Re: Creatine & Blood Clots

[Guest guest]

>

> Subject: Creatine & Blood Clots

> To: Supertraining

> Date: Thursday, September 25, 2008, 5:42 AM

> Dear All,

>

> One of the teenage rowers that I help coach had his arm

> swell up this morning. I am not sure of all the details but

> he stopped soon after and went to hospital where it was

> diagnosed as a blood clot. The treating doctor said it was

> due to creatine supplementation.

>

> Please could you let me know if you have heard of /know

> of/aware of any connection between creatine usage and blood

> clots as I am unaware of any? I am sceptical the two are

> related.

>

> Regards,

>

> Grant

> Brisbane, Australia

I did a quick medical search and found no evidence tha creatine causes blood

clots and can think on no scientific reason why that it should.

I found an extensive review on creatine and will post a discussion on possible

adverse reactions of creatine.

Ralph Giarnella MD

Southington Ct USA

************************

Creatine: A Review of Efficacy and Safety

from Journal of the American Pharmaceutical Association

Angie S. Graham, Randy C. Hatton

To Print: Click your browser's PRINT button.

NOTE: To view the article with Web enhancements, go to:

http://www.medscape.com/viewarticle/406673

Creatine: A Review of Efficacy and Safety

Angie S. Graham, Randy C. Hatton

J Am Pharm Assoc 39(6):803-810, 1999. © 1999 American Pharmaceutical Association

Abstract and Introduction

Abstract

Objective: To provide an overview of the data on the efficacy and safety of the

nutritional supplement creatine.

Data Sources: Human studies in English in MEDLINE, Current Contents, BIOSIS,

Science Citation Index, and the popular media (including a LEXIS-NEXIS search

and information from the World Wide Web and lay media) for 1966 to July 1999

using the search terms creatine, creatine supplement#, creatine monophosphate,

and creatine NOT kinase.

Data Synthesis: Creatine use is common among professional athletes. Its use has

spread to college athletes, recreational athletes, and even children. Most

creatine supplement regimens include a loading dose of 20 to 30 grams divided in

4 equal doses for 5 to 7 days, followed by a 2 gram per day maintenance dose.

The increased creatine in the muscle may allow larger stores of phosphocreatine

to build, and provide extra energy in the form of adenosine triphosphate.

Despite the many clinical trials, high-quality research is lacking. Laboratory

investigations of endurance isotonic exercises, strength and endurance during

isotonic exercises, isokinetic torque, isometric force, and ergometer

performance have yielded roughly an equal number of published studies showing a

positive effect or lack of effect. Field studies (i.e., on subjects

participating in sports activities) are less impressive than laboratory studies.

Performance was more often improved for

short-duration, high-intensity activities. Reports have linked creatine to

weight gain, cramping, dehydration, diarrhea, and dizziness. Creatine may

decrease renal function, but only two case reports of this effect have been

published. Creatine appears to be well tolerated in short-term trials.

Conclusion: While creatine may enhance the performance of high-intensity,

short-duration exercise, it is not useful in endurance sports. Because

commercially marketed creatine products do not meet the same quality control

standards of pharmaceuticals, there is always a concern of impurities or doses

higher or lower than those on the labeling. Consumers should balance the quality

of information supporting the use of creatine with the known and theoretical

risks of using the product, including possible renal dysfunction.

Introduction

Creatine use is common among professional athletes, for whom even minute

differences in performance can mean the difference between winning and losing.

They turn to this amino acid compound with hopes of improving muscle mass,

strength, and recovery time. Mark McGwire, Sammy Sosa, and others have openly

acknowledged their use of creatine supplements.[1] The Los Angeles Lakers are

reported to keep tubs of creatine in their locker room. It has been estimated

that 50% of National Football League players, and at least 25% of professional

hockey, baseball, and basketball players take creatine. Many college coaches and

trainers have been quick to follow the lead of the professionals, and there is

concern that high school students and children may use creatine in an attempt to

emulate their sports heros.[2] Because creatine is considered a nutritional

supplement, as defined by the Dietary Supplement and Health Education Act

(DSHEA) of 1994, it is available

over-the-counter in pharmacies, health food stores, and supermarkets.

Some coaches forbid or advise against creatine use because its long-term safety

profile is unknown.[2] The athletics director for the University of South

Carolina has prohibited creatine use without a prescription.[3] Although the

International Olympic Committee regulations state that consuming a substance in

abnormal quantities for the purpose of artificially and unfairly enhancing

performance is " doping, " Olympic athletes are permitted to use creatine because

of its classification as a nutritional supplement. While it could be argued that

creatine should be banned from professional sports, no reliable method currently

exists to test for creatine if such a rule is made.

In 1996 creatine sales were estimated at $50 million. Sales exceeded $100

million in 1997, and for 1998 total sales were expected to exceed $200

million.[2] In 1996 the American public purchased 1.2 million kilograms of

creatine. By 1998 consumption had risen to nearly 4 million kilograms.[4] With

popular magazines running articles with titles such as " The Rise of Creatine,

Nature's Steroid, " " Packaged Pep, " and " Eat Powder: Build Muscle: Burn

Calories, " [5-7] and personal endorsements from stars like the Baltimore Orioles'

Brady and Denver Broncos' Elway,[1] interest in creatine is

unlikely to wane. Every day, more people are considering creatine for its

purported benefits, and many will turn to their community pharmacist for advice.

This article summarizes the available literature on the efficacy and safety of

creatine.

Data Sources and Selection

Data were gathered from the current clinical literature, including MEDLINE,

Current Contents, BIOSIS, and Science Citation Index. Multiple literature

searches were performed in databases between 1966 and July 1999 using the search

terms creatine, creatine supplement# (truncated to capture the key words

" supplement, " " supplements, " " supplementation " ), creatine monophosphate, and

creatine NOT kinase. Citations were limited to human studies and the English

language. Hand searching the reference lists of articles identified additional

studies. A magazine and lay journal database available through Melvyl, the

database platform of the University of California at San Francisco library, was

also searched using the key word creatine. The World Wide Web was searched using

LEXIS-NEXIS and by entering the key word creatine into a metasearch engine,

scanning the results, and omitting any pages devoted strictly to advertising and

sales.

Proposed Mechanism

Creatine occurs naturally in foods, mostly in meat, fish, and other animal

products. A typical diet includes 1 to 2 grams of creatine daily. Vegetarians

consume much less creatine. Endogenous creatine is synthesized from arginine,

glycine, and methionine in the liver, pancreas, and kidney. It is then actively

transported from the plasma into skeletal muscle, the location of 95% of the

body's total creatine content. Until creatine is broken down to creatinine, it

is in dynamic equilibrium in the muscle as either creatine or phosphocreatine,

according to the following equation:

Phosphocreatine + ADP (adenosine diphosphate) creatine + ATP (adenosine

triphosphate)

In a 70 kg man, approximately 2 grams of creatine are converted to creatinine

and excreted every 24 hours.[8,9] Most creatine regimens involve intake of 20 to

30 grams divided into 4 equal doses each day, for 5 to 7 days, followed by a

maintenance dose of 2 grams per day divided into 4 doses.[10] Supplementation

regimens aim to increase the total creatine transported into muscle tissues.

Researchers have shown that supplementation can increase total muscle creatine

content by 10% to 20%, with 20% to 40% in the form of phosphocreatine.[11]

In resting muscle, aerobic respiration produces ATP, which is used not only to

meet basal energy requirements but also to donate a phosphate group to creatine

and replenish phosphocreatine stores. During brief periods of high-intensity

exercise, ATP demand may increase to several hundred times the amount used at

rest. Phosphocreatine acts as an immediate source of phosphate groups to

rephosphorylate ADP to ATP. When phosphocreatine stores run low, performance

deteriorates rapidly because the ATP supply is insufficient to meet demand, and

aerobic metabolic pathways take over. It has been estimated that both ATP and

phosphocreatine stores are depleted after about 10 seconds. By increasing the

amount of total creatine in the muscle, creatine supplements raise

phosphocreatine levels. Increased phosphocreatine increases ATP levels and

extends the duration of high-intensity exercise.[9] Therefore, creatine is

considered an ergogenic aid, defined as a " means to

enhance energy utilization, including energy production, control, and

efficiency. " [12]

Clinical Trials

The ability of creatine supplementation to increase strength and improve

athletic performance was first suggested by a study in which patients received

1.5 grams of creatine daily for 1 year.[13] Seven patients with gyrate atrophy

of the choroid and retina received creatine supplementation to slow the

progression of their disease. Patients experienced a 10% weight gain early in

their treatment, and some patients reported increased strength. One patient who

was an active runner improved his 100-meter sprint time by more than 10%, from

17 to 15 seconds.

Since the publication of the above study in 1981, dozens of clinical trials have

examined the effects of creatine supplementation on exercise performance;

however, small sample sizes and poor study designs have limited this research,

and results are inconsistent. Trials have enrolled between 6 and 36 subjects,

have used differing dosage regimens, and have involved both athletes and

untrained individuals. Even though one can speculate that increased availability

of ATP would dramatically enhance the performance of trained athletes, results

have varied in this group, as well. Because of the small sample sizes enrolled,

response differences generally must be of a large magnitude to achieve

statistical significance; however, a number of studies have shown that,

regardless of the characteristics of the subjects or the type of exercise

performed, creatine supplementation provides no positive benefit.[14-42]

Creatine supplementation studies have involved many

types of exercise, including isotonic strength and endurance; isokinetic

torque; isometric force; arm, cycle, and kayak ergometer performance;

high-intensity prolonged exercise; and endurance tasks at lower intensity. In

many cases, exercise tasks that can be measured and quantified in the laboratory

setting do not encompass the full spectrum of motion and muscle used in an

actual sports activity. Therefore, a positive effect in a laboratory test may

not be predictive of improved performance in a sporting event.

Eight trials measured the effect of creatine supplementation on strength and

endurance during isotonic exercise, described as muscle contraction against a

constant load (see Table 1).[14-17,43-46] Most of these studies involved bench

press measurements or other weight lifting activities performed by college

athletes. In five of the studies, creatine supplementation was associated with

improved performance,[14,43-46] but in three studies no statistically

significant change was observed.[15-17]

Five trials measured isokinetic torque and also produced variable

results.[15,18,19,45,47] Torque is the turning effect produced when force is

applied to a rotational axis; an isokinetic measurement of torque causes the

attached muscles to change length at a programmable, constant speed (e.g., arm

or leg curls using Nautilus equipment). Isokinetic torque production was

increased relative to placebo in three of the studies.[18,45,47] A fourth study

involving 20 female athletes found a statistically significant improvement in

isokinetic torque during the 10 weeks of maintenance supplementation with 5

grams/day, although no improvement was noted during the initial 4 days of

supplementation with 20 grams/day.[19] In the fifth study, also using female

athletes as subjects, no improvement was observed following creatine use.[15]

The trials are summarized in Table 1.

Four studies examined the effect of creatine supplementation on isometric force

(Table 1).[18,20,48,49] Isometric exercises maintain muscle contraction, so that

contraction produces increased tension at a constant overall muscle fiber

length. An isometric contraction occurs when a muscle develops tension but its

fibers never shorten, such as when one pushes against a wall or other immovable

object. The four studies of isometric exercise measured grip strength, ankle

extensions, voluntary contractions, and static quadriceps force production.

Improved performance was observed in three studies.[20,48,49] The results are

difficult to interpret, because the largest study involved only 10 subjects[49]

and because exercise activities seldom consist of isometric contractions alone.

Several studies have used arm, cycle, or kayak ergometer performance to measure

the effects of creative supplementation on exercise performance (Table

2).[16,21-31,44,50-57] In most of these trials, subjects cycled on a bicycle

ergometer. Study designs varied widely, with seven trials using athletes as

subjects[16,23,25,27,31,44,56] and the rest using healthy adults. Out of 22

studies of creatine's effects on muscular power, 13 showed a statistically

significant positive effect following supplementation,[16,21-23,44,50-57] 8

found no effect,[21,24-30] and 1 produced equivocal results, with 1 group from

the crossover study showing benefits and the other demonstrating no change.[31]

The results are summarized in Table 2.

Research has extended beyond the controlled setting of the laboratory to field

studies of actual athletic performance. A summary is provided in Table 3. Of six

studies assessing the effect of creatine on high-intensity, short-duration

sports such as sprint running and swimming,[14,17,25,32,33,58] only one

demonstrated a treatment effect.[58]

Creatine has also been studied in prolonged high-intensity exercise, such as

treadmill running or cycling to exhaustion (Table 3). Of eight

placebo-controlled laboratory studies,[20,22,34,35,55,59-61] four resulted in

performance improvement in subjects using creatine.[55,59-61] In field tests,

positive response was noted in only one[62] of six trials.[23,25,32,36,37,62]

Eleven studies have investigated the effects of creatine on endurance tasks (see

Table 4), involving prolonged aerobic exercise, such as distance running or

cycling. None of the six laboratory-based trials found a statistically

significant improvement in performance.[24,27,38-41] A statistically significant

positive difference between the placebo and treatment groups was observed in

two[58,62] of the five field trials.[36,38,42,58,62] These results suggest that

creatine supplementation is unlikely to improve performance of endurance sports.

In summary, creatine supplementation does appear to increase creatine levels in

muscle tissue.[11] Higher creatine levels in muscle tissue should correlate with

improved performance of short-duration, high-intensity tasks that are likely to

use the ATP-phosphocreatine system as a primary source of energy. Positive

results, however, have been difficult to attain and consistently replicate,

especially outside the laboratory setting. Some researchers have observed that

only those subjects whose baseline creatine concentrations were at the lower end

of the normal range benefited from supplementation.[63] This may account for the

variable results seen in clinical studies. Some variation in results may also be

attributed to a " placebo effect, " which is well known to be easily induced in

athletic events and not noted in any of these studies. Without further, more

careful research, the reasons for the discrepancies in trial results will remain

unclear.

Adverse Effects

Anecdotal reports have linked creatine supplementation with cramping,

dehydration, diarrhea, and dizziness.[2] The Food and Drug Administration (FDA)

has warned consumers to consult a physician before beginning creatine

supplementation.[10] The Association of Professional Team Physicians has

cautioned that creatine may cause dehydration and heat-related illnesses,

reduced blood volume, and electrolyte imbalances,[64] and some athletes drink

large quantities of water hoping to avoid such effects.[2] Creatine is known to

be osmotically active, so that higher intracellular creatine levels may

redistribute body water from extracellular fluids or from the general

circulation into muscle cells.[46] Judgingfrom the short-term clinical trials

performed to date, however, creatine appears to be well tolerated.

No adverse effects were noted in clinical trials, although many trials reported

increased body mass in the subjects receiving

supplementation.9,11,12,14,16,21,30,38,40,43,44,46,48,50,51,54,57,63 It was

previously hypothesized that weight gain observed in subjects using creatine

might result from an increased rate of contractile protein synthesis,[12] but

most researchers now agree that the additional body weight results from water

retention. Hultman and colleagues[65] reported significant reductions in urinary

output in the initial stages of creatine supplementation. Other researchers have

reported increases in skeletal muscle volume, total body water, and

intracellular fluid volume after a few days of supplementation. The weight gain

observed ranged from 0.7 to 2.0 kg following 5 to 14 days of

supplementation.[10] This much weight gain may hinder athletes engaged in

endurance sports.

Creatine is broken down and excreted by the kidney as creatinine. Creatine

supplementation has been shown to increase 24-hour creatine, creatinine, and

urate concentrations.[66] At least one study has found that creatine

supplementation increased serum creatinine levels significantly, although levels

remained between 1 and 1.5 mg/dL, a normal range for people undergoing intense

physical training.[11] The lack of any adverse renal effects in clinical trials

to date suggests that subjects with normally functioning kidneys can eliminate

the increased creatinine load that results from creatine supplementation;

however, some experts have warned that long-term creatine use could decrease

kidney function, and recent case reports[67,68] suggest that not all patients

are able to sufficiently process excess creatinine.

The April 25, 1998, issue of the Lancet[67] reported a case of renal dysfunction

following creatine use. The patient was a 25-year-old man receiving cyclosporine

for steroid-resistant focal segmental glomerulosclerosis. Although his

cyclosporine levels had been stabilized within the therapeutic range, his renal

function declined between appointments in June 1997 and mid-October 1997.

Between the two dates, serum creatinine concentrations increased from 1.2 mg/dL

to 1.8 mg/dL, with a corresponding decrease in creatinine clearance from 93

mL/minute to 61 mL/minute. The patient denied use of nephrotoxic medications,

but reported initiating creatine supplementation with a loading dose of 5 grams

3 times per day for 1 week, and a maintenance dose of 2 grams per day. Renal

function returned to baseline 1 month after creatine supplementation was

discontinued.

A second case report[68] describes interstitial nephritis in a previously

healthy 20-year-old man using creatine. The patient had begun using 5 grams of

creatine 4 times per day approximately 4 weeks prior to the onset of symptoms.

He presented to the hospital with a 4-day history of nausea, vomiting, and

bilateral flank pain, and was found during physical exam to be dehydrated and

experiencing diffuse abdominal tenderness. Laboratory studies revealed a serum

creatinine level of 1.4 mg/dL, and 4+ protein and 1+ blood in the urine. While

the patient was hospitalized and treated with pain medications and intravenous

fluids, his blood pressure rose from 140/90 to 160/100 mm Hg, his serum

creatinine reached a peak of 2.3 mg/dL, and his urinary protein excretion was

472 mg per day. Renal biopsy demonstrated acute focal interstitial nephritis and

focal tubular injury. The patient's laboratory values and symptoms eventually

normalized.

The studies included in this review reported no serious adverse effects, but few

included a mechanism for formally assessing adverse effects, and they all

involved short-term administration to young, healthy volunteers. It is not known

what effects may be produced in other patient populations. Bell from the

Houston Astros was hospitalized twice in 1998 for renal dysfunction, and has

publicly blamed creatine for his ailments.[1] It cannot be stated unequivocally

that creatine is harmful to the kidney, but until the relationship is clarified

it would be prudent to avoid creatine supplementation in all patients with

impaired renal function and to advise patients to seek medical attention

immediately if they experience flank pain, hematuria, nausea, or vomiting while

using creatine.

There are no controlled toxicology studies using the doses recommended to

enhance athletic performance. In fact, although most creatine manufacturers

recommend loading with 20 to 30 grams per day for 5 to 7 days and then cutting

back to a maintenance dose of 2 grams per day, some athletes choose to

" mega-dose " creatine. Brady of the Orioles told reporters that he uses

10 times the recommended dose.[1] Yet, even the maintenance dose recommended by

manufacturers has not been proven safe for long-term use.

All nutritional supplements carry a risk of contamination with impurities,

because their manufacturers are not bound by the same manufacturing practices

that FDA requires for drugs. The high doses recommended for creatine

supplementation, and the even higher doses used by some individuals, could

increase exposure to a toxic impurity.[8] Contamination, like that reported with

tryptophan and 5-hydroxytryptophan, is possible. Unsubstantiated reports on the

Internet claim that some creatine products are contaminated with dicyandiamide

and dihydrotriazine, which have unknown effects,[69] and others claim that some

creatine powders are mixed with baking soda, or certain impurities such as rat

hairs.[2] Studies should investigate whether contamination causes adverse

effects