Creatine monohydrate and Parkinson’s disease. There is still opportunity.

By Blaise Collins, PhD, ACSM-EP-C | Monthly Blog Contributor, Jenerise | Medical & Scientific Director | Neurology, Oncology, Hematology | Exercise Physiologist 

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that, at its core, is a dopamine disorder. Degeneration of dopaminergic pathways often manifests as bradykinesia, abnormal muscle tone, tremors, and postural instability, in addition to a number of non-motor symptoms, and altered markers of oxidative stress and mitochondrial function. Parkinson’s disease disproportionately affects men and tends to be diagnosed after the age of 60.

PD is often described with “On time” and “Off time”, where On time describes that the treatment, often levodopa, is working, presenting as improved independence, quality of life, and improved verbal and facial control. Off time presents as tremors, reduced muscle control, and a reduction in independence. Given the fatigue associated with muscle-related metabolic factors, it stands to reason that increases in Off time will require increased increments of On time in order to recover. 

Creatine monohydrate is widely known for its role in phosphocreatine-mediated ATP regeneration, but its biological effects extend well beyond this system. Creatine has shown to indirectly increase markers of anabolic signaling, such as increased mTOR (a master regulator protein kinase that senses nutrients and growth factors to control cell growth, proliferation, and survival) activity and increases in glycogen synthesis, maintenance of proteolysis, improvements in satellite cell function, stabilization of ATP-dependent ion pumps, neuroprotective mechanisms, and improved antioxidant and anti-inflammatory capacity. 

The use of creatine in people with PD makes sense at a foundational level. The increased energy usage of tremors could be offset by buffering stored ATP; the mitochondrial degradation of PD could be offset indirectly through improving the ATP-PC cycle, and the increase in reactive oxygen species with PD could be reduced through indirect actions of creatine. Essentially, from a mechanistic perspective, we could speculate that increasing ATP reserves could lead to increased energy and cell functioning during OFF periods.

While early, small studies demonstrated a slowing of functional decline and synergy with levodopa, the NET-PD Long-term Study 1 (LS-1, NCT00449865) was ended early after finding no clear benefit of creatine, despite no safety signals versus placebo.

…and this is where the research failed.

The LS-1 study was a Phase III randomized, multicenter clinical trial that included 1,741 participants, and the primary outcome was the effect of creatine on disease modification, the direct effect on the progression of the disease. While a solid clinical outcome for an investigational therapy, creatine is not and has never been meant as a standalone treatment. 

Creatine should not be discounted in this population, but rather, investigated using appropriate outcomes. Future research should use creatine as an add-on to levodopa, should involve an exercise or training component, and should investigate how metabolic biomarkers shift during On times and Off times. The data should be stratified by level of weekly exercise, severity of the disease, and On times versus Off times, to provide a clear picture of how the fundamental overlaps of creatine and PD still have much to be discovered.

Frequently Asked Questions

What is creatine and why do people supplement it?

Creatine is a natural substance your body already makes, and it helps your muscles produce immediate energy. Most people know it as a gym supplement, but it does a lot more than build muscle. It also helps protect the brain, reduce inflammation, and fight cell damage.

What does Parkinson's disease do to the body?

Parkinson's is a progressive brain condition that makes movement harder over time. It causes things like tremors, stiff muscles, and balance problems because the brain stops making enough dopamine. It can also cause fatigue, brain fog, and other symptoms that affect daily life.

Why would creatine be helpful for someone with Parkinson's?

Parkinson's burns through a lot of energy, especially because of tremors and muscle stiffness. Creatine helps the body maintain a large reserve of energy. It may also help protect the brain cells that Parkinson's slowly damages.

Has creatine been studied in people with Parkinson's?

Yes. Multiple small studies demonstrated positive benefits, with one large Phase III clinical study finding no major benefit, but researchers now believe creatine was tested the wrong way, on its own, instead of alongside medication and exercise. The science isn't closed on this one.

Should someone with Parkinson's try creatine?

That's a conversation to have with your doctor or care team. Creatine is considered safe for most people, but every Parkinson's journey is different. What works well alongside one person's treatment plan may not be the right fit for another. 

We all rise together,

Blaise

Reference

Writing Group for the NINDS NET-PD Investigators. A randomized clinical trial of creatine and dopamine progression in Parkinson disease. JAMA, 2015.