Organ Meats: Wild predators eat these juicy bits first, and so should you. Well, at least occasionally. Here’s why.

 

tip-eat-gross-organ-meats

 
For those who grew up eating traditional Western diets, the thought of eating kidneys or intestines can be cringe inducing. But organ meats have always been the preferred animal protein source for hunters across a wide range of cultures. In fact, even in the animal kingdom most predators go after organs first (namely the liver) before eating the more muscular cuts. What is it that these predators know about organ meats that most people don’t?

The Secret is Nutrient Density

Organ meats are some of the most nutrient dense foods on the planet. They’re quality protein sources that are also rich in essential fatty acids, vitamins, and minerals. When classifying the nutrient density of food (nutrients per serving divided by weight), organ meats top the list.

Compare 4 ounces of beef liver with 4 ounces of chicken breast (without skin). While the liver and chicken have pretty similar levels of protein and essential amino acids, the liver blows chicken breast out of the water when you look at the vitamin and mineral content.

The Best Bits

Liver

This can be eaten raw or cooked and can be prepared in a variety of ways: jerky, part of a pate, or ground up with other meat in burgers or meatballs. Liver is also a good source of vitamin A, all of the B vitamins, vitamin C, iron, phosphorous, selenium, copper, manganese, and zinc.

Vitamin A plays a role in immune function through the development of both t-cells and b-cells. Manganese plays a role in the metabolism of carbs, amino acids, and cholesterol. Zinc supplementation has been shown to augment the effects that exhaustive exercise has of decreasing thyroid and testosterone levels. In studies, the participants that supplemented with zinc had higher hormone values after four weeks.

Common sources: Beef, lamb, buffalo, chicken, turkey, duck, geese.

Heart

Since the heart is a tough muscle, it eats more like a steak or a roast. Heart can be grilled, charbroiled, or marinated. It’s a good source of B vitamins, iron, selenium, phosphorus, copper, and CoQ10.

B vitamins play a role in cellular energy production, red blood cell formation, and the metabolism of amino acids, glycogen, and fatty acid synthesis. Copper helps with iron absorption and thyroid function. Iron is necessary for oxygen transport and plays a role in cellular energy production.

CoQ10 is an antioxidant that can reduce lipid perioxidation, lower blood pressure, and increase blood flow. Another additional benefit is that when used by the body, CoQ10 becomes reduced to a compound known as ubiquinol. Studies have shown that ubiquinol can significantly improve maximum power output.

Common sources: Lamb, pork, beef, chicken.

Kidneys

Grill them or mix them with sauces or as part of a stir fry. Kidneys are a good source of B vitamins, iron, phosphorus, copper, selenium, zinc, and vitamin C.

Phosphorus deficiencies have been linked to muscular fatigue. Selenium offers neuroprotective benefits, is required for the synthesis and metabolism of thyroid hormones, and has been shown in studies to increase testosterone levels with as little as 200 mcg.

Common sources: Beef, lamb, pig, goat.

Tongue

One of the most tender cuts of meat because of its fat content, it can be stewed, pickled, slow-cooked, or poached. Tongue is a good source of zinc, potassium, B vitamins, choline, and monounsaturated fatty acids.

Choline plays a variety of roles in the body including cell structure and neurotransmitter synthesis. Potassium regulates fluid balance and plays a role in controlling the electrical activity of the heart and muscles.

Common sources: Beef, pork, goat, lamb.

organ-meat

Wait! But What About…

High cholesterol and saturated fat content?

For years, nutritionists, doctors, and other health experts have hammered away about the dangers of cholesterol. Well, in a 15 year study researchers followed over 12,000 adults and discovered that the groups with total cholesterol levels below 160 mg/dl and above 240 mg/dl were most at risk for cardiovascular diseases. The distribution of hazard ratios followed a U-shaped curve. Consumed in moderation, saturated fats and cholesterol are beneficial for the roles they play in regulating hormonal balance, production of vitamin D3, neural signaling, and immune function.

Toxicity?

Yes, the liver and kidneys act as filters. But it’s important to remember that while these organs function as filters, their jobs are to excrete toxins from the body, not store it. If it’s still a concern, just choose younger animals that have less exposure to pesticides and other toxins (like veal over beef) or opt for grass-fed animal products.

Taste?

It’s subjective. Our tastes are shaped by a combination of personal preference and sensitivities to certain flavors, and exposure to these foods. Some people rave about the unique flavor of organ meats; others say they’re acquired tastes, and others flat-out dislike them. Ease your way in by starting out with muscular cuts (heart, tongue) that are closer in flavor and texture to typically consumed cuts of meat, then transition to choices like liver and kidneys that have more distinctive flavors.

Where to Get Organ Meat

Another name for organ meat is offal. It’s become easier to find at most grocery stores due to the popularity of “nose to tail” eating. If your local chain isn’t up to speed, check out the specialty ethnic stores in your area.

References

  1. Kilic, M. (2007). Effect of fatiguing bicycle exercise on thyroid hormone and testosterone levels in sedentary males supplemented with oral zinc. Neuro Endocrinology Letters, 28(5), 681-685.
  2. Kil, M., Baltaci, A., Gunay, M., Okudan, N., & Cicioglu, I. (2006). The effect of exhaustion exercise on thyroid hormones and testosterone levels of elite athletes receiving oral zinc. Neuro Endocrinology Letters, 27(1), 2nd ser., 247-252.
  3. Alf, D., Schmidt, M. E., & Siebrecht, S. C. (2013). Ubiquinol supplementation enhances peak power production in trained athletes: A double-blind, placebo controlled study. J Int Soc Sports Nutr Journal of the International Society of Sports Nutrition, 10(1), 24.
  4. Safarinejad, M. R., & Safarinejad, S. (2009). Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study. The Journal of Urology, 181(2), 741-751.
  5. Bae, J., Yang, Y., Li, Z., & Ahn, Y. (2012). Low Cholesterol is Associated with Mortality from Cardiovascular Diseases: A Dynamic Cohort Study in Korean Adults. Journal of Korean Medical Science J Korean Med Sci, 27(1), 58.

Slow Reps vs. Fast Reps

lift-this-way_-build-muscle-3-times-faster

Repetition speed – how fast you lift a weight and how fast you lower a weight – has always been somewhat of a controversy among lifters.

Some say that the eccentric, or lowering phase, is everything when it comes to hypertrophy and the concentric, or lifting phase, is everything when it comes to strength. And there are plenty of really annoying guys who don’t know the difference between the two phases, don’t give a shit, and still grow.

But all you have to do is use a bit of Sherlock Holmesian deduction the next time you go in the gym. You’ll likely observe that many of the guys who lift purely for speed, strength, and explosivity don’t look as muscular as many of the bodybuilders, who, at least some of the time, play around with their lifting speeds.

Slow Reps vs. Fast Reps

It’s undeniable – despite the success of the annoying guys who grow regardless of what they do – that lifting speed alters important factors affecting hypertrophy and strength development; things like time under tension, muscle activation, and metabolic and hormonal responses.

How much does speed alter strength and hypertrophy? Scientists in Sao Paulo, Brazil, say “slow speed” reps can help you build muscle up to 3 times faster than “fast speed” lifting. However, in a surprising twist of accepted lifting principles, they also found that slow speed lifts can progress strength up to five times faster than fast-speed reps.

How They Proved It

The scientists rounded up 12 experienced male lifters and got them to do Scott curls twice a week for 12 weeks. Half of the men performed “slow speed” reps where they lifted the weight in one second, but lowered it over the course of three seconds.

The other half did “fast speed” reps where they took a second to lift the weight and a second to lower the weight.

The workouts consisted of the standard 3 sets of 8 reps (of which the 8th rep constituted failure). As far as testing methods, they employed ultrasound examination of cross-sectional area of the brachialis biceps muscle, along with before and after 1-rep curl maxes of each of the test subjects.

After 12 weeks, the men in the slow speed group showed nearly five times the progression of strength than that shown by the fast speed lifters. The slow speed lifters also built three times as much muscle as the fast speed lifters.

Does That Mean You Should Always Go Slow?

The results, while hugely impressive, don’t necessarily mean you should automatically turn into Eddy Eccentric and measure your sets in geological time. Instead, the lesson should be that it’s a great idea to periodically employ slow tempo lifting into your workouts for periods perhaps as long as 12 weeks, after which you can go back to faster tempos for a while.

Reference

  1. Pereira, et al. “Resistance training with slow speed of movement is better for hypertrophy and muscle strength gains than fast speed of movement,” International Journal of Applied Exercise Physiology, Vol. 5, No. 2.

 

source@https://biotest.t-nation.com/articles/tip-lift-this-way-build-muscle-3-times-faster

Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use

Image result for heart anatomy

Abstract

Background: Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.

Methods: Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).

Results: Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%; P<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second; P<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%; P<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second; P=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median [interquartile range] 3 [0, 174] mL3 versus 0 [0, 69] mL3P=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16–1.03 SD units]; P=0.008).

Conclusions: Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.

 

Introduction

An estimated 2.9 to 4.0 million Americans have used supraphysiologic doses of illicit anabolic-androgenic steroids (AAS), including testosterone and its synthetic relatives, to gain muscle mass for athletics or personal appearance.1 About 1 million of these individuals, almost all of whom are male, have developed AAS dependence, often leading to years of chronic AAS exposure.2 Illicit AAS use did not become widespread in the general US population until the 1980s.3 Thus, the oldest AAS users, who initiated AAS as youths in the 1980s, are only now reaching middle age, when the adverse effects of long-term use may become apparent. Therefore, these effects remain incompletely understood.

Previous studies have suggested an association between AAS use and cardiovascular disease, with a pathophysiologic link first proposed by early case reports of sudden cardiac death or ischemic stroke among young AAS-using men.46 Subsequently, preclinical studies have shown that AAS exposure at supraphysiologic doses causes dyslipidemia,79stimulates cardiomyocyte hypertrophy,10,11 impairs coronary arterial function,12,13 reduces cardiac β-adrenoreceptor sensitivity,14 potentiates oxidative cardiac stress,15 lowers arrhythmic thresholds,16 and induces myocyte apoptosis.17 Most recently, investigations utilizing noninvasive cardiac imaging in human users have demonstrated preliminary evidence of AAS cardiotoxicity in the forms of myocardial dysfunction,1822 myocardial fibrosis,23 and increased coronary artery calcification.24

In aggregate, data from these earlier studies suggest that illicit AAS use may cause a form of cardiomyopathy characterized by decreased left ventricular (LV) function18,19,2123,25,26 and may increase the risk of atherosclerotic disease.1,7,8,24 To date, definitive associations between AAS exposure and either myocardial or coronary artery disease have yet to be demonstrated in a large human study. To address this issue, we conducted comprehensive cardiovascular evaluations of 86 long-term AAS users and 54 nonusers.

 

Methods

Study Design

We conducted an observational study using a cross-sectional cohort design. We have previously presented the formal properties of this design,27 which has been used both explicitly2831 and implicitly32,33 in many earlier studies. This method identifies a dynamic cohort of individuals drawn from a given source population who in principle could have been enumerated in the past and followed to the present (termed the conceptual cohort). Instead of sampling from the conceptual cohort, one samples in the present from those currently available (the study cohort). With this design, estimates of effects derived from the study cohort are valid with respect to the conceptual cohort, subject to similar conditions for validity as other retrospective designs (eg, retrospective cohort and case-control studies).27 We chose the cross-sectional cohort design because it can efficiently assess the association of outcomes with an uncommon exposure (eg, AAS use) in the same manner that a case-control design can efficiently assess the association of exposures with an uncommon outcome.

For the present study, we sampled from a source population of men who lift weights in gymnasiums and then compared exposed (ie, AAS-using) and nonexposed (ie, non-AAS-using) men from this group. We chose this source population because almost all long-term AAS users are male2 and lift weights regularly.1,34 We did not recruit from sporting venues because most AAS users are not competitive athletes but simply recreational weightlifters.1,35,36

Although this approach minimized the effects of confounding variables inherent to weightlifting, we considered that weightlifting or its associated lifestyle might be associated with specific cardiovascular characteristics. Therefore, in an ancillary study, we recruited a group of nonweightlifting and non-AAS-using men (frequency-matched in age to the weightlifters but never weightlifting >30 minutes per week at any time since 18 years of age), drawn from a roster of potential study volunteers maintained by Massachusetts General Hospital, and compared these nonweightlifters to the subgroup of non-AAS-using weightlifters from the primary study. These 2 groups (AAS nonusers and nonweightlifting and non-AAS-using men) exhibited no scientifically important or statistically significant differences on measures of cardiovascular physiology or pathology (Tables I–III in the online-only Data Supplement), indicating that weightlifting per se, of the duration and intensity selected by our recruitment techniques, was associated with little or no cardiovascular adaptation or pathology.

Participants

As described in our previous cross-sectional cohort studies involving AAS,28,29 we advertised in gymnasiums for men 34 to 54 years of age who could bench-press 275 pounds for at least one repetition, currently or in the past to recruit AAS users and nonusers. On telephone screening, advertisement respondents were invited to participate without inquiring about AAS use to minimize selection bias that might arise if they knew in advance the exposure variable of interest. It is notable that AAS are typically ingested in courses or cycles, with deliberate intervening off-drug intervals.1 Thus, our design anticipated that the AAS-using weightlifters would include 2 subgroups: those on-drug and those off-drug at the time of evaluation. We excluded AAS users reporting <2 years of cumulative lifetime AAS exposure. We imposed no specific exclusions for medical or psychiatric history.

Evaluation

Qualifying participants were evaluated at a screening interview, where they provided written informed consent for the study as approved by the McLean Hospital Institutional Review Board. We then obtained demographic data, lifetime exercise history (ie, exercise modalities, duration, intensity, and consistency), and fat-free mass index, a validated measure of muscularity.29,37,38 Psychiatric and substance-use histories were obtained using the Structured Clinical Interview for DSM-IV.39 We next assessed history of AAS use, including age at onset of use, maximum weekly dose of AAS (calculated as mg of testosterone equivalent),40 cumulative lifetime years of use, lifetime dose ingested, time of most recent use, and types and doses of AAS taken during most recent (or current) use. We also assessed use of other performance-enhancing substances, including over-the-counter substances (eg, creatine) and illicit drugs (eg, human growth hormone, clenbuterol). Participants then provided urine samples to be tested for AAS29,38 and head or axillary hair to be tested for opiates, cannabis, phencyclidine, amphetamines, and cocaine.29,38 Men showing urine or hair findings inconsistent with their reported substance-use history were excluded from further evaluation. We also excluded men denying AAS use but exhibiting a fat-free mass index >26 kg/m2 together with body fat <10% based on previous work showing that a combination of leanness and muscularity beyond these limits strongly suggests surreptitious AAS use.37,41

Men found to qualify after the screening interviews were then referred for a cardiovascular evaluation performed by investigators blinded to AAS status to characterize LV structure, LV function, and coronary atherosclerosis. Two-dimensional transthoracic echocardiography (iE33, Philips Medical Systems) was used to develop profiles of LV structure and function as previously detailed by our group.42 The primary outcome variables for LV systolic and diastolic function were left ventricular ejection fraction (LVEF) as measured using the modified biplane method of disks43 and early LV relaxation velocity (E´; average of basal septum and lateral wall values44), respectively. Second, coronary computerized tomography angiography (CTA) was performed using a dual-source 128-slice CT scanner (Definition Flash, Siemens Medical Systems), with a primary outcome variable of total coronary artery plaque volume.45 Secondary CTA measures included number of atherosclerotic coronary segments, degree of stenosis of the worst segment, and Agatston calcium score.46 Detailed echocardiographic and CTA methods are provided in the online-only Data Supplement.

Statistical Analysis

Based on our pilot data18 and those of others,1,24 our primary hypotheses were that AAS users would exhibit: (1) decreased LVEF, (2) decreased E´, and (3) increased coronary plaque volume compared with non-AAS-using weightlifters. We further hypothesized that within the AAS-user group, greater pathology on these variables would be associated with currency of AAS use (ie, on-drug versus off-drug status at the time of evaluation) and with cumulative lifetime duration of AAS exposure.

Using linear regression, we estimated the mean difference between groups on the outcome measures (technically, the estimated mean difference was the estimated beta coefficient corresponding to group status in a linear model that also included a set of covariates and was fitted using ordinary least-squares linear regression). To control for confounding, our primary analysis adjusted for a set of plausible confounding variables including: age; race/ethnicity (modeled as black versus all others); history of tobacco use, cocaine dependence, and alcohol dependence; weekly hours of aerobic activity in the last 10 years (modeled in tertiles of the distribution); and reported family history of coronary artery disease as defined by the presence of angina, myocardial infarction, angioplasty/stent, or coronary bypass surgery in a first-degree relative. For echocardiographic measures, we additionally adjusted for body surface area as calculated by the Mosteller formula. To explore the relationship between LV mass, a potentially important mechanistic mediator of LV functional impairment, and our primary functional outcome variables, we performed post hoc analyses examining the association of LV mass index with LVEF and E´ among AAS users and nonusers. Specifically, we used linear regression with the same set of potential confounding variables and the addition of a term for AAS-user versus nonuser group status to examine the relationships between LV mass index (LV mass in g/body surface area in m2) and the primary cardiac function outcomes. Also, because resting heart rate could influence cardiac functional outcomes, we performed additional analyses of the primary cardiac functional outcomes by adding resting heart rate as a covariate. Note that heart rate may influence functional outcomes and also might be affected by current AAS use. In the latter eventuality, the estimated mean difference between groups adjusted for resting heart rate would likely be biased toward the null (ie, would potentially represent an overadjustment), thus producing an underestimate of the effect of AAS use.

In subsequent sensitivity analyses assessing the influence of adjustments using alternative sets of potential confounders, we repeated all comparisons (1) with no adjustment for any covariates, (2) with the adjustment covariates reduced to only age and race (plus body surface area for echocardiographic measures), and (3) with the adjustment covariates augmented to include hypertension and dyslipidemia (as defined in Tables X-X in the online-only Data Supplement). It is important to note that the augmented set of covariates would be expected to yield underestimates of the effect of AAS use because hypertension and dyslipidemia are often effects of AAS use,1,7,9,47 and adjustment for these variables would consequently adjust out effects of AAS mediated by these variables.

Because the distributions of coronary CTA measures contained many zero values (ie, no measurable coronary artery disease), we used ranked data for these analyses. Within the AAS-user group, we evaluated the association of all outcome measures with duration of use and currency of use (ie, on-drug versus off-drug) using linear regression with adjustment for the same set of covariates. To aid in interpretation of comparisons between groups and associations within groups involving rank-transformed data, we used standard deviation (SD) units to express the estimated difference in ranks for binary predictor variables and the estimated change in ranks for each 1-unit increase in continuous predictor variables. The SD units were calculated by dividing the estimated beta coefficient for the predictor variable from the linear regression model by the SD of the ranks for the entire sample used for a given model.

All models were fitted using Stata 14.1 software (StataCorp). We set α=0.05, 2-tailed. We did not perform corrections for multiple comparisons, so that the statistical significance of P-values for secondary outcomes, particularly those between 0.01 and 0.05, should be interpreted with caution.

 

Results

Participants

Sample

We screened 165 men, of whom 25 were excluded from medical evaluation as follows: 10 qualified for participation but withdrew before medical evaluation (9 AAS users, 1 nonuser), 12 reported AAS use of <2 years duration, and 3 showed findings on drug testing or fat-free mass index inconsistent with their self-reports. The remaining sample comprised 86 AAS users and 54 nonusers. Among the AAS users, 58 (67%) were on-drug and 28 (33%) off-drug at evaluation. The off-drug users had last used AAS a median (interquartile range) of 15 (5, 70) months before evaluation.

Characteristics

AAS users and nonusers were similar on most characteristics (Table 1), but users showed higher body mass index and fat-free mass index, consistent with known effects of AAS.

table1

 

Cardiometabolic Features

Compared with nonusers, AAS users displayed higher blood pressure (mean±SD systolic, 118±11 versus 115±10 mm Hg; diastolic, 76±9 versus 72±9 mm Hg) and a higher prevalence of dyslipidemia (N [%] with low-density lipoprotein cholesterol >160 mg/dL: 20 [23%] versus 7 [13%]).

 

Cardiac Structure and Function

For the primary outcome variables of LVEF and E´, AAS users showed significant deficits compared with nonusers (Table 2). In models further adjusted for resting heart rate, the estimated mean differences between groups were reduced by 15%, and this change had no impact on the statistical significance of these findings (P<0.001 for both). On other measures, AAS users exhibited higher LV mass index, thicker LV walls, and more concentric LV geometry than nonusers. On subsequent analyses examining the association of outcomes with duration and currency of AAS use, currency of use was strongly associated with greater pathology (Figure 1 and Table IV in the online-only Data Supplement). Specifically, 41 (71%) of the 58 on-drug users showed LVEFs falling below the normal threshold of 52%,43 whereas off-drug users showed largely normal LVEFs. Twenty-nine (50%) on-drug users fell below the normal E´ threshold of 8.5 cm/second,44 with off-drug users showing only partially normalized E´. Similar associations with currency of AAS use were found across other echocardiographic measures (Table IV in the online-only Data Supplement). In contrast, we found no significant associations between duration of AAS use and the primary outcome variables (for each additional 10 years of AAS exposure, the estimated mean change [95% confidence interval] in LVEF was −3.3% [−8.3 to 1.6], P=0.19; and the estimated mean change in E´ was 0.1 cm/second [−1.0 to 1.2 cm/second], P=0.90).

table1

F1.large
Left ventricular systolic and diastolic function in anabolic-androgenic steroid users and comparison nonusers. A, Boxplots of left ventricular ejection fraction in anabolic-androgenic steroid (AAS) users (N=86), shown as an entire group (Left) and as subgroups of individuals who were on-drug (N=58) and off-drug (N=28) at the time of evaluation (Middle); and nonusers (N=54) (Right). On this variable, the estimated mean difference (95% confidence interval) between on-drug and off-drug AAS users, adjusted for covariates as described in the text, is −9.5% (−13.8 to −5.2), P<0.001; for on-drug AAS users versus nonusers, the difference is −13.6% (−17.3 to −9.8), P<0.001; and for off-drug AAS users versus nonusers, the difference is −4.1% (−8.6 to 0.3), P=0.072. B, Left ventricular early relaxation velocity in the same 4 groups. On this variable, the mean difference between on-drug and off-drug AAS users is −1.1 (−2.1 to −0.1) cm/second, P=0.035; for on-drug AAS users versus nonusers, the difference is −2.2 (−3.1 to −1.4) cm/second, P<0.001; and for off-drug AAS users versus nonusers, the difference is −1.1 (−2.2 to −0.1) cm/second, P=0.035.

Because LVEF and E´ differed by group (ie, AAS user versus nonuser) and by subgroup based on currency of use (ie, current versus past AAS users), we further tested for interactions of group and subgroup status with LV mass index for each of these associations and found evidence for a significant interaction with AAS user group status (P=0.046 and P=0.016 for LVEF and E´, respectively) but not for currency of use among AAS users (P=0.21 and P=0.86, respectively). Therefore, we assessed the associations separately for AAS users and nonusers. Examining LVEF, among AAS users, a significant association occurred between increased LV mass index and decreased LVEF (estimated mean change [95% confidence interval] in LVEF for each 10 g increase in LV mass index −1.6% [−2.4 to −0.8], P<0.001). In contrast, among the nonusers, no significant association occurred between LV mass index and LVEF (estimated mean change in LVEF for each 10 g increase in LV mass index –0.2% [–1.5 to 1.2], P=0.80). Examining E´, among AAS users, a significant association occurred between increased LV mass index and reduced E´ (estimated mean change in E´ for each 10 g increase in LV mass index −0.31 cm/second [−0.49 to −0.13 cm/second], P<0.001). Among nonusers, the relationship was of approximately equal magnitude but in the opposite direction, with a significant association between increased LV mass index and increased E´ (estimated mean change in E´ for each 10 g increase in LV mass index 0.36 cm/second [0.04–0.68 cm/second], P<0.001).

Coronary Artery Atherosclerosis

AAS users showed significantly higher coronary plaque volume than nonusers (Table 3 and Figure 2). On examining the association of CTA measures with currency and duration of AAS use, we found strong associations between lifetime duration of use on all angiographic measures of coronary pathology (Table 4 and Figure 3). However, we found no significant association between currency of use and plaque volume (estimated mean difference between on-drug and off-drug users in ranks: −0.07 SD units [−0.56 to 0.41], P=0.76). It is notable that 3 (3%) AAS users had experienced earlier myocardial infarctions because of underlying atherosclerotic disease, documented by cardiac catheterization, occurring at 38 years of age (ST-segment myocardial infarction with complete occlusion of left anterior descending artery), 43 years of age (non-ST-segment myocardial infarction with 99% occlusion of both the right coronary and left circumflex coronary arteries), and 46 years of age (ST-elevation myocardial infarction with complete occlusion of a second obtuse marginal artery) and after 17, 11, and 5 years of cumulative lifetime AAS exposure, respectively. In addition, 1 AAS user had presented at 42 years of age after 20 years of cumulative lifetime AAS exposure with congestive heart failure and underwent stenting of the left circumflex and first obtuse marginal arteries. None of the 54 nonusers had a history of myocardial infarction or stenting.

 table1
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Figure 2.

Distribution of computed tomography coronary angiography measures in anabolic-androgenic steroid users and nonusers. Histograms displaying distribution of coronary artery plaque volume, degree of stenosis for most severe stenosis, number of diseased coronary artery segments, and coronary artery calcium for anabolic-androgenic steroid (AAS) users (N=84) and nonusers (N=53). The histograms for plaque volume and calcium score include for men with imputed values, as described in the footnote to Table 3.

 

F3.large.jpg

Figure 3.

Relationship between coronary artery plaque volume and cumulative lifetime duration of anabolic-androgenic steroid exposure. Scatter plot displaying coronary artery plaque volume and cumulative years of lifetime anabolic-androgenic steroid (AAS) exposure, with a median spline (red line) fitted to the data to aid in the visualization of the relationship between these variables. Because of the highly right-skewed distributions, the data are presented on a transformed scale (square root transformation for coronary artery plaque volume; logarithmic transformation for cumulative years of AAS use).

Sensitivity Analyses

Assessing the influence of alternative sets of potential confounders, using models with both reduced and augmented sets of covariates, we obtained results similar to those of the primary analysis, with <15% change in the estimates for the primary outcomes and preservation of statistical significance for all results identified as such in the primary analysis (Tables V–VII in the online-only Data Supplement). We also reanalyzed the echocardiographic findings while omitting the 3 men with previous myocardial infarctions. This analysis produced negligible changes in the findings, with the estimated mean differences between users and nonusers on the 2 primary outcome variables changing by <2% when these 3 men were excluded.

 

Discussion

Illicit AAS use is widespread, but its long-term adverse effects remain poorly understood. A growing literature, largely comprised of case reports and small observational studies, suggests that AAS use may cause cardiovascular disease. We undertook the present study to examine cardiovascular health measures among long-term AAS users and otherwise similar nonusers with the following 4 key findings. First, AAS users demonstrated substantial impairment of LV systolic function as assessed by LVEF and longitudinal strain. This finding was driven almost entirely by those AAS users who were on-drug at the time of evaluation, suggesting that LV dysfunction may be a dynamically related to AAS-use patterns. Second, AAS users also showed impaired LV diastolic dysfunction, both relative to nonusers and also as defined by current diagnostic criteria.44 In contrast to systolic function, which appeared largely normal among off-drug AAS users, LV diastolic function was impaired in both on-drug and off-drug users, suggesting a more permanent form of acquired pathology. Third, AAS users had significantly more LV hypertrophy, as reflected by LV mass index, than nonusers, suggesting an anabolic effect on cardiac muscle mass. In addition, the magnitude of LV hypertrophy among AAS users was directly related to the degrees of both systolic and diastolic function, suggesting a mechanistic link between LV hypertrophy and functional deterioration. Fourth, AAS use was associated with increased coronary atherosclerosis, and the severity of atherosclerotic disease was strongly associated with cumulative lifetime duration of AAS use. In aggregate, our findings suggest that long-term AAS use is associated with adverse cardiovascular phenotypes characterized by both myocardial pathology and coronary artery pathology, which may represent a clinically substantial and largely unrecognized public health problem.

Several scientific and clinical implications emerge from this study. First, improved identification of the adverse cardiovascular associations of AAS use may deter potential future users. Second, clinicians may be better informed about the potential adverse cardiovascular effects of AAS. It is important to note that participants in the present study were not elite or professional athletes, the small subset of the general population most commonly tied to AAS exposure, but rather a sample of middle-age men representing a reasonably broad socioeconomic and racial/ethnic distribution. Thus, when comparable men are found to have impaired LV function or premature coronary artery disease, it seems prudent for clinicians to now include AAS use on the differential diagnosis of possible causes. Third, data derived from the present cross-sectional study provide a foundation for critical future work. The hypothesis that some cardiovascular phenotypes associated with AAS use may wax and wane with drug exposure (eg, LV systolic dysfunction) while others may be more permanent, perhaps irreversible (eg, LV diastolic dysfunction and coronary atherosclerosis), deserves rigorous assessment. Longitudinal studies of illicit AAS users with hard clinical end points, and with interventions to impact drug exposure patterns and treat detected disease, are also of importance.

Limitations

Several threats regarding the internal validity of this study, as previously delineated in general for cross-sectional cohort studies,27,29 deserve consideration. First, bias might arise through exiting from the underlying conceptual cohort (ie, becoming unavailable for study in the present) that is differential with respect to exposure status. For example, AAS users might be more likely than nonusers to develop cardiovascular morbidity, stop weightlifting, and hence be unavailable for recruitment. Any resulting bias, however, would likely underestimate the effects of AAS use. Second, as in all observational studies, we cannot exclude residual confounding. However, given the lack of confounding seen with our measured potential confounders—as evidenced by similar estimates in sensitivity analyses using both reduced and augmented sets of potential confounders—it is unlikely that substantial residual bias remains because of unmeasured confounders. Third, because both AAS users and nonusers were weightlifters, the effects of AAS might be clouded if weightlifting contributed to cardiovascular pathology. However, our ancillary study comparing non-AAS-using weightlifters with nonweightlifters demonstrated that weightlifting alone (of the duration and intensity exhibited by our sample) had little effect on cardiac adaptation or pathology. Fourth, bias could arise from measurement error, particularly in the exposure variables (eg, misclassifying surreptitious AAS users as nonusers or inaccurately assessing the type, duration, dose, and currency of use). In particular, AAS users provided retrospective accounts, often spanning many years of time, of the use of illicit drugs of uncertain potency or authenticity. As such, estimates of participants’ lifetime duration of AAS use and total lifetime AAS dose were only approximations. The effect of these various sources of measurement error would be expected to be differential for between-group comparisons (because of the potential for inclusion of surreptitious AAS users in the nonuser group and the much less likely inclusion of individuals falsely reporting AAS use in the user group) and random for within-group comparisons among AAS users (because of the low likelihood of an association between cardiac outcomes and error in the predictor variables). Both of these sources would likely bias results toward the null, thereby yielding an underestimate of the effects of AAS use.

Potential threats to external validity (generalizability) also require consideration. First, we recruited AAS users from gymnasiums. Thus, our results might not generalize to other AAS-using groups (eg, elite athletes). However, most AAS users are recreational weightlifters, and thus our results likely generalize to the population of AAS users of greatest public health importance. Second, despite the demographic diversity of our sample, white non-Hispanic men were overrepresented, and therefore our results might not generalize to the full racial/ethnic spectrum of AAS users. Overall, however, these potential threats to internal and external validity appear modest. Thus, our findings likely represent reasonably unbiased estimates of the associations of AAS exposure with adverse cardiovascular phenotypes.

 

Conclusion

Our findings suggest that AAS use is associated with LV dysfunction and premature coronary artery disease. These findings may inform public health initiatives to curb drug exposure and provide clinicians with information that will translate into improved patient care.

 

Sources of Funding

This study was supported by grant R01 DA-029141 from the National Institute on Drug Abuse (to Drs Pope, Kanayama, Hudson, Baggish, Weiner, and Hoffmann).

 

Disclosures

Drs Pope, Kanayama, Hudson, Baggish, Weiner, and Hoffmann have received grant support for this study from the National Institute on Drug Abuse. Dr Hoffmann has received grants from HeartFlow and KOWA. Dr Pope has received expert witness fees for cases involving anabolic-androgenic steroids from the McNeil, Leddy, & Sheahan Law Firm and the US District Attorney for Eastern New York. Drs Kanayama and Weiner report no additional conflicts of interest. Dr Lu reports no conflicts of interest.

 

 

Clinical Perspective

What Is New?

  • Millions of individuals have used anabolic-androgenic steroids (AAS) to gain muscle for athletic purposes or personal appearance.

  • Preliminary findings have suggested that long-term AAS exposure may lead to both cardiomyopathy and atherosclerotic disease, but previous studies have been small or methodologically limited.

  • Here, in the first large controlled study of its type, we demonstrate that long-term AAS use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis.

  • Systolic functional deficits appear to recover after AAS discontinuation, whereas diastolic dysfunction appears less reversible.

  • Atherosclerotic disease appears strongly associated with lifetime duration of AAS exposure.

What Are the Clinical Implications?

  • Widespread illicit AAS use first appeared in the general population in the 1980s, and thus most AAS users are still young or middle-aged today.

  • Thus, when clinicians encounter young or middle-age men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity because of long-term AAS use should be considered in the differential diagnosis.

  • It is notable that ≈80% of contemporary AAS users are simply recreational weightlifters rather than competitive athletes, and thus the possibility of AAS use should be considered even in individuals who do not identify themselves as athletes.

Neuroscience Reveals What Fasting Does To The Brain (And Why Big Pharma and the Food Industry Won’t Study It)

I came across this TEDx talk given by Mark Mattson, the current Chief of the Laboratory of Neuroscience at the National Institute on Aging. It presents some fascinating details about fasting and why it isn’t as popular as it should be.

Many research studies are showing its benefits. This article by Authority Nutrition highlights 10 evidence-based health benefits of fasting that studies have found. These include weight loss, lower blood pressure and reduced cholesterol.

But the real interesting question is, why won’t the pharmaceutical industry study it?

Here is a transcript of a section of Mark Mattson’s talk which hints at these questions:

“Why is it that the normal diet is three meals a day plus snacks? It isn’t that it’s the healthiest eating pattern, now that’s my opinion but I think there is a lot of evidence to support that. There are a lot of pressures to have that eating pattern, there’s a lot of money involved. The food industry — are they going to make money from skipping breakfast like I did today? No, they’re going to lose money. If people fast, the food industry loses money. What about the pharmaceutical industries? What if people do some intermittent fasting, exercise periodically and are very healthy, is the pharmaceutical industry going to make any money on healthy people?”

Please watch and share so we can raise questions about our eating habits and how we can become more healthy.

To further back up the benefits of fasting, here is a quote from an author from The Power of Ideas who tried intermittent fasting for one month:

“Intermittent fasting has now become my way of life. It feels damn good and I find myself being clear and focused. My energy levels have sky rocketed. I used to always get that afternoon slump when I felt tired at about 3 PM, but I don’t experience this anymore.

Eating has also come to be an experience that’s enjoyed, rather than just food to scoff down as fast as I can. This has made it easy to keep intermittent fasting going.

Also, after a couple weeks, I decided to try exercising (running and weights) as soon as I woke up on an empty stomach. I thought I would feel light headed and faint from working out on an empty stomach, but the truth is, I had more grit and energy.

Research has found that there’s major perks to doing this: apparently it’s meant to supercharge your body’s fat-burning potential.”

Creatine

 

Creatine is a molecule that can rapidly produce energy (ATP) to support cellular function. It also exhibits performance-enhancing and neuroprotective properties. Creatine is well-researched and remarkably safe for most people.

Full article@https://examine.com/supplements/creatine/ 

Summary

All Essential Benefits/Effects/Facts & Information

Creatine is a molecule produced in the body. It stores high-energy phosphate groups in the form of phosphocreatine. Phosphocreatine releases energy to aid cellular function during stress. This effect causes strength increases after creatine supplementation, and can also benefit the brain, bones, muscles, and liver. Most of the benefits of creatine are a result of this mechanism.

Creatine can be found in some foods, mostly meat, eggs, and fish. Creatine supplementation confers a variety of health benefits and has neuroprotective and cardioprotective properties. It is often used by athletes to increase both power output and lean mass.

Stomach cramping can occur when creatine is supplemented without sufficient water. Diarrhea and nausea can occur when too much creatine is supplemented at once, in which case doses should be spread out throughout the day and taken with meals.

 

Things to Know

Also Known As

creatine monohydrate, creatine 2-oxopropanoate, a-methylguanidinoacetic acid

Do Not Confuse With

creatinine (metabolite), cyclocreatine (analogue), creatinol O-phosphate (analogue)

Things to Note

  • There have been some anecdotal reports of a subtle but noticeable stimulatory effect on alertness, but this may be a placebo effect.
  • There have been some anecdotal reports of restlessness when creatine is supplemented less than an hour before falling asleep.
  • The water retention usually seen with higher loading doses can exceed five pounds (more than two kilograms). Lower doses may cause less water retention. While water mass is not muscle mass (though both count as lean mass), prolonged creatine supplementation results in an increased rate of muscle growth.
  • Hyperhydration strategies (creatine plus glycerol) appear inefficacious as drug-masking strategies.[1]

How to Take

Recommended dosage, active amounts, other details

There are many different forms of creatine available on the market, but creatine monohydrate is the cheapest and most effective. Another option is micronized creatine monohydrate, which dissolves in water more easily and can be more practical.

Creatine monohydrate can be supplemented through a loading protocol. To start loading, take 0.3 grams per kilogram of bodyweight per day for 5–7 days, then follow with at least 0.03 g/kg/day either for three weeks (if cycling) or indefinitely (without additional loading phases).

For a 180 lb (82 kg) person, this translates to 25 g/day during the loading phase and 2.5 g/day afterward, although many users take 5 g/day due to the low price of creatine and the possibility of experiencing increased benefits. Higher doses (up to 10 g/day) may be beneficial for people with a high amount of muscle mass and high activity levels.

Stomach cramping can occur when creatine is supplemented without sufficient water. Diarrhea and nausea can occur when too much creatine is supplemented at once, in which case doses should be spread out over the day and taken with meals.

creatine research

LEVEL OF EVIDENCE

OUTCOME MAGNITUDE OF EFFECT

CONSISTENCY OF RESEARCH RESULTS

NOTES
Muscle Creatine Content

Strong

VERY HIGH

See all 18 studies

Creatine supplementation is the reference compound for increasing muscular creatine levels; there is variability in this increase, however, with some nonresponders.
Power Output

Strong

VERY HIGH

See all 66 studies

Creatine is the reference compound for power improvement, with numbers from one meta-analysis to assess potency being “Able to increase a 12% improvement in strength to 20% and able to increase a 12%…

See more

Weight

Strong

VERY HIGH

See all 28 studies

Appears to have a large effect on increasing overall weight due to water retention in persons who respond to creatine supplementation. Degree of increase is variable.
Creatinine

Notable

MODERATE 

See all 12 studies

Creatine supplementation usually increases serum creatinine levels during the loading phase (but usually not during maintenance), since creatinine is the breakdown product of creatine. This is noti

See more

Hydration

Notable

VERY HIGH

See all 9 studies

Appears to be quite notable due to the increase in water weight in skeletal muscle tissue following creatine supplementation.
Anaerobic Running Capacity

Minor

HIGH

See all 19 studies

Appears to increase anaerobic cardiovascular capacity, not to a remarkable degree however.
Lean Mass

Minor

VERY HIGH

See all 20 studies

Does appear to have inherent lean mass building properties, but a large amount of research is confounded with water weight gains (difficult to assess potency).
Kidney Function VERY HIGH

See all 13 studies

In otherwise healthy persons given creatine supplementation, there is no significant beneficial nor negative influence on kidney function.
Swimming Performance MODERATE

See all 17 studies

No reliable improvement in swimming performance. Acute supplementation prior to short sprint tests (50-100 m) may reduce time by around 2%.
Fatigue

Notable

HIGH

See all 7 studies

400 mg/kg/day in children and adolescents subject to traumatic brain injury reduces fatigue frequency from around 90% down to near 10%. Fatigue is also reduced, though to a lesser degree, in cases of…

See more

Blood Glucose

Minor

LOW

See all 4 studies

No apparent influence on fasting blood glucose, but an 11-22% reduction in the postprandial spike.
Bone Mineral Density

Minor

LOW

See all 3 studies

There is limited evidence in favor of improvements in bone mineral density.
Fatigue Resistance

Minor

MODERATE

See all 8 studies

Small degree of fatigue reduction during exercise, but appears unreliable.
Lipid Peroxidation

Minor

LOW

See all 3 studies

A minor reduction has been observed.
Muscle Damage

Minor

MODERATE

See all 6 studies

Not overly protective, but there appears to be a degree of protection.
Muscular Endurance

Minor

HIGH

See all 3 studies

Somewhat effective.
Subjective Well-Being

Minor

MODERATE

See all 11 studies

The influence of creatine on well being and general happiness is usually dependent on it treating a disease state; there does not appear to be a per sebenefit to well being.
Testosterone

Minor

HIGH

See all 6 studies

Degree of testosterone spike is not overly notable, although it appears to be present
Treatment of Myotonic Dystrophy

Minor

HIGH

See all 3 studies

Preliminary evidence seems to support a minor to moderate benefit with regard to Myotonic Dystrophy type II (DM2) and a mild benefit or none with regard to DM1.
VO2 Max

Minor

LOW

See all 6 studies

Improvements in VO2 max are not wholly reliable, and appear to be low in magnitude.
Aerobic Exercise VERY HIGH

See all 7 studies

Does not appear to confer any apparent benefit to prolonged cardiovascular exercise.
Blood Pressure VERY HIGH

See all 4 studies

Does not appear to significantly influence blood pressure.
Cognition (Omnivores) HIGH

See all 3 studies

No inherent benefit to omnivore cognition appears apparent, but it may benefit cognition in the sleep deprived.
Cortisol VERY HIGH

See all 4 studies

No effect on cortisol changes associated with sleep deprivation.
Exercise Capacity (with Heart Conditions) VERY HIGH

See all 3 studies

Although there may be a small reduction of power output (typical of creatine), the main parameter of interest (cardiorespiratory output) is mostly unaffected by creatine supplementation.
Exercise Capacity in COPD VERY HIGH

See all 3 studies

The main parameter of interest with exercise in COPD (cardiovascular capacity and aerobic exercise) is wholly unaffected with supplementation, although power output still can be increased.
Fat Mass VERY HIGH

See all 9 studies

Creatine reliably increases lean mass (water at first, then muscle with more prolonged supplementation) but does not appear to significantly alter fat mass.
Heart Rate VERY HIGH

See all 3 studies

No known influence on heart rate.
IGF-1 VERY HIGH

See all 5 studies

Insufficient evidence to support a role of creatine in increasing IGF-1
Insulin VERY HIGH

See all 3 studies

No effect on fasting insulin.
Lactate Production MODERATE

See all 6 studies

No apparent reduction or increase in lactate in swimmers after sprinting exercises.
Liver Enzymes VERY HIGH

See all 7 studies

No known influence on circulating liver enzymes, suggesting no liver toxicity in humans.
Lung Function VERY HIGH

See all 7 studies

No effect on healthy people or on disease states characterized by impaired lung function.
Total Cholesterol HIGH

See all 4 studies

No effect on overall cholesterol levels in otherwise healthy males.
Treatment of Amyotrophic lateral sclerosis (ALS) VERY HIGH

See all 6 studies

Short term usage may increase power output like usual, but prolonged supplementation of creatine has failed to alter the deterioration of muscle and lung function. While no reduction in mortality has…

See more

Treatment of COPD HIGH

See all 3 studies

No effect on cardiovascular exercise performance and lung and heart functions, the main parameters of concern when treating COPD.
Depression

Notable

VERY HIGH

See all 3 studies

Depression symptoms seem to improve noticeably. This improvement is probably related to serotonin (creatine supplementation appears to enhance SSRI therapy). Possible gender differences (a greater ef…

See more

Glycogen Resynthesis

Notable

See study
Degree of improvement is somewhat more potent than other supplemental options, and may be related to the improvements in glycemic control seen with creatine.
Growth Hormone

Notable

See all 4 studies
During exercise, creatine supplementation can suppress growth hormone secretion: up to 35% during loading; up to 5% during maintenance. At rest, creatine supplementation can spike growth hormone by u…

See more

Myostatin

Notable

See study
The reduction in circulating Myostatin, while notable (17%), is of uncertain practical relevance.
Body Cell Mass

Minor

See study
A possible increase in cell mass. Evidence is limited.
Cognition (Vegetarians)

Minor

VERY HIGH

See 2 studies

Appears to be reliable in increasing cognition in vegetarians, but is based on limited evidence and not yet compared to a reference drug.
DHT

Minor

See study
An increase in DHT independent of an increase in testosterone has been noted, but the study requires replication due to some potential issues (its location, the lack of biological plausibility, etc.).
DNA Damage

Minor

MODERATE

See 2 studies

Creatine supplementation appears to reduce exercise-induced DNA damage. This is potentially promising with regard to cancer prevention.
DNA methylation

Minor

See study
The effect of creatine supplementation on DNA methylation cannot be properly assessed due to a lack of comparisons with other agents.
Functionality in Elderly or Injured

Minor

MODERATE

See 2 studies

Possibly an effect, but the less reliable effects of creatine in the older population (which seem to respond less) seems to manifest here.
Glycemic Control

Minor

VERY HIGH

See 2 studies

Appears to be somewhat effective in diabetics for improving glycemic control.
Homocysteine

Minor

See study
Decrease in homocysteine (biomarker of inflammatory cardiovascular disease) was present, but not to a remarkable magnitude
Myonuclei proliferation

Minor

See study
Creatine supplementation appears to induce myonuclei proliferation, to a degree unknown relative to other agents.
Satellite Cell Recruitment

Minor

See study
Compared to reference drugs, creatine had no significant effect.
Symptoms of Duchenne Muscular Dystrophy Minor

VERY HIGH

See 2 studies

There appears to be a mild therapeutic effect of creatine supplementation (2-5g) to boys with DMD, mostly related to an improvement in handgrip strength and body composition with some parent-rated im…

See more

Symptoms of McArdles Disease

Minor

See 2 studies
Two trials have shown differing effects, for reasons currently unknown.
Symptoms of Osteoarthritis Minor

See study
Functionality seems to improve, although not to a remarkable degree.
Symptoms of Sleep Deprivation Minor VERY HIGH

See 2 studies

The cognitive dysfunction associated with prolonged sleep deprivation can be attenuated, to a small degree, with prior creatine loading.
Uric Acid  

Minor

VERY HIGH

See 2 studies

A minor reduction has been observed.
Adrenaline See study
No significant alterations in plasma adrenaline are seen with creatine supplementation during sleep deprivation.
Aldosterone See 2 studies
Anti-Oxidant Enzyme Profile See study
Attention See study
No effect on attention during sleep deprivation.
Bilirubin See all 3 studies
C-Reactive Protein See study
Cerebral Oxygenation See study
Dopamine See study
No significant alterations in plasma dopamine are seen with creatine supplementation during sleep deprivation.
Fat Oxidation See 2 studies
Food Intake VERY HIGHSee 2 studies
No effect on food intake.
General Oxidation See study
Glycogen content See 2 studies
HDL-C See 2 studies
Injury Rehabilitation Rate See study
Insulin Secretion See study
No effect on the insulin secretion in response to a test meal.
Insulin Sensitivity See study
No effect on insulin sensitivity.
LDL-C See 2 studies
Memory VERY HIGH

See 2 studies

No effect on short-term recall during sleep deprivation.
Muscle Oxygenation See study
Noradrenaline See study
No significant alterations in plasma noradrenaline are seen with creatine supplementation during sleep deprivation.
Proteinuria See study
There is no significant influence on protein losses in the urine (proteinuria).
Schizophrenia See study
Insufficient evidence to support a role in schizophrenia.
Skeletal Muscle Atrophy VERY HIGH

See 2 studies

The study that noted a prevention of lean mass loss did not distinguish between water and muscle, while the study that measured muscle mass specifically failed to find a protective effect during limb…

See more

Sprint performance See study
Symptoms of Mitochondrial Cytopathies See all 3 studies
TNF-Alpha See study
Training Volume VERY HIGH

See 2 studies

No effect on the training volume of swimmers.
Treatment of Huntington’s Disease VERY HIGH

See 2 studies

There is insufficient evidence to support a rehabilitative role of creatine supplementation.
Treatment of Parkinson’s VERY HIGH

See 2 studies

There is insufficient evidence to support an improvement in the symptoms of Parkinson’s.
Triglycerides See all 3 studies
Urea See all 4 studies
vLDL-C See study
Dizziness Notable

See study
Dizziness as a side-effect of traumatic brain injury is reduced with 400 mg/kg/day.
Treatment of Headaches

Notable

See study
400 mg/kg/day in children and adolescents subject to traumatic brain injury reduces headache frequency from around 90% down to near 10%.
Alertness

Minor

VERY HIGH

See 2 studies

Increases in alertness tend to be during sleep deprivation or stress, rather than outright increases in alertness. Not overly potent
Blood Flow

Minor

VERY HIGH

See 2 studies

One study has found that creatine can increase blood flow to the calf and leg when combined with resistance training in healthy men. Creatine alone was found to have no effect.
Catabolism Minor

See study
Uncertain practical relevance.
Range of Motion Minor
See study
One study, that needs to be replicated, noted a reduction in range of motion.
Metabolic Rate See study
Symptoms of Cystic Fibrosis See study
An increase in well-being and muscular strength has been noted in youth, but the main parameters under investigation (lung and chest symptoms) seemed unaffected.

Sources and Structure

1.1. Sources

Creatine phosphate (phosphocreatine) functions as a phosphate reservoir.[5] It is found in high levels in the skeletal muscles and the heart, but also to some degree in almost every cell of all vertebrates and various invertebrates.[6]

Some (uncooked) meats have high levels of creatine:

  • Beef, with minimal visible connective tissue: 5 g per 1.1 kg,[7] or 2.15-2.5 g/lb[8] (4.74-5.51 g/kg)
  • Chicken: 3.4 g/kg[9]
  • Rabbit: 3.4 g/kg[9]
  • Cardiac tissue (ox): 2.5 g/kg[9]
  • Cardiac tissue (pig): 1.5 g/kg[8]

Some (uncooked) meats have low levels of creatine:

  • Liver:[9] 0.2 g/kg[8]
  • Kidney: 0.23 g/kg[8]
  • Lung: 0.19 g/kg[8]

Creatine accumulates in the same organs in meat products as in humans. Tissues with a high creatine content include the heart and the skeletal muscles.

Other compounds containing creatine include:

  • Blood: 0.04%[8]
  • Skim milk, dried (no water content): 0.88%[8]
  • Human breast milk:[10] 60-70 μM[11]

Dairy products have minimal creatine content, but beyond meat products they are the only significant source of dietary creatine.

According to the NHANES III survey, the average daily consumption of creatine from food sources among Americans (19-39 years old) is about 7.9 mmol (1.08g) for men and 5 mmol (0.64g) for women.[12] This is below the “2g/day consumed via the diet” estimate that many studies reference.

Creatine from food is digested slower than creatine taken as a supplement, but total bioavailability is identical.[13]

 

1.2. Properties and Structure

Creatine is a small peptide — a structure composed of amino acids. Specifically, creatine is composed of L-arginineglycine, and methionine. Its molecular structure is depicted below.

91

92

1.3. Food Processing

Depending on the cooking temperature and the presence of a reducing sugar, such as glycogen, carnosine and aspartic acid will degrade into acrylic acid and acrylamides.[14] At the same time, creatine will degrade into methylamine, which will then bind to acrylic acid and acrylamides to turn into the toxic substance N-methylacrylamide (C4H7NO).[14]

Creatine can also be converted to the biologically inactive creatinine through the removal of a water molecule.[15] Approximately 30% of meat-bound creatine can be lost in exudate or degrade into creatinine when cooking to medium-well.[16]

Finally, creatine can also participate in the formation of heterocyclic amines,[17] a process that can be partially inhibited by marination.[18][19][20]

1.4. Biological Significance

Carbohydrates provide quick energy in an anaerobic environment (high-intensity exercise), while fats provide sustained energy during periods of high oxygen availability (low-intensity exercise or rest). The breakdown of carbohydrates, fats, and ketones produces ATP (adenosine triphosphate). When cells use ATP for energy, this molecule is converted into adenosine diphosphate (ADP) and adenosine monophosphate (AMP). Creatine exists in cells to donate a phosphate group (energy) to ADP, turning this molecule back into ATP.[21][22][23][24]

By increasing the overall pool of cellular phosphocreatine, creatine supplementation can accelerate the reycling of ADP into ATP. Since ATP stores are rapidly depleted during intense muscular effort, one of the major benefits of creatine supplementation is its ability to regenerate ATP stores faster, which can promote increased strength and power output. Over 95% of creatine is stored in muscle at a maximum cellular concentration of 30uM. Creatine storage capacity is limited, though it increases as muscle mass increases.[25] A 70 kg male with an average physique is assumed to have total creatine stores of approximately 120g.[26] The body can store a lot more energy as glycogen in the liver, brain, and muscles,[27][28] and even more as fat.

Creatine is an energy substrate: a small peptide serving as a reservoir for high-energy phosphate groups that can regenerate ATP, the main currency of cellular energy. An increase in creatine intake (through food or supplementation) increases cellular energy stores, promoting the regeneration of ATP in the short term. Stores are limited, however, and glucose or fatty acids are responsible for ATP replenishment over longer durations.

Without supplementation, creatine is formed primarily in the liver, with minor contributions from the pancreas and kidneys. The two amino acids, glycine and arginine, combine via the enzyme Arginine:Glycine amidinotransferase (AGAT) to form ornithine and guanidoacetate. This is the first of two steps in creatine synthesis, and although rare, any deficiency of this enzyme can result in mild mental retardation and muscular weakness.[29] AGAT is also the primary regulatory step, and an excess of dietary creatine can suppress activity of AGAT to reduce creatine synthesis[30] by reducing AGAT mRNA levels, rather than resulting in competitive inhibition.[31]

Guanidoacetate (made by AGAT) then receives a methyl donation from S-adenosyl methionine via the enzyme guanidinoacetate methyltransferase (GAMT), which produces S-adenosylhomocysteine (as a byproduct) and creatine. Deficiencies in GAMT are more severe (although equally rare) relative to AGAT, resulting in severe mental retardation and autism-like symptoms.[32]

For the most part, the above reactions occur in the liver,[33] where most systemic creatine is synthesized, but the AGAT and GAMT enzymes have been located in lesser amounts in kidney and pancreatic tissue (the extra-hepatic synthesis locales[34]). Neurons also possess the capability to synthesize their own creatine.[35]

The amino acids glycine and arginine are enzymatically combined to form guanidoacetate, which is then methylated to form creatine. Diseases associated with errors in creatine synthesis can result in muscle disorders and mental retardation.

As mentioned above, S-adenylmethionine must be converted to S-adenylhomocysteine in order for guanidoacetate to convert into creatine, during a process known as methylation.[36] It has been suggested that the production of creatine accounts for up to 40% of the S-adenylmethionine used in the body for methylation processes.[36][37]

Creatine supplementation alleviates the intrinsic burden of producing creatine. Supplementation reduces the expected increase in homocysteine[38] after intense exercise and may be a reason why creatine is seen as cardioprotective around the time of exercise.

After supplementation of creatine monohydrate (loading phase, followed by 19 weeks maintenance), creatine precursors are decreased by up to 50% (loading) or 30% (maintenance), which suggests a decrease in endogenous creatine synthesis during supplementation.[39] This appears to occur through creatine’s own positive feedback and suppression of the l-arginine:glycine amidinotransferase enzyme, the rate-limiting step in creatine synthesis, as levels of intermediates before this stage are typically elevated by up to 75%.[39]

A suppression of creatine synthesis occurs when enough creatine is supplemented to cover the vital needs (approximately 4g daily, 2g of which would have been synthesized). This suppression may be beneficial to health, due to the inherent costs associated with creatine synthesis.

Creatine is stored in the body in the form of creatine and as creatine phosphate, otherwise known as phosphocreatine, which is the creatine molecule bound to a phosphate group.[40] Creatine phosphate is thought to maintain the ATP/ADP ratio by acting as a high-energy phosphate reservoir.[41] The more ATP a muscle has relative to ADP, the higher its contractility is, and thus its potential strength output in vivo.[42][43] This pro-energetic mechanism also affects nearly all body systems, not just skeletal muscle. [40] During periods of rest and anabolism, creatine can gain a phosphate group through the creatine-kinase enzyme pathway, up to a cellular concentration of 30uM[25] to be later used for quick ATP resupply, when needed.[44][45]

Creatine kinase enzymes (of which there are numerous isozymes) exist in both the mitochondria and the cytosol of the cell.[46][41] The four isozymes of creatine kinase include the Muscle Creatine Kinase (MCK), present in contractile muscle and cardiac muscle, and the Brain Creatine Kinase (BCK), expressed in neuron and glial cells and several other non-muscle cells. These two creatine kinases are met with Sarcolemmic Mitochondrial Creatine Kinase (sMitCK), expressed alongside MCK, and the ubiquitous Mitochondrial Creatine Kinase (uMitCK), which is expressed alongside BCK everywhere else.[26][40]

Supplementation of creatine monohydrate increases stores of both of these compounds in myocytes, neurons, eyes, kidneys and testes. Muscle comprises more than 95% of bodily creatine stores.[47][48]

Creatine and creatine phosphate form a couplet in cells, which sequesters phosphate groups. These phosphate groups are then donated to ADP to regenerate ATP. This donation is faster than any other process in a cell for replenishing energy, and higher cellular creatine levels result in more phosphate donation and subsequent energy replenishment.

Increasing cellular survival (preventing ATP depletion allows cells to survive longer) against hypoxia, oxidative damage, and some toxins that damage neurons and skeletal muscle cells is a mechanism of creatine supplementation mediated via creatine-kinase.[40][49][50] This has also been shown to have efficacy against toxin-induced seizures.[51]

Expressing the creatine-kinase enzyme in cells that do not normally express it (and thus enabling these cells to use creatine) exerts protective effects,[52] while inhibiting this enzyme reduces survival rates.[53]

Creatine and phosphocreatine surplus in a cell serves as an energy reservoir that can protect cells during periods of acute stress, and may enhance cell survival secondary to its bioenergetic effects.

Creatine kinase appears to be subject to sexual dimorphism, meaning differences exist in males and females, with males exhibiting increased enzyme activity.[54][55][56]

Black people appear to have higher activity of the creatine kinase system compared to both white and hispanic people, with hispanic people having greater levels than whites.[54][56] The differences between races are more pronounced in men.[57]

When splitting a sample into exercisers and non-exercisers, it appears that exercise as a pre-requisite precedes a higher range of activity. Inactive people tend to be on the lower end of creatine kinase activity and relatively clustered in magnitude, while exercise generally increases activity, but also introduces a larger range of possible activity.[57]

Men appear to have higher active creatine-kinase systems, and racial differences favor black people over hispanic people over white people in terms of the activity of the creatine-kinase system. This system is more variable in men, independent of supplementation. Exercise may increase the activity of the creatine-kinase system independent of supplementation.

1.5. Deficiency States

Creatine is also a neurological nutrient. People who cannot produce endogenous creatine suffer from a form of mental retardation with autistic-like symptoms due to deficiencies in the enzymes of creatine synthesis (AGAT or GAMT).[58]

The main storage area of creatine in the human body is the skeletal (contractile) muscle, which holds true for other animals. Therefore, consumption of skeletal muscle (meat products) is the main human dietary source of creatine. Since vegetarians and vegans lack the main source of dietary creatine intake, which has been estimated to supply half of the daily requirements of creatine in normal people, both vegetarians and vegans have been reported to have lower levels of creatine.[59][60] This also applies to other meat-exclusive nutrients, such as L-Carnitine.[59]

Due to this relative deficiency-state in vegetarians and vegans, some aspects of creatine supplementation are seen as more akin to normalizing a deficiency, rather than providing the benefits of supplementation. In young vegetarians, but not omnivores, creatine supplementation can enhance cognition.[61][62] The increased gain in lean mass may be more significant in vegetarians, relative to omnivores.[60] Supplementation of creatine in vegetarians appears to normalize the gap in storage between vegetarians and omnivores.[63] This is possibly related to a correlation seen in survey research, where vegetarianism and veganism appear to be more commonly affected by some mental disorders like anxiety and depression.[64]

The importance of supplemental creatine is elevated in vegetarian and vegan diets due to the elimination of creatine’s main dietary sources.

1.6. Formulations and Variants

Creatine monohydrate is the most common form of creatine, and if not otherwise mentioned is the default form of creatine used in most studies on creatine.[65] It has fairly decent intestinal absorption[66][13] (covered more in depth in the pharmacology section) and is the standard form or “reference” form of creatine, which all other variants are pitted against.

This basic form of creatine comes in two forms, one of which involves the removal of the monohydrate (which results in creatine anhydrous) that converts to creatine monohydrate in an aqueous environment,[67][68] but due to the exclusion of the monohydrate it is 100% creatine by weight despite creatine monohydrate being 88% creatine by weight, as the monohydrate is 12%. This allows more creatine to be present in a concentrated formula, like capsules.[69]

Creatine monohydrate can also be micronized (commonly sold as “Micronized Creatine”) which is a mechanical process to reduce particulate size and increase the water solubility of creatine. In regard to supplementation, it is equivalent to creatine monohydrate.

Creatine is most commonly found in the basic form of creatine monohydrate, which is the standard form and usually recommended due to the low price. It can also be micronized to improve water solubility, or the monohydrate can be temporarily removed to concentrate creatine in a small volume supplement. Neither alteration changes the properties of creatine.

Creatine hydrochloride (Creatine HCl) is a form of creatine characterized by the molecule being bound to a hydrochloric acid moiety. It is claimed to require a lower dosage than creatine monohydrate, but this claim has not been tested.

Creatine hydrochloride likely forms into free creatine and free hydrochloric acid in the aqueous environment of the stomach, which would mean it is approximately bioequivalent to creatine monohydrate.

Creatine HCl is touted to require a lower dosage, but this has not been proven through studies and seems unlikely, since the stomach has an abundance of HCl anyway and creatine will freely dissociate with HCl in the stomach. Thus, both creatine HCl and creatine monohydrate form free creatine in the stomach.

Liquid creatine has been shown to be less effective than creatine monohydrate.[70] This reduced effect is due to the passive breakdown of creatine over a period of days into creatinine, which occurs when it is suspended in solution.[71] This breakdown is not an issue for at-home use when creatine is added to shakes, but it is a concern from a manufacturing perspective in regard to shelf-life before use.

Liquid creatine is ineffective as a creatine supplement due to its limited stability in solution. This shouldn’t be an issue for people preparing a creatine solution at home, since it takes a few days to for creatine to degrade. This is a problem for the manufacturers, where creatine in solution has a limited shelf-life.

Buffered creatine (Kre-Alkylyn is the brand name) is touted to enhance the effects of creatine monohydrate due to a higher pH level, which enables better translocation across the cytoplasmic membrane and more accumulation in muscle tissues.

This claim has not been demonstrated at this time, and a recent comparative study of buffered creatine against basic creatine monohydrate found no significant differences between the two in 36 resistance trained individuals, in regard to the effects or the accumulation of creatine in muscle tissue.[72] There also were no significant differences in the amount of adverse side-effects reported.

“Buffered” creatine (Kre-Alkylyn) is suggested to be a better absorbed form of creatine supplementation, but it can be rapidly neutralized in the stomach if it is not in an enteric coating. Even if it is enteric coated, there is no evidence to support its efficacy above creatine monohydrate.

Creatine ethyl ester increases muscle levels of creatine to a lesser degree than creatine monohydrate.[73] It may also result in higher serum creatinine levels[74] due to creatine ethyl ester being converted into creatinine via non-enzymatic means in an environment similar to the digestive tract.[75][76] At equal doses to creatine monohydrate, ethyl ester has failed to increase water weight after 28 days of administration (indicative of muscle deposition rates of creatine, which are seemingly absent with ethyl ester).[77]

Creatine ethyl ester is more a pronutrient for creatinine rather than creatine,[75] and was originally created in an attempt to bypass the creatine transporter. It is currently being studied for its potential as a treatment for situations in which there is a lack of creatine transporters (alongside cyclocreatine as another possible example).[78] Its efficacy may rely on intravenous administration, however.

Direct studies on creatine ethyl ester show it to be less effective than creatine monohydrate, on par with a placebo.[73]

Creatine ethyl ester is 82.4% creatine by weight, and thus would provide 8.2g of active creatine for a dosage of 10g.[69]

Creatine ethyl ether is likely ineffective as a creatine supplement for general use. Despite being able to passively diffuse through cell membranes in vitro, it degrades into creatinine rapidly in the intestines.

Magnesium-chelated creatine typically exerts the same ergogenic effects as creatine monohydrate at low doses.[79] It was created because carbohydrates tend to beneficially influence creatine metabolism and magnesium is also implicated in carbohydrate metabolism and creatine metabolism.[80][81] Magnesium chelated creatine may be useful for increasing muscle strength output with a similar potency to creatine monohydrate, but without the water weight gain, as there are noted differences, but they are statistically insignificant.[81][82]

Creatine magnesium chelate has some limited evidence for it being more effective than creatine monohydrate, but this has not been investigated further.

Creatine nitrate is a form of creatine in which a nitrate (NO3) moiety is bound to the creatine molecule, which has been demonstrated to enhance solubility in water by approximately 10-fold, with the pH of 2.5 or 7.5 not significantly affecting the solubility.[83] Beyond increased solubility, no other studies have been conducted using creatine nitrate.

Creatine nitrate is a highly water soluble form of creatine, and while it is theoretically possible that it can provide the benefits of both creatine and nitrate, this has not been investigated.

Creatine citrate is creatine bound to citric acid, or citrate. Creatine citrate does not differ greatly from monohydrate in regard to absorption or kinetics.[84] Note that creatine citrate is more water-soluble than monohydrate,[85] but creatine absorption is generally not limited by solubility. The increased water solubility may play a factor in palatability.

It can be found in varying ratios of creatine:citrate, including 1:1 (creatine citrate[86][87]), 2:1 (dicreatine citrate[88][89][90]), and 3:1 (tricreatine citrate[91]).

Creatine malate is the creatine molecule bound to malic acid. There might be some ergogenic benefits from malic acid on its own,[92] but this has not been investigated in conjunction with creatine. Malic acid/malate also has a sour taste[93] and may negate the sensation of bitterness, which is common among some supplements.

Creatine citrate and creatine malate are variants of creatine with increased water solubility.

Creatine pyruvate (also known as creatine 2-oxopropanoate) in an isomolar dose relative to creatine monohydrate has been shown to produce higher plasma levels of creatine (peak and AUC) with no discernible differences in absorption or excretion values.[84] The same study noted increased performance from creatine pyruvate at low (4.4g creatine equivalence) doses relative to citrate and monohydrate, possibly due to the pyruvate group.

Creatine pyruvate is 60% creatine by weight.[69]

Creatine pyruvate has once been noted to reach higher levels of plasma creatine relative to an isomolar dose of creatine monohydrate. The lone study failed to note differences in absorption, however, which conflicts with the observation of increased serum levels. This result has not been replicated.

Creatine α-ketoglutarate is the creatine molecule bound to an alpha-ketoglutaric acid moiety. Little research has been done on creatine α-ketoglutarate.[94]

Creatine α-ketoglutarate is 53.8% creatine by weight.[69]

Creatine α-ketoglutarate is thought to be an enhanced form of creatine supplementation (similar to Arginine α-ketoglutarate, which has an increased rate of absorption) but this has not been investigated.

Sodium creatine phosphate is 51.4% creatine by weight.[69]

Sodium creatine phosphate appears to be about half creatine by weight, and it is not certain if this variant offers any advantages over conventional forms.

Polyethylene glycosylated creatine seems to be as effective as creatine monohydrate at a lower dose (1.25-2.5g relative to 5g monohydrate), but does not seem to be comparable in all aspects.[95][96]

Polyethylene glycosylated creatine (PEG creatine) appears to be somewhat comparable to creatine monohydrate.

Creatine gluconate is a form of creatine supplementation in which the creatine molecule is bound to a glucose molecule. It currently does not have any studies conducted on it.

Creatine gluconate is sort of a glycoside of creatine, and it is thought to be better absorbed when taken alongside food, since many other gluconate molecules, particular in the context of minerals like magnesium, are absorbed better with food. However, there are currently no studies on this particular variant.

Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) is a synthetic analogue of creatine in a cyclic form. It serves as a substrate for the creatine kinase enzyme system, acting as a creatine mimetic. Cyclocreatine may compete with creatine in the CK enzyme system to transfer phosphate groups to ADP, as coincubation of both can reduce cyclocreatine’s anti-motility effects on some cancer cells.[97]

The structure of cyclocreatine is fairly flat (planar), which aids in passive diffusion across membranes. It has been used with success in an animal study, where mice suffered from a SLC6A8 (creatine transporter at the blood brain barrier) deficiency, which is not responsive to standard creatine supplementation.[98] This study failed to report increases in creatine stores in the brain, but noted a reduction of mental retardation associated with increased cyclocreatine and phosphorylated cyclocreatine storages.[98] As demonstrated by this animal study and previous ones, cyclocreatine is bioactive after oral ingestion[98][99] and may merely be a creatine mimetic, able to phosphorylate ADP via the creatine kinase system.[98]

This increased permeability is noted in glioma cells, where it exerts anti-cancer effects related to cell swelling,[100][101] and in other membranes, such as breast cancer cells[102] and skeletal (contractile) muscle cells.[103] The kinetics of cyclocreatine appear to be first-order,[102] with a relative Vmax of 90, Km of 25mM and a KD of 1.2mM.[104]

In regard to bioenergetics, phosphorylated cyclocreatine appears to have less affinity for the creatine kinase enzyme than phosphorylated creatine in terms of donating the high energy phosphate group (about 160-fold less affinity) despite the process of receiving phosphorylation being similar.[105][106]When fed to chickens, phosphorylated cyclocreatine can accumulate up to 60mM in skeletal muscle,[107] which suggests a sequestering of phosphate groups before equilibrium is reached.[106]Cyclocreatine still has the capacity to donate phosphate, however, as beta-adrenergic stimulated skeletal muscle (which depletes ATP and glycogen) exhibits an attenuation of glycogen depletion (indicative of preservation of ATP) with phosphocreatine.[103]

Cyclocreatine appears to be passively diffused through membranes and not subject to the creatine transporter, which can be beneficial for cases where creatine transporter function is compromised (creatine non-response and SLG6A8 deficiency). Similar to other forms of creatine, it buffers ATP concentrations, although its efficacy as a supplement in otherwise healthy people is currently unknown.

Molecular Targets

2.1. Cellular Hydration

When creatine is absorbed it pulls water in with it, causing cells to swell. This “cell volumization” is known to promote a cellular anabolic state associated with less protein breakdown and increased DNA synthesis.[108][109][110] An increase in cellular viability assessed via phase angle (measuring body cell mass[111]) has been noted in humans during supplementation of creatine.[112]

Glycogen synthesis is known to respond directly and positively to cellular swelling. This was demonstrated in an earlier study, during which rat muscle cells were exposed to a hypotonic solution in vitro to induce cell swelling, which increased glycogen synthesis by 75%. In contrast, exposing these same cells to a hypertonic solution hindered glycogen synthesis by 31%. These changes were not due to alterations in glucose uptake, but are blocked by hindering the PI3K/mTOR signaling pathway.[113] It was later noted that stress proteins of the MAPK class (p38 and JNK) as well as heat shock protein 27 (Hsp27) are activated in response to increasing osmolarity.[114][115] Furthermore, activation of MAPK signaling in skeletal muscle cells is known to induce myocyte differentiation[116]via GSK3β and MEF2 signaling, which can induce muscle cell growth.[117][118]

The increase in cellular swelling (water retention within the cell) per se appears to have a positive influence on muscle cell growth, since the increase in swelling is met with the activation of stress response proteins of the MAPK class, which then influences muscle protein synthesis. These mechanisms do not involve the creatine kinase cycle.

Inducing hypertonicity (a reduction in cellular swelling) is known to actually increase the mRNA of the creatine transporter,[119] thought to be due to increasing cellular creatine uptake to normalize creatine levels. This has been noted in both muscle cells and endothelial cells, but is thought to apply to all cells.[119]

This regulation of creatine uptake is similar to other osmolytic agents such as myoinositol or taurine, which have their uptake into cells enhanced during periods of hypertonia in order to increase cellular swelling.

Cellular hydration status is tied to creatine influx and efflux by modulating the expression of the creatine transporter and thus cellular uptake. This is similar to other osmolytes in the human body.

2.2. Cytoprotection

Phosphocreatine, the higher energy form of creatine, can associate with and protect cell membranes.[120] This was first observed in Drosophilia, which do not express the creatine kinase enzyme (and cannot use creatine for energy purposes) yet still received cellular protection from creatine.[121]

In a later study, it was found that biologically relevant concentrations (10-30mM) of creatine bind synthetic membranes with lipid compositions mimicking the inner mitochondrial membrane or plasma membrane in a concentration-dependent manner. This also conferred a degree of protection, increasing membrane stability in response to challenge from a number of destabilizing agents. Phosphocreatine was more effective than creatine in this context, although both were able to bind and stabilize membranes.[120]

Cyclocreatine (an analogue of creatine) has been shown to protect microtubules in a cell and protect its structure, but it is not known whether these benefits can be expanded to creatine.[122][120]

Phosphocreatine can bind to cellular membranes due to its phosphate group. This seems to exert a protective effect by increasing membrane stability. This protective effect is not related to either cell hydration or the creatine kinase system, and its relevance in vivo is not clear at this time.

2.3. Methyl Donation

Creatine is involved indirectly in whole body methylation processes. This is due to creatine synthesis having a relatively large methyl cost, as the creatine precursor known as guanidinoacetate (GAA) requires a methyl donation from S-adenosyl methionine (SAMe) in order to produce creatine. This may require up to half of the methyl groups available in the human body.[36][123]

Creatine supplementation will downregulate the body’s own production of creatine by suppressing the enzyme that mediates the above conversion (Guanidinoacetate methyltransferase or GAMT)[124], and because of this it is thought that SAMe gets backlogged and is more available for other processes that require it.

SAMe is the primary methyl donor in the human body, and supplements that preserve SAMe (such as trimethylglycine; TMG) promote a variety of benefits in the human body, like a reduction in homocysteine and reduced risk of fatty liver. Creatine has been implicated in both reducing homocysteine[125] and preventing fatty liver in rodents[126], thought to be secondary to preserving SAMe.

Creatine synthesis requires a large amount of S-adenosyl methionine (SAMe). Downregulating creatine synthesis (via supplementation) indirectly preserves SAMe levels in the body. This is thought to indirectly promote the benefits of SAMe supplementation by reducing its consumption, acting in a similar manner to TMG.

Longevity

3.1. Rationale

Creatine supplementation may be able to enhance lifespan, secondary to increasing intracellular carnosine stores. Carnosine is the metabolic compound formed from beta-alanine supplementation, and in a mouse-model for premature aging (senescence-accelerated premature aging, SAMP8) creatine supplementation without any beta-alanine has been shown to increase cellular carnosine stores.[127] That being said, the aforemented SAMP8 study noted an increase in carnosine levels at middle age, but not old age in the mice.[127] A human study using 20g of creatine for one week in otherwise healthy people failed to find an increase in intracellular carnosine stores.[127]

Creatine been noted to increase intracellular carnosine stores in a mouse model for premature aging. While this is thought to have an anti-aging effect in mice, oral ingestion of creatine has not been shown to increase carnosine levels in humans, and there is currently no evidence to support an anti-aging effect.

Pharmacology

4.1. Absorption

In the stomach, creatine can degrade by about 13% due to the digestive hormone pepsin, as assessed by simulated digestion.[128] Although creatinine is a known byproduct of creatine degradation, simulated gastric digestion did not increase creatinine levels, indicating that other breakdown products were formed. However, creatinine was noted to increase in the presence of pancreatin, a mixture of pancreatic enzymes.[128]

Stomach acid can degrade a small amount of creatinine, which does not appear to be too practically relevant, judging by the multitude of studies noting benefits after oral creatine monohydrate supplementation.

The overall bioavailability of creatine is quite good, ranging from 80%[129] up to nearly 100%[84]depending on the dose ingested, since higher acute doses are absorbed less efficiently.

The specific mechanism of intestinal uptake for creatine is not clear, although transporters have been identified in rat jujenum, and confirmed at the mRNA level in humans.[130][131] The observation that creatine can be absorbed against a concentration gradient to a max ratio of 8:1 (8 times more creatine in the intestinal cell post absorption, relative to the lumen) supports transporter-mediated uptake, and the dependence on sodium and chloride implicate SLC6A8 (Creatine Transporter 1) as the operative transporter.[103]

In standard dosages (5-10g creatine monohydrate) the bioavailability of creatine in humans is approximately 99%,[69][84] although this value is subject to change with different conjugates (forms) of creatine and dosages.[84] Coingestion of cyclocreatine (an analogue) can reduce uptake by about half[132] and coincubation of taurinecholine, glycine, or beta-alanine had minimal attenuation of absorption, which is likely not practically relevant.[132] The inhibition noted with cyclocreatine may be due to receptor saturation.

There is also evidence to suggest that increased ingestion of creatine leads to an increased fecal creatine value, suggesting that the intestinal uptake can be saturated.[47]

Intestinal uptake is most likely mediated by SLC6A8 or a related sodium-dependent transporter. Absorption does not appear to be hindered by other common supplements, although too much creatine at one time (greater than 10 g) can saturate receptors, leading to excretion.

4.2. Serum

Assuming absolutely no supplementation and standard dietary intake, basal (fasted) creatine concentrations in humans are in the range of 100-200µM,[7][133] which is lower than observed in rats (140-600µM[134][135]).

Under fasting and nonsupplemental conditions, concentrations of creatine in the human body are in the micromolar range.

After the ingestion of 5g creatine in otherwise healthy humans, serum levels of creatine were elevated from fasting levels (50-100µM) to 600-800µM within one hour after consumption.[136] The receptor follows Michaelis-Menten kinetics with a Vmax obtained at concentrations higher than 0.3-0.4mmol/L,[137] with prolonged serum concentrations above this amount exerting most of its saturation within two days.[138]

Researchers observed that it took 2.5 hours after the ingestion of a 20g bolus of creatine for serum levels to increase up to over 2000µM.[139]

Creatine in serum follows a dose-dependent relationship, with more oral creatine ingested causing more serum increases. The rate of accrual into muscle cells may be maximized at a serum concentration achievable with 5g of creatine supplementation.

4.3. Cellular Kinetics (Creatine Transporter)

The creatine transporter is a sodium[140][141] and chloride[142][143] dependent membrane-associated transporter that belongs to the Na+/Cl-dependent family of neurotransmitter transporters.[144] In muscle cells and most other cell types,[132][142] the isomer of the creatine transporter is known as SLC6A8 (solute carrier family 6, member 8). SLC6A8 is encoded by the gene present on the Xq28 region of the human X-chromosome and is expressed in most tissues.[145] A related gene encoding a creatine transporter variant has also been identified at 16p11.1 that is expressed exclusively in the testes.[146] These two transporters share 98% homology.[145][146]

The creatine transporter is a sodium- and chloride-dependent transporter of the SLC family, also known as SLC6A8. It is the sole mechanism for the transport of creatine from the blood into cells.

Creatine transport has been shown to increase when muscle creatine stores are depleted. This was only noted to occur in muscle with particular fiber types (soleus and red gastrocnemius), while other fiber types, such as white grastrocnemius, did not show any clear trend.[147] This indicates that transport in relation to total creatine levels varies across different muscle fiber types.

In muscle cells, the creatine transporter is predominantly localized to the sarcolemmal membrane. Western blot analysis of creatine transporter expression revealed the presence of two distinc protein bands, migrating at 55kDa and 70kDa on reducing SDS-PAGE gels.[148][149] The 73kDa band has been reported to be the predominant band in humans, with no differences based on gender.[149] A more recent report demonstrated that the 55kDa creatine transporter variant is glycosylated, forming the 73 kDa protein. Therefore, the 55 and 75kDa protein bands are actually immature and mature/processed forms of the creatine transporter protein, respectively.[150]

The creatine transporter exists in two forms: an immature form with a molecular weight of 55 kDa, and a mature form that is processed by glycosylation, increasing the molecular weight to 73 kDa.

In general, muscle content of creatine tends to be elevated to 15-20% above baseline (more than 20mM increase) in response to oral supplementation. People who get a sufficiently high influx of creatine are known as responders.[151][152][153][154] A phenomena known as “creatine nonresponse” occurs when people have less than a 10mM influx of creatine into muscle after prolonged supplementation.[155] Quasi-responders (10-20mM increase) also exist.[155] Nonresponse is thought to explain instances where people do not benefit from creatine supplementation in trials, since some trials that find no significant effect do find one when only investigating people with high creatine responsiveness.[156] There are clear differences between those who respond and those who do not, in regard to physical performance.[157] People who are creatine responsive tend to be younger, have higher muscle mass and type II muscle fiber content, but this has no correlation with dietary protein intake.[155][158]

Creatine non-response is when muscular loading of creatine is under a certain threshold (10mmol/L), while “response” to creatine means having more muscular creatine loading (20mol/L or more). There also exists a “grey area” inbetween, where some benefits are achieved but not as many as pure responders will experience. Response appears to be positively correlated with muscle mass and type II muscle fibers.

4.4. Positive Regulators (Cellular Uptake)

Creatine is only taken up by its transporter, and changes in the activity level of this transporter are wholly causative of changes in creatine uptake. The transporter is regulated by mostly cytosolic factors as well as some external factors that affect creatine transport activity, [144] including extracellular creatine.[141] Agents affecting creatine transport are further divided into positive regulators (those that increase activity of the transporter) and negative regulators (those that suppress activity).

The creatine transporter (CrT) is positively regulated by proteins known to be involved in sensing and responding to the cellular energy state, including the mammalian target of rapamycin (mTOR[159]). Upon activation, mTOR stimulates SGK1 and SGK3[160][161] to act upon PIKfyve[162] and subsequently PI(3,5)P2[163] to increase CrT activity.[162] Beyond mTOR, SGK1 also is stimulated by intracellular calcium[164] and a lack of oxygen (ischemia).[165] Because transient ischemia is associated with increased reactive oxygen species (ROS) production after blood flow is restored (reperfusion) it has been hypothesized that muscle contraction may increase creatine uptake through a similar ROS-mediated mechanism.[166]

Stress-inducible kinases (SGK1, SGK3) increase the activity of the creatine transporter, and these proteins are increased by any intracellular stress (such as a lack of oxygen or calcium release from inside the cell). Creatine transport activity is also activated by mTOR, an important nutrient sensor and “master-regulator” of protein synthesis.

Some other cytokines and hormones may increase the receptor activity. These include growth hormone (GH) which acts upon the growth hormone receptor (GHR)[167][168] to stimulate c-Src[169][170]which directly increases the activity of the CrT via phosphorylation. This is known to occur with the 55kDa version of c-Src but not the 70kDa version and requires CD59 alongside c-Src.[171]

There is a nuclear receptor known as TIS1 (orphan receptor, since there are no known endogeouns targets at this time) which positively influences transcription of new creatine transporters[172] and, in C2C12 myotubes, seems to be responsive to cAMP or adenyl cyclase stimulation from forskolin (from Coleus Forskohlii) with peak activation at 20µM.[172][173]

Both growth hormone and TIS1 increase the activity of the creatine transporter in a manner different than the cellular stresses, since growth hormone directly activates it via another pathway (c-Src) while TIS1 is involved in making more of the receptors overall. TIS1 seems to respond to intracellular cAMP levels.

Finally, starvation (nutrient deprivation for four days) appears to increase activity of the creatine transporter secondary to decreasing serine phosphorylation (SGK target)[174] with no influence on tyrosine phosphorylation (c-Src target).[174] Starvation-induced increases in creatine influx do not necessarily mean more phosphocreatine, however, due to a depleted cellular energy state.[174]

Starvation increases creatine uptake into cells, but without appreciable conversion into phosphocreatine. Because phosphocreatine is the energetically useful form of creatine in the cell, starvation is not a viable means to increase the efficacy of creatine supplmentation.

In vitro, insulin promotes creatine uptake in mouse[175] and human muscle cells.[176] In the human cells, insulin infusion was effective at 55-105mU, but not 5-30mU.[176]

In regard to practical interventions, concurrent glycogen loading has been noted to increase creatine stores by 37-46% regardless of whether the tissue was exercised prior to loading phase.[177] It is important to note, however, that creatine levels in response to the creatine loading protocol were compared in one glycogen-depleted leg to the contralateral control leg, which was not exercised.[177]This does not rule out a possible systemic exercise-driven increase in creatine uptake, and the increase in creatine noted above[177] was larger than typically seen with a loading protocol (usually in the 20-25% range). Consistent with an exercise-effect, others have reported that exercise itself increases creatine uptake into muscle, reporting 68% greater creatine uptake in an exercised limb, relative to 14% without exercise.[154]

Exercise itself appears to stimulate creatine uptake into muscle, although reports have been mixed. Given the positive effect of metabolic stress on CrT activity, it is also possible that the more metabolically intense the exercise is on the tissue level, the more creatine uptake is increased.

4.5. Negative Regulators (Cellular Uptake)

Negative regulators of the creatine transporter (CrT) are those that, when activated, reduce the activity of the CrT and overall creatine uptake into cells. As noted above, CrT activity is positively regulated by mTOR.[159] Consistent with the well-known role of AMPK as a suppressor mTOR signaling,[178] CrT activity has also been shown to be inhibited in response to AMPK activation in kidney epithelial cells.[179] Since AMPK suppresses mTOR via upstream TSC2 activation,[180] the negative regulation of AMPK on CrT activity in these cells appears to occur through an indirect mechanism. Although indirect, activation of AMPK has been noted to reduce the Vmax of the CrT without altering creatine binding, and is involved in internalizing the receptors.[179] This pathway seems to max out at around 30% suppression, with no combination of mTOR antagonists and AMPK inducers further suppressing creatine uptake.[179]

In contrast to kidney epithelial cells, others have reported that creatine transport is increased by AMPK in the heart,[5] indicating that CrT is likely regulated in a cell-and tissue specific manner in response to local energy demands. Regulation of CrT by AMPK in a tissue-specific manner has not been explored.

Activity of the creatine transporter (CrT) protein is controlled by AMPK in an apparent cell and/or tissue-specific manner. More research is needed to determine the effect of AMPK on CrT activity in various tissues, which could be relevant to nutrition and supplementation strategies to optimize creatine stores in skeletal muscle.

Extracellular creatine (creatine outside of a cell) appears to influence creatine uptake into a cell. It seems that prolonged and excessive levels of creatine actually suppress uptake (a form of negative regulation to prevent excessive influx).[181]In vitro studies in rat muscle cells have shown that including 1mM creatine into cell culture medium substantially reduces creatine uptake into cells. The inhibitory effect was partially negated by protein synthesis inhibitors, suggesting that high levels of creatine induce the expression of a protein that suppresses creatine transporter activity.[181] Similar findings were reported in a later study in cultured mouse myoblasts, which noted a 2.4-fold increase in intracellular creatine levels in the presence of the protein synthesis inhibitor cyclohexamide.[175]

High extracellular creatine concentrations induce the expression of a factor that inhibits the creatine transporter (CrT). To date, neither the identity of nor mechanism for this putative CrT-suppressing factor has come to light. Future studies that are able to identify this creatine transport-suppressing factor and how it works may provide valuable insight into possible supplementation strategies that might be used to increase creatine uptake into muscle cells.

More recent studies on the regulation of CrT creatine transport activity have identified the protein kinase (Janus-Activating Kinase 2) JAK2, which suppresses the rate of creatine uptake via CrT without affecting creatine binding.[182] JAK2 is a regulatory protein involved in stabilizing the cellular membrane and controlling water concentrations in response to osmotic stress.[183][184] Similar to c-Src (a positive creatine transport regulator), Jak2 can also be activated by growth hormone signaling.[170][185] The growth hormone receptor seems to activate these two factors independently, as gh-mediated activation of c-Src does not require JAK2.[169] Given that c-Src is a positive regulator of CrT, JAK2 is a negative regulator, and the fact that downstream signals from both are induced by growth hormone, it is tempting to speculate that JAK2 activation downstream of the gh receptor may function as a homeostatic response to limit c-src induced creatine uptake. This has not been studied, however, and the effects of gh-induced JAK2 signaling on CrT activity have not been examined.

JAK2 (Janus-Activating Kinase 2) is a novel protein that has been shown to suppress the activity of the creatine transporter CrT in vitro. The effects of JAK2 on CrT are not well-understood in vivo, however. Given that growth hormone activates both c-src (increases CrT activity) and JAK2- which has been found to decrease CrT activity, it is plausible that JAK2 may function as a negative-feedback regulator of creatine uptake. Future research is needed to better understand the role of JAK2 on CrT activity in vivo.

4.6. Neurological Distribution

Creatine is vital for proper neural functioning, and true creatine deficiency results in mental retardation.[2] Deficiency can occur through either hindered synthesis (lack of enzymes to make creatine, can be treated with supplementation) or by a lack of transport into the brain (untreatable with standard creatine).

Entry into neural tissues in general is mediated by the secondary creatine transporter (CrT-2) known as SLC6A10,[186] which is the same transporter that is active in a male’s testicles.[146] CrT-2 belongs to the family of SLC6 transporters that act to move solutes across the membrane by coupling transport with sodium and chloride.[187][188] Genetic deletions in the 16p11.2 region, which encodes both SLC6A8[189] and SLC6A10[186] can result in severe mental retardation in humans and is one of the causes of “Creatine Deficiency Syndrome.” Creatine Deficiency Syndrome is not only caused by lack creatine transporter expression, however, as creatine synthesis is also critical for neural function.[190].[189] Retardation caused by defective creatine synthesis[32] can be reversed with creatine supplementation and dietary changes.[191]

In regard to the blood brain barrier (BBB), which is a tightly woven mesh of non-fenestrated microcapillary endothelial cells (MCECs) that prevents passive diffusion of many water-soluble or large compounds into the brain, creatine can be taken into the brain via the SLC6A8 transporter.[192]In contrast, the creatine precursor (guanidinoacetate, or GAA) only appears to enter this transporter during creatine deficiency.[192] More creatine is taken up than effluxed, and more GAA is effluxed rather than taken up, suggesting that creatine utilization in the brain from blood-borne sources[192] is the major source of neural creatine.[193][192] However, “capable of passage” differs from “unregulated passage” and creatine appears to have tightly regulated entry into the brain in vivo[193]. After injecting rats with a large dose of creatine, creatine levels increased and plateaued at 70uM above baseline levels. These baseline levels are about 10mM, so this equates to an 0.7% increase when superloaded.[193] These kinetics may be a reason for the relative lack of neural effects of creatine supplementation in creatine sufficient populations.

Creatine is vital for brain function, which has mechanisms to take up creatine, as well as regulate its intake. Although the diet appears to be the major source of creatine (and thus lack of dietary intake could cause a non-clinical deficiency) excess levels of creatine do not appear to “super-load” the brain similar to muscle tissue. Due to kinetics, creatine appears to be more “preventative” or acts to restore a deficiency in the brain. This is in contrast to creatine effects in muscle cells, where it can affect performance substantially on an acute timescale.

In addition to the BBB, SLC6A8 is also expressed on neurons and oligodendrocytes,[192] but is relatively absent from astrocytes, including the astrocytic feet[193][194] which line 98% of the BBB.[195]Creatine can still be transported into astrocytes (as well as cerebellar granule cells) via SLC6A8, as incubation with an SLC6A8 inhibitor prevents accumulation in vitro. It seems to be less active in a whole brain model, relative to other brain cells.[196]

That being said, many brain cells express both AGAT and GAMT, two enzymes that mediate creatine synthesis. Neural cells have the capacity to synthesize their own creatine.[197][190]

4.7. Elimination

Without supplementation, approximately 14.6mmol (2g) of creatinine, creatine’s urinary metabolite, is lost on a daily basis in a standard 70kg male ages 20-39. The value is slightly lower in females and the elderly due to a presence of less muscle mass.[36] This amount is considered necessary to obtain in either food or supplemental form to avoid creatine deficiency. Requirements may be increased in people with higher than normal lean mass.[36][198] Creatine excretion rates on a daily basis are correlated with muscle mass, and the value of 2g a day is derived from the aforementioned male population with about 120g creatine storage capacity.[36] Specifically, the rate of daily creatine losses is about 1.6%[199]-1.7%,[26] and mean losses for women are approximately 80% that of men due to less average lean mass.[36] For weight-matched elderly men (70kg, 70-79 years of age) the rate of loss of 7.8mmol/day,[50] or about half (53%) that of younger men.

Creatine appears to have a “daily requirement” like a vitamin to maintain sufficient levels, at or around 2g assuming a “normal” 70 kg male body.

Creatine levels in the blood tend to return to baseline (after a loading with or without the maintenance phase) after 28 days without creatine supplementation.[153][200][201] This number may vary slightly from one individual to another, and for some may exceed 30 days.[202] Assuming an elimination rate of creatinine (creatine’s metabolite) at 14.6mmol per day,[36][201] six weeks of cessation is approaching the upper limit for serum creatine to completely return to baseline.

Despite this decrease to baseline levels, muscle creatine and phosphocreatine levels may still be elevating and provide ergogenic effects.[202]

Creatine can be elevated above baseline after supplementation of more than 2 grams, and depending on the degree of loading it may elevate bodily creatine stores for up to 30 days.

4.8. Loading

Creatine retention (assessed by urinary analysis) tends to be very high on the first loading dose (65±11%) and declines throughout the loading phase (23±27%).[203] This is likely due to increased muscular uptake when creatine stores are relatively low, which has been noted in vegetarians. So, creatine absorption is very high initially, but decreases througout the loading phase, as muscle creatine stores increase.[204]

Coingestion of creatine with carbohydrate is known to increase glycogen accrual in skeletal muscle (possibly resulting in increased cell volume)[177] although the creatine content in muscles does not appear to be significantly increased.[177]

4.9. Maintenance

Creatine maintenance is known as the period following loading (if the user chooses to load) and its duration may be indefinite. The goal of maintenance is to find the lowest daily dose required to optimize creatine stores and benefits of supplementation while reducing potential side-effects of loading, like intestinal and gastric distress.

Sedentary people who undergo a loading period (2g of creatine daily for up to six weeks) are able to retain much of the creatine loading into skeletal muscles. Studies following this protocol note that (total free creatine) a 30.6% increase with loading is attenuated to 12.9%.[205]

This partial preservation of creatine stores with 2g may be wholly irrelevant in athletes, as assessed by elite swimmers where 2g as maintenance (no loading phase) failed to alter creatine content in muscle whatsoever.[206]

A maintenance phase of 2g daily appears to technically preserve creatine content in skeletal muscle of responders either inherently or after a loading phase, but in sedentary people or those with light activity, creatine content still progressively declines (although it still higher than baseline levels after six weeks) and glycogen increases seem to normalize. This maintenance dose may be wholly insufficient for athletes, a 5g maintenance protocol may be more prudent.

When looking collectively at the benefits accrued during loading and maintenance, it appears that changes in body mass are additive during this phase (increased during loading, further increased during maintenance).[203]

Despite a possible decreasing creatine content in the muscles when maintenance is deemed suboptimal, the overall retention of weight and lean mass is merely additive over time. This is thought to be due to increases in skeletal muscle production (increase in body weight) compensating for the progressive declines in water and glycogen content (decreases in body weight).

When total free creatine declines (from 30.6% to 12.9%), the increase in glycogen seen during loading appears to normalize at a faster rate, so 2g of maintenance may not be sufficient to preserve glycogen either.[207]

4.10. Mineral Bioaccumulation

Creatine at a concentration of 3mM does not appear to bind to nor modify the oxidant effects of iron in vitro.[208]

Neurology

5.1. Glutaminergic Neurotransmission

In vitro, creatine (0.125mM or higher) can reduce excitotoxicity from glutamate, which is thought to be secondary to preserving intracellular creatine phosphate levels.[209] Glutamate-induced excitotoxicity is caused by excessive intracellular calcium levels resulting from ATP depletion. Since high levels of calcium inside the cell are toxic, ATP preserves membrane integrity,[210] in part by promoting calcium homeostasis. When ATP is depleted, the sodium-potassium ATPase pump (Na+,K+-ATPase) stops working, leading to sodium accumulation in the cell. This reduces the activity of the sodium-calcium exchange pump, which, alongside a lack of ATP, reduces calcium efflux through the Na+,K+-ATPase. Thus, ATP depletion leads to intracellular calcium overload, loss of membrane potential, and excitotoxic cell death. Therefore, by helping preserve ATP levels, creatine is protective against excitotoxicity. This protective effect was noted after either creatine preloading or addition up to 2 hours after excitotoxicity.[209] Protection from glutamate-induced toxicity also extends to glial cells[211] and is additive with COX2 inhibition.[212]

Creatine has been confirmed to be neuroprotective against excitotoxicity at a dietary level of 1% in rats (with no protective effect against AMPA or kainate receptors).[213]

Creatine appears to be neuroprotective against glutamate-induced excitotoxicity. By helping maintain intracellular ATP levels, creatine prevents the toxic accumulation of calcium inside cells, a driver of excitoxicity.

Creatine has been noted to increase the amplitude (0.5-5mM) and frequency (25mM only) of NMDA receptors, although concentrations of 0.5-25mM also reduced signaling intensity. This was credited to creatine causing an increase in ligand binding of glutamate with an EC50 of 67µM and maximal activity at 1mM creatine (158±16% of baseline).[214] Creatine appears to modulate the polyamine binding site of the NMDA receptor, as it is abolished by arcaine and potentiated by spermidine.[215]This binding site is known to modify NMDA receptor affinity.[216][217]

Activation of NMDA receptors is known to stimulate Na+,K+-ATPase activity[218] secondary to calcineurin,[219] which which has been confirmed with creatine in hippocampal cells (0.1-1mM trended, but 10mM was significant). This is blocked by NMDA antagonists.[220] This increase in Na+,K+-ATPase activity is also attenauted with activation of either PKC or PKA,[220] which are antagonistic with calcineurin.[219][221]

Creatine appears to positively regulate the polyamine binding site of NMDA receptors, thereby increasing signaling through this receptor and the effects of agonists such as glutamate or D-aspartic acid. This is a potential mechanism for cognitive enhancement.

In a prolonged study on mice,[222] it was found that there was a two-fold upregulation of the transporter protein SLC1A6, which mediates glutamate uptake into cells. This may underlie the reduction of brain glutamate levels by creatine seen in Huntington’s disease.[223]

This is thought to be relevant since, in a study on subjects with amyotrophic lateral sclerosis (ALS), 15g of creatine daily was found to result in a significant reduction in combined glutamate and glutamine levels in the brain (not seen after 5-10g daily).[224]

Creatine may also promote uptake glutamate into cells. How this influences signaling and neuroprotection is not yet clear.

5.2. GABAergic Neurotransmission

In isolated striatal cells (expressing creatine kinase), seven day incubation of 5mM creatine (maximal effective dose) appears to increase the density of GABAergic neurons and DARPP-32 (biomarker for spiny neurons[225]) with only a minor overall trend for all cells[226] and showed increased GABA uptake into these cells, as well as providing protection against oxygen and glucose deprivation.[226]

5.3. Serotonergic Neurotransmission

One rat study that compared male and female rats and used a forced swim test (as a measure of serotonergic activity of anti-depressants[227]) found that a sexual dimorphism existed, and females exerted a serotonin-mediated anti-depressant response while male rats did not.[228] It appears that these anti-depressive effects are mediated via the 5-HT1A subset of serotonin receptors, as the antidepressant effects can be abolished by 5-HT1A inhibitors.[229]

In females, the combination of SSRIs (to increase serotonin levels in the synapse between neurons) and creatine shows promise in augmenting the anti-depressive effects of SSRI therapy[230]. Another pilot study conducted on depression and females showed efficacy of creatine supplementation.[231]The one study measuring male subjects noted an increase in mood and minimal anti-depressive effects, but it is not know whether this is due to gender differences or the model studies (post-traumatic stress disorder).[232]

There is insufficient evidence to refute the idea that creatine supplementation only exerts anti-depressive effects in females. The evidence to suggest that creatine is an anti-depressant (via serotonergic mechanisms) appears to be much stronger for women than men.

In humans, studies that investigate links between serotonin and creatine supplementation find that 21 trained males, given creatine via 22.8g creatine monohydrate (20g creatine equivalent) with 35g glucose, relative to a placebo of 160g glucose, was found to reduce the perception of fatigue in hot endurance training, possibly secondary to serotonergic modulation, specifically attentuating the increase of serotonin seen with exercise (normally seen to hinder exercise capacity in the heat[233]) while possibly increasing dopaminergic activity (conversely seen to benefit activity in the heat[234]).[156]

Conversely, the suppression of serotonin spikes seen in males may enhance physical performance during periods when the body would normally overheat. The idea that this does not work in females cannot be refuted at this time.

5.4. Dopaminergic Neurotransmission

Creatine may preserve dopamine synthesis in the striatum of mice (while protecting against dopaminergic depletion) when fed to mice at 2% of the diet for one week prior to MPTP toxicity[230]. This is possibly secondary to increasing tyrosine hydroxylase activity, the rate-limiting step of dopamine biosynthesis.[210][235] Two percent creatine was as protective as 0.005% rofecoxib (a COX2 inhibitor), but the two were additive in their protective effects (highly synergistic in regard to DOPAC by normalizing it, but not synergistic in preserving HVA).[230]

The neuroprotective effects of creatine appear to exist in regard to dopamine biosynthesis, and the suppression of dopamine synthesis seen with some neurological toxins appears to be partially attenuated with dietary intake of creatine. The protective effect is weak to moderate in animal research, but appears to be additive with anti-inflammatories.

5.5. Cholinergic Neurotransmission

Oral intake of 5-15g of creatine daily, over 1-15 days, has failed to modify neural concentrations of choline in subjects with amyotrophic lateral sclerosis (ALS) despite brain creatine increasing at 15g.[224]

5.6. Neuroprotection

Creatine, through its ability to act as an energy reserve, attenuates neuron death induced by the MPTP toxin that can produce Parkinson’s disease-like effects in research animals,[235] reduces glutamate-induced excitotoxicity,[236] attenuates rotenone-induced toxicity,[121]L-DOPA induced dyskinesia,[237] 3-nitropropinoic acid,[238] and preserves growth rate of neurons during exposure to corticosteroids (like cortisol), which can reduce neuron growth rates.[239] Interestingly, the energetic effect also applies to Alzheimer’s disease, during which creatine phosphate per se attenuates pathogenesis in vitro, yet creatine per se did not.[240]

These effects are secondary to creatine being a source of phosphate groups and acting as an energy reserve. The longer a cell has energy, the longer it can preserve the integrity of the cell membrane by preserving integrity of the Na+/K+-ATPase and Ca2+-ATPase enzymes.[241][235][236] Preserving ATP allows creatine to act via a nongenomic response (not requiring the nuclear DNA to transcribe anything), and appears to work secondary to MAPK and PI3K pathways.[226]

A protective effect on neurons by creatine, secondary to its ability to donate phosphate groups, exists and appears to be quite general in its protective effects.

When assessing the antioxidant effects of creatine, it does not appear to sequester superoxide and may not be a direct antioxidant.[241] Additionally, creatine failed to protect neurons from H2O2incubation to induce cell death via pro-oxidative means.[241] These results are in contrast to previously recorded results suggesting creatine acts as a direct anti-oxidant.[242]

Some reports suggest that creatine may be a direct anti-oxidant, but these have failed to be replicated. Creatine most likely does not possess anti-oxidant potential.

5.7. Neurogenesis

The concentration of creatine that increases mitochondrial respiration in skeletal muscle is 20mM.[243] This concentration also appears to work similarly in hippocampal cells.[244] This promotes endogenous PSD-95 clusters and subsequently synaptic neurogenesis (thought to simply be secondary to promoting mitochondrial function).[244]

Mitochondrial function per se appears to promote neuronal growth and proliferation, and at least in vitro, creatine is known to do the same and promote growth.

5.8. Oxygenation and Blood Flow

One of the studies noting a reduction in fatigue in healthy subjects given creatine (8g) for five days prior to a mathematical test noted a relative decrease in oxygenation hemoglobin in the brain and an increase in deoxygenated hemoglobin, which normally indicates a reduction in cerebral oxygenation.[245] The authors made note of how cytoplasmic phosphocreatine can increase oxygen uptake into cells (noted in vitro in a concentration dependent manner between 0-25mM[245]) and suggested that either cells were taking up more oxygen from hemoglobin, or that increased mitochondrial efficiency resulted in less of a need for oxygen.[245]

5.9. Depression

Creatine has been investigated for its effects on depression, due to the significant changes occurring in brain morphology and neuronal structure associated with depression[246] and low brain bioenergetic turnover in depression[247], perhaps related to abnormal mitochondrial functioning, which reduces available energy for the brain.[248][249] The general association of low or otherwise impaired phosphate energy systems (of which creatine forms the energetic basis of) with depression, has been noted previously.[250][247][251] Due to associations with cellular death and impaired bioenergetics with depression, creatine was subsequently investigated.

Oral ingestion of 1-1000mg/kg bodyweight of creatine in mice was able to exert an anti-depressive effect, which was blocked by dopamine receptor antagonists. A low dose of creatine (0.1mg/kg) was able to enhance the dopaminergic effects of dopamine receptor activators, suggesting supplemental creatine can positively influence dopamine signaling and neurotransmission.[252]

Mechanically, creatine may exert anti-depressant effects via mixed dopaminergic and serotonergic mechanisms. The exact mechanisms are not clear at this time.

Anti-depressive effects have been noted in woman with major depressive disorder when 5g of creatine monohydrate was supplemented daily for 8 weeks in combination with an SSRI. Benefits were seen at week two and were maintained until the end of the 8-week trial.[253] The improvement in depressive symptoms was associated with significantly increased prefrontal cortex levels of N-acetylaspartate, a marker of neuronal integrity,[254] and rich club connections, which refers to the ability of nerons to make connections to one another.[255]

These effects were noted before in a preliminary study of depressed adolescents (with no placebo group) showing a 55% reduction in depressive symptoms at 4g daily when brain phosphocreatine levels increased.[231] Other prelimnary human studies suggest creatine might lessen unipolar depression[256] and one study on Post-Traumatic Stress Disorder (PTSD) noted improved mood as assessed by the Hamilton Depression Rating Scale.[232]

It is possible that females could benefit more than males due to a combined lower creatine kinase activity as well as having altered purine metabolism during depression,[257] but no human comparative studies have been conducted yet. One rat study noted that creatine monohydrate at 2-4% of feed had 4% creatine able to exert anti-depressive and anxiolytic effects in female rats only.[228]

Intervention studies with creatine supplementation and depression show promise, but only one well-conducted study (used alongside SSRI pharmaceuticals) has been done, while other studies have flaws. This effect is promising, but no conclusions can be made at this time.

5.10. Brain Injury

Most causes of brain injury (calcium influx, excitotoxicity, lipid peroxidation, reactive oxygen intermediates or ROIs) all tend to ultimately work secondary to damaging the mitochondrial membrane and reducing its potential, which ultimately causes cellular apoptosis.[258][259][260][261]Traumatic brain injuries are thought to work vicariously through ROIs by depleting ATP concentrations.[262][263] Creatine appears to preserve mitochondrial membrane permeability in response to traumatic brain injury (1% of the rat’s diet for four weeks),[264] which is a mechanism commonly attributed to its ATP-buffering ability.

Brain injuries tend to cause continued damage to cells, secondary to ATP depletion, and creatine appears to preserve mitochondrial membrane permeability in response to brain injury, which is thought to be due to its ability to preserve ATP.

In rats and mice given creatine injections (3g/kg) for up to five days prior to traumatic brain injury, supplementation was able to reduce brain injury by 3-36% (time dependent, with five days being more protective than one or three), and dietary intake of creatine at 1% over four weeks halved subsequent injuries.[264]

Daily intake of creatine in rats appears to be capable of halving the effects of brain injuries.

In children and adults with tramautic brain injury (TBI), six months of creatine supplementation of 400mg/kg bodyweight appears to significantly reduce the frequency of headaches (from 93.8% to 11.1%), fatigue (from 82.4% to 11.1%), and dizziness (from 88.9% to 43.8%), relative to unblinded control.[265]

Preliminary evidence suggests that headaches and dizziness associated with brain injury can be attenuated with oral supplementation of creatine.

5.11. Addiction and Drug Abuse

Due to a combination of its neuroprotective effects and dopaminergic modulatory effects, creatine has been hypothesized in at least one review article to be of benefit to drug rehabilitation.[266] This study used parallels between drug abuse (usually methamphetamines) and traumatic brain injury[267][268] and made note of creatine being able to reduce symptoms of brain trauma, such as headaches, fatigue, and dizziness in clinical settings in two pilot studies.[269][270] No studies currently exist that examine creatine supplementation and drug rehabilitation.

5.12. Memory and Learning

Acute administration of creatine (intra-cranial) appears to enhance learning from a previous stimuli, vicariously through the NDMA receptor and was enhanced via coincubation of spermidine,[215] which amplifies NMDA currents.[271]

In rats, an enhancement of spatial learning appears to be apparent and mediated via the NMDA receptor. This is a similar mechanism to the one found in preliminary studies on D-Aspartic Acid.

Studies conducted in vegetarians tend to show cognitive enhancement in youth, possibly due to a creatine deficiency, as compared to omnivores.[272][61][62] Vegetarian diets have lower levels of circulating creatine prior to supplementation, but attain similar circulating levels as omnivores when both groups supplement.[272][273] Building on the latter, supplementation of creatine monohydrate in a loading protocol (20g daily in orange juice) in omnivores does not alter levels of creatine in white matter tissue in the brain (test subjects: competitive athletes).[274] In most of the parameters that vegetarians experience benefits, omnivores fail to experience statistically significant benefits[275], except possibly when sleep deprived, where the cognitive improvements rival that seen in vegetarians.[276] Elderly people who are omnivorous may also experience increases in cognition to a similar level, in regard to long-term memory as well as forward number and spatial recall, although the study in question failed to find any significant benefit on backward recall or random number generation,[39] the latter of which is a test for executive working memory.[277]

Creatine has been demonstrated to increase cognition (memory, learning, and performance) in people with no dietary creatine intake, like vegetarians and vegans. These benefits also appears to extend to the sleep deprived and elderly people without any saliant cognitive decline.

In a rested state, young omnivores may experience an increase in reaction speed.[61]

One study that did not control for dietary or lifestyle choices, but was conducted in young healthy adults, noted that 8g of creatine supplementation daily (spread out in multiple doses) for 5 days was able to reduce fatigue during a mathematical test (Uchida-Kraepelin test).[278]

Creatine has limited potential in increasing cognition in otherwise healthy young omnivores, but it does possess a general pro-cognitive effect.

5.13. Sedation and Sleep

Researchers found that 5g of creatine four times daily for a week (loading) before sleep deprivation for 12-36 hours was able to preserve cognition during complex tasks of executive function at 36 hours only, without significant influence on immediate recall or mood.[279] A similar protocol replicated the failure to improve memory and attention, but noted less reports of fatigue (24 hours) and less decline of vigor (24 hours) although other mood parameters were not measured.[276]

Gut Health Inflammation and Mood Disorders

Evidence is making it very clear that there is a strong association between gut health, brain function and mood.

brain-gut-connection

It has long been known that stress can wreak havoc with our digestive tract. It appears now that problems in the GI tract can also negatively impact the brain. Potentially causing anxiety and depression.

In other words, what is transpiring in your gut may directly influence central nervous system function. Hence gut health influences neural circuitry and can therefore have an effect (positive or negative) on behavior.

The newest research suggests, for instance, that how your digestive tract evolves in the first few years of life can influence the health of your brain. This also means it will subsequently affect your behavior in the future. This hypothesis is predicated upon the way in which a healthy GI floral population positively influences neurons involved in motor control and behavior. In the case of those with overwhelming populations of gut pathogens or gut dysbiosis, it can pave the way for the development of anxiety and depression later in life.

Microbiota, Inflammation, Autoimmunity, Depression

Gut health and gastrointestinal compromise can be a mechanism for the origins of systemic inflammation and autoimmunity. Since both inflammation and autoimmune conditions have also been associated with the genesis of mood disorders. It is only reasonable to suggest, again, that an intimate relationship between gut health, brain function and mental health exists. As one recent study demonstrates, inflammatory bowel disease in animal experiments can have an adverse effect on the hypothalamus. It does so by increasing the sensitivity of the HPA axis to stress.

Regarding the inflammatory process and depression, one study took interest in new moms. It went as far as to suggest that addressing inflammation in new moms could possibly go a long way in helping to prevent the symptoms of postpartum depression. Another study suggested a cause and effect relationship between GI inflammatory/intestinal permeability and the pathogenesis of alcoholism.

As some of the previous studies have established, it appears quite irrefutable that there is constant communication between our microbial symbiotic gut inhabitants and ourselves. In this case it is more precisely between our central nervous system through GABA receptors in the vagus nerve.

Probiotics

Taking this discussion a step further, could it be that certain human strains of probiotics have a therapeutic effect? Could they positively influence mood? Could we further emphasize this special symbiotic relationship? Several studies have shown that this is indeed the case.

One particular strain, Bifidobacterium infantis, was shown to significantly influence the stress response. It does so by normalizing specific measurements of the HPA axis. It also improves the immune response and cytokine modulation. So, this particular strain offers an interesting modulation of stress and depression.

Researchers continue to find evidence to support the opinion that the brain can directly communicate with the microbiota. These diverse bacterial populations make up the natural environment of the GI tract. In fact, the microbiota has intimate control of the function of the GI tract through the vagus nerve. According to one study, “Since the interactions of microbes with host lead to a complex balance of host genes, alteration of microbiota population can cause several metabolic disorders.”

This implies the importance of maintaining the health of the digestive system’s bacterial micro-environment. And makes the significance of probiotic use quite evident.

The relationship and communication between our gut and brain is profound and intimate. This knowledge further brings into focus the importance of maintaining an optimally functioning gastrointestinal tract. This also strengthens the view that perhaps the gastrointestinal system be a priority in the evaluation of new patients. Since if overlooked or taken for granted may lead us away from an important cause of many chronic diseases.

References:

1) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology, 2011 Aug;141(2):599-609, 609.e1-3. doi: 10.1053/j.gastro.2011.04.052. Epub 2011 Apr 30

2)  Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults  PLOS ONEDOI: 10.1371/journal.pone.0019498

3)  A new paradigm for depression in new mothers: the central role of inflammation and how breastfeeding and anti-inflammatory treatments protect maternal mental health,International Breastfeeding Journal, 2007, 2 :6 doi:10.1186/1746-4358-2-6

4) Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects, Brain Behav Immun.,2012 Aug;26(6):911-8. doi: 10.1016/j.bbi.2012.04.001. Epub 2012 Apr 10

5) Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depressionNeuroscience. 2010 Nov 10;170(4):1179-88. doi: 10.1016/j.neuroscience.2010.08.005. Epub 2010 Aug 6.

6) Gut-central nervous system axis is a target for nutritional therapies, Nutrition Journal 2012, 11:22  doi:10.1186/1475-2891-11-22

7) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5. doi: 10.1073/pnas.1102999108. Epub 2011 Aug 29

The Effects of Mild Cycles

The-effects-of-mild-cycles

 

Note: I’m not an advocate of steroid use. The average guy should be able to get really good results with intelligently designed, drug-free training. The risks, including legal problems, usually aren’t worth it unless you’re an actor or professional athlete, where millions of dollars are at stake.

Original article @t-nation.com

The Debate

The mainstream media propogates some incredibly ignorant hype and hysteria regarding anabolic steroids. They’d have you believe a single dianabol tablet will turn you into a roid-raged zombie. T Nation readers probably have more informed views. You probably know that “roid rage” is largely a myth, and you know that there’s a big difference between use and abuse.

Still, the debates rage on, even if the users do not. What is a “mild,” “moderate,” or “intelligent” cycle of steroids? What effects does it really have? Some say that the effects are profound. Others will say that mild usage produces minimal results. The answer? Let’s look to science.

 

The Study

A study from 2007 seems to have slipped under the radar, and it provides insights to many of our questions.

The primary intent of the study was to see if a steroid cycle could make measurable changes in size and strength in less than 6 weeks. The answer seems like an obvious “yes,” and there’s a plethora of anecdotal evidence to confirm this. But this double-blind, placebo-controlled study answers the question more objectively.

Sixteen men were match-paired, with one group receiving testosterone enanthate injections and the other receiving a placebo. Their strength and lean mass were tested after training for three, then six weeks. Here are some of the things we can learn from it:

 

1 – Even a modest steroid cycle will produce results.

The subjects who received steroids did get a supraphysiologic dose of testosterone, meaning the dose was higher than what the body would normally produce or higher than what one would receive from testosterone replacement therapy. For comparison:

  • A male receiving TRT from his doctor may get around 100 mg. per week to bring his T levels up to “high normal.”
  • A competitive bodybuilder may use 1000 to 3000 mg. of testosterone or testosterone analogs per week.
  • In this study, participants not in the placebo group received 275-315 mg. per week depending on body weight, which is about three times the normal or natural production. This is however less than the dosage of a typical “beginner” steroid cycle, which might be around 500-600 mg/week.

There are two schools of thought when it comes to first-time steroid cycles. One is to go ahead and do a full-fledged, higher dose cycle in order to maximize gains and take advantage of “virgin” receptor sites. The other is to do a more moderate dosage (like the one used in this study) in order to make gains while minimizing side effects.

This study shows that you can make gains on a more moderate cycle if that’s the route you want to take. There’s quite a bit of anecdotal evidence of guys getting good results from a 250 mg/week cycle.

 

2 – Steroids work, and they work quickly.

The primary purpose of the study was to see if anything significant happened within the first 3-6 weeks of a cycle compared to a placebo. The answer was a resounding “yes.”

Those who were taking testosterone enanthate saw their bench press increase beyond their placebo-using peers at week three and week six. But what was remarkable was the increase in body mass: the steroid users were over TEN pounds heavier than the placebo group after just six weeks.

Based on this evidence, it’s amusing to hear people minimize the benefit of these drugs. Use whatever you want, but let’s be honest about the difference between natural and “enhanced” trainees.

 

3 – Lower dosage steroid/testosterone cycles are not always easily detected.

Here’s another really intriguing finding from this study: 4 out of 9 testosterone-using subjects tested negative for steroid use under the WADA urinary testosterone/epitestosterone (T/E) ratio tests.

Remember, none of these guys were doing anything to try to “beat” the urine test. They weren’t even sure if they were getting testosterone or a placebo. It makes you wonder just how many professional athletes have used these kind of cycles in order to gain an advantage in competition while avoiding detection.

 

A Little Beyond Natural

You may have considered doing a steroid cycle in order to get faster results in the gym, to go beyond your natural genetic potential, or to offset the effects of aging. A lower dose cycle (250-300 mg of testosterone a week) may give you the best of both worlds: significant results with lower risks of side effects. It’s always good to know your options.

As always, the best advice is to see what you can accomplish naturally before making a decision about steroids. Find a solid workout program and spend a few years building your foundation before you even think about taking your body beyond its natural potential.

 

 

 

Reference

  1. J Strength Cond Res. 2007 May;21(2):354-61. The effect of short-term use of testosterone enanthate on muscular strength and power in healthy young men. Rogerson S1, Weatherby RP, Deakin GB, Meir RA, Coutts RA, Zhou S, Marshall-Gradisnik SM.

 

Modafinil

moda2-update

 

Modafinil is a prescription medicine for narcoleptics that increases alertness and prevents sleep. It just so happens to also increase cognition and memory, and is a potent and highly regarded supplement in the category of nootropics.

This page features 60 unique references to scientific papers.

Original article @https://examine.com/supplements/modafinil/

 

Summary

All Essential Benefits/Effects/Facts & Information

Modafinil is an a wakefulness enhancing drug that was created for treatment of daytime sleep related disorders such as Narcolepsy. It seems to have benefits for cognition via increasing levels of stimulatory neurotransmitters in the brain, and is used recreationally as a smart-drug.

Things to know

Also Known As

2-(Diphenylmethyl) sulfinylacetamide, Provigil, Modalert, Modapro, Alertex

Do Not Confuse With

Adrafinil

Things to Note

  • At least in the US and Canada, Modafinil is labeled a prescription drug and may not be easily acquirable. It is a Schedule IV controlled substance in the US.

 

How to Take

Recommended dosage, active amounts, other details

Standard dosages are 100-200mg, or perhaps 4mg/kg bodyweight, either taken in a sleep deprived state (if the user desires to not fall asleep) or taken first thing in the morning if the user does not wish to impair sleep.

 

Structure and Properties

1.1. Origin

Modafinil is a pharmaceutical designed for usage in sleep-related disorders, and is related to improved mental function in a sleep deprived state.

1.2. Forms of Modafinil

The term ‘modafinil’ refers to a racemic mixture of two isomers, R-modafinil and S-modafinil. The R-isomer by itself is referred to as armodafinil.

Modafinil is a racemic mixture of S-modafinil and R-modafinil, whereas Armodafinil is just the R-modafinil by itself

 

Pharmacology

2.1. Serum

The half-life of modafinil appears to be 13-15 hours, and steady state concentrations in serum are reached 2 days following supplementation.[3] Although the S-isomer by itself seems to have a short elimination half-life (4-5 hours) whereas the R-isomer is more prolonged (15 hours)[4][5] ingesting armodafinil does not appear to significantly differ from modafinil.[3][6][7]

An analysis of studies has noted, however, that armodafinil has an 18% higher Cmax value (5.44+/-1.64µg/mL relative to 4.61+/-0.73µg/mL) with a more rapid Tmax (1.8 hours relative to 2.5)[3]and that the overall AUC of armodafinil appears to be 32-40% greater than modafinil.[3]

Although the two variants of modafinil (modafinil and armodafinil) appear to have similar half-lives, armodafinil has a higher overall exposure to the body (assessed by AUC) as well as a higher and more rapid peak in the blood

2.2. Localization

According to c-Fos immunocytochemistry (c-Fos being a gene that rapidly activates in response to stimuli[8][9] and can be detected following neuronal stimulation[10][11] or sleep deprivation[12]), modafinil administration to cats is associated with strong c-Fos activation in the anterior hypothalamic nucleus and surrounding areas with weaker activation in the dorsal portion of the suprachiasmatic nuclei (SCN) with minimal activation in other brain regions such as the cortex or striatum.[13] This selective activation of the hypothalamus has been noted elsewhere, and the amygdala also implicated.[14][15] Modafinil has been confirmed in humans to have a different profile than does amphetamine.[16]

In contrast to amphetamine or methylphenidate induced wakefulness (characterized by widespread neuronal activation), modafinil appears to be somewhat selective for the hypothalamus and amygdala with some influence on the SCN

 

Neurology

3.1. Dopaminergic interactions

Modafinil seems to be able to increase extracellular levels of dopamine in the rat nucelar accumbens[17] and prefrontal cortex[18] and the dog caudate nucleus.[19] It has been shown to occupy both the dopamine and noradrenaline receptors (in the striatum)[20] and prevention of dopamine receptor occupancy abolishes the sleep-promoting effects in mice[21], suggesting this mechanism of action is crucial to the sleep-promoting effects.[22]

Past studies have noted a lack of potency of modafinil on dopaminergic systems[23][24][25] which may be due to the lower dosages they used in those studies relative to more recent ones.

3.2. Adrenergic interactions

The wakefulness effects of modafinil are significantly attenuated by antagonists of adrenergic receptors (both alpha and beta subunits)[26] although inhibiting catecholamine synthesis via α-methylparatyrosine does not appear to impair these effects.[26][27][28]

3.3. Serotonergic interactions

3.4. Orexinergic interactions

In those with faulty orexin levels (narcoleptics)[29], modafinil shows benefit possibly by acting on orexic neurons directly.[30][31] This effect is more potent in orexin-knockout mice than in normal mice[32], and the effects of modafinil on the orexin system of healthy persons is unknown.[2]

3.5. Sedation and Alertness

Some studies assess the effects of modafinil on intentional sleep deprivation, and modafinil (300mg) appears to be effective in reducing the disturbed mood and cognition seen during sleep deprivation with a potency comparable to 20mg D-amphetamine.[33][1] Elsewhere, it has been noted that the impairment of self-monitoring (ability to accurately assess oneself and their environment) is effectively reversed to a degree where an overconfidence effect (higher percieved assessment of skills relative to actual skills) is seen.[34]

These studies have extended up to 64 hours (two nights sleep deprivation) with a single dose of modafinil every 15 hours.[33][1]

Modafinil intervention prior to sleep can highly disrupt the sleep cycle and accompanying sedation, and usage of modafinil in this manner can attenuate the side-effects of sleep deprivation (cognitive and mood impairment)

Rebound hypersomnia is the phenomena where an anti-sleep agent is successful in reducing sleep, but after the effects of the drug wear off the user is significantly sleepier than before. Unlike amphetamine based drugs, modafinil does not appear to be associated with rebound hypersomnia in the cat[26][35] nor rats[36][37][38] or mice.[39] In humans who miss two nights sleep due to modafinil intervention (64 continuous hours awake), there does not appear to be any rebound hypersomnia like is seen with D-amphetamine.[1]

Modafinil does not appear to be associated with rebound hypersomnia

The increase in alertness during sleep deprivation seen with 300mg modafinil appears to be comparable to 20mg D-amphetamine over the course of 10-12 hours following one-time administration.[33][16][1][34]

The anti-sleep efficacy of modafinil (300mg) appears to be comparable to 20mg D-amphetamine

The sleep wake cycle of the brain is a balance of the ‘ascending arousal system’ consisting of arousing neurotransmitters (catecholamines, acetylcholine, orexin, etc.) and the neurotransmitters (GABA, Galanin) which act to suppress stimulation and promote sleep.[40][41] Varying levels of arousing and depressing neurotransmitters form an ‘on-off’ switch for arousal and sleep.[2]

Overall regulation of the wakefulness and rest cycle seems to be in part due to the circadian rhythm, mediated by the Suprachiasmatic Nuclei (SCN), and in part due to homeostatic needs for sleep that are gained during wakefulness.[40][41]

Modafinil seems to be able to interact with a multitude of stimulatory systems including serotonergic, noradrenergic, dopaminergic, glutaminergic, histaminergic, and orexinergic pathways; and also influences GABAergic pathways.[42]

Some studies that use modafinil for the treatment of some other states note that the side-effect of insomnia persists more than placebo[43] and modafinil is able to prevent participants from voluntarily falling asleep when taken prior to sleep.[44]

Supplementation of modafinil is able to preserve cognition in fatiged states.[44]

 

3.6. Memory and Cognition

In otherwise healthy persons, 100mg or 200mg of modafinil taken two hours prior to cognitive testing is able to improve working memory (digit span tests), visuospatial planning, and reaction time[45] whereas elsewhere it was found to improve cognition (task enjoyment, planning, and working memory) in completely normal and non-sleep deprived persons at 200mg.[46] Working memory and processing accuracy have been found to be improved with 200mg elsewhere.[47]

Alongside the improvements in working memory are improvements in the actual performance of the task, most notably an increase in motivation and enjoyment for undergoing the task.[46]

There is some cognitive enhancing properties of modafinil acute usage in otherwise healthy persons, and may increase motivation and enjoyment from doing a cognitive task

In methamphtamine dependent persons (known to have a degree of cognitive impairment[48][49]), modafinil at 400mg for three days is able to improve working memory and trended to improve fatigue in those with worse baseline scores yet was unable to improve performance in those with higher baseline scores[50] and 200mg for a single dose does not appear to be cognitive enhancing in this same population.[51]

In persons with possible cognitive decline associated with methamphetamine usage, modafinil has the potential to improve cognition although acute usage doesn’t appear to be effective and the overall cognitive enhancement is relatively minor

3.7. Appetite

Studies that assess the effects of modafinil sometimes report a reduction in appetite as a side-effect, measured at 16% (164 persons[43])

Studies that note reductions in appetite sometimes note trends towards weight loss over a period of weeks, but usually do not reach statistical significance.[43]

3.8. Attention

Supplementation of modafinil in the range of 170–425mg for six weeks (dose titrated up from 170mg to 425mg unless tolerance was compromised) was able to reduce symptoms of ADHD as assessed by both CGI-I and ADHD-RS-IV in youth.[43]

3.9. Addiction

Due to the inability for modafinil to activate neuronal pathways involved in addiction, it is thought to have a low abuse potential relative to other drugs.[52][53]

It is thought that modafinil has a low potential for wide-spread drug abuse

Response inhibition (the ability to inhibit a prepotent response,[54] and thought to be indicative of impulsivity in persons undergoing drug abuse[55]) is improved in rats[56] and humans (alcohol dependence,[57] methamphetamine dependence,[51] and gambling[58]) with modafinil, but only in those with worse baseline scores rather than the whole group.

It is possible for modafinil to reduce impulsivity in persons addicted to drugs or some addictive behaviours, although this only appears to be significantly effective for persons with worse impuslivity prior to testing

 

Interaction with Medical Conditions

4.1. Multiple Sclerosis

Acute supplementation of armodafinil (250mg) in persons with multiple sclerosis has noted improvements in memory recall relative to placebo, although other measured parameters (fatigue, executive function, processing speed) were unaffected by supplementation.[59] This inefficacy on fatigue and arousal has not been noted elsewhere, where modafinil is attributed to possessing an antifatigue effect in MS.[60]

 

 

Safety and Toxicology

5.1. General

Adverse effects usually reported in trials are predominantly headache, dizziness, increased diuresis, palpitations and tachycardia, restlessness, nervousness, gastrointestinal complains such as nausea, dry mouth and abdominal pain. Despite these isolated adverse events, they usually do not differ significantly from placebo and thus modafinil is seen as well tolerated.

Reported side-effects that sometimes occur significantly more than placebo include insomnia and sleeplessness as well as appetite reduction.[43]

General side-effects of modafinil include insomnia and/or sleeplessness as well as a reduction in appetite

 

Scientific Support & Reference Citations

References

  1. Buguet A, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleepJ Sleep Res. (1995)
  2. Approved and Investigational Uses of Modafinil: An Evidence-Based Review.
  3. Darwish M, et al. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studiesClin Drug Investig. (2009)
  4. Wong YN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteersJ Clin Pharmacol. (1999)
  5. Wong YN, et al. Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjectsJ Clin Pharmacol. (1999)
  6. Robertson P Jr, Hellriegel ET. Clinical pharmacokinetic profile of modafinilClin Pharmacokinet. (2003)
  7. Darwish M, et al. Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studiesClin Drug Investig. (2009)
  8. Sheng M, Greenberg ME. The regulation and function of c-fos and other immediate early genes in the nervous systemNeuron. (1990)
  9. Morgan JI, Curran T. Stimulus-transcription coupling in neurons: role of cellular immediate-early genesTrends Neurosci. (1989)
  10. Shiromani PJ, et al. Cholinergically induced REM sleep triggers Fos-like immunoreactivity in dorsolateral pontine regions associated with REM sleepBrain Res. (1992)
  11. Fritschy JM, Frondoza CG, Grzanna R. Differential effects of reserpine on brainstem catecholaminergic neurons revealed by Fos protein immunohistochemistry.Brain Res. (1991)
  12. Pompeiano M, Cirelli C, Tononi G. Effects of sleep deprivation on fos-like immunoreactivity in the rat brainArch Ital Biol. (1992)
  13. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat.
  14. Engber TM, et al. Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinilNeurosci Lett. (1998)
  15. Scammell TE, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulnessJ Neurosci. (2000)
  16. Chapotot F, et al. Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG.Psychopharmacology (Berl). (2003)
  17. Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats.
  18. de Saint Hilaire Z, et al. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in ratsNeuroreport. (2001)
  19. Dopaminergic Role in Stimulant-Induced Wakefulness.
  20. Madras BK, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitroJ Pharmacol Exp Ther. (2006)
  21. Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors.
  22. Dopheide MM, et al. Modafinil evokes striatal {(3)H}dopamine release and alters the subjective properties of stimulantsEur J Pharmacol. (2007)
  23. Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: In vivo voltammetry studies.
  24. Mignot E, et al. Modafinil binds to the dopamine uptake carrier site with low affinitySleep. (1994)
  25. Akaoka H, et al. Effect of modafinil and amphetamine on the rat catecholaminergic neuron activityNeurosci Lett. (1991)
  26. Lin JS, et al. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the catBrain Res. (1992)
  27. Simon P, et al. Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in miceEur Neuropsychopharmacol. (1995)
  28. Duteil J, et al. Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animalsEur J Pharmacol. (1990)
  29. The hypocretin/orexin system in health and disease.
  30. Chemelli RM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulationCell. (1999)
  31. Hypothalamic Arousal Regions Are Activated during ModafinilInduced Wakefulness.
  32. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates.
  33. Pigeau R, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperatureJ Sleep Res. (1995)
  34. Baranski JV, Pigeau RA. Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placeboJ Sleep Res. (1997)
  35. Lin JS, et al. Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the catJ Sleep Res. (2000)
  36. Wisor JP, et al. Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the ratPharmacol Biochem Behav. (2006)
  37. Touret M, Sallanon-Moulin M, Jouvet M. Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat.Neurosci Lett. (1995)
  38. Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the ratJ Pharmacol Exp Ther. (1997)
  39. Willie JT, et al. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermatesNeuroscience. (2005)
  40. Hypothalamic regulation of sleep and circadian rhythms.
  41. Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback.
  42. Modafinil: A Review of Neurochemical Actions and Effects on Cognition.
  43. Biederman J, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose studyPediatrics. (2005)
  44. Gill M, et al. Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.Acad Emerg Med. (2006)
  45. Turner DC, et al. Cognitive enhancing effects of modafinil in healthy volunteersPsychopharmacology (Berl). (2003)
  46. Müller U, et al. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteersNeuropharmacology. (2013)
  47. Müller U, et al. Effects of modafinil on working memory processes in humansPsychopharmacology (Berl). (2004)
  48. Seiden LS, Fischman MW, Schuster CR. Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeysDrug Alcohol Depend. (1976)
  49. Woolverton WL, et al. Long-term effects of chronic methamphetamine administration in rhesus monkeysBrain Res. (1989)
  50. Kalechstein AD, De La Garza R 2nd, Newton TF. Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairmentAm J Addict. (2010)
  51. Dean AC, et al. Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humansJ Stud Alcohol Drugs. (2011)
  52. Myrick H, et al. Modafinil: preclinical, clinical, and post-marketing surveillance–a review of abuse liability issuesAnn Clin Psychiatry. (2004)
  53. Jasinski DR, Kovacević-Ristanović R. Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy.Clin Neuropharmacol. (2000)
  54. Evenden JL. Varieties of impulsivityPsychopharmacology (Berl). (1999)
  55. Impulsivity and Inhibitory Control.
  56. Eagle DM, et al. Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixolPsychopharmacology (Berl). (2007)
  57. Schmaal L, et al. Effects of modafinil on neural correlates of response inhibition in alcohol-dependent patientsBiol Psychiatry. (2013)
  58. Zack M, Poulos CX. Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivityJ Psychopharmacol. (2009)
  59. Bruce J, et al. Impact of armodafinil on cognition in multiple sclerosis: a randomized, double-blind crossover pilot studyCogn Behav Neurol. (2012)
  60. Niepel G, et al. Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinilNeuropharmacology. (2013)

 

Tendon Rupture and Antibiotics

You know the warning labels that come with the antibiotics you’ve been prescribed over the years? You should read them. And so should your doctor.

 

Unfortunately, many patients and physicians are unaware of the potentially devastating side effects of antibiotics. Indeed, antibiotics such as fluoroquinolones link to cases of tendon rupture.

Fluoroquinolones are broad-spectrum antibiotics that are routinely used for respiratory infections, urinary tract infections, and skin infections. The most common fluoroquinolones are Cipro, Levaquin, and Avelox.

 

Antibiotics and Tendon Ruptures

Under normal circumstances, tendon ruptures are rare. They usually occur spontaneously as a result of sports injuries. Studies estimate an annual rate of 6 to 37 cases per 100,000 people. However, reports show that the likelihood of a rupture increases by three to four times that rate with the use of fluoroquinolones. Additionally these ruptures have been reported with little or no inciting event.

Fluoroquinolones can cause tears or ruptures in the Achilles, shoulder, hand, patella, or quadriceps tendon. The Achilles tendon seems to be the most vulnerable to injury during weight-bearing activities, such as walking or running. But it is important to note that use of these antibiotics may also weaken tendons and set you up for ruptures down the road. Moreover, tendon pain, swelling, or inflammation (tendonitis) can lead to degenerative changes in the tendon, or tendinosis, which may cause a rupture—even one year after discontinuing the antibiotic.

We do not completely understand the link between fluoroquinolones and tendinopathy and tendon rupture yet.  In fact, researchers believe the drugs’ toxic effects somehow alter the structure and biomechanical properties of the connective tissue.

 

Risk Factors for Tendon Rupture

People over 60 years old are at a greater risk of developing tendon disorders with the use of this class of drugs. In addition, other contributing factors include, but are not limited to, corticosteroid use, chronic renal disease, diabetes, rheumatoid arthritis, and other musculoskeletal disorders.

 

Red Flag

In 1995, the Food and Drug Administration (FDA) updated the warning label for this class of antibiotics to include a warning about tendinopathy and tendon rupture. The label recommended that patients discontinue taking the drug and refrain from exercise at the first sign of tendon pain or inflammation.

This red flag, however, did not do enough to bring awareness to the problem. Reports of tendon injuries associated with fluoroquinolones continued. So, in 2006, Public Citizen, a Washington, D.C.-based watchdog group, and Illinois Attorney General Lisa Madigan petitioned the FDA for a more prominent boxed warning about these tendon risks.

A boxed warning, sometimes referred to as a black-box warning, is the strongest warning issued by the FDA. It signifies that medical studies show a significant risk of serious or life-threatening side effects.

Besides the black-box warning, the petition also requested that the FDA require a medication guide for patients and a letter from the manufacturers to the doctors detailing the tendon risks.

In 2008, the FDA finally agreed to require boxed warnings and a medication guide for patients. But they did not require the drug makers to include a letter to doctors detailing the risks.

 

Awareness

Despite the black-box warning, many practitioners are still unaware of these adverse effects and continue to prescribe fluoroquinolones without determining whether the patient is at risk of developing tendinopathy or rupture.

Hence, patients who are over 60 or have other risk factors listed on the warning label should consult with their healthcare provider about being prescribed a non-fluoroquinolone antimicrobial drug. But I think we need to go one step further. For athletes and exercise enthusiasts, this class of antibiotics should also be considered off limits.

Tendinopathy and tendon rupture are serious and debilitating. It takes the average person months, or even a year, to recover from a complete rupture that requires surgical repair. For athletes, a rupture can be a career-ending injury. Consequently, it is not worth the risk, especially considering there are alternative treatment options.

 

Empowered Autonomy

In conclusion, the link between fluoroquinolones and tendon disorders has been known for nearly 20 years. But awareness remains an issue. It is up to you to ask about the risks and read the warning labels. If your doctor prescribes fluoroquinolones, like Cipro, ask for an alternative!

 

Sources:

Greene, B. (2002, December). Physical Therapist Management of Fluoroquinolone-Induced Achilles Tendinopathy. Journal of American Physical Therapy Association. Retrieved December 19, 2013, from http://ptjournal.apta.org/content/82/12/1224.full

Kim, G. et al. (2010, April). The Risk of Fluoroquinolone-induced Tendinopathy and Tendon Rupture. The Journal of Clinical and Aesthetic Dermatology, 3(4); 49–54.

Landers, S. (2008, July 28). FDA requires black-box warnings for fluorquinolones. American Medical News. Retrieved December 19, 2013, from http://www.amednews.com/article/20080728/health/307289979/7/

Miller, K. (2013, August 27). Some Antibiotics Linked to Serious Nerve Damage. WebMD. Retrieved December 19, 2013, from http://www.webmd.com/brain/news/20130826/fda-strengthens-fluoroquinolone-warning

Postmarket Drug Safety Information (2008) U.S. Food and Drug Administration. Retrieved December 19, 2013, from http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformatio

 

Original article – http://www.strengthsensei.com/tendon-rupture-antiobiotics/