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MOTS-c Caffeine Interaction Profile: What You Need to Know Before Combining Them

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At a glance

  • Published interaction data / none; no human exposure data for MOTS-c [1]
  • Where MOTS-c effects have been shown / cells and mice only [2][3]
  • Caffeine main clearance enzyme / CYP1A2, an FDA clinical index substrate [4][5]
  • Caffeine half-life, healthy non-smokers / group means about 3.4 to 6.2 hours [6][7][8]
  • MOTS-c regulatory status / not FDA-approved; absent from FDA's pharmacy list [9][10][11]

What is known about MOTS-c?

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, first described in Cell Metabolism in 2015 [2]. In mice it prevented diet-induced obesity and insulin resistance and activated AMPK in skeletal muscle [2]. Later mouse work found better physical capacity with age, and intermittent treatment started late in life lengthened median lifespan from 912 to 970 days [1][3].

In people, FDA found no clinical study in which MOTS-c was given to a human; the 12 papers the nominator cited were not clinical studies [1]. Human work covers only the body's own MOTS-c: exercise raises it, and a randomized study of 30 healthy adults found only a trend toward higher circulating MOTS-c after endurance exercise [3][12].

MOTS-c is not an FDA-approved drug, and FDA found no pharmacokinetic data for it in humans or live animals; the one kinetic observation is rapid breakdown in human blood in vitro [1]. Its safety in people is unknown: FDA's adverse-event database through March 9, 2025 held no MOTS-c reports, and there are no human exposure or animal toxicity studies [1]. For injected peptides, FDA's stated concern is immunogenicity from aggregates and peptide impurities [1].

How does caffeine behave?

Caffeine is cleared mainly by CYP1A2, which FDA lists as a clinical index substrate for that enzyme [4][5]. Group mean half-lives in healthy non-smokers run about 3.4 to 6.2 hours [6][7][8]; in one 26-person comparison, smokers averaged 3.5 hours and non-smokers 6.0 hours [13].

Strong CYP1A2 inhibition changes this sharply: with fluvoxamine, median total clearance fell from 107 to 21 mL/min and median half-life rose from 5 to 31 hours in 8 volunteers [14]. FDA cites 400 mg a day as an amount not generally associated with negative effects in most adults, roughly two to three 12-fluid-ounce cups of coffee, while noting wide variation in sensitivity and clearance [15].

Do the two overlap on AMPK?

Both touch AMPK, but not in the same setting. In the discovery paper, MOTS-c's cellular actions inhibited the folate cycle, leading to AMPK activation, with skeletal muscle as its main target in mice [2]. Caffeine raised AMPK phosphorylation in incubated rat muscle at bath concentrations of 3 mmol/L or more [16]. These are separate findings in different animal tissues, not a test of the two together.

Bottom line

Caffeine has human pharmacokinetic data; MOTS-c has never been given to a person in a published study [4][1]. Claims about how the two behave together are inference, not measurement.

Frequently asked questions

Is there a known interaction between MOTS-c and caffeine?
No interaction has been measured. FDA found no published study in which MOTS-c was given to a person at all [1], so any statement about how caffeine affects MOTS-c is inference.
Does caffeine cancel out MOTS-c?
That has not been measured. A change in MOTS-c's effects from caffeine has been neither shown nor excluded.
How long does caffeine stay in the body?
Mean elimination half-life in healthy non-smokers is about 3.4 to 6.2 hours across studies [6][7][8]. Strong CYP1A2 inhibition lengthens it far more: with fluvoxamine the median half-life went from 5 to 31 hours [14].
Is MOTS-c approved or legal to compound?
MOTS-c is not an FDA-approved drug and appears in none of the three categories on FDA's list for state-licensed pharmacies [9][10][11]. A draft HHS enforcement-discretion policy names MOTS-c acetate and says HHS does not intend to take enforcement action under stated conditions, but the draft is not an approval, does not put MOTS-c on an FDA list and is not binding [17][18].
Will MOTS-c show up in anti-doping testing?
WADA names MOTS-c in section S4.4.1 as a metabolic modulator, prohibited at all times in and out of competition, and it stays on the 2027 List [19][20].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-54. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
  3. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
  4. Kot M, Daniel WA. Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat. Pharmacol Rep. 2008;60(6):789-97. Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat
  5. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA
  6. Abernethy DR, Todd EL. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. Eur J Clin Pharmacol. 1985;28(4):425-8. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives
  7. Patwardhan RV, Desmond PV, Johnson RF, Schenker S. Impaired elimination of caffeine by oral contraceptive steroids. J Lab Clin Med. 1980;95(4):603-8. Impaired elimination of caffeine by oral contraceptive steroids
  8. Knutti R, Rothweiler H, Schlatter C. Effect of pregnancy on the pharmacokinetics of caffeine. Eur J Clin Pharmacol. 1981;21(2):121-6. Effect of pregnancy on the pharmacokinetics of caffeine
  9. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  10. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  11. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA. Bulk Drug Substances Used in Compounding of the FD&C Act | FDA
  12. von Walden F, Fernandez-Gonzalo R, Norrbom J, Emanuelsson EB, Figueiredo VC, Gidlund EK, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021;131(3):1035-1042. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans
  13. Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther. 1978;24(1):40-5. Effect of smoking on caffeine clearance
  14. Jeppesen U, Loft S, Poulsen HE, Brśen K. A fluvoxamine-caffeine interaction study. Pharmacogenetics. 1996;6(3):213-22. A fluvoxamine-caffeine interaction study
  15. Spilling the Beans: How Much Caffeine is Too Much? | FDA. Spilling the Beans: How Much Caffeine is Too Much? | FDA
  16. Egawa T, Hamada T, Kameda N, Karaike K, Ma X, Masuda S, et al. Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles. Metabolism. 2009;58(11):1609-17. Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles
  17. Official web page. Official web page
  18. Official web page. Official web page
  19. World Anti-Doping Agency. World Anti-Doping Agency
  20. World Anti-Doping Agency. World Anti-Doping Agency
Evidence overview for MOTS-c Caffeine Interaction Profile: What You Need to Know Before Combining Them