MOTS-c vs SS-31 vs NAD+: differences, evidence and safety

SS-31 (elamipretide) is the only one of the three with an FDA approval, as Forzinity for Barth syndrome (FDA). MOTS-c prevented diet-induced insulin resistance and obesity in mice (Lee 2015) [Animal], but no human treatment trial has been published. NAD+ is a coenzyme, not a peptide. NMN, the oral precursor of NAD+, raised blood NAD+ levels in a randomized trial of 80 adults (Yi 2023) [Human RCT, n=80].

NAD+ vs NMN in brief: NAD+ is the molecule cells actually use. NMN (nicotinamide mononucleotide) is one step earlier in the pathway, and its availability is a rate-limiting factor in how the body makes NAD+ (Yoshino 2021). Oral NMN has far more human evidence. A 2026 meta-analysis pooled 15 randomized trials and found it well tolerated in the short term, but with no broad metabolic benefit. Direct IV NAD+ has only pilot data. In a 14-person clinic review, the 6 people given IV NAD+ reported moderate to severe side effects during the drip (Reyna 2026) [Human, retrospective, n=14].

All of these are promoted for “mitochondrial health” and energy. None has human trial evidence for general anti-aging use. In a 2026 briefing document, FDA reviewers wrote that they found no clinical studies or human exposure data for MOTS-c by any route.

Item	MOTS-c	SS-31 (elamipretide)	NAD+ / NMN
US FDA status	Not approved; FDA “has not identified any human exposure data” (FDA)	Approved as Forzinity for Barth syndrome (≥30 kg), accelerated approval 2025-09-19 (FDA)	Neither is an approved drug. On 2025-09-29 FDA concluded NMN is not excluded from the dietary-supplement definition (FDA letter)
Compounding (503A)	Withdrawn from Category 2. The advisory committee voted 7–5 (2 abstentions) on 2026-07-23 to recommend listing (as reported by AJMC). HHS published a draft enforcement-discretion policy on 2026-10-30 (Federal Register). Not on the 503A list.	Approved brand product (Forzinity) only; no other SS-31 product is approved	NAD and NADH in Category 1, “under evaluation”, in FDA’s list dated 2026-05-14 (FDA list)
WADA 2026 (2027 List)	Prohibited at all times, S4.4.1 (WADA); no 2027 change listed by USADA	Not named in 2026; from 2027, S0 names “peptides” in general; check Global DRO	Not named; IV infusions over 100 mL per 12 hours are prohibited (M2.2)
Strongest evidence	Animal	Approved label (one rare disease); RCTs elsewhere mostly negative	Human RCT (oral NMN, n up to 80); IV NAD+ pilot only
Human trials	Analog phase 1, no results posted (NCT03998514); no registered trial of MOTS-c itself	Several registered, e.g. phase 3 (NCT03323749)	NMN trials registered on ClinicalTrials.gov (searched 2026-11-05), e.g. NCT03151239
Next regulatory step	HHS comment period closes mid-November 2026; any 503A listing needs a final FDA rule; no date announced	Confirmatory phase 3b/4 trial recruiting; primary completion estimated 2029-09-30 (NCT07531251)	NAD and NADH remain under FDA evaluation for the 503A list; no date announced
Last checked	2026-11-05	2026-11-05	2026-11-05

MOTS-c vs SS-31 vs NAD+ at a glance

Feature	MOTS-c	SS-31	NAD+ / NMN
What it is	16-amino-acid peptide encoded in mitochondrial DNA	Synthetic four-amino-acid peptide (elamipretide)	Coenzyme in every cell; NMN is its precursor; neither is a peptide
Class	Mitochondrial-derived peptide	Cardiolipin binder	Dinucleotide; precursors NMN and NR
Main target	AMPK signaling via the folate cycle (mice, cells)	Cardiolipin in the inner mitochondrial membrane	Co-substrate for many metabolic enzymes
Research focus	Insulin resistance, obesity, age-related decline in mice	Barth syndrome, mitochondrial myopathy, dry AMD, heart failure	Insulin sensitivity, walking and aerobic capacity, Parkinson’s, muscle aging
Human evidence	No published MOTS-c treatment trial	RCTs up to phase 3 (n=218)	NMN: 15 RCTs in a 2026 meta-analysis; IV NAD+: pilots
Approval	None	Forzinity, Barth syndrome only	None as a drug; NMN and NR sold as supplements
WADA	Prohibited (S4.4.1)	Not named	Not named; 100 mL IV rule applies
Routes studied	Subcutaneous (analog trial)	Subcutaneous; single IV infusion; eye drops	Oral NMN and NR; IV NAD+ (pilot)
Timelines in studies	None in humans	Strength gains after the 12-week RCT, in the extension	NAD metabolites up by day 8 (NMN)
Main safety concerns	Unknown in humans; immunogenicity concern	Injection-site reactions; hypersensitivity	Oral: few in short trials; IV NAD+: GI symptoms, chest pressure

What is MOTS-c?

MOTS-c is a 16-amino-acid peptide encoded inside the mitochondrial genome, first described in 2015. In that Cell Metabolism study, MOTS-c prevented age-dependent and diet-induced insulin resistance in mice [Animal]. The body makes it naturally, and exercise raises its levels in human muscle and blood (Reynolds 2021) [Human, observational]. Synthetic MOTS-c has not been tested in a published human trial (FDA briefing). We compare it with another metabolic research compound in MOTS-c vs 5-amino-1MQ, and with an exercise-mimetic in SLU-PP-332 vs MOTS-c.

What is SS-31 (elamipretide)?

SS-31 is the research code for elamipretide, a synthetic four-amino-acid peptide. The Forzinity label describes it as “a mitochondrial cardiolipin binder”. It is indicated “to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kg” [Approved label]. Barth syndrome is a rare, life-threatening mitochondrial disease. The approval is accelerated, so continued approval may depend on a confirmatory trial. That trial, a 48-patient placebo-controlled study with a 72-week primary endpoint, started recruiting in July 2026 (NCT07531251). Every other use, from aging to athletic recovery, is unapproved.

What is NAD+, and how does NMN differ?

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that energy-metabolism enzymes need to work. “NAD” is the general name. FDA’s compounding list names two forms separately: NAD and NADH. NMN and nicotinamide riboside (NR) are “NAD+ intermediates”, molecules the body converts into NAD+. How they move through tissues is “still under intensive investigation” (Yoshino 2018 review). In a 12-month mouse study, oral NMN was quickly turned into NAD+ in tissues and eased age-related decline (Mills 2016) [Animal]. NAD+ itself is also given by IV infusion, which has only pilot data (Grant 2019).

NAD+ vs NMN: which has the evidence?

The two are compared constantly, but no trial has compared them with each other. No randomized trial has tested NMN against NAD+ itself. None of the NMN records on ClinicalTrials.gov compares NMN with NAD+. One recruiting trial compares NMN with NR and two other precursors (NCT06991712) (all searched 2026-11-05). So any “which works better” answer uses numbers from different trials, and those comparisons are cross-trial.

Feature	NAD+ (direct, IV)	NMN (oral)
What reaches the blood	Human pilot n=11: “rapidly and completely removed” from plasma in the first 2 h (Grant 2019)	Human RCT n=32: blood NMN 1.7–3.7 times baseline at day 14 (Pencina 2023)
Effect on NAD+ levels	Retrospective n=14: could not be measured (Reyna 2026)	Human RCT n=80: up at days 30 and 60, p ≤ 0.001 (Yi 2023)
Best outcome result	None from a controlled trial	Human RCT n=25: muscle insulin sensitivity up (Yoshino 2021)
Pooled evidence	None	Meta-analysis of 15 RCTs (Yang 2026)
Reported side effects	Retrospective n=6: GI symptoms, faster heart rate, chest pressure	Meta-analysis: no rise in adverse events or liver enzymes vs placebo
US status	Unapproved; Category 1 (interim) for compounding	Not excluded from the supplement definition (FDA, 2025)

What NMN may offer. In the largest dose-ranging trial, 80 healthy middle-aged adults took NMN or placebo for 60 days (Yi 2023) [Human RCT, n=80]. Blood NAD rose in every NMN group, and six-minute walk distance improved more than on placebo (p < 0.01). In 48 trained runners, six weeks of NMN raised oxygen use at the ventilatory thresholds, though VO2max did not change (Liao 2021) [Human RCT, n=48]. In 60 older adults, 12 weeks of NMN shortened 4-meter walking time and improved sleep-quality scores (Morifuji 2024) [Human RCT, n=60].

Where NMN falls short. The Morifuji trial missed its primary outcome, a stepping test. In 36 middle-aged adults, arterial stiffness did not differ from placebo after 12 weeks (Katayoshi 2023) [Human RCT, n=36]. Across trials, the 2026 meta-analysis found no effect on weight, BMI, fasting glucose, HbA1c, lipids or systolic blood pressure, and only a slight drop in diastolic pressure. A 2025 meta-analysis found no effect of NMN or NR on muscle mass, grip strength or gait speed.

What direct NAD+ shows. In an 11-person pilot, NAD+ infused over 6 hours was rapidly and completely removed from the plasma for at least the first 2 hours. The pattern of breakdown products pointed to enzymes that break NAD+ down (Grant 2019) [Human pilot, n=11]. The only comparison with another form is a records review of 6 IV NAD+ and 8 IV NR patients at a wellness-clinic chain (Reyna 2026). Its authors were employed by the chain, which funded the study, and blood NAD+ changes could not be measured. NR, the other common precursor, has its own small RCTs; its rows in the head-to-head table below come from those.

How they work differently

• MOTS-c: in cells and mice, it inhibits the folate cycle and purine synthesis. That activates AMPK, an energy-sensing enzyme, mainly in skeletal muscle (Lee 2015) [Animal, Lab]. Under metabolic stress, it moves into the cell nucleus and regulates antioxidant-response genes (Kim 2018) [Lab]. FDA reviewers still describe its molecular targets as unknown (FDA briefing).
• SS-31: binds tightly to cardiolipin, a fat in the inner mitochondrial membrane needed for the folds where ATP is made. In rats, it protected those folds during kidney ischemia (Birk 2013) [Lab, Animal].
• NAD+ / NMN: not a signal or a membrane binder but a raw material. Oral NR raised the NAD+ metabolome in the muscle of 12 older men, without changing mitochondrial energy output (Elhassan 2019) [Human RCT, n=12].

Evidence head-to-head

Each cell gives the best evidence level found for that outcome and the study behind it. “None found” means no study of that type turned up on PubMed or ClinicalTrials.gov (searched 2026-11-05). The figures come from different trials, so comparisons across columns are cross-trial, not head-to-head.

Outcome	MOTS-c	SS-31	NAD+ / NMN
Raising NAD+	None found	None found	Human RCT n=80: NMN raised blood NAD (Yi 2023)
Insulin sensitivity	Animal: prevented insulin resistance in mice (Lee 2015)	None found	Human RCT n=25: NMN +25% (Yoshino 2021); RCT n=40: NR no effect (Dollerup 2018)
Physical function	Animal: better performance in young, middle-aged and old mice (Reynolds 2021)	Human RCT n=218: no gain in walk distance (MMPOWER-3)	Human RCT n=80: longer 6-minute walk (Yi 2023); meta-analysis: no muscle benefit (Prokopidis 2025)
Muscle energetics	None found in humans	Human RCT n=39: ATP capacity up after one infusion, gone by day 7 (Roshanravan 2021)	Human RCT n=12: NR, no change (Elhassan 2019)
Heart	None found in humans	Human RCT n=71: no change in heart volumes in HFrEF (PROGRESS-HF)	Animal: NMN restored systolic function in old mice (Whitson 2020)
Rare mitochondrial disease	None found	Approved label: Barth syndrome (Forzinity label)	Human, open-label: niacin raised NAD+ and strength in mitochondrial myopathy (Pirinen 2020)
Dry macular degeneration	None found	Human RCT n=176: primary endpoints missed (ReCLAIM-2)	None found
Brain	None found	None found	Human RCT n=30: NR raised brain NAD in Parkinson’s (NADPARK)
Safety data	None in humans (FDA)	Approved label; injection-site redness in 12 of 12 patients	Meta-analysis of 15 RCTs (10 with safety data): no rise in adverse events (Yang 2026)

The Barth syndrome evidence deserves a closer look. In the label’s clinical studies section, the randomized crossover trial in 12 patients missed both primary endpoints, the 6-minute walk and a fatigue score [Human RCT, n=12]. In the open-label extension, 8 patients reached week 168, with a median knee-strength gain of 63 newtons. The TAZPOWER extension paper reported a 96.1-meter total improvement in walk distance by week 168 [Human, open-label, n=10]. The study was funded by the manufacturer, Stealth BioTherapeutics. Uncontrolled extensions can overstate benefit, which is why the confirmatory trial matters.

Which fits which goal?

These are evidence statements, not recommendations to use any of them.

• Barth syndrome: SS-31 has the only regulatory-grade evidence, an accelerated approval based on muscle strength (FDA).
• Raising NAD+ levels: oral NMN has the most evidence, from several RCTs (Yi 2023). IV NAD+ has pilot data only, and no trial has compared the two.
• Insulin sensitivity: NAD+ precursors have more human evidence: one positive NMN trial (Yoshino 2021) and one null NR trial (Dollerup 2018). MOTS-c has mouse data only.
• SS-31 vs MOTS-c for muscle and endurance: SS-31 has human trials, but its phase 3 in mitochondrial myopathy found no gain in walk distance (MMPOWER-3). MOTS-c’s performance data are from mice (Reynolds 2021). Neither has shown a benefit in people with healthy muscles.
• Weight loss: none has human weight-loss evidence, and the NMN meta-analysis found no effect on body weight (Yang 2026). FDA reviewers noted that approved obesity drugs exist (FDA briefing). We compare those drugs in retatrutide vs tirzepatide vs semaglutide.
• Aging in general: all rest on animal data for this goal. A small open-label elamipretide study in older adults is recruiting (NCT07275424).

Whether any of these is appropriate is for a clinician who knows the person’s history to decide.

Can they be combined?

Clinic and vendor pages often present these as a “mitochondrial stack”, and NAD+ drips are often paired with oral NMN. The only direct test of a combination was in animals. In old mice, SS-31 partly reversed a decline in diastolic heart function and NMN reversed a deficit in systolic function. Together, they raised resting NAD(H) levels more than either did alone, which the authors called synergistic (Whitson 2020) [Animal]. No controlled human study of any combination of MOTS-c, SS-31, NAD+ and NMN was found on PubMed or ClinicalTrials.gov (searched 2026-11-05). Interactions and combined side effects are unknown.

Safety and regulatory status

United States: FDA and HHS

• MOTS-c: not approved. It is listed among substances withdrawn from Category 2 by their nominators (FDA). FDA’s reviewers proposed not adding it to the 503A bulks list, citing immunogenicity concerns for an injected 16-amino-acid peptide (FDA briefing). The advisory committee then voted 7–5 with 2 abstentions to recommend listing, as reported by AJMC. That advice is non-binding, and FDA had posted no vote summary at our 2026-11-05 check (FDA meeting page). On 2026-10-30, HHS published a draft enforcement-discretion policy (Federal Register 2026-22192). It says HHS “does not intend to take enforcement action against a State-licensed pharmacy, Federal facility, or licensed physician” compounding the peptides in its appendix. NCPA and AJMC report that MOTS-c is one of the six listed. The policy is not binding, and HHS may revisit it if “a safety signal or product quality issue arises.” Listing still requires rulemaking (FDA 503A page). We explain the background in our FDA peptide compounding vote explainer.
• SS-31: approved only as Forzinity. The label warns of hypersensitivity reactions, including serious allergic reactions that need emergency care. It also warns of benzyl alcohol toxicity in newborns and is not approved for neonates. Injection-site reactions were the most common side effects.
• NAD+ and NMN: NAD and NADH are in 503A Category 1, “under evaluation” (FDA list). That is an interim enforcement policy, not an approval. In 2025, FDA concluded that NMN is not excluded from the dietary-supplement definition (FDA letter). That is a decision about legal category, not a review of safety or effectiveness.

Sport: WADA and USADA

• MOTS-c is named in S4.4.1 (AMPK activators) of the 2026 Prohibited List and is prohibited at all times. USADA adds that it is not FDA-approved for use in humans.
• SS-31 is not named on the 2026 List. The 2027 List, in force from 2027-01-01, names “peptides” in general under S0 (USADA 2027 advisory). Because elamipretide has a US approval, its status is not obvious. Athletes should check Global DRO or their anti-doping agency.
• NAD+ and NMN are not named. WADA method M2.2 prohibits IV infusions or injections of more than 100 mL per 12 hours outside hospital and similar settings, “even if the substance being injected or infused is permitted” (USADA).

What is known about side effects

For MOTS-c, safety in humans is unknown (FDA briefing, above). For elamipretide, the label’s safety table shows injection-site redness in 12 of 12 patients on the drug versus 3 of 12 on placebo, and injection-site pain in 9 versus 5. The phase 3 myopathy trial found most adverse events mild to moderate (MMPOWER-3). For oral NMN, a meta-analysis of RCTs lasting 14 days to 24 weeks found no rise in adverse events or liver enzymes (Yang 2026). Its authors still call for “larger and longer trials” to confirm long-term safety. For IV NAD+, the 6 patients in the clinic review reported “moderate to severe gastrointestinal symptoms, increased heart rate, and chest pressure” during infusions that averaged 97 minutes. The symptoms resolved when the infusions ended (Reyna 2026) [Human, retrospective, n=6].

Anyone who suspects a side effect from MOTS-c, SS-31, NAD+, NMN or any other drug or product can report it to the FDA through MedWatch.

How long do effects take in studies?

• SS-31: in Barth syndrome, knee-strength gains were not seen in the 12-week randomized phase. They appeared during the extension, measured from week 12 to week 168 (Forzinity label). A single infusion raised muscle ATP capacity at once, with no difference by day 7 (Roshanravan 2021).
• NMN and NR: NAD metabolites were higher by day 8 of NMN (Pencina 2023), and blood NAD was up at day 30 (Yi 2023). NR raised muscle NAD+ markers within 21 days (Elhassan 2019). The insulin-sensitivity change was measured after 10 weeks (Yoshino 2021).
• MOTS-c: no human timeline exists, and no trial of MOTS-c itself is registered.