Phosphocreatine

• Rapid ATP regeneration
• Enhanced energy availability during high-intensity exercise
• Support for cellular energy homeostasis
• Potential neuroprotective effects

• Cellular pH buffering
• Temporal energy buffering
• Spatial energy transport within cells
• Support for mitochondrial function
• Potential cardioprotective effects

Phosphocreatine (PCr) is a high-energy phosphate compound that plays a critical role in cellular energy metabolism, particularly in tissues with high and fluctuating energy demands such as skeletal muscle, cardiac muscle, and brain. The primary mechanism of action of phosphocreatine centers on its ability to rapidly regenerate adenosine triphosphate (ATP), the universal energy currency of cells, through a reversible reaction catalyzed by the enzyme creatine kinase (CK). This reaction, known as the Lohmann reaction, is represented as: PCr + ADP + H+ ⇄ ATP + Cr. The standard free energy of hydrolysis of phosphocreatine (-10.3 kcal/mol) is greater than that of ATP (-7.3 kcal/mol), making the transfer of the phosphoryl group from PCr to ADP thermodynamically favorable.

This energy difference enables PCr to serve as an immediate energy buffer during periods of high ATP demand. When cellular ATP is rapidly consumed during intense activity, such as high-intensity exercise or neuronal firing, the PCr system can regenerate ATP much faster than other metabolic pathways like glycolysis or oxidative phosphorylation. This temporal energy buffering function allows cells to maintain relatively constant ATP levels despite dramatic fluctuations in energy demand. Beyond its role in ATP regeneration, PCr also functions as a spatial energy buffer through the ‘phosphocreatine shuttle’ system.

Different isoforms of creatine kinase are strategically located within cells – at sites of energy production (e.g., mitochondria) and at sites of energy consumption (e.g., myofibrils in muscle). This arrangement allows energy to be efficiently transported from production sites to utilization sites via the PCr/Cr system. Additionally, PCr serves as an important intracellular pH buffer. During high-intensity exercise, the hydrolysis of PCr consumes a hydrogen ion (H+), helping to counteract the acidification that occurs from lactate production during anaerobic glycolysis.

This buffering effect may delay fatigue during intense exercise. In the brain, the PCr system is particularly important for maintaining energy homeostasis in neurons, which have high and fluctuating energy demands but limited capacity for energy storage. Neuronal PCr helps sustain ATP levels during periods of intense activity, supporting functions such as neurotransmission, ion pumping, and signal transduction. It’s important to note that phosphocreatine itself is not directly available as an oral supplement.

Instead, oral creatine supplementation (typically as creatine monohydrate) increases the total creatine pool in tissues, which can then lead to increased phosphocreatine levels through the action of creatine kinase. The effectiveness of this indirect approach varies by tissue, with skeletal muscle showing the most significant increases in PCr following creatine supplementation.

Phosphocreatine (PCr) is not directly available as an oral supplement for general consumption. The phosphorylated form of creatine cannot effectively cross cell membranes

when administered orally, and

it is rapidly degraded in the gastrointestinal tract. Instead, phosphocreatine levels in tissues are typically increased indirectly through oral supplementation with creatine monohydrate or other creatine forms. In medical settings, injectable phosphocreatine (also called creatine phosphate) is sometimes used for specific clinical conditions, particularly in some countries for cardiac protection during surgery or for treating certain cardiac disorders, but

this is administered under medical supervision and is not available as a dietary supplement.

Phosphocreatine (PCr) has extremely poor oral bioavailability and is not effectively absorbed when taken orally. The phosphorylated form of creatine cannot efficiently cross cell membranes or the intestinal barrier due to its size, polarity, and charge characteristics. Additionally, phosphocreatine is unstable in the acidic environment of the stomach and is rapidly degraded before absorption can occur. For these reasons, direct oral supplementation with phosphocreatine is not a viable approach for increasing tissue PCr levels.

Instead, oral supplementation with creatine monohydrate or other creatine forms is used to increase the total creatine pool in tissues, which can then lead to increased phosphocreatine levels through the action of creatine kinase within cells. When creatine monohydrate is supplemented orally, it has a relatively high bioavailability of approximately 80-100%. Once absorbed, creatine is transported to various tissues, particularly skeletal muscle, where it can be phosphorylated to form phosphocreatine. The extent to which oral creatine supplementation increases phosphocreatine levels varies by tissue, with skeletal muscle showing increases of approximately 20% in PCr concentration following standard creatine loading protocols.

Oral phosphocreatine supplementation is not effective; instead, focus on methods to enhance creatine absorption, Consuming creatine with carbohydrates and/or protein can enhance creatine uptake into muscle cells through insulin-mediated mechanisms, Exercise prior to creatine ingestion may increase creatine uptake into the exercised muscles, Maintaining adequate hydration supports optimal creatine transport and utilization, Dividing the daily creatine dose into smaller portions (especially during loading phases) may improve overall absorption, Some research suggests that consuming creatine with alpha-lipoic acid may enhance creatine uptake, though evidence is limited, Avoiding caffeine consumption at the same time as creatine may be beneficial, as some studies suggest caffeine might interfere with creatine retention

Since phosphocreatine cannot be directly supplemented orally, timing recommendations focus on creatine supplementation to indirectly increase phosphocreatine levels. For creatine supplementation, consistency is generally more important than specific timing. However, some evidence suggests that taking creatine post-workout may be slightly more effective than pre-workout for increasing muscle creatine retention, though the differences are likely minimal. During the loading phase (if used), spreading the daily dose into 4-5 smaller doses throughout the day may help maximize absorption and minimize potential gastrointestinal discomfort.

Taking creatine with meals, particularly those containing carbohydrates and protein, may enhance uptake through insulin-mediated mechanisms. For maintenance dosing, a single daily dose is typically sufficient, and can be taken at any consistent time of day. For individuals using creatine primarily for cognitive or neurological benefits, some evidence suggests that morning dosing might be preferable, though research in this area is limited.

• Not applicable for oral supplementation as phosphocreatine is not directly available as an oral supplement
• For injectable phosphocreatine (medical use only): potential for injection site reactions
• For injectable phosphocreatine (medical use only): allergic reactions in rare cases
• For creatine monohydrate (used to indirectly increase phosphocreatine): potential gastrointestinal discomfort
• For creatine monohydrate: potential water retention during initial loading phase

• For injectable phosphocreatine (medical use only): hypersensitivity to the active substance or excipients
• For injectable phosphocreatine (medical use only): severe renal impairment (as determined by medical professionals)
• For creatine supplementation to increase phosphocreatine: pre-existing kidney disease (theoretical concern, though research with creatine monohydrate suggests minimal risk in healthy individuals)
• For creatine supplementation: pregnancy and breastfeeding (due to insufficient safety data)
• For creatine supplementation: individuals with disorders of creatine metabolism

• For injectable phosphocreatine (medical use only): specific interactions should be evaluated by medical professionals
• For creatine supplementation to increase phosphocreatine: nephrotoxic medications (theoretical concern)
• For creatine supplementation: NSAIDs (theoretical concern for combined kidney stress, though evidence is limited)
• For creatine supplementation: caffeine (may potentially reduce creatine retention, though evidence is mixed)
• For creatine supplementation: diuretics (may affect hydration status and potentially creatine effectiveness)

Not applicable for oral phosphocreatine supplementation as

it is not directly available as an oral supplement. For injectable phosphocreatine (medical use only), dosages are determined by medical professionals based on the specific condition and patient characteristics. For creatine monohydrate supplementation (used to indirectly increase phosphocreatine levels), doses up to 30 g/day for short periods (loading phase) and 5 g/day for years of continuous use have been shown to be safe in healthy individuals with normal kidney function.

However , most protocols recommend 20-25 g/day for the loading phase and 3-5 g/day for maintenance.

Phosphocreatine (PCr) itself is not FDA-approved as a dietary supplement or drug in the United States. Injectable phosphocreatine sodium salt (also called creatine phosphate sodium) is not FDA-approved for any medical condition in the US. However, creatine monohydrate, which is used to indirectly increase phosphocreatine levels in tissues, is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As a dietary supplement, creatine monohydrate is not subject to the same pre-market approval process as pharmaceutical drugs.

Manufacturers are responsible for ensuring the safety of their products and the truthfulness of their label claims, but the FDA does not review or approve dietary supplements before they are marketed. The FDA can take action against unsafe products or false claims after they reach the market.

Eu: In the European Union, phosphocreatine itself is not approved as a dietary supplement. Injectable phosphocreatine sodium salt is approved as a pharmaceutical in some EU countries, particularly for cardiac indications, though availability varies by country. Creatine monohydrate is regulated as a food supplement. The European Food Safety Authority (EFSA) has approved the health claim that ‘creatine increases physical performance in successive bursts of short-term, high-intensity exercise’ for products providing at least 3g of creatine per day.

Russia: Injectable phosphocreatine sodium salt (marketed as Neoton) is approved as a pharmaceutical drug for various cardiac indications. It has been used clinically in Russia and some Eastern European countries for decades, particularly for myocardial protection during cardiac surgery and for treating certain cardiac conditions.

China: Injectable phosphocreatine sodium salt is approved as a pharmaceutical in China for certain cardiac indications. Creatine monohydrate is available as a dietary supplement, though specific regulations may differ from those in Western countries.

Japan: Phosphocreatine is not approved as a dietary supplement in Japan. Creatine monohydrate is available as a dietary supplement, though it is subject to specific Japanese regulations for food additives and supplements.

Australia: The Therapeutic Goods Administration (TGA) does not approve phosphocreatine as a dietary supplement. Creatine monohydrate is regulated as a complementary medicine and is widely available.

Not applicable for direct supplementation

Phosphocreatine is not directly available as an oral supplement due to poor bioavailability and stability issues. Instead, phosphocreatine levels are typically increased indirectly through creatine monohydrate supplementation. Creatine monohydrate is one of the most cost-effective supplements available, typically costing between $0.03 and $0.10 per gram. At the standard maintenance dose of 3-5 grams per day, this translates to approximately $0.09 to $0.50 per day or $2.70 to $15 per month.

The loading phase (if used) of 20-25 grams per day for 5-7 days would cost approximately $0.60 to $2.50 per day during that period. Injectable phosphocreatine (sodium phosphocreatine) for medical use is significantly more expensive and is only available through medical channels in certain countries. The cost varies widely depending on the country, healthcare system, and specific formulation.

When considering the value of increasing phosphocreatine levels through creatine monohydrate supplementation, the cost-benefit ratio is exceptionally favorable for most users. Creatine monohydrate is one of the most thoroughly researched and consistently effective supplements available, with a well-established ability to increase muscle phosphocreatine levels by approximately 20%. This increase translates to meaningful performance benefits for high-intensity, short-duration activities, particularly those involving repeated efforts. For strength and power athletes, the performance benefits relative to the low cost make creatine monohydrate one of the highest-value supplements available.

For general fitness enthusiasts, the benefits may be less pronounced but still significant relative to the minimal cost. For older adults, creatine supplementation may offer additional value through potential benefits for muscle mass preservation and cognitive function, though more research is needed in these areas. The value proposition is particularly strong when considering that many other supplements marketed for similar purposes (strength, power, muscle gain) are significantly more expensive and often have less scientific support. It’s worth noting that approximately 20-30% of individuals may be ‘non-responders’ to creatine supplementation, experiencing minimal increases in muscle phosphocreatine content and corresponding performance benefits.

For these individuals, the value is obviously reduced. Additionally, vegetarians and vegans typically have lower baseline muscle creatine and phosphocreatine levels and may experience greater relative benefits from supplementation, potentially increasing the value proposition for these populations.

Phosphocreatine is highly unstable in solution and particularly in acidic environments, making it unsuitable for oral supplementation. In its pure form, phosphocreatine sodium salt (used for injectable formulations in medical settings) typically has a shelf life of 2-3 years when stored properly under controlled conditions. Once in solution, phosphocreatine degrades much more rapidly, with significant degradation occurring within hours at room temperature. Injectable phosphocreatine formulations for medical use typically have a shelf life of 1-2 years when stored properly, but once reconstituted, they must be used within a short time frame as specified by the manufacturer (typically 24 hours or less when refrigerated).

In the body, phosphocreatine has a relatively rapid turnover rate, with approximately 1-2% of the total phosphocreatine pool being degraded and resynthesized per minute at rest.

For injectable phosphocreatine formulations (medical use only): Store in a cool, dry place according to manufacturer’s instructions, typically between 15-25°C (59-77°F). Protect from light and moisture. Once reconstituted, store according to manufacturer’s instructions, typically refrigerated (2-8°C) and use within the specified time frame. For creatine monohydrate supplements (used to indirectly increase phosphocreatine levels): Store in a cool, dry place away from direct sunlight.

Keep the container tightly closed when not in use to prevent moisture absorption. Avoid exposure to high temperatures (above 30°C/86°F) which can accelerate degradation. If the original packaging includes a desiccant packet, keep it in the container. After mixing creatine monohydrate in liquid, consume promptly as creatine gradually degrades to creatinine in solution, particularly in acidic beverages.

Acidic conditions (phosphocreatine rapidly degrades in acidic environments), Hydrolysis in aqueous solutions (phosphocreatine is unstable in water), Elevated temperatures (accelerate degradation reactions), Enzymatic degradation by phosphatases, Exposure to certain metal ions that can catalyze degradation, Prolonged storage in solution, Freeze-thaw cycles (for solutions), Exposure to light (particularly UV light), Microbial contamination (for solutions), Extreme pH conditions (both highly acidic and highly alkaline)

Synthesis Methods

Natural Sources

Quality Considerations

Phosphocreatine (PCr) has a relatively short history as a recognized biochemical compound compared to many other nutritional supplements. The compound was first discovered in 1927 by Philip Eggleton and his wife Grace Eggleton, who identified a labile phosphorus compound in muscle tissue that was distinct from ATP. Shortly thereafter, Cyrus Fiske and Yellapragada Subbarow independently isolated the same compound and named it phosphocreatine. The fundamental role of phosphocreatine in energy metabolism was elucidated in 1934 by Karl Lohmann, who described the reversible reaction between phosphocreatine and ADP to form ATP and creatine, catalyzed by the enzyme creatine kinase.

This reaction, now known as the Lohmann reaction, established phosphocreatine’s critical role in cellular energy homeostasis. Throughout the mid-20th century, research on phosphocreatine focused primarily on its biochemical properties and physiological role in muscle metabolism. The development of 31P nuclear magnetic resonance spectroscopy in the 1970s and 1980s allowed for non-invasive measurement of phosphocreatine levels in living tissue, greatly advancing our understanding of its dynamic role in energy metabolism during exercise and recovery. While phosphocreatine itself has never been widely available as an oral supplement due to its poor bioavailability and stability, injectable phosphocreatine (as sodium phosphocreatine) has been used medically in some countries, particularly in Eastern Europe and Russia, since the 1980s.

These injectable formulations have been used primarily for cardiac protection during surgery and for treating certain cardiac conditions. The most significant development related to phosphocreatine supplementation came in the 1990s with the popularization of creatine monohydrate as a sports supplement. Following the 1992 Barcelona Olympics, where several medal winners reportedly used creatine supplements, research and commercial interest in creatine supplementation exploded. The primary ergogenic mechanism of creatine supplementation was understood to be its ability to increase muscle phosphocreatine stores, thereby enhancing high-intensity exercise performance.

Landmark studies by Paul Greenhaff and colleagues in the early 1990s demonstrated that oral creatine supplementation could increase muscle phosphocreatine content by approximately 20% and enhance phosphocreatine resynthesis following intense exercise. This research established the scientific basis for creatine supplementation as an indirect means of increasing phosphocreatine levels. In the 21st century, research on phosphocreatine has expanded beyond its role in muscle to include its importance in brain energy metabolism and potential neuroprotective effects. Studies have shown that oral creatine supplementation can increase brain phosphocreatine levels, albeit to a lesser extent than in muscle, opening new avenues for therapeutic applications in neurological conditions.

Today, while phosphocreatine itself remains unavailable as an oral supplement, creatine monohydrate and other creatine forms are among the most widely used and thoroughly researched sports supplements, with their primary mechanism of action being the enhancement of phosphocreatine stores in tissues.

Investigation of creatine supplementation on brain phosphocreatine levels and cognitive function in aging populations, Studies examining the effects of creatine supplementation on phosphocreatine levels and muscle function in various clinical populations, Research on the potential neuroprotective effects of increased brain phosphocreatine through creatine supplementation in neurodegenerative conditions, Exploration of novel creatine delivery methods to enhance phosphocreatine synthesis in target tissues