An Interview with Dr. Alfredo Franco-Obregon

As regular readers know, one of my biggest peeves is the media writing uninformed articles about nutrition without bothering to check the facts. It is hard to tell which nutrient draws the most misinformation from the media, but creatine ranks high on the list. Why do so many in the media confuse a healthy nutrient with an unhealthy drug. Why are so many in the media under the impression that eating creatine (which the body uses naturally) is akin to taking performance-enhancing drugs such as steroids that change body chemistry?

As regular readers know, one of my biggest peeves is the media writing uninformed articles about nutrition without bothering to check the facts. It is hard to tell which nutrient draws the most misinformation from the media, but creatine ranks high on the list. Why do so many in the media confuse a healthy nutrient with an unhealthy drug. Why are so many in the media under the impression that eating creatine (which the body uses naturally) is akin to taking performance-enhancing drugs such as steroids that change body chemistry?

Richard A. Passwater

Performance enhancing? Creatine is no more of an independent performance enhancer than proteins, vitamins or minerals. Creatine, along with intense exercise and a good diet, will help build strength. On the other hand, anabolic steroid drugs hand-build muscle without exercise and they have deadly side effects. Creatine is a nutrient and it is also made in the body. Caffeine improves performance, but caffeine is not a nutrient. Why doesn’t the media attack caffeine? Maybe it is because so many need a couple cups of java to start real work. Yes, caffeine enhances mental performance as well as physical performance, but since it seems that it is a sacred cow for the media. Is caffeine a performance-enhancing drug? It certainly is neither a nutrient nor is it made in the body.

Beneficial to athletes? Yes, creatine can be used beneficially by various types of athletes—just as good diet and exercise can—and creatine has benefits for non-athletes as well. Should coaches be fired or sued because they allow their athletes to use creatine as a dietary supplement? This illogical notion is caused by misinformation spread in the media. Allowing athletes to supplement their diets with creatine is no different from allowing them to supplement their diet with other nutrients such as a multivitamin, protein powder or electrolyte drinks. Supplements are intended to be just that—supplements to a good diet and used properly in the proper amounts.

Just how should creatine be used? We have discussed proper creatine usage in the column several times. In fact, the first article published on creatine was here in an interview with Dr. Paul Greenhaff in 1996 discussing the experience of British swimmers in the 1992 Barcelona Olympics. The most recent discussion was with Anthony Almada in January and February 2006. However, the body of scientific literature supporting creatine benefits continues to grow and it’s time for another update. So, let’s chat about that with creatine expert Dr. Alfredo Franco-Obregón, Ph.D.

SolgarDr. Franco-Obregón has over 20 years of research experience in major scientific laboratories worldwide. He has carried out research at the University of California at San Francisco, the University of Seville in Spain, the Mayo Clinic, Harvard Medical School and the Swiss Federal Institute of Technology in Zürich. He currently conducts basic research on muscle development and teaches in the graduate program in Biomedical Engineering at the Swiss Federal Institute of Technology in Zürich. His primary scientific interest is elucidating the biophysical mechanisms influencing muscle cell growth and survival. His interest in creatine is an extension of this scientific endeavor.

Passwater: It is interesting to me that a neuroscientist is an expert in creatine biochemistry.

Franco-Obregón: Yes, I am a neuroscientist. More specifically, however, I am a biophysicist, and even more precisely, I am an electrophysiologist. My primary scientific interest is how cells communicate electrically as well as translate common environmental stimuli into electrical signals that allow them to elicit an appropriate cellular response. And, although many cell types of the body are electrically responsive in this way, this phenomenon was first described in detail in the nervous system. Hence, for reasons of tradition, persons interested in electrophysiology first had to become neuroscientists—at least, in my day. Today, things are a little more open.

Therefore, although I was educated as a neuroscientist, my principal interest lies peripheral to the nervous system, skeletal muscle, heart muscle and smooth muscle (as in the gut). All these forms of muscle are electrically responsive. These electrical responses allow them to develop as well as adapt to the physical stresses placed upon them.

Passwater: What brought you to muscle physiology and exercise physiology?

Franco-Obregón: Again, skeletal muscle has always been a focus of mine, as an athlete and a scientist. Even in grade school, I was intrigued by the fact that muscles, seemingly unlike most other tissues of the body, respond to exercise by growing in strength and size. My fascination with the topic has not diminished since childhood, although I now see the process through somewhat different eyes and with a new focus of helping the ill and elderly recuperate lost muscle mass.

It turns out that muscles generate force as well as develop from stem cells into adult skeletal muscle fibers through an electrical phenomenon. These two processes, moreover, are coupled as the electrical current that instigates both muscular force generation and development (on the genetic level) is carried by calcium ions. Importantly, the charging of the “calcium battery” requires energy.

Passwater: How did this lead you to your interest in creatine?

Franco-Obregón: Understanding how muscle establishes and maintains the electrical gradients that keep it functioning is the question that keeps me awake at night and, conversely, gets me out of bed in the morning anxious to start the next experiment, particularly when the question is in reference to calcium ions and the important role that they play in almost every aspect of cellular behavior. The energetics of maintaining ionic (calcium, sodium, potassium and chloride) harmony within the cell is where creatine fits into my grand scientific question. In essence, creatine is the first line of attack when a cell urgently needs energy to reestablish its ionic gradients. But, what is energy really in cellular terms?

To employ a popular metaphor, the cell’s “energy currency” is a molecule known as Adenosine TriPhosphate, or ATP, for short. ATP stores energy in its phosphate bonds, principally the third. The cell liberates this phosphate and in breaking this chemical bond, releases energy for its use. However, in liberating this phosphate energy, ATP becomes ADP, or Adenosine DiPhosphate, a phosphate (and energy) depleted state. Accordingly, ADP is not a broad-scale energy donor for cellular processes.

All this would all be pointless, however, if there was not some way of recharging ADP with a replacement phosphate to recreate ATP. The cell has two pathways with which to do this. The first is to harness the electron energy held within nutrients and then convert it into phosphate energy—a relatively slow process. The second is to recreate ATP in a single step with the assistance of creatine—a nearly instantaneous process, since it entails a phosphate-to-phosphate transition.

In essence, creatine acts as a phosphate reservoir; after we consume creatine in the diet, it is modified within the cell with the addition of a phosphate. Creatine phosphate is then held in reserve for the regeneration of ATP. Most cells use the creatine pathway during moments of high-energy demand when the rate of ATP regenerated from nutrients just isn’t fast enough to keep cellular processes going at full throttle.

Now, back to my science…To reiterate, calcium is an extremely important biochemical mediator of cell behavior. Hence, its levels are strictly controlled within the cell at great energetic expense. Calcium activates enzymes (some degenerative, others productive), changes cellular membrane permeability, supports muscle contraction and very importantly, regulates the reading of genes that are involved in muscle development. My doctorate work focused on the most common forms of muscular dystrophies in humans, Duchenne and Becker, and how disturbances in cellular calcium homeostasis contribute to their manifestation. Suffice it to say that creatine-based energy production is essential in maintaining cellular calcium levels within a safe concentration range. This project started me thinking about creatine back in the early 1990s.

In fact, creatine energy depletion is characteristic of many skeletal muscle disorders. Thus, it is plausible that many neuromuscular disorders may respond positively to creatine supplementation. This possibility is very exciting to me.

The Muscular Dystrophy Association is currently planning a multi-center trial to test the effectiveness of creatine in humans with amyotrophic lateral sclerosis (ALS). There is some indication that ALS arises from an inability of nerve cells to combat oxidative stress—the inefficient processing of oxygen to yield reactive oxygen species (ROS). ROS destroy cell membranes and proteins, thereby killing the cell. Creatine has been shown in animal models of ALS to enhance the ability of nerve cells to neutralize ROS by fortifying the cell’s energy-producing machinery, hence, increasing life expectancy. Therefore, the possibilities for creatine are many.
Details of ongoing clinical trials with creatine can be found at the following Web site:

Passwater: Your new book, Creatine: A Practical Guide, summarizes creatine research very well. Please tell us a little about why you decided to write it.

Franco-Obregón: My research with creatine has mostly stayed within the paper domain—reading and summarizing what is known about creatine based on published peer-reviewed scientific studies. My personal scientific research with creatine has thus far concerned a method to impede muscle loss during space travel, a process called “Space Atrophy.” It has implications that can bring creatine into the realm of space travel and aging, but must be evolved somewhat before it gets published. My creatine guide is based mostly on the first.

Passwater: Let’s start at the beginning. One of my pet peeves is to read incorrect information in the press by well-meaning, but poorly informed persons about creatine. Is creatine a natural nutrient found in foods?

Franco-Obregón: Creatine per se is as natural as it gets. Creatine is a natural component of skeletal muscle. In fact, creatine is such a prominent component of skeletal muscle that its name is derived from the Greek word for meat (kreas). The man largely credited with its discovery was the French scientist and philosopher, Michel-Eugène Chevreul, who first isolated creatine from meat nearly one and three-quarter centuries ago (1832). Evolutionarily, creatine appeared on the scene over 400 million years ago with the appearance of vertebrates. Obviously, creatine is not exotic to us mammals, by any means.

The strength-promoting attributes of meat were understood long before the identification of creatine—the agent largely responsible for this effect. I suppose that early attempts at creatine supplementation (although mostly unwittingly) involved the ingestion of large quantities of meat, or extracts thereof, to improve physical performance.

Near the turn of the last century, the first scientific studies examining the effects of creatine feeding were conducted, where it was noticed that not all the creatine fed to animals could be recovered in the urine. Soon afterwards, two Harvard scientists (Otto Folin and W. Dennis [1912–1914]) demonstrated that the body’s predominant sink for ingested creatine is muscle.

Therefore, nearly one century ago, scientists had already come full circle from discovering that skeletal muscle is the richest natural source of creatine to the body’s largest sink for dietary creatine. Nevertheless, until quite recently, the manner in which to best promote creatine absorption by skeletal muscle remained largely elusive. In this respect, a huge leap forward was made with the relatively recent finding that insulin assists in the absorption of creatine into skeletal muscle. This is the reason why so many new creatine formulations contain reputed, or substantiated, insulin agonists to enhance creatine uptake by muscle. Other avenues to increase creatine’s bioavailability are to increase its absorption from the digestive tract and solubility once within the bloodstream.

Passwater: Does creatine have nutritional uses beyond muscle performance such as mental function?

Franco-Obregón: Creatine is turning out to be one very exciting little molecule. Although most of the body’s creatine content is held within muscle, other cell types also utilize creatine for a similar purpose; that is, to enhance cellular energetics. The brain is one such organ that relies heavily on creatine-based energy production. Abstracting a thought, perceiving a sensation from the outside world or initiating the movement of a limb takes a lot of energy.

One recent study elegantly demonstrated the profound effect that creatine has over mental processes. In this study, subjects who were administered creatine exhibited improved short-term memory, were better able to problem solve under time pressure and had higher general IQ scores.

Quoting directly from the manuscript: “Supplementation with creatine significantly increased intelligence compared with placebo.”

More information about this provocative study can be found at

Due to its broad physiological importance, creatine supplementation is currently being tested in clinical trials for certain human disorders in which cellular energy deficits contribute to the manifestation of the condition. Anyone interested in understanding the intricacies of how creatine supplementation might be used to clinically combat several human diseases is kindly directed to a new book that just appeared in the scientific press, Creatine and Creatine Kinase in Health and Disease (ISBN 978-1-4020-6485-2). Dr. Markus Wyss, one of the authors of the book, is a good friend of mine as well as an internationally respected expert on creatine metabolism. A warning in advance, however, this book is very advanced in scope (intended for a more sophisticated scientific audience) as well as rather expensive (~$300) given that it is intended for university libraries rather than domestic bookshelves. Pharmaceutical companies and university libraries should certainly make a point of having this book among their references.

I also wrote a layperson’s guide on proper creatine use that might be a better option for those who want a more “watered down,” yet comprehensive, reference on the topic. Moreover, in response to the many questions I receive from athletes from around the globe, my guide also explains how to most effectively combine exercise, nutrition and creatine supplementation for optimal muscle anabolics. With this information in hand, you will then be able to take your creatine use to the next level. The guide sells in downloadable format at

Passwater: What is the advantage to an athlete of ensuring that he/she is well nourished with creatine?

Franco-Obregón: As all exercise requires energy, all forms of exercise will benefit to varying degrees from creatine supplementation. The pathway through which energy is produced, however, differs with the type of exercise, which will, in turn, determine their dependency on muscular creatine levels.

Endurance exercise recruits aerobic energy production, which produces energy (ATP) from the oxidation of nutrients. The term oxidation reflects the fact that oxygen assists in the process of releasing and capturing the energy inherent to nutrients used as fuel. Although relatively inexhaustible, this system produces ATP rather slowly. Hence, the amount of energy it produces on a per-second basis is not huge and consequently, the amount of power it generates is not great. Of importance to this interview, aerobic exercise draws little from our creatine reserves. Nevertheless, despite the fact that creatine supplementation will not benefit aerobic exercise noticeably, it will create an anabolic environment that is more conducive for tissue recovery following prolonged exercise. Examples of predominantly aerobic exercise include walking, distance running and cycling, tasks that can be maintained for extended periods at submaximal power output.

Anaerobic (non-aerobic) energy production, on the other hand, is fast and by definition, occurs independently of oxygen. Anaerobic energy production fuels explosive bursts of power that can increase cellular energy demand several-hundred fold in mere seconds. Anaerobic energy production is why you can jump or sprint for a few seconds without taking a breath. Creatine is the predominant energy substrate used during anaerobic exercise of less than a few tens of seconds duration. Importantly, more replete creatine reserves will also shorten your time to recover between bouts of exercise. Expectedly, the effect of creatine supplementation will be especially pronounced during anaerobic exercise. Examples of anaerobic sports include bodybuilding and powerlifting.
Exercises of mixed aerobic/anaerobic characteristics will depend on both forms of energy production and will have intermediate sensitivities to creatine supplementation.

Passwater: If I remember correctly, creatine was first brought to world attention by the British Olympic swimming team decades ago. Then, creatine became a favorite of the power athletes and bodybuilders. Is creatine beneficial to finesse athletes such as baseball players?

Franco-Obregón: Creatine use will help most athletes, since it increases rapid energy production. The extent of the benefit, however, will depend on the sport in question as explained in my previous answer.

At this point, however, there is another effect of creatine supplementation that merits mentioning as it influences which sports benefit the most from creatine supplementation, a process known as muscle volumizing. During creatine supplementation, muscles literally inflate with water. This has the effect of increasing the size and weight of muscles.

Although an increase in body mass may be a welcome, and even sought after consequence, for some sports such as bodybuilding and power sports, an increase in body weight may be disadvantageous in sports such as distance running or cycling. Baseball players, since they are required to make sudden explosive movements to excel in their sport, will benefit from creatine supplementation to a degree that offsets any negative impact that an increase in body mass might impose.

Details of muscle volumizing are given at

Passwater: Would the weak elderly benefit from creatine supplementation?

Franco-Obregón: Indeed. In fact, this is one aspect of creatine supplementation that I find extremely promising. The human race is aging at an alarming rate. It is estimated that in the United States, the number of individuals over 65 years of age will double in only 25 years, creating an economic crisis as age-related diseases begin to predominate in the clinical arena. Importantly, many of these age-related disorders lie downstream of the severe muscle loss that inflicts the elderly. We can talk more about this at a later date, if you wish. Obviously, finding effective ways to preserve muscle mass in the rapidly aging population is of benefit to us all.

Our intramuscular creatine reserves dwindle as we enter advanced age, contributing to the aforementioned muscle loss in the elderly. This condition, in combination with creatine’s described neuroprotective effects make creatine supplementation a potentially beneficial option for the elderly. Several key scientific studies have already demonstrated that creatine supplementation provides a marked benefit to the elderly often relatively greater than that observed in middle-aged subjects supplementing under similar conditions. And, although the effect of creatine supplementation on mental processes in the elderly remains to be studied, I am confident that potential studies in this area will provide similarly important findings.

Anyone interested in organizing studies in this area and in need of consultation, please feel free to contact me at my Web site.

After receiving permission from their doctors, I would recommend that the elderly take moderate doses of creatine for a week to see how their digestive systems tolerate it; gastrointestinal distress is an accepted side effect of creatine supplementation. If all goes well with the trial run, then I would suggest the dosing regimen I outline in my guide for the elderly:

Given the propensity of the elderly to renal dysfunction, this dosing regimen omits the loading phase of supplementation.

The specifics of a typical loading phase is given at the following site: A description of creatine’s accepted side effects can be found here:

Passwater: Good information. Okay, let’s take a break and come back and discuss more about creatine biochemistry and the specifics on how to properly use creatine as a dietary supplement next month. WF

Part two of this article is available here.

Dr. Richard Passwater is the author of more than 40 books and 500 articles on nutrition. He is the vice president of research and development for Solgar, Inc. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1984. More information is available on his Web site,

Published in WholeFoods Magazine, June 2009