Rhabdomyolysis: Does Caffeine or Creatine Increase Your Risk?
I’m a Tufts University alumna and so my algorithm quickly spotlighted the lacrosse team’s “voluntary, supervised 45-minute workout with a Navy SEAL graduate” that resulted in three athletes being hospitalized for rhabdomyolysis. (1)
What increasingly caught my attention was within the CNN Health article that quoted a sports physician doctor: “certain nutritional supplements, including increased caffeine and creatine, can add to the risk of rhabdomyolysis.” (1) Really?
So, in this article, I’m going to review:
What rhabdomyolysis is.
Research connecting rhabdo with caffeine.
Research connecting rhabdo with creatine.
What is Rhabdomyolysis?
It’s the excessive breakdown of muscle cells, allowing its inner parts to leach out into circulation (the bloodstream) and the area immediately outside the muscle cell (the extracellular fluid). Upon hospital admission, blood markers used to track rhabdo involve electrolytes and those supposed-to-be-in-the-muscle-cell components, including myoglobin, creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), aldolase, and alanine. (2) Although there is no defined diagnostic value for CK in the presence of rhabdo, values ranging from 1,500 to greater than 100,000 IU/L have been measured, with normal limits being 100-400 IU/L. (2,3)
Rhabo is a serious medical condition that is life threatening, resulting in hospitalization and aggressive rehydration with IV fluids and/or dialysis. The rush of fluids is to help protect the kidneys from damage.
Humans have two kidneys that function to filter the blood. Kidneys can retain molecules and return them into circulation or filter molecules out into the urine and out of the body. In rhabdo, the kidneys cannot filter the damaged muscle cell contents fast enough, resulting in kidney damage.
One of the causes of rhabdo is intense, unaccustomed exercise resulting in muscle weakness, muscle pain, localized swelling, and possibly a dark, coffee-colored urine (occurs in only ≤10% of cases). (3) Along with the unaccustomed exercise, the risk of rhabdo is increased in a “hot environment especially where dehydration is a factor.” (4)
Exercise aside, there are plenty of other causes of rhabdomyolysis. You can read more about those here: https://www.ncbi.nlm.nih.gov/books/NBK448168/
What Does the Research Say? Caffeine and Rhabdo
Read more about caffeine and daily doses in an article I’ve previously written.
I was able to find 11 case reports connecting caffeine with rhabdomyolysis:
5/11 involved a suicide attempt.
4/11 involved intense exercise.
2/11 involved an effort to stay awake at night or schizophrenia with water intoxication and hyponatremia (clinically low levels of circulating sodium in the bloodstream).
Case Study | Reason for Consuming Caffeine | Caffeine Dose | Caffeine Source |
Wrenn & Oschner (1989) (6) | Suicide attempt. | 3.57 grams | 10 Magnesium 357 tablets (each contained 357 milligrams caffeine) |
Michaelis et al. (1991) (5) | Suicide attempt. | 1.45 grams | 29 Spalt N tablets (also contained phenazone and acetaminophen)
|
Campana et al. (2014) (7) | Suicide attempt. The male suffered from schizophrenia and caffeine pill abuse.
| 24 grams | 120 No-Doz tablets (each contained 200 milligrams caffeine)
|
Emohare & Ratnam (2006) (8) | Suicide attempt. The male overdosed on caffeine and a self-inflicted gunshot wound.
| 17.5 grams | Pro-plus (caffeine-containing stimulant) |
Chakraborty & Rajeswaran (2007) (5) | Suicide attempt. | 15 grams | Over-the-counter stimulant |
Chiang et al. (2014) (5) | To stay awake during the night. | 0.565 grams | 1-liter of black coffee
|
Kamijo et al. (1999) (5) | Schizophrenia. Water intoxication and hyponatremia also existed. | 3 grams | 15 liters of oolong tea
|
Sung et al. (2018) (9) | Prior to exercise. The male “showed a relatively high sensitivity to caffeine” | 0.45 grams | 1.362 liters of S’s coffee within 30 minutes of starting his exercise routine (had been doing resistance training for 1 hour, 4 days per week, for at least the past year)
|
Ryu et al. (2016) (10) | Caffeine consumed prior to a hard intensity spin class. | The value was not provided by the authors. | Ephedra-containing herbal medicine marketed for weight loss consumed before the spin class.
|
Tinawi (2022) (11) | Caffeine consumed prior to a strenuous workout program with heavy weightlifting, and heavier than normal during this session.
| 0.375 grams | A single energy drink (the brand was not noted by the authors). Other ingredients: dicaffeine malate (100 mg), citrulline malate (6 g), beta-alanine (3.2 g), taurine (1 g), agmatine sulfate (1 g), cocophenols (25 mg). |
Iyer at al. (2016) (12) | Caffeine consumed prior to a 2-hour workout (weightlifting and treadmill running) and in the presence of mild dehydration. The patient had not exercised in the past year and had progressively gained weight. | 0.160 grams | A single energy drink, Neon Volt brand. Other ingredients: beta-alanine (1.6 g), L-citrulline (0.5 g), agmatine sulfate (0.25 g), bitter orange (50 mg), rhodiola rosa (40 mg), olive (25 mg), NADH (1.6 mg) |
Lethal oral doses of caffeine have been documented above 10-gram doses. (7)
Besides the intentional overdose and suicidal attempts, the case report by Chiang et al. (2014) stood out to me based on the lower dose of 0.565 grams, which is the equivalent to 32 ounces or two Starbucks grande coffees. (5) Five of the case studies list over-the-counter drugs with known doses per tablet, whereas a brewed coffee or tea is harder to quantify. With emergency department case reports (and the reliance on published case studies), self-reported information from the patient is recorded. I’m hesitant to believe that a lower dose compared to the other cases fully resulted in the rhabdo, but the authors reported no other sources of caffeine or medical concerns.
For those involving energy drinks, who knows if the caffeine dose listed on the drink’s label is accurate. This is why sport dietitians recommend third-party certified products. Certifiers like Informed-Sport and NSF Certified for Sport test every lot produced for a supplement. They test to ensure the ingredients and doses listed on a label are accurate, and that other ingredients, allergens, or banned substances aren’t within the product. I've written previously about third party certification, which you can read here.
Public health and sport nutrition recommendations for caffeine intakes differ, with no minimum daily dose being recommended—only a maximum. Sticking with public health recommendations of no more than 400 milligrams caffeine per day is likely sound.
Take-home messages for caffeine:
1-2 cups of coffee a day probably won’t result in a hospital admission for rhabdo.
If consuming caffeine within a preworkout powder or energy drink, choose a third-party certified option.
Be mindful of caffeine sensitivity: Sung et al (2018) wrote that “a person who has a relatively high caffeine sensitivity or combines exercise and high caffeine intake for weight loss should be made aware of the risks for rhabdomyolysis.” (9) Fair, given their case's low tolerance for caffeine.
What Does the Research Say? Creatine and Rhabdo
Rawson et al. (2017) reviewed the literature on this topic to better understand creatine’s role in the presence of exertional rhabdomyolysis—to which they found it did not. (4) An overarching argument stemmed from creatine’s protective effect against rhabdo.
Resistance Exercise
Rawson et al. (2007), Machado et al. (2009), Veggi et al. (2013) evaluated creatine supplementation’s effect on recovery from high-intensity weightlifting workouts. Creatine doses ranged from 2-20 daily grams. Collectively, the studies showed either zero effect or a reduction in markers of CK, LDH, muscle soreness, swelling, and range of motion. (4,14-16)
Endurance Exercise
Granted, endurance exercise typically isn’t a “clinically relevant” driver of rhabdo cases. Studies from Bassit et al. (2008, 2010), Deminice et al. (2013), and Santos et al (2004) monitored participants having completed half- and full-distance Ironman triathlons, six 35-meter sprints, or a 30-km race who had been supplementing with daily creatine doses of ~20 grams*. In the presence of rhabdo, certain blood markers would be expected to increase (e.g., CK, LDH), yet researchers found these markers to have been reduced—meaning creatine supplementation reduced markers of muscle damage and inflammation. (4, 17-20)
*Deminice et al. (2013) used 0.3 g/kg creatine. For reference, this would be ~20 grams creatine for a 150-lb. person. (19)
Case Studies: Creatine Supplementation in the Presence of Rhabo
Rawson et al. (2017) found six case studies in the literature connecting rhabdo cases with creatine supplementation. They collectively concurred that the cases “occurred in young men performing the most common known factor to induce rhabdomyolysis (unaccustomed, heavy exercise) and some were taking other drugs accepted by the FDA as being linked to adverse cardiovascular events (ephedrine), the link with creatine use is highly tenuous, circumstantial, and the likely reason why rational scientific evaluations have not implicated creatine use even in extreme cases of death after excessive exercise and/or dehydration.” (4)
The below table is from that paper. Of the six studies, half did not list a dose for creatine (so...), one listed a dose not currently recommended (25 grams/day), and all occurred in the presence of new or intense exercise (four of the six cases had unknown training histories). (4)
Along the right-hand side of the table, references are [144] = Robinson et al. (2000) (21), [23] = Kuklo et al. (2000) (22), [145] = Sandhu et al. (2002) (23), [146] = Sheth et al. (2006) (24).
Take-home messages for creatine:
Creatine is unlikely connected with increased risk of rhabo and is more likely to protect muscles from damage, soreness, and inflammation.
Reasonable, science-based recommendations for creatine include:
A possible loading phase 20 grams/day (or 0.3 g/kg) for 5-7 days followed by 3-5 grams daily (upwards of 10 grams for larger athletes),
Beginning with 3-5 grams daily, or
Beginning with 0.1 g/kg bodyweight (for a 150-pound person, this would be ~7 grams daily. (25,26)
References
(1) Watson, M. (2024, September 24). 3 Tufts University lacrosse players remain hospitalized after workout with Navy SEAL graduate. CNN Health. https://www.cnn.com/2024/09/23/health/five-tuftsuniversity-students-remain-hospitalized-afternavy-seal-style-workout/index.html
(2) Stanley, M., Chippa, V., Aeddula, N.R., Rodriguez, B.S.Q., & Adigun, R. Rhabdomyolysis. [Updated 2023 April 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448168/
(3) Bhai, S., & Dimachkie, M.M. (2024). Rhabdomyolysis: clinical manifestations and diagnosis. UpToDate. Retrieved September 25, 2024, from https://www.uptodate.com/contents/rhabdomyolysis-clinical-manifestations-and-diagnosis
(4) Rawson, E.S., Clarkson, P.M., & Tarnopolsky, M.A. (2007). Perspectives on exertional rhabdomyolysis. Sports Med,47(Suppl 1):33-49. https://pubmed.ncbi.nlm.nih.gov/28332112/
(5) Chiang, W.F., Liao, M.T., Cheng, C.J., & Lin, S.H. (2014). Rhabdomyolysis induced by excessive coffee drinking. Hum Exp Toxicol,33(8):878-881. https://pubmed.ncbi.nlm.nih.gov/24220878/
(6) Wrenn, K.D., & Oschner, I. (1989). Rhabdomyolysis induced by a caffeine overdose. Ann Emerg Med,18(1):94-97. https://pubmed.ncbi.nlm.nih.gov/2642675/
(7) Campana, C., Griffin, P.L., & Simon, E.L. (2014). Caffeine overdose resulting in severe rhabdomyolysis and acute renal failure. Am J Emerg Med,32(1):111. https://pubmed.ncbi.nlm.nih.gov/24079989/
(8) Emohare, O., & Ratnam, V. (2006). Multiple cardiac arrests following an overdose of caffeine complicated by penetrating trauma. Anaesthesia,61(1):54-56. https://pubmed.ncbi.nlm.nih.gov/16409343/
(9) Sung, D.J., Choi, E.J., Kim, S., & Kim, J. (2018). Rhabdomyolysis from resistance exercise and caffeine intake. Iran J Public Health,47(1):138-139. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756592/
(10) Ryu, H., Kim, H.S., Choi, H., Kim, J., & Sung, D.J. (2016). Rhabdomyolysis from spinning exercise and ephedra-contained herbal medicine. J Sport Health Sci,5(2):248-249. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188734/
(11) Tinawi, M. (2022). Severe rhabdomyolysis due to strenuous exercise with a potential role of a high-caffeine energy drink. Cureus,14(1):e20867. https://pubmed.ncbi.nlm.nih.gov/35145774/
(12) Iyer, P.S., Yelisetti, R., Miriyala, V., Siddiqui, W., & Kaji, A. (2016). A remarkable case of rhabdomyolysis associated with ingestion of energy drink 'neon volt'. J Community Hosp Intern Med Perspect,6(5):32528. https://pubmed.ncbi.nlm.nih.gov/27802855/
(14) Rawson, E.S., Conti, M.P., & Miles, M.P. (2007). Creatine supplementation does not reduce muscle damage or enhance recovery from resistance exercise. J Strength Cond Res,21(4):1208-1213. https://pubmed.ncbi.nlm.nih.gov/18076246/
(15) Machado, M., Pereira, R., Sampaio-Jorge, F., Knifis, F., & Hackney, A. (2009). Creatine supplementation: effects on blood creatine kinase activity responses to resistance exercise and creatine kinase activity measurement. Braz J Pharm Sci,45(4):751-757.
(16) Veggi, K.F., Macahdo, M., Koch, A.J., Santana, S.C., Oliveria, S.S., & Stec, M.J. (2013). Oral creatine supplementation augments the repeated bout effect. Int J Sport Nutr,23(4):378-87. https://pubmed.ncbi.nlm.nih.gov/23349298/
(17) Bassit, R.A., Curi, R., & Costa Rosa, L.F. (2008) Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids,35(2):425-431. https://pubmed.ncbi.nlm.nih.gov/17917696/
(18) Bassit, R.A., Pinheiro, C.H., Vitzel, K.F., Sproesser, A.J., Silveira, L.R., & Curi, R. (2010). Effect of short-term creatine supplementation on markers of skeletal muscle damage after strenuous contractile activity. Eur J Appl Physiol,108(5):945-955. https://pubmed.ncbi.nlm.nih.gov/19956970/
(19) Deminice, R., Rosa, F.T., Franco, G.S., Jordao, A.A., & de Freitas, E.C. (2013). Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition,29(9):1127-1132. https://pubmed.ncbi.nlm.nih.gov/23800565/
(20) Santos, R.V.T., Bassit, R.A., Caperuto, E.C., & Costa Rosa, L.F.B.P. (2004). The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci,75(16):1917-1924. https://pubmed.ncbi.nlm.nih.gov/15306159/
(21) Robinson, T.M., Sewell, D.A., Casey, A., Steenge, G., & Greenhaff, P.L. (2000). Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function. Br J Sports Med,34(4):284-288. https://pubmed.ncbi.nlm.nih.gov/10953902/
(22) Kuklo, T.R., Tis, J.E., Moores, L.K., & Schaefer, R.A. (2000). Fatal rhabdomyolysis with bilateral gluteal, thigh, and leg compartment syndrome after the Army Physical Fitness Test. A case report. Am J Sports Med,28(1):112-116. https://pubmed.ncbi.nlm.nih.gov/10653554/
(23) Sandhu, R.S., Como, J.J., Scalea, T.S., & Betts, J.M. (2002). Renal failure and exercise-induced rhabdomyolysis in patients taking performance-enhancing compounds. J Trauma,53(4):761-763. https://pubmed.ncbi.nlm.nih.gov/12394880/
(24) Sheth, N.P., Sennett, B., & Berns, J.S. (2006). Rhabdomyolysis and acute renal failure following arthroscopic knee surgery in a college football player taking creatine supplements. Clin Nephrol,65(2):134-137. https://pubmed.ncbi.nlm.nih.gov/16509464/
(25) Kreider, R.B., Kalman, D.S., Antonio, J., Ziegenfuss, T.N., Wildman, R., ... & Lopez, H.L. (2017). International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr,14:18
(26) Cooper, R., Naclerio, F., Allgrove, J., & Jimenez, A. (2012). Creatine supplementation with specific view to exercise/sports performance: an update. J Int Soc Sports Nutr,9(1):33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407788/
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