety data exists, because no human has been given it in the published record. That is not a reassurance.
WHAT THIS MEANS FOR YOU
The animal work is genuinely interesting and the human work shows only that your body makes more of this when you train. Taking it is a bet on the animal work transferring, made without a single human trial to check it against. Take it to a doctor who knows you before you begin.
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Get startedThe honest summary for energy.
Of the two compounds on an energy protocol, one has randomised human trials of a related oral form and a pilot of the injected form, and the other has none at all. Neither has a trial measuring the thing people actually want, which is more usable energy in the afternoon of an ordinary working day.
That does not make the protocol pointless. It makes the measurement your job: a number written down on day one and compared at day 90, because the published literature will not tell you what happened to you. The tracker exists for that reason.
Questions
Is injected NAD+ better than oral?
No fetched trial compares them. Almost all the randomised human evidence is for oral precursors; the injected and infused form has a pilot in healthy people and one randomised trial in a hospital heart failure population. Anyone telling you the injection is better is ahead of the published record.
Has MOTS-c been tested in people?
Not as a treatment. Every fetched human paper measured it in blood or muscle; none gave it to anybody. The performance results are in mice.
Why cite oral trials for an injected compound?
Because they are what exists, and hiding them would be worse than labelling them. The table names the form each trial used so you can weigh it yourself.
Does NAD+ do anything for tiredness?
No fetched trial measured tiredness or afternoon energy. Trials measured blood levels, insulin sensitivity, walking distance, blood pressure and cholesterol in specific populations.
Sources
Every record below was fetched on the date shown. Nothing on this page is cited that did not fetch.
- 01Yu X, et al. Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial. Am J Cardiovasc Drugs 2026. PubMed 40954388 · doi · read 2026-09-07
- 02McDermott MM, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun 2024. PubMed 38871717 · doi · read 2026-09-07
- 03Pencina KM, et al. Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. J Clin Endocrinol Metab 2023. PubMed 36740954 · doi · read 2026-09-07
- 04Yi L, et al. 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 2023. PubMed 36482258 · doi · read 2026-09-07
- 05Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021. PubMed 33888596 · doi · read 2026-09-07
- 06Grant 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. PubMed 31572171 · doi · read 2026-09-07
- 07Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 2018. PubMed 29599478 · doi · read 2026-09-07
- 08Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021. PubMed 33473109 · doi · read 2026-09-07
- 09von Walden F, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985) 2021. PubMed 34351816 · doi · read 2026-09-07
- 10D'Souza RF, et al. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY) 2020. PubMed 32182209 · doi · read 2026-09-07
- 11Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PubMed 25738459 · doi · read 2026-09-07
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