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Creatine is a trendy supplement these days, judging by how many people ask me about it lately. My intuition has always been that it’s fine to use for a short-term event, like before a hard workout, a competition, or maybe an intense exam… but probably not for energy on a daily basis, mostly because I’d wonder why it was needed. It seemed like a band-aid to me, regenerating already used ATP because ongoing production is insufficient to sustain metabolic demands. Not only that, but since ATP is a very biochemically “expensive” molecule, I suspected that those who rely on creatine regularly might more or less be “running on fumes,” and would be likely to crash once they’d completely depleted their reserves. I’ve seen several patients who have experienced exactly this after creatine supplementation.
In light of the Cell Danger Response Cycle, I think this makes even more sense.
Creatine, ATP, and Uric Acid Accumulation
Briefly, ATP is Adenosine Tri-Phosphate (three phosphate groups attached to an adenosine molecule, a type of purine). The energy is in the phosphate bonds; releasing one phosphate for energy then renders the remaining molecule ADP (Adenosine Di-Phosphate). Creatine is basically just a delivery mechanism for the phosphate groups — it donates its own phosphate to ADP, thus regenerating ATP so that the molecule can be used for energy a second time.
During intense exercise, this is important, as ATP gets used up rapidly, while ADP and AMP (adenosine mono-phosphate) accumulate. If you have creatine phosphate on hand, the existing ATP pool goes further.
Once all the phosphates the creatine brings to the table are used up, the body can borrow an extra phosphate from the ADP pool, combining two ADPs to make one more ATP, and one AMP.
AMP eventually can’t get used anymore, and it gets broken down into uric acid—so, not surprisingly, this too accumulates during intense exercise. Uric acid levels rise significantly higher with increasing exercise intensity. This makes sense: high demand in the moment means we need to wring every last phosphate out of that original ATP molecule. More moderate intensity exercise doesn’t raise uric acid levels nearly as much.
CDR1, ATP Dumping, and Uric Acid
Based on the characteristics Naviaux described for the three stages of the Cell Danger Response, I speculated here on blood markers that might correspond to someone locked into one of the three stages, rather than progressing through them with full resolution.
CDR1 is characterized by cells dumping their ATP into the extracellular space, sending signals to the rest of the body that something is wrong, and thus recruiting the immune system’s inflammatory response. Like ATP used in exercise, that ATP too should get broken down into uric acid—so we’d expect uric acid to accumulate for those locked in an unresolved CDR1 state. (This is just my reasoning at this point—I’m not familiar with any studies that corroborate this, but it makes sense based on the mechanisms.)
So, someone with cells locked in CDR1 of the cell danger response should experience low energy due to ATP depletion—but that’s an adaptive mechanism. It’s what the body is trying to do in order to recruit an inflammatory response against a perceived threat.
If that individual then takes creatine, and manages to limp along for awhile by regenerating already used ATP, he’ll be working at cross purposes against what the body is trying to do. This isn’t a time to put a brave face on and keep going; it’s a time to stop and repair. Not only that, but in theory, the uric acid accumulating from the increased ATP expenditure might amplify the CDR1 signal, which might (again, in theory) hinder resolution and progression to CDR2.
It also very likely sets up a harder crash later on. I see something very similar occur in people whose adrenals are severely under-functioning due to a systemic depletion of energetic resources. If we add adrenal support, suddenly they feel much better, and decide it’s time to tackle the “to-do” list they never had the energy to get to before. But if the underlying problem hasn’t yet been corrected, it’s not uncommon for people to “overdo” it, and then pay for it for days after the fact. If this cycle repeats too many times, it can eventually lead to Chronic Fatigue Syndrome.
Suppressing symptoms always forces the body to compensate in some other way—hindering, rather than working with the natural process of healing.
Who Shouldn’t Take Creatine?
One warning signal that creatine might actually make the problem worse is if someone experiences increased fatigue post-exertion: feeling more tired after a workout than you did beforehand, for example. Post-exertional malaise is associated with low adenosine (the building block for ATP, ADP, and AMP)—in other words, there’s no “reserves.” Taking creatine for someone like this would be like living on credit cards with a high interest rate, and with no savings to pay it back. It’s not a long-term strategy, and it’ll hurt worse in the end. Or, alternatively: if your house is on fire, you follow the smoke until you locate the fire, and then you put it out… you don’t turn off the fire alarm and go back to bed. There’s a problem somewhere, and the cause needs to be found and addressed.
Those who actually have Chronic Fatigue Syndrome or Myalgic Encephalomyelitis are further along in this process, and very likely already stuck in a cell danger response. The patients I’ve seen who have experienced a severe post-creatine crash usually fall into this category, though I’ve seen variations on the severity of the crash—probably because there’s a spectrum here.
Who Can Safely Take Creatine?
Those who don’t experience post-exertional fatigue are less likely to have a problem with occasional creatine use.
I still wouldn’t use it on a daily basis, only because I’d imagine someone who wasn’t in a cell danger response shouldn’t notice much of a benefit from using it daily (unless you’re working out hard on a daily basis). If you’re noticing a marked benefit just for daily activities, that indicates there’s likely a problem that needs to be found and addressed. At least I suspect so.
