Creatine Responders and Nonresponders. What is the verdict?
By Dr Blaise Collins, PhD, ACSM-EP-C | Monthly Blog Contributor, Jenerise | Medical & Scientific Director | Neurology, Oncology, Hematology | Exercise Physiologist
“I don’t know” is sometimes the best starting point
I was recently on a webinar for Jenerise covering creatine supplementation in adolescent athletes, and I was asked a question I didn’t have a good answer to; “What do you think about creatine responders vs non-responders?” I knew the concept, but when I started to answer, I realized what I had was speculation.
Maybe it’s amount of change in creatine saturation?
Maybe vegetarians have a more robust increase due to the lack of animal protein?
Maybe innate fiber types dictate response?
In short, my answer was “I don’t know… but I can speculate.” I did a casual dive on PubMed to seek further, and saw it as an excellent opportunity to show how that process works. Overall, I was quite disappointed with the lack of any recent data. There also appears to be debate between how to actually define “creatine response”, which only serves to further muddle the picture. Some studies use sprint performance, some use change in lean mass, while others use brain creatine concentration and muscle creatine saturation. While current research has yet to establish definitive mechanistic explanations or strong genetic correlations, this remains an evolving area of study, and future scientific inquiry may provide greater clarity.
The art of scientific inquiry
Typically, we would look at funding sources, conflicts of interest, who the authors were, and compare the data. All of these are highly relevant information, but for the purposes of this article, I only used one search term string. Please note, in a real-world scenario, we would align on several lines of search terms which are dictated by our hypothesis and outcomes. Here is how I structured my rabbit hole:
Observation – Variation in response to creatine could be viewed as distinct buckets of responders and non-responders.
Question – Is the response to supplemental creatine due to genetic factors? Phenotypical factors? Diet?
Hypothesis – Creatine monohydrate has differential effects dependent on lifestyle and genetics
Experiment – Search of PubMed using “Creatine” AND “responder”, filter for “Past 5 years” and “Clinical Trial” and ”Randomized Control Trial”
Analysis & Search Limitations – The broad search returned 2,359 results from 1964 to present. Applying the 5-year and trial filters narrowed it to 23 results. Curiously, 13 of those 23 studies were for upadacitinib—a JAK inhibitor used in oncology and autoimmune trials. Why? Because these trials monitored creatine kinase as a safety biomarker, illustrating how keyword searches can yield off-target results.
Furthermore, limiting the search to the past 5 years created an artificial blind spot: it excluded the foundational 1990s and 2000s studies that first established how baseline muscle creatine levels influence response.
Investigations into responders vs nonresponders are missing in the 2020s
Using this search term, I found remarkably little recent literature directly investigating creatine responder classifications. This was surprising, given how this question does pop up periodically. Following the same process, I saw similar results. I would speculate that there were likely a handful of studies and anecdotal data highlighting a potential avenue of research, but the results weren’t compelling to further investigation. Granted, it could also be a shift in interest or funding priorities, but I’m leaning more towards lack of data.
The scientific consensus doesn’t appear to include responder and nonresponder categories
In science, we have levels of evidence. At the bottom is anecdotal data, or what someone posts on social media or reports from personal experience. Anecdotal data tends to come with a lot of subjectivity, so the reports must be taken with a metric tonne of salt; however, anecdotal data does sometimes bring up good questions. In that event, we would then move up to case reports or case series, and animal or laboratory studies. IF patterns emerge from those studies, we then move into controlled case studies, cohort studies, randomized controlled trials, and finally into meta-analyses and systematic reviews. Each ascending level of evidence involves more stringent controls, more regulatory guidance, and ultimately a greater impact. If findings persist across all, we eventually see a shift in clinical guidelines.
With those levels of evidence in mind, I repeated the initial exercise, using the same search terms, but removed the time constraints. I also set the filters to “Meta-Analysis”, “Review”, and “Systematic Review”. This gave me 187 results going back to 1979. In reviewing the title and abstract for each, aside from factors like creatine deficiency or comorbidities, I did not identify evidence that would compel me to conclude that biologically distinct responder and non-responder groups have been established.
In science, “Truth” appears over decades, not over individual studies
Science advances through replication, rather than isolated findings. A single study can generate an interesting hypothesis, but confidence in those results require multiple independent investigations arriving at a similar conclusion. The question is not whether one study found creatine responders, but rather, it is whether decades or research have consistently demonstrated that biologically distinct responder groups exist… which, based on the currently available literature, has not been convincingly demonstrated.
What we do know is that there are a number of modifiable physiological factors that could affect how creatine works within the body. The apparent “response” to creatine can be influenced by numerous biological, lifestyle, supplementation, and methodological factors, including baseline muscle creatine stores, muscle fiber composition, training status, and dosing strategy. Consequently, an individual may appear to be a “responder” in one study and a non-responder in another simply because the study is built differently. Variation in outcomes does not necessarily imply the existence of discrete categories.
When we expand our view to the broader body of evidence—including meta-analyses, systematic reviews, and classic literature—a clearer picture emerges. Rather than an "on/off switch" where people are strictly "responders" or "non-responders," human response to creatine exists on a continuous, graded spectrum.
While classic clinical trials focused primarily on baseline dietary and physiological stores, science doesn't stand still. An emerging layer of research is exploring the genetic mechanisms behind why baseline stores and transport rates differ in the first place. Recent reviews and studies in elite athletic populations point to key gene variants—such as SLC6A8 (which governs the creatine transporter), GATM, and GAMT (involved in endogenous creatine synthesis).
While classical trials evaluated response purely by measuring muscle saturation changes after the fact, modern nutrigenomics is looking upstream. Identifying these polygenic variations helps explain where an individual sits on that continuous spectrum—ranging from those who naturally maintain high baseline stores to those who require targeted dosing strategies to achieve saturation.
We all rise together,
More articles by Dr Blaise
Frequently asked questions
Q: What is a creatine "responder"?
A "responder" is a name people use for someone whose body seems to react strongly to creatine, like gaining more strength or muscle. A "nonresponder" is someone who doesn't seem to react as much.
Q: Why do some people seem to respond to creatine more than others?
It may come down to things like how much creatine is already stored in your muscles, your muscle fibre type, how you train, and how much creatine you take. These factors can make results look different from person to person. When we take into account additional factors like age, sex, and diet, the idea of "responding" becomes far more varied.
Q: Is there a test to find out if I'm a responder?
Given that there is not an agreed-upon definition of what constitutes the response, we do not currently have tests to determine that status.
Q: Does being a "nonresponder" mean creatine won't work for me?
Not necessarily. What looks like a weak response in one study might look different in another, simply because the studies measure things differently. As an example, we may expect greater performance outcomes for athletes engaging in power sports (e.g., baseball, powerlifting), as opposed to endurance training.
Q: What does the science actually say about responders and nonresponders?
After reviewing decades of research, no strong evidence supports the idea that these are true, separate biological groups. Differences in results are more likely explained by lifestyle, training, and how each study was designed.
Further Reading and References
Baseline Physiology & Response Heterogeneity
The earliest foundational work establishing that baseline creatine levels influence supplementation response demonstrates that muscle creatine uptake is greatest in subjects with low initial total creatine content. Research from the 2000s built directly on this finding, formally classifying responders and non-responders by baseline physiology. Reviews consistently cite baseline tissue creatine as a primary confounding variable dictating the dose required to produce a meaningful response (Candow et al., 2024; Ribeiro et al., 2021; Li, 2026).
Harris RC, et al. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci, 1992.
Greenhaff PL, et al. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol Endocrinol Metab, 1994.
Syrotuik D, et al. Acute Creatine Monohydrate Supplementation: A Descriptive Physiological Profile of Responders vs. Nonresponders. J Strength Cond Res, 2004.
Solis M, et al. Effect of age, diet, and tissue type on PCr response to creatine supplementation. J Appl Physiol, 2017.
Genetics & Emerging Research
Research evaluating specific genetic factors (SLC6A8, GATM, GAMT) remains preliminary.
Ostojic SM, et al. Genetic Determinants of Creatine Bioavailability and Responsiveness: Emphasis on Common Low-Impact Variants. Lifestyle Genomics, 2026.
Varillas-Delgado D, et al. Association of Genetic Profile with Muscle Mass Gain and Muscle Injury Prevention in Professional Football Players after Creatine Supplementation. Nutrients, 2024.
Methodological Note: The Varillas-Delgado paper evaluated downstream physical outcomes (muscle mass gain and injury prevention) rather than direct intramuscular creatine content. The gene variants studied (ACE, AMPD1) predicted overall physiological response to supplementation rather than tissue uptake or storage efficiency.
Are creatine responders and nonresponders real biological categories or just an artefact of how studies are built? Dr Blaise Collins provides a behind-the-scenes look at how we identify gaps in knowledge and the process we utilise to bridge those gaps, using the concept of creatine response to visualise the process.