Tired on a GLP-1: What NAD+ and MOTS-c Have Actually Been Tested For, and What Nobody Has Tested

Our heart rate, HRV and fatigue article already covers the retatrutide fatigue numbers in full, and seven NAD+ articles plus three MOTS-c articles on this site cover those compounds on their own terms. None answers the question here: people who feel flattened on a GLP-1-class drug reach for NAD+ or MOTS-c, and nobody has tested whether that does anything. What follows is what the trials measured, what our community corpus reports, including the reports that cut against the practice, stated plainly and without a recommendation.

What people are actually doing

Our Reddit corpus, the 12 months to 6 August 2026, covers 148,085 posts from r/Retatrutide, r/tirzepatidecompound, r/Peptides, r/Biohackers, r/PeptideDiscussion, r/Semaglutide, r/BPC157 and r/sarmsourcetalk: a community report, not a scientific sample.

Within the 2,248 fatigue posts, mentions by compound run: MOTS-c in 74, NAD+ or NMN in 56, CJC-1295 or ipamorelin in 15, tesamorelin in 12, and sermorelin in 2. This article evaluates NAD+, MOTS-c and sermorelin only; the rest are reported as corpus counts.

The 114 posts break down as r/Retatrutide 59, r/tirzepatidecompound 19, r/Biohackers 15, r/Peptides 14, r/PeptideDiscussion 6 and r/Semaglutide 1. Seven duplicate clusters covering 15 posts mean roughly 99 to 107 independent voices rather than 114, worth keeping in mind wherever that count appears below.

Nine of the 114 report the compound making fatigue worse, not better. By thread title only, with no usernames or links: "Adding MOTS-c while in big deficit made me feel way worse. Normal or mitochondria issue?"; "Feeling tired/fatigued from Mots-C?"; "NAD+ dose weird side effect"; "Stacking"; "Tirz + NAD+ I'm feeling hungrier and more tired"; "Ss-31"; "2 MONTHS progress and details so far"; "Fatigue on 5 Amino 1hq?"; "Sensitive to peptides- advice." One describes a dose-response the poster worked out for themselves: heaviness and short-lived exhaustion 15 to 30 minutes after each administration, resolving when they reduced the amount. That is the poster's own report, not a recommendation, and the only community dosing detail repeated here.

Other threads describe the practice itself rather than an adverse report: "Reta Tesa Mots-C might be the ultime shred stack"; "Energy loss after 6mo of Retatrutide"; "A Nod to NAD+." Section 7 returns to why these threads disagree with each other.

What the trials recorded about fatigue

Fatigue is a named adverse event with a comparator in the retatrutide and semaglutide records, while SURMOUNT-1 did not list it above its own reporting threshold. Every rate below carries its denominator and its comparator arm.

The retatrutide arms sum to a safety population of 337, but that total includes the 70 placebo participants: the drug-arm rate is 19 of 267 (7.1%), never "22 of 337." No fatigue, asthenia, lethargy or malaise term appears among SURMOUNT-1's 174 serious-event terms in any arm, and no asthenia term appears alongside STEP 1's fatigue count.

None of this is a measurement. No trial of retatrutide, tirzepatide or semaglutide used a validated fatigue instrument (FACIT-Fatigue, PROMIS Fatigue, MFI-20) as a prespecified outcome, and nine PubMed queries crossing all three drugs with all three instruments return nothing on point. Every number above is a spontaneously reported adverse event, not a scale anyone administered.

The closest a prespecified patient-reported outcome comes from the sleep-apnea program, not the obesity program: across two 52-week SURMOUNT-OSA trials, tirzepatide participants reported significantly improved sleep, activity and quality-of-life scores against placebo at week 52 (PMID 40774158). A post-hoc analysis, Study 1 only, numerically greater with no significance testing reported, found larger changes among participants fatigued at baseline, for example FOSQ Activity Level 0.33 versus 0.05 (PMID 42412744; six of its seven authors are employees of the manufacturer).

Because this is an EU shop, the EU label is worth stating. The Mounjaro summary of product characteristics lists fatigue as a common adverse reaction (at least 1 in 100, fewer than 1 in 10 by EU convention), footnoted that "fatigue includes the terms fatigue, asthenia, malaise, and lethargy," very common in one cardiovascular-outcomes trial and common in the weight-management, sleep-apnea, heart-failure and diabetes trials, over a safety base of 15,169 adults (EU product information, Mounjaro SmPC). So the EU label treats fatigue as an expected class reaction, even in the one trial that did not report it above its own threshold.

Four reasons to be tired that are not a missing molecule

Lean-mass loss is a class effect, not an isolated finding. A network meta-analysis of 22 randomized trials with 2,258 participants, searched through 12 November 2024, found total body weight change of -3.55 kg, fat mass -2.95 kg and lean mass -0.86 kg, with lean-mass loss comprising approximately 25% of total weight loss, while relative lean mass as a percentage of baseline was unaffected; tirzepatide 15 mg and semaglutide 2.4 mg were the most effective doses for weight and fat loss and among the least effective at preserving lean mass (PMID 39719170). In the STEP 1 DEXA sub-population, total fat mass fell 9.3 kg on semaglutide 2.4 mg (n=83) against 1.5 kg on placebo (n=39), and lean body mass fell 5.8 kg against 1.8 kg. This registry submission has no journal publication located, and gives no body-weight change for the DEXA subset, so no share-of-weight-lost percentage can be calculated from it.

Volume depletion is on the label. The tirzepatide US prescribing information warns of acute kidney injury due to volume depletion: "There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists," mostly in patients with gastrointestinal reactions "leading to dehydration such as nausea, vomiting, or diarrhea" (US prescribing information).

Reduced intake carries its own micronutrient risk. An endocrinology expert consensus, 13 experts producing 44 statements, opens by stating that these drugs "cause gastrointestinal adverse effects and alter dietary intake, leading to nutritional deficiencies and loss of muscle mass and bone density," and recommends nutritional assessment, protein, micronutrients, hydration and resistance exercise. This is expert opinion, not trial data; the quote is background framing, not a voted statement (expert consensus).

Pharmacovigilance treats fatigue as noise, not signal. The largest recent FDA adverse event database analysis for tirzepatide, 67,305 cases across 144 significant signals, does not list fatigue among them, naming it once, in its limitations, as prone to over-reporting from consumer self-reports (PMID 41531800). In the European database, fatigue reached a significant signal in exactly one of twelve pairwise drug comparisons, semaglutide against tirzepatide, while asthenia and malaise showed none (PMID 42356493).

None of this requires a missing molecule: a large, sustained energy deficit is itself fatiguing.

NAD+: what rises, and what does not

Blood NAD+ rises reliably and dose-dependently under oral precursors. An 8-week randomized trial in overweight healthy adults found whole-blood NAD+ up 22%, 51% and 142% at 100, 300 and 1,000 mg of nicotinamide riboside within two weeks, with no adverse-event difference against placebo (PMID 31278280; funded by the ingredient manufacturer, two authors were its employees). A 2026 randomized trial in 65 healthy participants over 14 days found nicotinamide riboside and NMN, but not nicotinamide, comparably increased circulating NAD+ (PMID 41540253), and a phase 1 study in 6 healthy participants and 6 with Parkinson disease found blood NAD plateaued after about two weeks at 1,200 mg per day (PMID 41858901).

Muscle NAD+ does not rise, the most load-bearing fact here, and it is three studies for three.

Oral precursors raise blood NAD+ and muscle NAD+ turnover markers, but no human trial reviewed here has shown the muscle NAD+ pool itself rising.

The single most on-topic trial in this literature is also a null result. Thirty overweight or obese adults aged 45 and over were randomized 2 to 1 to a microcrystalline NMN product at 2,000 mg per day or placebo for 28 days. Muscle strength, muscle fatigability, aerobic capacity and stair-climbing power did not differ significantly between groups, and insulin sensitivity, hepatic fat and intra-abdominal fat did not change in either group (PMID 36740954). This is the only human randomized trial located that measured muscle fatigability under an NMN product, in a population, overweight or obese middle-aged and older adults, close to the one this article is about.

Fatigue outcomes elsewhere are null or sit next to their own moving placebo arms. In long COVID, a 24-week trial in which the continuous group received nicotinamide riboside at 2,000 mg per day for 20 weeks (58 participants, randomized 2 to 1) raised NAD+ 2.6 to 3.1-fold and found no between-group difference in fatigue (p = 0.59) or three other measured outcomes (PMID 41357333; funded by the ingredient manufacturer, with equity and advisory-board disclosures). In 108 older Japanese adults given NMN 250 mg per day for 12 weeks in morning or evening arms, the five-times-sit-to-stand test improved in all four groups including both placebo arms; the evening NMN arm simply had a larger effect size (d = 0.72) than the evening placebo arm (PMID 35215405). Read as a timing signal against a moving placebo, not an NMN-versus-placebo win.

Where NMN did move a performance endpoint, in 48 amateur runners over 6 weeks, it was submaximal: ventilatory-threshold submeasures improved at higher doses, but maximal oxygen uptake and peak power did not change in any group, and blood NAD+ was never measured (PMID 34238308). Safety otherwise looks favorable, with one irony: a systematic review of 10 randomized trials with 489 participants found all included studies reported some side effects, most commonly muscle pain and fatigue (PMID 37971292), the very symptom the compound is proposed against.

Nothing tests the actual question. No randomized trial of NMN or nicotinamide riboside has been conducted in people on a GLP-1-class drug, in a calorie deficit, or during active weight loss. Injected NAD+ has been studied in people intravenously, in a 6-hour infusion pharmacokinetic pilot (PMID 31572171) and in a randomized placebo-controlled trial in ischemic heart failure (PMID 40954388), but no published human pharmacokinetic or outcome study of SUBCUTANEOUS NAD+ was located, and neither intravenous study addressed fatigue during GLP-1-class treatment. See NAD+ vs. NMN vs. NR and NAD+ delivery routes and bioavailability.

MOTS-c: the compound with no published human results

MOTS-c is a mitochondrial-derived peptide encoded in the mitochondrial 12S rRNA region. Its founding paper reports that it inhibits the folate cycle and de novo purine biosynthesis, leading to AMPK activation, that its primary target organ "appears to be" skeletal muscle, and that MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity (PMID 25738459). Three points matter for what follows: the muscle-targeting statement is hedged by its own authors, the verb is prevented rather than reversed since the mice were treated before or alongside the metabolic insult, and no fatigue, energy, exercise-capacity or human endpoint appears anywhere in the paper, which also never uses the phrase "mitochondrial biogenesis."

The strongest animal performance numbers come with their own nulls attached. In aged mice, MOTS-c-treated animals ran 2-fold longer and 2.16-fold farther than untreated animals, and 17% of the old treated mice reached the final, highest-speed running stage while none of the untreated group did (PMID 33473109). In the same paper's young-mouse experiment, MOTS-c improved rotarod performance but did not improve grip strength or maze learning and memory, and the lifespan curve "trended towards increased median and maximum lifespan" without reaching significance (p = 0.23). The widely circulated claim that MOTS-c extends lifespan is not what that paper reports.

No published study has reported giving MOTS-c to a person. A PubMed search crossing MOTS-c with human and randomized-controlled-trial publication types returns four records, and every one measures the endogenous circulating peptide as a biomarker inside a trial of something else: heat stress, metformin treatment, cancer-survivor exercise, and acute exercise. One interventional human trial does now exist on the registry: a phase 2 study of subcutaneous MOTS-c for insulin sensitivity in adults with prediabetes and overweight or obesity, sponsored by a biotechnology company, with a listed study start of 2 February 2026, a record first posted on 1 April 2026, a status of recruiting and no results posted (NCT07505745). So the honest statement is not that MOTS-c has never been administered, but that no completed trial, no published dose, no published duration and no published safety window for administered MOTS-c in humans exists yet, and that the registered trial measures insulin sensitivity rather than fatigue.

The human observational data that exists is mixed. In a randomized 16-week exercise trial in 49 breast cancer survivors, circulating MOTS-c rose significantly against baseline and usual care in non-Hispanic White participants (p < 0.01) but not Hispanic participants (PMID 34413391). After a single bout of exercise in 30 participants, humanin rose significantly while MOTS-c showed only a non-significant trend (PMID 34351816).

The fatigue-adjacent human datapoint is a transcript, not a peptide, and cuts against a simple supplementation story. Monocyte RNA sequencing in four matched groups of 10 found the MOTS-c-encoding transcript expressed lower in Q fever fatigue syndrome and in chronic fatigue syndrome than in healthy controls, log2 fold changes of -4.9 in Q fever fatigue syndrome and -4.4 in chronic fatigue syndrome against healthy controls, and -3.2 in Q fever seropositive controls (PMID 31088495). Protein was measured only for humanin, not MOTS-c: a lower endogenous transcript in a fatigued population is not evidence that giving the peptide would help.

The one study touching both a GLP-1-class drug and MOTS-c points away from the practice. In 163 patients with type 2 diabetes on insulin, liraglutide, empagliflozin or the combination, "only treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c": a GLP-1 receptor agonist alone did not raise it (PMID 40008510; observational, propensity-score matched, not randomized). See MOTS-c research.

Sermorelin, the third name

Sermorelin is the third compound named alongside NAD+ and MOTS-c in community threads about GLP-1 fatigue, and it is nearly absent from both sides of the record. It appears in only 2 of the 2,248 fatigue posts in our corpus, and no evidence connecting it to fatigue or energy outcomes was located. That is the whole finding: not a null trial, not a mixed signal, simply an absence of anything on point.

What the community reports back

Return to the nine threads from section 1 that report the compound made fatigue worse. Posters there share a reasoning pattern: they treat mitochondrial function as the explanation for how they feel, reach for a compound that acts on mitochondria, and argue from mechanism rather than from any trial, then disagree with each other about whether it helped, hurt or did nothing.

The one dose-response report is the poster described in the opening section. Whatever caused that pattern, pharmacological or a placebo-adjacent expectation effect, the poster's own report is the observation; nothing in the trial literature above tests it, and nothing here recommends a dose based on it.

Expectation is a documented confound in exactly this territory, not a rhetorical dismissal. The Japanese NMN trial's sit-to-stand test improved in every arm, placebo included; only the size of the improvement, not its direction, separated drug from placebo. A community arguing from mechanism, with no trial behind either compound in this context, sits close to the conditions under which that kind of moving placebo shows up.

What a study would have to do to answer this

Until a study meets all four, the question stays open.

Where these compounds sit in our catalog

Frequently asked questions

Sources

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32. Internal analysis of a public Reddit archive, 148,085 posts from r/Retatrutide, r/tirzepatidecompound, r/Peptides, r/Biohackers, r/PeptideDiscussion, r/Semaglutide, r/BPC157 and r/sarmsourcetalk, 12 months to 6 August 2026.

Research use only. NAD+, MOTS-c and the GLP-1-class compounds discussed in this article, including retatrutide, tirzepatide and semaglutide, are referenced here for their published research record. Products sold on this site are supplied for laboratory research, not for human or animal administration, and not as medicines. Nothing in this article is dosing, protocol or combination guidance, and nothing here claims that any product works or that adding one compound changes how a person feels on another.