Drug Summary: Creatine (Cr) is a molecule produced naturally in the human body at a rate of about one gram per day in the liver, pancreas, and kidneys. People also consume about one gram of creatine per day in their diets, mostly from meat. Creatine is distributed throughout the body, but about 95% is found in skeletal muscles. Once creatine reaches the muscles, it exerts several effects that are believed to be responsible for the improvement of muscle function and energy metabolism. Creatine supplements, as discussed below, have several potential therapeutic benefits in Huntington’s disease. Increasing the amount of creatine in the body can prevent energy depletion, stabilize biological membranes, and initiate other mechanisms that protect cells from damage.
Creatine as an energy buffer^
In muscles, creatine undergoes a chemical reaction that converts it to phosphocreatine (PCr), the molecule that results when a phosphate group is attached to a creatine molecule. When more creatine is ingested the amount of phosphocreatine inside our cells also increases. This can be helpful because phosphocreatine acts as a reservoir for the energy rich molecule ATP in the muscle. When there is not enough ATP in cells, phosphocreatine undergoes a reaction in which it loses the phosphate group and is transformed back to creatine. The phosphate group from phosphocreatine binds to a molecule called ADP and converts it to ATP, thus providing an additional energy supply to cells. The reaction is shown below:
During periods of low energy:
The above reaction effectively increases the amount of ATP molecules available in the cell.
It is important to note that the reaction is reversible. During periods when the cell has sufficient ATP, creatine is converted back to phosphocreatine. At the same time, ATP is converted back to ADP. Phosphocreatine and ADP are then retained in the muscle and serve as forms of energy storage. If energy is depleted again, the reaction is reversed once more, and creatine and ATP are produced. Below is the reaction between creatine and ATP:
During periods of high energy:
Creatine and phosphocreatine also act as shuttles that connect sites of energy production to sites of energy consumption. They transport ATP from the mitochondria, the cell’s energy generator, to the cytosol, the part of the cell where most energy consuming activities occur.
It is tempting to think that phosphocreatine supplements ought to offer the same beneficial effects as creatine supplements since phosphocreatine is the molecule needed to generate ATP. However, research to date has not confirmed this prediction.
Creatine’s role in stabilizing membranes^
Creatine could potentially prevent tissue damage by stabilizing biological membranes, particularly the membranes that form the outer boundary of nerve cells. Inside such cells, the protein mtCK (mitochondrial creatine kinase) exists in two different forms. When activated, it exists in a form that binds to certain molecules in the cell membrane, making the membrane more stable. But various toxic substances called free radicals can inactivate mtCK,making the membrane less stable. (For more information about free radicals, click here.) Once mtCK is inactivated, it transforms into a less stable form that does not bind to membrane molecules, making the membrane less stable. Decreased stability of the membrane allows essential molecules to pass through, leaving the cell susceptible to the loss of important substances. Furthermore, the unstable membrane can allow the entrance of foreign substances that are toxic to the cell. Creatine and phosphocreatine have been found to decrease the release of glutamate, thereby reducing the toxic effects of glutamate on nerve cells.
Other neuroprotective effects^
Researchers speculate that glutamate, an excitatory neurotransmitter, exerts toxic effects on nerve cells due to increased sensitivity of the nerve cells to glutamate. (Click here for background on the neurobiology of HD.) Experiments have shown that phosphocreatine has the ability to decrease the release of glutamate, thereby reducing the toxic effects of glutamate on nerve cells.
Research on Creatine^
Ferrante, et al. (2000)inserted expanded C-A-G repeats into the genes of a group of mice so that they exhibited symptoms similar to human HD. (For more on CAG repeats & HD, click here.) The researchers then supplemented the mice with 1, 2, or 3% creatine, or non-supplemented diets. Assuming that the average 70-kg man eats a mixed diet providing 2,700 kcal/day, a supplementation of 1% Cr would amount to about 6 grams of Cr per day. The researchers found that survival rates increased as supplementation increased from 1% to 2%. However, administration of 3% Cr only marginally improved survival and was not as effective as either 1 or 2% creatine supplementation. Mice supplemented with 1% and 2% Cr also showed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. It is unclear why mice models with diets supplemented with 3% Cr did not exhibit significant improvements. Researchers believe that creatine may be toxic at very high concentrations.
Matthews, et al. (1998) used a toxic compound known as 3 – NP (3- nitroproprionic acid) to mimic the changes in energy metabolism seen in people with HD. (Click here for more on abnormalities in energy metabolism.) 3-NP interacts with one of the protein complexes involved in the respiratory chain and produces lesions in cells due to energy depletion. The researchers discovered that administration of 1% Cr after 2 weeks showed a decrease in nerve cell lesions. The supplemented animals also showed improved energy production compared to non-supplemented mice. Scientists then wondered whether creatine analogs —that is, drugs that are structurally related to creatine but may have different chemical or biological properties—would exert similar neuroprotective effects. Additional experiments showed that animals treated with cyclocreatine, a creatine analog, showed no improvements. Results even indicated that cyclocreatine may be toxic to animals.
The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester are currently conducting a phase III clinical trial to assess the effects of creatine supplements on slowing the progression of symptoms in HD patients. The study is called the Creatine, Safety, Tolerability, & Efficacy in Huntington’s Disease, or CREST-E. Participants are randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study is a fairly large clinical trial. It will involve 44 research centers from around the world and enroll up to 650 participants. The study will last 37 months and is estimated to be completed in December of 2014. (For the most updated information on this study, click here.)
Because creatine is naturally produced by the body and is often consumed in diet, few side effects have been reported thus far, with the exception of two case reports of renal dysfunction due to creatine supplementation. However, most studies show that short-term creatine supplementation produces no adverse side effects. Nevertheless, there has been concern about the effects of long-term supplementation. Some researchers are concerned that long-term supplementation could lead to reduction in the production of creatine by the body or decrease in its transporters. A reduction in creatine transporters was reported in rats fed 4% Cr for 3 to 6 months, equivalent to 24 g/day if given to a 70 kg male. (Conversion Factor: approximately 0.1 g/kg/day) However, a study in young male athletes supplemented with 10g/day of Cr for 2 months did not result in lower transporters. The difference in results has been attributed to the much larger dose of creatine given to the rats.
In conclusion, current studies indicate that short-term creatine supplementation may be safe, but the effects of long-term supplementation are still unknown. Please check back for updates on the phase III clinical trial.
Update (7/1/19): CREST-E, which began in 2008, has since been terminated, with the last update in early 2016. The reason given for why the study was terminated is that “Results of an interim analysis showed that it was unlikely that creatine was effective in slowing loss of function in early symptomatic Huntington’s Disease.” For more information, please click here.
For further reading^
- Ferrante, et al. “Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington’s Disease.” The Journal of Neuroscience. 2000, Jun 15; 20(12): 4389-4397.
A technical article describing the role of creatine in improving symptoms in mouse models of HD
- Matthews, et al. “Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease.” The Journal of Neuroscience. 1998, 18: 156-163.
Very technical article describing the possible therapeutic effects of oral administration of creatine in animal models of HD.
- Persky, et al. “Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate.” Pharmacological Reviews. 2001, Jun; 53(2): 161-176.
Descriptive article on the function of and science behind creatine supplementation
. Website for the Huntington Study Group phase III clinical trial
-A. Zhang, 1-12-11