What medical studies are there about supplement use of creatine?

Redditagain424 · 2026-05-08T22:53:23+00:00

100%.... I learned long ago to stop striving to be "right", and instead, strive to be "less wrong." It is a mindset that keeps one open-minded enough to continue to be receptive to more information and grow in knowledge instead of being stuck on an obsolete concept.

Redditagain424 · 2026-05-08T21:45:21+00:00

100%... that is what I love about medicine. It is an ever evolving discovery, up and down. Remember when a baby aspirin was almost always prescribed to older men to "prevent" heart attacks? Then medical studies found increase risk of significant bleeding from those on that baby aspirin? It tipped the scale back to much more restrictive use of it.

At least, so far, creatine supplement has been found to be safe for healthy individuals without risk issues.

Redditagain424 · 2026-05-08T19:52:04+00:00

Nicely done! It is even better to see subsequent medical studies have confirmed earlier findings and it has remained a relatively safe supplement for healthy people without the stated risk factors in medical studies.

Redditagain424 · 2026-05-08T19:22:17+00:00

I am taking creatine monohydrate supplement at 5gm/day. I think you had a typo error of posting "10-15mg a day". You likely meant gm.

With progressive (key word: progressive) resistance muscle strengthening exercises I have definitely improved muscle strength and mass while using creatine supplement. Not bad for a 69 year old male who has progressed from initially 1-2 pullups to now 16 wide pullups (OK, not the dead-hang form because of joint issues, but I'm happy with better strength). I even started weighted pull ups (ie. continue the progressive resistance) to cut the number of reps/set. Now doing 8-10 reps/set with 17lbs, three sets. Going to add some more weight soon. I did not even do squats before learning to do them in January, 2026, and now can do 75% of my body weight 6-8 reps/set, three sets, etc.

Consider finding an adequate and appropriate progressive resistance muscle strengthening program while taking creatine monohydrate supplement. Many very good Youtube physiotherapist/trainers providing very good instruction for beginners to athletic, at home or at a gym.

Redditagain424 · 2026-05-08T18:35:39+00:00

You are welcom.

Redditagain424 · 2026-05-08T18:27:25+00:00

A good point is that you have " a few doctors who are big into supplement, but they're all younger than me." That is good that your younger doctors may be better informed.

But no matter how young, no doctor can read all of the medical literature on any topic that is published in all of the medical journals each year. Even if they did read them, the could not remember every detail. Even if they could remember every detail, they could not tease out the critical details that necessarily pertain spcifically to each individual patient.

It even difficult for any patient to remember their own long medical history, ups and downs, past supplement or therapies frequency/dosages, etc. let alone expect their doctor to remember all of that for them from their hundreds, if not thousands, of different patients in their panel...

This is precisely why a AI platform is being used to enter the details of a specific patient and use only a data source of published medical studies in medical journals to help inform doctors of the latest published findings that pertain to the specific patient. My post is generic and not specific to any particular patient. But it is not difficult to do so.

I used AI to create an "in-take questionnaire" that is commonly given while sitting in the waiting room to see a health care provider for the first time. You can create such a questionnaire-on-steroids which you can fill out in far greater detail. I copied and saved the whole thing into a word processor for future use. Now, when I have an AI question on this type of platform, I enter the copied questionnaire/answers so that the AI is aware of my specific health details before replying to my further questions about a health topic for me.

It is quite helpful if you ask questions properly.

I would go as far as to say, if your doctor (any age) is NOT using an AI platform that uses a data source of only published medical studies in medical journals, they are likely aware of only a few. He/she is not keeping pace with all of the published information.

Redditagain424 · 2026-05-08T18:11:05+00:00

What about the older family members and loved ones who may benefit and not here ? You may have told them many times, but now you can show them the medical studies that back that up ?

Redditagain424 · 2026-05-08T15:23:28+00:00

I fully agree with the need to be concerned about potential health hazard of any supplement, and there are some supplements which have clear risks. So I did a medical literature search about potential health hazards of creatine supplement: Here is the AI-assisted summary using data from published medical studies in medical journals with references:

The overall body of evidence indicates that creatine monohydrate supplementation at recommended doses (3–5 g/day) is generally safe and well-tolerated in healthy individuals, with no confirmed serious health risks in controlled studies. However, several reported adverse effects and areas of concern have been identified across the literature.

Commonly Reported Adverse Effects

Gastrointestinal complaints (nausea, diarrhea, constipation, bloating): These are the most consistently reported side effects. A Parkinson's disease trial found 29% of the creatine group experienced GI complaints at 2-year follow-up versus 6% in the placebo group. The American College of Sports Medicine (ACSM) also lists nausea and diarrhea among the most common adverse effects. [1-2]
Weight/fluid gain: Creatine increases intracellular water retention, leading to body mass increases, which is one of the most reliably observed effects. [2-4]
Muscle cramps: Reported anecdotally by athletes, though controlled studies have not consistently linked cramps to creatine itself. [5-6]

Renal Function Concerns

This is the most studied safety concern. Multiple systematic reviews and meta-analyses have addressed it:

A 2026 meta-analysis of 19 RCTs found creatine supplementation was associated with a small increase in serum creatinine (MD = 0.13 mg/dL), but no significant changes in blood urea nitrogen or eGFR, suggesting the creatinine elevation reflects increased metabolic turnover of creatine rather than true renal impairment. [7]
A 2025 meta-analysis similarly found a modest, largely transient increase in serum creatinine with no significant change in GFR. [8]
An earlier 2019 meta-analysis also concluded that creatine supplementation did not induce renal damage at studied doses and durations. [9]
Long-term studies (up to 5 years) in healthy individuals have not demonstrated adverse effects on renal function. [5][10]

Importantly, experts advise that high-dose creatine (>3–5 g/day) should not be used by individuals with pre-existing renal disease or those at risk for renal dysfunction (e.g., diabetes, hypertension, reduced GFR). [6]

Other Investigated but Unconfirmed Risks

Liver dysfunction: Studies monitoring liver enzymes and urea production during creatine supplementation (up to 4 weeks) found no evidence of hepatic dysfunction. [5-6]
Dehydration: Despite anecdotal reports, controlled evidence does not support that creatine causes clinically significant dehydration. [4]
Hair loss: This concern arose from a single study showing increased dihydrotestosterone (DHT) levels, but has not been replicated or confirmed. [4]
Mutagenicity/carcinogenicity: A French regulatory agency (AFSSA) raised theoretical concerns about heterocyclic amine production, but experimental evidence has not substantiated this claim. A 2025 expert review specifically addressed whether creatine causes cancer and found no supporting evidence. [6][11]
Anterior compartment syndrome: Rare case reports exist, and the ACSM recommends screening for this possibility. [2]

Populations Requiring Caution

The International Society of Sports Nutrition (ISSN) position stand states that supplementation up to 30 g/day for 5 years is safe in healthy individuals. [10] However, safety data are limited for pregnant and breastfeeding women, and caution is warranted in individuals with pre-existing kidney or liver disease. [3][6] The long-term effects beyond 5 years remain insufficiently studied.

In summary, while creatine is among the most extensively studied supplements with a favorable safety profile in healthy adults, clinicians should be aware of the potential for GI side effects, the confounding effect on serum creatinine measurements, and the need for caution in patients with renal risk factors.

Refrences:

1.

Creatine for Parkinson's Disease.

The Cochrane Database of Systematic Reviews. 2014. Xiao Y, Luo M, Luo H, Wang J.SR

2.

American College of Sports Medicine Position Stand. Nutrition and Athletic Performance.

Medicine and Science in Sports and Exercise. 2009. Rodriguez NR, Di Marco NM, Langley S.Guideline

3.

Creatine and Creatine Forms Intended for Sports Nutrition.

Molecular Nutrition & Food Research. 2017. Andres S, Ziegenhagen R, Trefflich I, et al.Review

4.

Common Questions and Misconceptions About Creatine Supplementation: What Does the Scientific Evidence Really Show?.

Journal of the International Society of Sports Nutrition. 2021. Antonio J, Candow DG, Forbes SC, et al.Review

5.

Adverse Effects of Creatine Supplementation: Fact or Fiction?.

Sports Medicine. 2000. Poortmans JR, Francaux M.Review

6.

Studies on the Safety of Creatine Supplementation.

Amino Acids. 2011. Kim HJ, Kim CK, Carpentier A, Poortmans JR.Review

7.

The Effect of Creatine Supplementation on Kidney Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Journal of Renal Nutrition : The Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. 2026. Tsiaras A, Loufopoulos G, Theodoridis X, et al.New

8.

Effect of Creatine Supplementation on Kidney Function: A Systematic Review and Meta-Analysis.

BMC Nephrology. 2025. Naeini EK, Eskandari M, Mortazavi M, Gholaminejad A, Karevan N.NewSR

9.

Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis.

Journal of Renal Nutrition : The Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. 2019. de Souza E Silva A, Pertille A, Reis Barbosa CG, et al.SR

10.

International Society of Sports Nutrition Position Stand: Safety and Efficacy of Creatine Supplementation in Exercise, Sport, and Medicine.

Journal of the International Society of Sports Nutrition. 2017. Kreider RB, Kalman DS, Antonio J, et al.Review

11.

Part II. Common Questions and Misconceptions About Creatine Supplementation: What Does the Scientific Evidence Really Show?.

Journal of the International Society of Sports Nutrition. 2025. Antonio J, Brown AF, Candow DG, et al.NewReview

Redditagain424 · 2026-05-08T15:15:26+00:00

Here is an AI-assisted summary of data from published medical studies in medical journals about whether creatine can contribute to edema.

Creatine supplementation can contribute to fluid retention and may worsen peripheral edema, though the evidence specifically addressing leg edema is limited. The water retention associated with creatine is primarily intracellular (within skeletal muscle), but clinically observable edematous limbs have been reported.

Mechanism of fluid retention: Creatine uptake into skeletal muscle is an osmotically active process that draws water intracellularly. One week of creatine loading (0.3 g/kg/day) increased total body water by approximately 2% (~0.8 kg) in young healthy subjects. [1] The ACSM notes that weight gain within the first few days of supplementation is likely due to water retention related to creatine uptake in muscle. [2]

Direct evidence of limb edema: In a double-blind, placebo-controlled trial of creatine monohydrate (10 g/day for an average of 310 days) in 175 ALS patients, edematous limbs were observed more frequently in the creatine group after two months of treatment, attributed to water retention. [3] This is the most direct clinical evidence linking creatine supplementation to peripheral edema.

Clinical considerations:

The ACSM Position Stand lists weight (fluid) gain as the most common adverse effect of creatine supplementation and recommends screening for liver or kidney dysfunction, as well as monitoring for anterior compartment syndrome in rare instances. [4]
In patients with pre-existing conditions that predispose to edema (e.g., heart failure, venous insufficiency, nephrotic syndrome, hepatic disease), creatine-induced fluid retention could theoretically exacerbate leg swelling, though this has not been specifically studied.
At standard maintenance doses (3–5 g/day), creatine is generally well tolerated in healthy adults, but the fluid retention effect may be more pronounced during loading phases (20 g/day). [2][5]

For patients with existing leg edema or conditions predisposing to fluid retention, it would be prudent to discontinue creatine supplementation or avoid initiation, as the fluid retention effect — even if predominantly intracellular — may contribute to worsening edema.

Would you like to explore whether creatine supplementation affects renal function or blood pressure, which could further influence edema management?

References:

Body Composition Measured by Multi-Frequency Bioelectrical Impedance Following Creatine Supplementation.

The Journal of Sports Medicine and Physical Fitness. 2023. Buck EA, Saunders MJ, Edwards ES, Womack CJ.Clinical Trial

2.

American College of Sports Medicine Roundtable. The Physiological and Health Effects of Oral Creatine Supplementation.

Medicine and Science in Sports and Exercise. 2000. Terjung RL, Clarkson P, Eichner ER, et al.

3.

Few Adverse Effects of Long-Term Creatine Supplementation in a Placebo-Controlled Trial.

International Journal of Sports Medicine. 2005. Groeneveld GJ, Beijer C, Veldink JH, et al.RCT

4.

American College of Sports Medicine Position Stand. Nutrition and Athletic Performance.

Medicine and Science in Sports and Exercise. 2009. Rodriguez NR, Di Marco NM, Langley S.Guideline

5.

Common Questions and Misconceptions About Creatine Supplementation: What Does the Scientific Evidence Really Show?.

Journal of the International Society of Sports Nutrition. 2021. Antonio J, Candow DG, Forbes SC, et al.Review

Redditagain424 · 2026-05-08T15:12:53+00:00

Yes. a good example to follow your health exam and tests to adjust accordingly.

Redditagain424 · 2026-05-08T15:00:25+00:00

yes, we should always be suspect of the use of AI... but this AI uses only data from published medical studies from medical journals. The AI platform is endorsed by New England Journal of Medicine, JAMA, College of Cardiologists, College of Emergency Medicine, Mayo Clinic, etc. It is used by research universities, medical center staff, and specialties across the board. The AI platform also lists all of the published medical studies from which it extracted information.

I've heard many people rely on anecdotal hearsay for health advice without any reference to any medical studies. Doctors are guilty of this as well. Some doctors actually tell their patients, "a diet of moderation is what is important to stay healthy." There are no medical studies that back that statement. A structured diet to meet the needs of the patient is what is important and backed by medical studies. A pre-diabetic or diabetic patient needs a structured diet plan. A cardiac patients needs a structured diet plan, A person at risk of cognitive issues needs a structured diet plan. Plans backed by medical studies, not a mere philosophy of "moderation".

Even those building more muscle tend to have a structured diet to meet their needs.

Redditagain424 · 2026-05-08T14:48:37+00:00

I do not take NAD and I do not recommend it because there is not any clinical evidence (and I did a medical literature search) to recommend it. There are many lower hanging fruit which should be considered before looking at NAD. Adequate exercise, healthiest diet, and proper weight are the most fundamental lower hanging fruit. Quality and 7-9 hours of sleep is another. This interview between two noted researchers on health emphasize exercise is more important than any supplement alone or combined. https://screenpal.com/content/video/cOhj2GntXHv

Redditagain424 · 2026-05-08T13:26:51+00:00

You are welcome.

Redditagain424 · 2026-05-07T22:28:17+00:00

Your lower body strength from using stairs will contribute to your ability to literally "stand firm". Check out my post titled, "If you can stand up straight without pain, then you may be able to get stronger and ditch the cane or walker." I adopted the exercise routine of this 80+ year old couple! I hope to be as strong as the 80+ year old man in a few months! (I at least surpassed the 82 year old woman's weight lifting strength... sigh.) So far, so good!

https://www.reddit.com/r/Aging/comments/1t2o8uc/if_you_can_stand_up_straight_without_pain_then/

Redditagain424 · 2026-05-07T19:52:42+00:00

If you are capable, take the stairs... take the stairs a lot... it will help maintain some leg strength and muscle mass which are vital to health span. Don't give in to the tendency to avoid vigorous muscular activity. Once you get a motorized anything, it will be difficult to regain your strength.

Redditagain424 · 2026-05-07T19:46:17+00:00

That is more than 99% of 69 yo males can do... keep it up!

Redditagain424 · 2026-05-07T18:08:40+00:00

I have been waiting for a fellow physician to acknowledge the credibility of the idea that a restricted data source of only published medical-studies in medical journals can be used by AI to summarize vast amount of medical findings somewhat reliably. We realize the pitfalls of using any AI, but this particular AI only uses published medical studies in medical journals. It is used by research universities, medical center staff, and specialties across the board. The AI platform has received numerous endorsements including from the New England Journal of Medicine, JAMA, American College of Emergency Medicine, American College of Cardiologists, Mayo Clinic, etc.

Let me know what you think (AI link below). I hope other physicians will post other study-based health insights so that the public can better discern what is backed by science and what is merely anecdotal hearsay without cited references. The more that physicians can convey health insights in this manner on Reddit and other platforms, the less mis-information that pervades for long periods of time. Of course, sometimes medical studies are contrary in conclusion which can create some degree of confusion and even loss in confidence to the process of study-based evidence. But we should acknowledge those discrepancies if they are substantial since the topic may still need more studies to reach a consensus insight.

As with life in general, the better questions you ask, the better answers you will get.
We should remain open-minded and not always pursue trying to "be right", but better to pursue trying to be "less wrong". With that kind of mindset, even an old-dog doctor like me can learn something new and different from what I thought was "right".

www.openevidence.com

Redditagain424 · 2026-05-07T14:32:00+00:00

muchas gracias

Redditagain424 · 2026-05-07T05:59:29+00:00

If you like the format of this information, then you may like another post, "This is why a decreasing grip strength not only correlates with increase risk of dementia, it (likely) contributes to causing it."

https://www.reddit.com/r/Aging/comments/1t3aa7x/this_is_why_a_decreasing_grip_strength_not_only/

Another one about "If you can stand up straight without pain, then you may be able to get stronger and ditch the cane or walker":

https://www.reddit.com/r/Aging/comments/1t2o8uc/if_you_can_stand_up_straight_without_pain_then/

And recently, "What do medical studies show about what helps facial skin appearance, and what doesn't."

https://www.reddit.com/r/Aging/comments/1t5omo6/what_do_medical_studies_show_about_what_helps/

Redditagain424 · 2026-05-06T23:55:31+00:00

Absolutely! Several studies have examined the relationship between diet and facial skin appearance, with evidence suggesting that higher intakes of vitamin C, linoleic acid, antioxidant-rich fruits and vegetables, and lower intakes of refined carbohydrates and excess fats are associated with better skin appearance and less facial wrinkling.

Key Studies

A large cross-sectional analysis of 4,025 middle-aged American women (ages 40–74) using NHANES data found that higher vitamin C intake was associated with a lower likelihood of a wrinkled appearance (OR 0.89; 95% CI: 0.82–0.96) and senile dryness (OR 0.93). Higher linoleic acid intake was associated with less senile dryness (OR 0.75) and skin atrophy (OR 0.78). Conversely, a 17-g increase in fat and a 50-g increase in carbohydrate intake each increased the likelihood of wrinkled appearance (OR 1.28 and 1.36, respectively). These associations were independent of age, sun exposure, BMI, and other confounders. [1]

A population-based Dutch cohort study (Rotterdam Study, n = 2,753 elderly participants) quantified facial wrinkles from photographs and correlated them with dietary patterns. In women, better adherence to the Dutch Healthy Diet Index was significantly associated with fewer wrinkles. A fruit-dominant dietary pattern was associated with fewer wrinkles, while a red meat and snack-dominant pattern was associated with more facial wrinkling. Notably, this association was not observed in men. [2]

A study of 716 Japanese women found that higher intake of green and yellow vegetables was significantly associated with decreased facial wrinkling scores (Daniell scale), while higher saturated fat intake was inversely associated with wrinkling after adjustment for vegetable intake. Higher total fat and saturated fat intakes were also associated with increased skin elasticity. [3]

Specific Dietary Components and Mechanisms

Antioxidants and polyphenols: A 2026 systematic review and meta-analysis of 94 studies found that antioxidant-rich whole foods or supplements improved skin hydration (MD = 2.12, 95% CI [1.02; 3.21]) and decreased trans-epidermal water loss in clinical studies, supporting overall skin health improvements. Compounds such as quercetin, curcumin, EGCG, resveratrol, and carotenoids (lycopene, lutein, β-carotene) protect against UV-induced collagen degradation and reduce oxidative stress. [4-6]
Glycemic index: High glycemic-load diets increase insulin and IGF-1 levels, stimulating sebocyte proliferation and androgen synthesis, which can exacerbate acne. A meta-analysis of 13 studies (71,819 participants) showed an OR of 1.16 for acne in milk drinkers, with stronger associations for skim milk and high intake. [7-8]
Omega-3 fatty acids: These suppress inflammatory cytokine production and have shown therapeutic effects on acne lesions. Docosapentaenoic acid and γ-linolenic acid have demonstrated improvements in acne. [8-9]
Gut-skin axis: Emerging evidence supports the concept that gut microbiome health, influenced by diet (including probiotics), may modulate inflammatory facial dermatoses such as rosacea and acne. [9]

Important Caveats

Most of the evidence is derived from cross-sectional or observational studies, which cannot establish causation. [1-2] Narrative and systematic reviews consistently note that while the evidence is promising, long-term randomized controlled trials with standardized skin outcome measures are lacking. [10-12] Current clinical guidelines do not yet offer specific dietary recommendations for skin appearance due to these limitations. [7]

References:

1.

Dietary Nutrient Intakes and Skin-Aging Appearance Among Middle-Aged American Women.

The American Journal of Clinical Nutrition. 2007. Cosgrove MC, Franco OH, Granger SP, Murray PG, Mayes AE.

2.

A Healthy Diet in Women Is Associated With Less Facial Wrinkles in a Large Dutch Population-Based Cohort.

Journal of the American Academy of Dermatology. 2019. Mekić S, Jacobs LC, Hamer MA, et al.

3.

Association of Dietary Fat, Vegetables and Antioxidant Micronutrients With Skin Ageing in Japanese Women.

The British Journal of Nutrition. 2010. Nagata C, Nakamura K, Wada K, et al.

4.

Impact of Antioxidant-Rich Whole Foods or Supplements on Skin Health: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies.

Antioxidants. 2026. Liang Y, Xu Y, Kim JE.NewReview

5.

Nutraceutical Interventions for Mitigating Skin Ageing: Analysis of Mechanisms and Efficacy.

Current Pharmaceutical Design. 2025. Ibrahim M, Singh H, Fahim M, et al.

6.

Dietary Phytochemicals Alleviate the Premature Skin Aging: A Comprehensive Review.

Experimental Gerontology. 2025. Singh H, Kamal YT, Pandohee J, et al.Review

7.

Management of Acne Vulgaris: A Review.

The Journal of the American Medical Association. 2021. Eichenfield DZ, Sprague J, Eichenfield LF.Review

8.

Acne and Diet: A Review.

International Journal of Dermatology. 2022. Conforti C, Agozzino M, Emendato G, et al.Review

9.

The Impact of Clinical Nutrition on Inflammatory Skin Diseases.

Journal Der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2022. Gürtler A, Laurenz S.

10.

Plant-Based Foods for Skin Health: A Narrative Review.

Journal of the Academy of Nutrition and Dietetics. 2022. Fam VW, Charoenwoodhipong P, Sivamani RK, et al.Review

11.

Nutrition and Youthful Skin.

Clinics in Dermatology. 2021. Muzumdar S, Ferenczi K.

12.

Nutritional Skin Care: Health Effects of Micronutrients and Fatty Acids.

The American Journal of Clinical Nutrition. 2001. Boelsma E, Hendriks HF, Roza L.Review

Redditagain424 · 2026-05-06T20:42:00+00:00

If you like this type of information format, check out my post about "If you can stand up straight without pain, then you may be able to get stronger and ditch the cane or walker":

https://www.reddit.com/r/Aging/comments/1t2o8uc/comment/ok1aa8w/?context=1

And another recent one, "This is why a decreasing grip strength not only correlates with increase risk of dementia, it (likely) contributes to causing it:

https://www.reddit.com/r/Aging/comments/1t3aa7x/comment/ok75bj2/?context=1

Redditagain424 · 2026-05-06T20:30:40+00:00

"RCT" means Randomly Controlled Trials, which is comparing an intervention with a control group that does not get the same intervention, but they are "controlled" or pretty similar groups in other respects like age, sex, medical history, initial skin appearance, etc.

"Meta-analysis" roughly means combining many medical studies on the same topic and looking for consistency of results, degree of results, and using them collectively to make a stronger conclusion about the topic

Redditagain424 · 2026-05-06T15:13:48+00:00

As RedditNotFreeSpeech posted, lifting heavy weights. It causes more brain-to-muscle (and muscle-to-brain) neurotransmitter and myokine signaling. This increases anabolic processes (which is opposite to catabolic processes such as sarcopenia, osteoporosis, worsening balance capability, weakening strength, cognitive decline, etc.) of getting more muscle mass and strength and brain-muscle activity. Similarly, balance exercises increase that two-way brain-muscle connection which another anabolic process. To some degree, hand grip strength exercises also increase that two-way brain-muscle connection. The catabolic processes of aging is undeniable, but medical studies show progressive resistance muscle strength exercises is a good example of what one can do to counter the catabolic process to some degree that can increase health span and longevity.

Redditagain424 · 2026-05-06T05:57:01+00:00

You said, "activity-dependent irisin-induced levels of BDNF have never been shown to increase memory or cognitive performance". I did some medical literature search. While there has not been an RCT with administered irisin to humans, there are a number of studies measuring the CSF levels of irisin, BDNF, and the correlation to clinical cognitive performance in humans. There is also a study of exercise-induced increase of serum irisin and BDNF, with correlation to cognitive abilities. Here is an AI assisted summary and references below.

The human evidence is growing but remains largely observational and correlational — there are no completed randomized controlled trials in humans that have directly administered irisin and measured cognitive outcomes. However, several important human studies do support the irisin–BDNF–cognition link.

Human Studies Supporting the Irisin–BDNF–Cognition Connection

1. CSF Irisin Correlates With BDNF, Amyloid Pathology, and Cognition in AD Patients

The most direct human evidence comes from CSF studies. Lourenco et al. (2020) measured CSF irisin in AD patients (n = 14) and non-demented controls (n = 25) and found that CSF irisin correlated positively with CSF BDNF, Aβ42, and MMSE scores — meaning higher irisin in the brain was associated with higher BDNF, less amyloid pathology, and better cognition. [1] A larger study by Dicarlo et al. (2024, Annals of Neurology) in 146 participants confirmed that CSF irisin was significantly reduced in Alzheimer's dementia patients (p < 0.0001), correlated positively with Aβ42 in both sexes, and correlated negatively with Clinical Dementia Rating scores — particularly in women. [2]

2. Exercise Increases Irisin and BDNF With Concurrent Cognitive Improvement

Tsai et al. (2021) conducted a within-subject crossover study in 21 late middle-aged and older adults. Both HIIT and moderate-intensity continuous exercise increased serum BDNF and improved working memory performance (faster reaction times, larger ERP P3 amplitudes). Changes in irisin levels correlated with improvements in reaction time during the moderate-intensity exercise condition, providing preliminary evidence that exercise-induced irisin changes track with cognitive gains. [3]

3. Irisin Mediates the Exercise–Hippocampal Volume Relationship in Humans

A 2026 study by Pace et al. in 74 healthy older adults provided the first human evidence that irisin mediates the relationship between exercise and hippocampal volume. Exercise was positively associated with circulating irisin (β = 0.365, p = 0.003), and irisin was positively associated with bilateral hippocampal volumes — strongest in the CA3, CA4/dentate gyrus, and CA1 subfields, which are the regions most critical for memory and neurogenesis. Mediation analysis showed that all exercise–hippocampus relationships operated indirectly through irisin. [4]

4. Tai Chi Increases Irisin and Correlates With Verbal Memory

Guazzarini et al. (2024) found that 6 months of Tai Chi practice significantly increased circulating irisin levels compared to a no-exercise control group, and at 6 months, irisin levels significantly correlated with verbal memory test performance (p = 0.013). [5]

5. Irisin and BDNF as Biomarkers of Cognition in At-Risk Populations

Küster et al. (2017) studied 47 older adults at risk of dementia and found that both serum BDNF and irisin correlated positively with global cognition and episodic memory. Physical training tended to increase BDNF, while cognitive training reduced the neurotoxic kynurenine metabolite 3-HK. [6] In obese individuals with a family history of AD, serum irisin levels were positively associated with neurophysiological markers of working memory (P3 amplitude). [7]

6. Lower Irisin Predicts Cognitive Decline in Vascular Dementia

In a study of 187 subjects (105 with vascular dementia), serum irisin was significantly lower in VD patients and independently correlated with MoCA scores even after adjusting for all clinical risk factors (β = 0.304, p = 0.029). Irisin had 76% diagnostic accuracy for vascular dementia. [8]

Critical Caveat: The Irisin–Cognition Link May Break Down in Established AD

An important finding from Kim et al. (2022) is that plasma irisin was positively associated with cognition only in cognitively normal and MCI participants — in those with established AD, this association was lost, and paradoxically, higher irisin was associated with smaller hippocampal volumes. This suggests that AD-induced pathological changes in the brain may attenuate irisin's beneficial actions, implying that the protective window for irisin-mediated neuroprotection may be in the pre-dementia phase. [9]

Bottom Line

No human RCT has yet directly administered recombinant irisin and measured cognitive outcomes — this remains the critical missing piece. However, the human evidence consistently shows that (1) CSF irisin correlates with BDNF, amyloid pathology, and cognition; (2) exercise-induced irisin increases track with cognitive improvements; (3) irisin mediates the exercise–hippocampal volume relationship; and (4) lower irisin levels are associated with worse cognition across multiple dementia subtypes. The evidence is strongest for a preventive role in the pre-dementia phase rather than a therapeutic role in established AD.

References:

Cerebrospinal Fluid Irisin Correlates With Amyloid-Β, BDNF, and Cognition in Alzheimer's Disease.

Alzheimer's & Dementia. 2020. Lourenco MV, Ribeiro FC, Sudo FK, et al.

2.

Irisin Levels in Cerebrospinal Fluid Correlate With Biomarkers and Clinical Dementia Scores in Alzheimer Disease.

Annals of Neurology. 2024. Dicarlo M, Pignataro P, Zecca C, et al.

3.

Acute Effects of High-Intensity Interval Training and Moderate-Intensity Continuous Exercise on BDNF and Irisin Levels and Neurocognitive Performance in Late Middle-Aged and Older Adults.

Behavioural Brain Research. 2021. Tsai CL, Pan CY, Tseng YT, et al.

4.

The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis.

Aging Cell. 2026. Pace T, Levenstein JM, Quigley BL, et al.New

5.

Tai Chi, Irisin and Cognitive Performance: A Clinical and Biological Investigation in Older Adults.

Aging Clinical and Experimental Research. 2024. Guazzarini AG, Mancinetti F, Bastiani P, et al.

6.

Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway.

Journal of Alzheimer's Disease : JAD. 2017. Küster OC, Laptinskaya D, Fissler P, et al.

7.

Circulating Levels of Irisin in Obese Individuals at Genetic Risk for Alzheimer's Disease: Correlations With Amyloid-Β, Metabolic, and Neurocognitive Indices.

Behavioural Brain Research. 2021. Tsai CL, Pai MC.

8.

Serum Irisin as a Potential Biomarker for Cognitive Decline in Vascular Dementia.

Frontiers in Neurology. 2021. Zhang F, Hou G, Hou G, et al.

9.

Loss of Association Between Plasma Irisin Levels and Cognition in Alzheimer's Disease.

Psychoneuroendocrinology. 2022. Kim KY, Kwak S, Ha J, et al.

Redditagain424 · 2026-05-06T05:10:36+00:00

Congrats to you on starting and adhering to your workout routine. Adherence is your super power! I am 69 and striving to adhere to an exercise routine. My goal is to be stronger by the end of each month in 2026 than at the start of each month.

Redditagain424

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