Peptides, SARMs, & Prohormones: Where it Starts

GHRP (growth hormone releasing peptide)
GHRP 2, 6
ACVR2B (Ace-031)
BPC 157

Ligandrol (LGD-4033)
Ipamorelin MK677

Superdrol (Methasterone)
1AD (1-Androstenediol)
Laxogenin 100

The effect of 6 days of Alpha-GPC on isometric strength


Ergogenic aides are widely used by fitness enthusiasts and athletes to increase performance. Alpha glycerylphosphorylcholine (A-GPC) has demonstrated some initial promise in changing explosive performance. The purpose of the present investigation was to determine if 6 days of supplementation with A-GPC would augment isometric force production compared to a placebo.

Thirteen college-aged males (Means ± SD; Age: 21.9 ± 2.2 years, Height: 180.3 ± 7.7 cm, Weight: 87.6 ± 15.6 kg; VO2 max: 40.08 ± 7.23 ml O2*Kg−1*min−1, Body Fat: 17.5 ± 4.6 %) gave written informed consent to participate in the study. The study was a double blind, placebo controlled, cross-over design. The participants reported to the lab for an initial visit where they were familiarized with the isometric mid thigh pull in a custom squat cage on a force platform and upper body isometric test against a high frequency load cell, and baseline measurements were taken for both. The participant then consumed either 600 mg per day of A-GPC or placebo and at the end of 6 days performed isometric mid thigh pulls and an upper body isometric test. A one-week washout period was used before the participants’ baseline was re-measured and crossed over to the other treatment.

The A-GPC treatment resulted in significantly greater isometric mid thigh pull peak force change from baseline (t = 1.76, p = 0.044) compared with placebo (A-GPC: 98.8. ± 236.9 N vs Placebo: −39.0 ± 170.9 N). For the upper body test the A-GPC treatment trended towards greater change from baseline force production (A-GPC: 50.9 ± 167.2 N Placebo: −14.9 ± 114.9 N) but failed to obtain statistical significance (t = 1.16, p = 0.127).

A-GPC is effective at increasing lower body force production after 6 days of supplementation. Sport performance coaches can consider adding A-GPC to the diet of speed and power athletes to enhance muscle performance.

Keywords: Alpha glycerylphosphorylcholine, Strength, Human performance, Sport supplements


Performance in sport is often determined by moments of extreme force production and power output [1]. While much of this can be attributed to muscular strength [23], some adaptations to training can be neural in nature [4]. A study by Pensini, Martin and Maffiuletti [5] demonstrated that increases in torque associated with 4 weeks of eccentric exercise were likely the result of central (or neural) adaptation. Based upon current knowledge it appears that both central and peripheral adaptations are necessary to enhance performance in athletes. Therefore, it is important to study nutritional interventions that have the potential to augment either potential site of adaptation.

α Glycerylphosphorylcholine (A-GPC) is a substance that could potentially augment human performance by facilitiating neuro-muscular interaction. A-GPC has been shown to augment acetylcholine levels in neurons in rat CNS [6], and has been shown to maintain reaction time in humans following exhaustive exercise [7]. Additionally A-GPC is generally considered safe for consumption in moderate to high doses [89]. Ingested A-GPC is converted to phosphatidylcholine, a source of choline [10]. Dietary choline levels are linked to the rate of biosynthesis of acetylcholine [11]. Given that cholinergic nerves trigger muscle contraction, and that choline availability is linked to acetylcholine synthesis substances that could augment choline availability might have the potential to influence muscular performance. To date some work has been done examining the ability of phospholipids to restore choline levels after exercise, but there is a dearth of information regarding the ability of compounds like A-GPC to acutely enhance performance [11]. The purpose of this study was to examine the effects of 6 days of supplementation with A-GPC on measures of isometric force production in the upper and lower body.


The Institutional Review Board at the University of Louisiana at Lafayette reviewed the present investigation for ethics. The study was a double-blind, placebo-controlled crossover with a 1-week washout period that included 13 healthy, college-aged males (Means ± SD; Age: 21.9 ± 2.2 years, Height: 180.3 ± 7.7 cm, Weight: 87.6 ± 15.6 kg; VO2 max: 40.08 ± 7.23 ml O2*Kg−1*min−1, Body Fat: 17.5 ± 4.6 %). Subjects reported to the lab and give informed consent, which included consent to publish, prior to baseline assessments which included height and weight, an assessment of maximum aerobic capacity via a COSMED CPET system (COSMED, Rome ITL) with integrated electronically braked cycle ergometer as outlined in previous studies [12], and body fat percentage via air displacement plethysmography (Bod Pod Gold Standard System, COSMED Rome, ITL) . The following week trial one (random order: either placebo or 600 mg of A-GPC) began. For the trials baseline performance testing was done and they were given an initial dose (placebo or A-GPC) while in the lab, 1 h later the performance testing (isometric mid thigh pull, upperbody isometric test) was repeated. The subjects were then given 6 days of additional pre-packaged supplement to take (morning and evening). The subjects reported back on day 6 of this period to repeat performance testing after the final dose of supplement. After a 1-week washout period, the subjects repeated the trial with the other treatment. (see Fig. 1).

Flowchart of Experimental Procedures

The treatments consisted of 600 mg daily of A-GPC (AlphaSize®, ChemiNutra, Austin, TX) or a placebo. Both treatments were administered in the same capsules (gel caps) and were the same color (white). The A-GPC capsules were supplied with a certificate of analysis from a third party lab confirming the amount of active ingredient. The placebo capsule consisted of microcrystalline cellulose and magnesium stearate (Nature’s Supplements, Carlsbad, CA USA). Both the participant and researcher were unaware of the identity of either treatment until the end of the study.

The participants were instructed to take doses in the morning and evening that would deliver a total of 600 mg of A-GPC per day and were given the pills in a non-distinct plastic bottle marked only with a code. The participants returned the bottles at the end of the study. The participants reported 100 % compliance with taking the required doses.

Upper body isometric test (UBIST)

The participants were positioned on three elevated platforms with the chest directly suspended over a load cell anchored into the concrete floor of the lab (iLoad Pro, Loadstar Sensors, Fremont CA). The load cell had a capacity of greater than 5000 N and a listed accuracy of 0.25 % for the full scale of measurement. The participants were placed in a push-up style position, with the hands at 150 % of biacromial width, and the elbows at 90° of extension (measured via a goniometer). A thick, non-elastic strap was run over one shoulder and under the opposite shoulder and connected with metal rings to a chain that was tethered to the load cell.

The participants were instructed to keep their backs flat, and push with their hands maximally until told to stop by the researcher. Prior to data capture the load cell was tared to ensure the weight of the load cell and apparatus were accounted for. The researcher started data collection and verbally instructed the participant to “push as hard as possible”. The participants were verbally encouraged during data collection, which was terminated when the force production declined by 50 N from the peak value registered. The load cell was set to capture data at maximum rate (150Hz) and the data was exported and analyzed in JMP 11.0 (SAS Institute Inc, Cary NC). Peak force values were isolated from the data and used for subsequent analysis. The test was performed three times with 5 min rest between assessments. The validity and reliability of this test have been reported in the literature [14].

Statistical analysis
Reliability was assessed for the isometric tests via Intra Class Correlation Coefficients (ICC). Repeated measures Ancovas were used to examine acute (baseline and 1 h post) and chronic (baseline and day 6) changes in performance between treatments. Order of administration (Placebo first, A-GPC first) was entered into the model as a covariate. G*Power software [15] was used to determine effect size (Cohen’s d), all other analyses were performed using a modern statistical software package (JMP, version 11.0 SAS Institute Inc., Cary, NC). Magnitude based inferences were calculated to assist with interpretation of results [16]. The use of magnitude based inference is an attempt to expand the interpretation of findings to include harmful, trivial and beneficial as interpretations, rather than just significant, non-significant [17]. This interpretations in not without controversy [18], as such the authors have chosen to include it alongside a more traditional statistical approach.


Reliability of isometric tests
The isometric tests demonstrated reliability when the triplicate measurements were examined via ICC (range: 0.969–0.984). Measurements were not different at any time points (p > 0.05). Therefore in subsequent analysis the peak value from the set of three measures was used.

Treatment effects—acute
Repeated measures Anova did not reveal any main effects (F = 0.003, p = 0.9584) nor interaction effects of treatment*time (F = 0.114, p = 0.738) for IMTP performance 1 h after the initial dose of A-GPC or Placebo. Similar results were revealed when UBIST performance was analyzed.

Treatment effects—chronic
Repeated measures Anova revealed a significant interaction effect for treatment (A-GPC vs Placebo) by time (baseline, day 6) for IMTP peak performance (F = 3.12, p = 0.04; change from baseline A-GPC: 98.8. ± 236.9 N vs Placebo: −39.0 ± 170.9 N, ES = 0.961). See Fig. 2.

Mean change in Isometric Mid Thigh Pull Peak force after 6 days of supplementation with A-GPC. Error bars represent +/− 1 SEM

For the upper body test the A-GPC treatment trended towards greater change from baseline force production (A-GPC: 50.9 ± 167.2 N Placebo: −14.9 ± 114.9 N) but the interaction effect of treatment by time failed to obtain statistical significance (F = 1.36, p = 0.127). However, this data (see Fig. 3) demonstrated a large effect size (ES = 0.714). This suggests that the variability of the subject’s upper body strength limited the statistical power, however, it if likely that a real effect exists in this data. Magnitude based inferences suggest that the A-GPC was 68.3 % likely beneficial for increasing upper body isometric force and 86.5 % likely beneficial for increasing lower body isometric force production.


The results of this study support the use of A-GPC to enhance strength, particularly in the lower body after 6 days of administration of a 600 mg dose. The literature does not contain controlled experimental data regarding the effects of A-GPC on aspects of human performance directly related to isometric strength, and thus this study represents a first step in the evaluation of this product for such use. The literature does contain some evidence that choline itself is important to consider in regard to endurance performance [1920]. The current literature does contain some information about A-GPC and performance measurements. Jagim et al. [21] reported that a multi-ingredient supplement that contained A-GPC enhanced mean power during a maximal effort sprint test on a non-motorized treadmill but did not produce any changes in counter movement jumping performance peak or mean power. Parker et al. [22] reported acute supplementation with 200 mg or 400 mg of A-GPC did not statistically enhance performance, thought the authors did note a non-significant trend in vertical jump peak power. Acute supplementation with 600 mg of A-GPC has been shown to augment bench press power in a small sample of men with 2 years of training experience [23]. This study is similar in finding to the present investigation in dose of A-GPC administered (600 mg) and suggests enhancements in performance. These previously reported studies on A-GPC vary greatly in design, measurements and administrations. The lack of consistency of doses (200–600 mg) and time of administration (30–90 min prior to activity) may explain the lack of consistent findings. Given the present evidence in the literature, further studies will be needed to confirm the results reported from this experiment, the data represent a promising start and suggest alternative uses for A-GPC.

The potential mechanism by which A-GPC could confer enhanced strength and power performance involves increased bio-available choline, which may result in augmented acetylcholine synthesis in neurons. A-GPC has been shown to augment acetylcholine levels in CNS neurons [6]. Evidence suggests that when administered intramuscularly A-GPC can increase plasma choline levels [24]. A-GPC has also been shown to increase growth hormone secretion though the action of acetylcholine stimulated catecholamine release [25]. This increase in cholinergic tone and associated increased growth hormone release was also reported in old and young subjects after administration of growth hormone releasing hormone in conjunction with A-GPC [26]. In the present investigation it is unlikely a moderate increase in growth hormone over the course of 7 days would have impacted maximum strength although this evidence suggests that longer chronic studies of A-GPC may be warranted as chronic elevations in growth hormone could potentially further augment performance.

While the present study presents positive preliminary findings for A-GPC augmenting strength, it is not without limitation. The present investigation is limited by sample size. The study will need to be replicated with larger study populations and alternative measures of human performance, likely those that have the capacity to measure power not just peak force. Additionally, different does of A-GPC need to be explored to determine any potential dose-response, or lower limit for meaningful effect. We suggest that in vitro studies may also be warranted to demonstrate that A-GPC has the potential to augment neurotransmitter levels in motor neurons. These studies can help to clarify the timing of A-GPC administration, which may in turn result in studies with a more targeted and informed dosing scheme.


The results of the study suggest that A-GPC is effective at increasing lower body force production after 6 days of supplementation. A similar trend was noted in upper body isometric strength, however; this failed to attain statistical significance. Given that in many sports it is understood that a very small change in performance, often times less than 2 %, can significantly affect outcomes it is important to note that the 6 days of A-GPC resulted in greater than a 3 % increase in lower body isometric strength. Sport performance coaches can consider adding A-GPC to the diet of speed and power athletes to potentially enhance muscle performance.


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Overview and Summary


Alpha GPC is a naturally occurring choline intermediary that is formed when the body breaks down cell membranes for choline. As a supplement Alpha GPC is a highly bio available form of choline that crosses the blood brain barrier and raises brain levels of choline. Inside the brain choline supports cell membrane and neurotransmitter synthesis. Of all the supplemental forms of choline, GPC is probably the most cholinergic per gram, as it’s 40% choline by weight and appears to be well absorbed.

All of the available research is discussed below, a summary of the research finds that GPC is able to:

  • Support cell membrane synthesis and cell membrane fluidity (10)
  • Reduce age related declines in muscarinic (M1) receptors (2)(10)
  • Support acetylcholine synthesis (7)(13)(15)(16)
  • Increase pre-synaptic choline transporters (11)(12)
  • Prevent anti-cholinergic induced cognitive deficits (7)(13)(15)(16)
  • Raise memory/recall above baseline in a small pilot study (15)
  • Enhance growth hormone output (4)(8)
  • Enhance peak muscular force during exercise (4)
  • Improve cognitive function in elderly dementia patients (5)(9)(14)
  • Remain free of side effects at therapeutic doses (2.4% total reported in dementia patients) (17)

Other Names

A-GPCAlpha-glycerophosphocholine, choline alphoscerate, GPC.

Important Information


600mg pre-exercise was shown to enhance power output, endurance and growth hormone release (4)

1200mg daily (3 doses 400mg) has been administered in clinical trials to relieve cognitive decline in patients with dementia (5). This dose was also able to prevent scopolamine related amnesia in healthy young humans (15)

For nootropic purposes, 300mg taken once or twice per day seems a reasonable starting point.

Relevant Articles

  1. Which Choline Source Is Best?
  2. Good Starting Stacks For Newcomers


GPC appears to be mostly hydrolysed (broken down) in the gut via phosphodiesterase into various metabolites such as glycerophosphate, choline and phosphorylcholine. One study in rodents using radiolabeled Alpha GPC showed various choline metabolites to be formed following oral administration (1). The authors remarked in the discussion that each of these metabolites likely have their own abortion, tissue distribution and elimination profiles.

In contrast to this, another rodent study showed that intraperitoneal injection of GPC was able to reduce age related decreases in acetylcholine receptors whereas GPC metabolites (glycerophosphate, choline and phosphorylcholine) were not able to do the same. (2)

Since it’s known that Alpha GPC can cross the blood brain barrier intact (1), and that GPC is superior to choline in improving clinical symptoms (3), it’s reasonable to assume that some of an oral dose is absorbed intact and crosses the blood brain barrier.

Looking at the research there’s no clear study in humans that shows GPC by mouth goes straight into the brain, but empirically we know that GPC is superior to lecithin derived choline at improving cognitive function. We also know that GPC in rodents can cross the BBB and that its metabolites are inferior to the whole molecule. From this it’s safe to assume some oral GPC is absorbed intact and crosses the BBB in humans.

Benefits of Alpha GPC

Memory and Learning

One study involving young healthy rodents showed that GPC improved learning in an active avoidance task. (6)

Active avoidance is where rodents are subjected to a small shock following a stimulus, such as a sound playing. The rats are typically presented with an escape compartment to avoid the shock. The quicker the rats learn that the sound = incoming shock, the better it performs. Administration of GPC increased the number of times the rats avoided shock and also decreased the latency, i.e. the time it took them to do so.

Another rodent study showed GPC was able to reduce the amnesiac effects of scopolamine, a potent anticholinergic drug. Its hypothesised GPC did so by increasing acetylcholine synthesis. (7)

In humans two trials have shown GPC is able to reduce scopolamine induced cognitive deficits in young healthy volunteers. (15)(16) Interestingly, GPC was unable to protect against benzodiazepine induced amnesia, supporting the idea that GPC’s cognitive enhancement effects are mediated through acetylcholine synthesis and cholinergic mechanisms.

GPC appears to be prevent the amnesiac effects that typically occur when scopolamine (a potent anti-cholinergic) is administered. Currently the two human trials aren’t available online, though both are discussed vicariously through reference 16. Perhaps the key take home point was that GPC was able to increase cognitive function above baseline for young healthy subjects, a “holy grail” of any nootropic.

Cognitive Decline (Alzheimer’s and Dementia)

A large meta-analysis involving 1570 patients across 10 clinical studies concluded that GPC significantly improves patient conditions, as assessed by mini mental state examination (MMSE) and sandoz clinical assessment geriatric scale (SGAG) (5)(9)(14). Both MMSE and SCAG are frequently used to assess cognitive impairment in patients with dementia.

brain scan

Muscular Power and Growth Hormone

One small pilot study involving 7 men showed increased peak force output in the bench by 14% following ingestion of 600mg Alpha GPC (4). The study also noted a significant elevation in growth hormone.

A second study involving 8 males showed 1000mg of Alpha GPC was able to significantly increase growth hormone and markers of fat oxidation (8)


Alpha GPC’s Mechanism Of Action

Cell Membrane Synthesis and Maintenance

Alpha GPC increases brain choline content. As choline is a required building block for cell membranes it’s no surprise that Alpha GPC supports cell membrane upkeep by increasing the brain’s supply of choline.

Research involving young and aged rats showed chronic treatment of GPC (200mg/KG) was able to restore muscarinic receptor density (specifically M1) to youthful levels in both the hippocampus and striatum (2). A similar study also found GPC was able to partially restore M1 muscarinic density to youthful levels. (10)

Research also indicates GPC is partially able to restore cell membrane fluidty (in part) to youthful levels in the striatum and hippocampus. (10)

Neurotransmitter Synthesis

Alpha GPC produced when cell membranes are taken apart for their choline content, a process known as auto cannibalisation (18)(19). It’s no stretch then, that oral GPC supplements support acetylcholine synthesis by providing the brain with the raw materials.



Increasing Cholinergic Transporters

A seven day treatment of 150mg/kg a day Alpha-GPC found GPC increased frontal cortex acetylcholine concentration. The research indicated that cholinergic transporters VAChT (Vesicular acertylcholine transporter) and ChAT (choline acetyltransferase) were significantly expressed more in both the striatum and cerebellum following GPC. (11) Further research showed 100mg/KG GPC restored AhCE (acetylcholinesterase) to more youthful levels in aged rats. (12)

Supporting Acetylcholine Synthesis

4 studies in total have been conducted with GPC and the anticholinergic drug scopolamine.  Two involving rodents showed GPC was able to prevent scopolamine induced amnesia by supporting acetycholine synthesis (7)(13)

A study involving 32 healthy human volunteers showed 10 day pre-treatment with GPC was superior to placebo at blocking the negative cognitive effects of scopolamine.  The dosage used was 1200mg per day. Specifically GPC was able to help maintain attention scores and improve word recall. Interestingly GPC improved baseline performance for the word recall test, suggesting cognitive enhancement in young healthy individuals (15). (Full paper unavailable online, though abstract available and paper is discussed here (

The same researchers conducted a second study involving 48 young men and women. Volunteers were pre-treated with either; GPC (1200mg/Day), idebenone or aniracetam for 7 days.  Cognitive performance, particularly in verbal memory and working memory was significantly protected by GPC.  Alpha-GPC was found to be superior to aniracetam and idebenone in these respects.   (Full paper unavailable online, paper is discussed in ref 16)


Safety and Side Effects

GPC appears to be a remarkably safe nootropic that processes few-little side effects in the therapeutic dose range.  One trial reported side effects in 2.4% of all patients, which consisted by mainly of nausea (0.5%), heartburn (0.7%) and insomnia (0.4%) at a dose of 1200mg/day. (17)

The LD50 for GPC is 10,000mg / Kilo for rodents when administered orally. A drop in food consumption and increase in bodyweight was noted in rodents at a dose of 1000mg/kg. (17)





Original article @smarternootropics




PRL-8-53 Overview


PRL-8-53 is a nootropic research compound first synthesized in the 1970’s by Dr Nikolaus Hansl while working at Creighton University. The compound takes its name from creator’s company Pacific Research Labs (3) who were also the (now expired) patent holders (3). Very little research on this compound is available online. What is available appears to have been conducted by the old patent holder.

The single study involving humans showed PRL-8-53 improved word recollection scores both 24 and 96 hours after initial memorization. Given the low amount of evidence available for this nootropic, we thought it relevant to reference a journal article in which the creator discusses the compound and numerous other human trials it was used in.

Anecdotal reports for this seem favorable, though in the absence of reliable published research and data for prolonged use in humans, it’s not something we can recommend.

Other Names:

Methyl 3-[2-[benzyl(methyl)amino]ethyl]benzoate hydrochloride


Important Information


PRL-8-53 In A Nootropic Stack

The limited research for this nootropic suggests that it’s memory enhancing. The compound creator also discusses other benefits, which we cover below. Given the low amount of research on this compound and an unknown mechanism of action, we can’t advise on what to stack this with. If you do decide to experiment with it, consider taking PRL-8-53 without other nootropics to reduce possible interactions.

Dosing PRL-8-53

The single published human study used 5mg of PRL-8-53 and found it enhanced recall on a word-remembering test. (1) The patent for the compound mentions an oral dose of 0.01mg/kg per dose, taken 3 times per day. (3)

PRL-8-53’s Structure and Absorption

PRL-8-53 is derived from benzoic acid and phenylmethylamine. The compound is a benzoic acid methyl ester.  We’re unable to find any absorption data for this compound, though it can be assumed to cross the blood brain barrier.


Benefits of PRL-8-53



The single published study for PRL-8-53 shows a slight improvement of word acquisition during a memorization task. Participants were given 5mg of PRL-8-53 2 hours prior to testing and then were then asked to listen to a recording of 12 words in a particular sequence and recite them at future time points (shortly after testing, a day after and 4 days after). Minor benefits were found for immediate acquisition, but an over 80% improvement was noted for people tested later on who had initially scored poorly for the test (6/12 words correctly or below) [1].

Unpublished (Possible) Benefits – Geometric Pattern Exercise

Interestingly, the compound creator also discusses other trials which appear to be unavailable or unpublished. In a Journal published in 1978, Dr Hansl mentions that PRL-8-53 statistically improved scores in a geometric pattern cognitive exercise. Participants were shown a series of geometric patterns and ask to draw them from memory, a statistical improvement was noted.

Mental Arithmetic Exercise

In the same article, Dr Hansl mentions a number based cognitive exercise where participants had to subtract 7, add 1, subtract 7, add 2 and so on until a “goal” number was reached. Shorter times to the “goal” number were noted in the PRL-8-53 group.

Verbal Fluency Test

Dr Hansl discusses a test where subjects were asked to form words from a series of letters and dots. For example “U.R.” had to be turned into any word by adding letters at the start and end of the word, while replacing the dots with a letter. “U.R.” could be “current” for example. A statistically significant improvement was found in participants who had taken the drug.

It should be noted that all of the discussed “possible” benefits are sourced from an article (4) in 1978 where Dr Hansl was discussing the compound. Sadly, Dr Hansl passed away in 2011 We are unable to find published research that proves or disproves these claims

PRL-8-53’s Mechanism Of Action


The mechanism of action for this nootropic is currently unknown but may, in part, lie with cholinergic mechanisms. Dr Hansl, the creator of the compound discusses in the Phi Delta Kappan journal that PRL-8-53 enhances brain’s the response to acetylcholine, and the compound is not a stimulant (4). The patent for PRL-8-53 mentions cholinergic mechanisms. (3)

An animal test involving rodents showed 4mg/KG increased apomorphine (dopamine agonist) increased compulsive gnawing in rats, suggesting that PRL-8-53 to some extent is a dopamine agonist (2). The same study noted an improvement in conditioned avoidance learning. This nootropic does not enhance amphetamine’s actions in rats and doesn’t appear inhibit MAO activity. (2) The single study in humans briefly mentions that PRL-8-53 potentiates dopamine release and causes partial inhibition of serotonin (1).


PRL-8-53 Safety and Side Effects

The LD-50 for this nootropic is 800mg/KG in rodents (2) and reduced motor activity has been noted at 100mg/kg in mice. In human trials, the 5mg dosage used noted no side effects (1). The patent for PRL-8-53 mentions the compound is well tolerated in dogs and monkeys at 50mg/kg.





Image result for nootropic

Original article@smarternootropics




IDRA-21 is a relatively new nootropic compound. It works as an ampakine stimulant drug and is currently being researched in regards to its effects in memory improvement, cognitive enhancement, stimulation, and reversing cognitive deficits. It’s likely it was developed in 1994 or 1995 as the first clinical trials and peer-reviewed research articles appear in the literature in 1995.

Other Names

IDRA-21, 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, C8H9ClN2O2S

IDRA-21 In A Nootropic Stack

Due to potential AMPAkine excitotoxicity, it is not recommended to combine IDRA-21 with other ampakine drugs such as Aniracetam. Little is known about toxicity in humans. Other Nootropics which increase glutamate should be avoided as well.

IDRA-21 Dosing

IDRA-21 currently has only had animal trials. Dosing in a study with Patas Monkeys was 3 or 5.6 mg/kg p.o. in addition with 30 mg/kg p.o. of Aniracetam[1]. This study indicated that IDRA-21 was 10-fold more potent than Aniracetam at reducing learning defects. A water maze study in rats showed cognitive enhancement at oral dosages of 4-120 mumol/kg[5].

Human dosages have no history of peer-reviewed clinical studies. Some reading online suggested positive human activity at 5-25mg orally[2].

IDRA-21 Structure

IDRA-21 is a benzothiazone derivative. It’s structurally unrelated to Aniracetam, another ampakine drug. It’s a chiral molecule, with the dextrorotary isomer being the active form[6].

Image result for IDRA-21

IDRA-21 Absorption

There is very little information about absorption rates. Most rat and monkey studies determined efficacy with oral dosing, which would seem to indicate that oral is an effective route.

IDRA-21 Benefits

  • Increases in cognition (Matching sample tasks performed by Rhesus Monkeys)[7]

  • Increased Task Accuracy[7]

  • Increases in Short Term Memory[8]

  • Potential Therapeutic Effects On Schizophrenia[8]

  • Potental Therapeutic Effects On Depression[8]

  • Neuroprotection[5]

  • Benefits Against Alprazolam-induced Cognitive Deficit[1]

IDRA-21 Mechanism Of Action

IDRA belongs to a class of compounds known as ampakines. Ampakines are allosteric modulators of AMPA receptors in the brain. AMPA receptors are responsible for fast synaptic transmission [9] and are implicated in synaptic plasticity and long term potentiation [10].

As an Ampakine, IDRA-21 works by modulating AMPA receptors in the brain. Specifically IDRA-21 binds to the allosteric site of the AMPA receptor and induce positive modulation, this is sometimes called allosteric activation.

Initial research on IDRA-21 suggests that it may prevent AMPA receptor desensitization (1) and therefore increase synaptic responses and support memory and learning.

IDRA-21 Safety and Side Effects

IDRA-21 is a potent Ampakine. AMPA activation has been shown to exacerbate hippocampal neural damage[3]. IDRA-21 when administered with glutamate killed rat hippocampal neurons through AMPA excitoxicity[3]. This is potentially dangerous in patients with conditions that excessively activate AMPA such as strokes and seizures.

In another study, the dosages of IDRA-21 that induced neurotoxicity were several orders of magnitude higher than the doses that achieved cognitive enhancement in rats and monkeys, leading the researchers to conclude that IDRA-21 has relatively low neurotoxicity in therapeutic doses[4].














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@ 


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




Muscle Creatine Content



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



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




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.



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




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



See all 19 studies

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



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%.



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



See all 4 studies

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



See all 3 studies

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



See all 8 studies

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



See all 3 studies

A minor reduction has been observed.
Muscle Damage



See all 6 studies

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



See all 3 studies

Somewhat effective.
Subjective Well-Being



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.



See all 6 studies

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



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



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.

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.

See all 5 studies

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

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.



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


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


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



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


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



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.


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



See 2 studies

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


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



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



See 2 studies

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


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


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


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


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


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  



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

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


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%.



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



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.



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.


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.


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]


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]




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 @



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


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



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



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


  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.



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!



Greene, B. (2002, December). Physical Therapist Management of Fluoroquinolone-Induced Achilles Tendinopathy. Journal of American Physical Therapy Association. Retrieved December 19, 2013, from

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

Miller, K. (2013, August 27). Some Antibiotics Linked to Serious Nerve Damage. WebMD. Retrieved December 19, 2013, from

Postmarket Drug Safety Information (2008) U.S. Food and Drug Administration. Retrieved December 19, 2013, from


Original article –


Noopept is the brand name for N-phenylacetyl-L-prolylglycine ethyl ester, a Nootropic molecule similar to Piracetam. Noopept may alleviate cognitive decline.


This page features 45 unique references to scientific papers.



All Essential Benefits/Effects/Facts & Information

Noopept is the brand name for N-phenylacetyl-L-prolylglycine ethyl ester , a synthetic nootropic molecule.

Noopept has a similar effect to piracetam, in that it provides a mild cognitive boost after supplementation. Noopept also provides a subtle psychostimulatory effect.

Noopept has a much lower standard dose than piracetam (10-30mg, compared to 4800mg), and it provides a general neuroprotective effect after supplementation. This neuroprotective effect occurs during various states of cognitive trauma, including oxidative stress and physical trauma. There is, however, no evidence to suggest Noopept provides benefits for people with no cognitive ailments.

More studies are needed to determine the main mechanisms responsible for Noopept’s neuroprotective effect.

The only human study comparing Noopept and piracetam suggests the two have a comparable effect, once the smaller effective dose is taken into account.


Things to Know

Also Known As

N-phenylacetyl-L-prolylglycine ethyl ester, Noopeptide, Ноопепт, GVS-111

Do Not Confuse With

Piracetam (Basic racetam, but different molecule)

Things to Note

  • Noopept is not technically a racetam molecule (due to not having a 2-oxo-pyrollidine skeleton), but is generally grouped together in the same category


How to Take

Recommended dosage, active amounts, other details

To supplement Noopept, take 10 – 30 mg, once a day, for up to 56 days at a time. More research is needed to determine the optimal human dose for Noopept.


Editors’ Thoughts on Noopept

In essence, it appears to be a buffed up version of Piracetam. Piracetam itself had pretty weak evidence for cognitive enhancement in healthy persons (where it occurred, but fairly unreliably so and not to a large degree) and although Noopept has potential to succeed where Piracetam failed this needs to be investigated further.
Kurtis Frank



Sources and Structure

1.1. Sources

The molecule N-phenylacetyl-L-prolylglycine ethyl ester is commonly referred to as ‘Noopept’, and is a synthetic molecule commonly said to be in the racetam class (although this is technically not true, due to Noopept not having a 2-oxo-pyrollidine nucleus); in Russia (home of the patent holder) it is also referred to as Ноопепт or GVS-111. It was synthesized in 1996[1] and was based off of the endogenous neuropeptide cycloprolylglycine[1][2] and is said to be anxiolytic and mildly psychostimulatory while promoting cognitive health and memory.[3]

It is commonly said to be 1000-fold as potent as piracetam (derived from the abstract of a German review[4]) although elsewhere it has been claimed to be more variable, at somewhere between 200 and 50,000 when comparing the two molecules on a dose-per-dose basis.[5] On a structural basis, Noopept is a dipeptide conjugate of Piracetam.

Noopept is a water-soluble proline containing dipeptide structure, and while it per se is not detectable in serum even after high injected concentrations[6] it increases concentrations of Cycloprolylglycine and, as such, is a Cycloprolylglycine pro-drug.

Noopept is a synthetic racetam structure that is a Cycloprolylglycine pro-drug, with bioactivities of Noopept being related to increased Cycloprolylglycine concentrations



2.1. Absorption and Serum

Despite most animal evidence using injections as a method of administration, Noopept appears to have bioactivity following oral ingestion in humans.[3] It can cross the gastrointestinal tract in rats following an oral dose of 50mg/kg, where it possesses a Tmax of 0.116 hours (7 minutes) and reaches a Cmax of 0.82mcg/mL in serum; the authors noted that the serum concentrations and excretion kinetics of 50mg/kg oral Noopept rivalled that of 5mg/kg injections.[7]

When looking at brain concentrations, the Cmax of 50mg/kg in rats after oral ingestion (human equivalent of 8mg/kg) reaches 1.289mcg/mL at a Tmax of 0.115 hours (7 minutes); due to the lack of difference between serum and neural concentrations it is said Noopept can easily cross the blood brain barrier.[7]

The half-life of Noopept is around 16 minutes in rats[7] although this study is limted as it did not assess serum levels of the currently thought bioactive cycloprolylglycine;[7] the metabolites are thought to be vital as Noopept is not being detectable in serum 25 minutes following oral ingestion, effects have been noted on brain wave function for over 70 minutes (following injections, which have similar excretion kinetics).[8]Furthermore, there appear to be interspecies differences with rats having more rapid metabolism of Noopept in serum relative to humans.[9]

Oral ingestion of Noopept results in a very rapid absorption and metabolism of Noopept, although the kinetics of metabolites (which are thought to be bioactive) is not yet known

A true bioavailability study has not been conducted, although it appears that an oral dose is about the equivalent of one tenth an injected dose (10% bioavailability)



2.2. Metabolism

The major metabolite of administered Noopept appears to be structurally similar to the endogeous neurodipeptide known as Cycloprolylglycine (Proline and Glycine in a cyclic configuration). Noopept per se is not reliably detectable in serum[6] as it is rapidly metabolized within 25 minutes of oral ingestion.[7]Additionally, cycloprolylglycine itself has nootropic potential when injected, although to a lesser degree than Noopept.[10]

In vitro, the conversion of Noopept to cycloprolylglycine (which increased 2.4-fold in neural tissue following 5mg/kg injections, from 2.8nmol/g to 6.7nmol/g wet brain weight) appeared to also occur in neural slices which the authors hypothesized was due to deacetylation to phenylacetic acid and spontaneous reconfiguation into cycloprolylglycine; this was not outright demonstrated in this study, and no serum phenylacetic acid was detected.[6]

Currently thought that Noopept acts as a pro-drug for cycloprolylglycine and that the latter molecule exerts a deal of the benefits observed with supplementation

However, one study has noted that while injections and oral ingestion of Noopept (0.5mg/kg and 10mg/kg respectively) were able to confer an anti-amnesiac effect that appears to build up over subchronic loading for 9 days, that injections of cycloprolylglycine did not have a buildup effect.[10] This study noted that the 50% of rats experiencing an increase in memory from the latter drug was decreased to 33% after nine days of loading, which may be associated with impairment of memory retrieval with the latter.[10][11]

May not have 100% similarity to cycloprolylglycine administration, as Noopept has been associated with a subchronic buildup effect whereas cycloprolylglycine has not




3.1. Mechanisms

It has been noted that Piracetam and Noopept display similar EEG patterns.[8]

Noopept (0.2mg/kg) has been noted to increase spindle-like activity and alpha wave function in all tested brain regions (rat data) similar to Piracetam (400mg/kg) while in the right cortex and hippocampus a greater increase in beta 1 wave function decrease of the delta function was noted with Noopept.[8] While all these effects were abolished with the NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) for Piracetam, they were attenuated for Noopept at the same concentration of CPP (0.1nM; 1nM was able to abolish the effects of Noopept) and chronic injections of Noopept appeared to be assocaited with increased beta function spreading to the whole brain rather than localized.[8] Another study assessing comparative potency of Piracetam and Noopept found that, in animals subject to amnesia via electic shock that more animals experienced cognitive enhancement with Noopept at an oral dose of 10mg/kg (70% with an acute dose, 90% with nine days of dosing) than did 200mg/kg Piracetam (53% and 57% respectively).[10]

Comparatively, following injections Piracetam produced quicker but shorter lived effects (active within 10 minutes and lasting for 40) relative to Noopept (active in 30, still active at 70).[8]

Appears to be similar in mechanisms as to Piracetam at much lower concentrations when looking at whole brain function (EEG), and may be more long lasting in its effects; NMDA receptors appear to be related to the effects of Noopept

3.2. Memory and Cognitive Decline

Mechanistically, single doses of noopept at 0.5mg/kg (as well as 28 days of chronic dosing at the same dose) noted increases in both NGF and BDNF mRNA concentrations in the rat hippocampus, with a greater relative increase in NGF and no apparent tolerance developing over 28 days.[12] The authors hypothesized that the increase in these factors (neurotrophin factors) is associated with chronic improvement in memory associated with Noopept, as some trials noted greater improvements following chronic dosing (rats[13] and humans[3]) while neurotrophins are known to be associated with long-term memory enhancement.[14]

Additionally, it has been noted that Noopept (in vitro) appears to have a ‘cholinosensitizing’ effect[12] as in isolated neurons from helix pomatia that Noopept (10pM-1μM concentration range; or 10-6 to 10-11M) stimulated the reaction to microiontophoretic delivery of acetylcholine to the neuron.[14]

One study has noted species-dependent effects in mice, where BALB/c mice (C57BL/6J and DBA/2J unaffected) experienced improvements in long-term memory and in a test on the ability to extrapolate the direction of a stimuli there were benefits associated with Noopept in both C57BL/6J and BALB/c strains, but again no effect in DBA/2J mice.[15] DBA mice are known to have a cholinergic deficit[16] as well as alterations in hippocampal formation and function.[17][18]

Two possible mechanisms of action for enhancing cognition are a sensitizing effect on acetylcholine processes or induction of neurotrophin production, both of which theoretically enhance memory formation

In mice, it has been noted (from unpublished results, cited in this study[6]) that maximal learning influence on otherwise healthy rats occurs 1 hour prior to the learning activity. This timing scheme has been noted elsewhere with efficacy, although in application to injections.[19] At least one study, however, has noted that acute administration of Noopept 24 hours after a learning process is still associated with a degree of memory enhancement in rats.[4]

In studies looking at dose-response and oral ingestion, in rats where amnesia was induced via electroshock therapy it was noted that oral ingestion of 0.5mg/kg was associated with memory retention as was 10mg/kg, but an oral intake of 1.2mg/kg and 30mg/kg were both without effect; the pattern appeared to be bimodal, and the two effective rat oral doses correlated to an estimated human dose of 0.08mg/kg and 1.6mg/kg respectively (with 1.2mg/kg correlating to 0.192mg/kg).[10]

Injections (in rats) appear to be used acutely one hour prior to learning tasks with efficacy, although it does not appear that this is an outright prerequisite for cognitive enhancement. In regards to dosing, there appears to be a biphasic pattern of efficacy

0.01mg/kg injections of Noopept for 21 days in rats has failed to increase memory in otherwise healthy rats, but appeared to restore memory in rats subject to a bulbectomy (removal of olfactory bulb).[19] This restorative effect on memory has been noted in rats subject to compression damage (research model of concussion),[20][21] in stroke[11] and cerebral hypoxia,[22][23] oxidative stress,[24][22] scopolamine (cholinergic toxin) injections[25] and with usage of anticholinergics,[13] excitotoxicity via glutamate,[22]prefrontal cortex photothrombosis,[26][27] and in a bilateral frontal lobectomy.[28] Protective effects, at least on oxidative damage, have been noted at concentrations in the nanomolar range (10nM) although the IC50appears higher (1.27mM).[24]

One rat study has noted that, similar to Piracetam, administration of Noopept to otherwise healthy rat pups (8-20 days of age) results in an impairment of memory formation (declarative and procedural) without influencing locomotion.[29]

Over the course of 56 days of treatment in persons with cerebrovascular insufficiency, Noopept at 20mg is more effective than 1200mg Piracetam in improving global MMSE scores and was effective in persons with post-traumatic cerebral insufficiency (Piracetam was only effective in those with vascular disease and not trauma patients).[3]

Very general neuroprotective effects in research animals (usually rodents) given Noopept injections, and this has been replicated in one human study with 20mg oral Noopept; these studies mostly report a unanimous improvement in memory (secondary to reducing the decline seen with brain damage) although no studies currently exist on otherwise healthy humans or animals using Noopept for cognitive enhancement (ie. Noopept taken in a model not characterized by brain damage)

3.3. Anxiety

Mechanistically, One study assessing hippocampal cells in vitro measurings inhibitory postsynaptic currents (IPSCs) noted that while Noopept (1μM) increased spontaneous IPSC amplitude and frequency (269+/-39%) which was thought to be due to direct depolarization of inhibitory synaptic transmission (as Noopept did not affect currents evoked by rapid application of GABA or glutamate).[30] This was thought to be related to anxiety by the authors due to a high concentration of benzodiazepine receptors in the hippocampus[31] and anxiety being related to the hippocampus.[32]

At least one study suspects that an increase of tonic inhibition in the hippocampus may be related to the observed anxiolytic effects of Noopept

Noopept’s major metabolite appears to induce an anxiolytic effect in rodents as assessed by an elevated maze plus test at the injected dose of 0.05mg/kg (0.1mg/kg appeared less effective and 0.2mg/kg was ineffective)[2] where only the L-isomer is active and the D-isomer is wholly inactive.[2]

In humans, one study[3] investigated 53 persons with cognitive ailment (37 with vascular cerebral damage and 17 with post-traumatic damage; 41 finishing the trial) at two daily doses of 10mg compared to the active control of Piracetam (1200mg daily) over 56 days noted universal improvement on parameters of vascular cerebral damage and improvement on half of measured parameters of trauma. Fatigue, anxiety, irritability, apathy, and affective lability were improved in both groups while further benefits were noted on mood, sleep, and wakefullness in those with cognitive ailment stemming from vascular damage.[3]Noopept was more effective over 56 days in improving the MMSE score relative to Piracetam, while it was effective in post-trauma patients (Piracetam was not) although when comparing all scores on MMSE, BPRS, and CCSE there was no significant difference.[3]

Appears to have anxiolytic properties, which have been demonstrated in otherwise normal rats but not yet in otherwise healthy humans (has been confirmed in humans who may have increased anxiety secondary to cognitive degeneration)

3.4. Depression

Two animal studies have noted that Noopept is associated with abolishing the effects of learned helplessness in rats at 0.05-0.10mg/kg injections,[33][34] which is thought to be a model of depression as it is related to extraneous factors. Currently, the only study in humans assessing depression noted that in persons with cognitive injury there was less depressive symptoms associated with 20mg Noopept for 56 days as assessed by MMSE, BPRS, and CCSE.[3]

Two animal studies suggest that an anti-depressive effect may occur, but this has not been thoroughly evaluated

3.5. Alzheimer’s and Parkinson’s

In vitro, Noopept appears to accelerate the fibrillization rates of α-synuclein (the one day lag phase seen in vitro without Noopept was eliminated) in a concentration dependent manner (molar ratios of Noopept to α-synuclein) and appeared to influence a β-sheet formation of α-synuclein.[5] Direct binding with monomeric α-synuclein did not seem apparent.

When assessing the cytotoxicity of α-synuclein upon SH-SY5Y neuroblastoma cells, Noopept at a 1:1 ratio or ten-fold greater appeared to abolish α-synuclein-induced cytotoxicity without per se affecting viability.[5]Cell necrosis as assessed by propidium iodide and Annexin V appeared to be normalized to healthy control cells under the influence of Noopept, while necrosis was evidenct in α-synuclein control as was associated with less ROS production in cells.[5] An increase in immunostaining of prefibrill proteins, but not to lysozyme amyloid nor S100b, has been noted in vivo in rats injected with 0.01mg/kg Noopept for 21 days.[19]

Production of β-sheet formation is generally seen as protective as alternate formations such as the oligomeric and protofibrillar species are more cytotoxic to neurons.[35][36][37] Shorter species may also induce necrotic cell death[38] while Noopept appears to influence longer fibril formation.[5]

In vitro, Noopept appears to influence fibrillization of α-synuclein towards β-sheets and away from oligomeric formation while promoting fibril length; the cumulative effect of which is less cytotoxic formations of these protein structures and more relative cell viability

Noopept has been found to increase immunoreactivity to Aβ amyloid in an Alzheimer’s disease mice model following olfactory bulbectomy operation[19] and in an animal model of Alzheimer’s Disease (beta-amyloid25-35 injection) injections of 0.5mg/kg Noopept for 7 days prior to treatment fully prevented amnesiac properties of the amyloid injections; some rehabilitative effects were noted when Noopept was administered after amyloid.[39]

Some bioactivity and protective effects have been noted in rats given Noopept, although there is currently no study assessing the potency relative to a reference drug

3.6. Excitation

Noopept has been claimed to have a subtle psychostimulatory effect.

In isolated synaptoneurosomes, Noopept (as well as the endogenous peptide cycloprolylglycine) appear to modulate neuronal membrane potential, causing depolarization but and being able induce hyperpolarization in a calcium-dependent manner (hyperpolarization abolished in calcium-free medium); Noopept was more effective than cycloprolylglycine in this regard but the two were competitive rather than additive.[40] The researchers noted this effect could be due to blocking calcium channels (noted previously in snail neurons[41] where 10nM Noopept as well as both Piracetam at 100mM and Vinpocetine at 30mM at inhibiting slow inactivating potassium channels without influencing calcium or fast acting potassium channels[42]) and would result in increased excitatory potential of neurons. However, as Noopept is also associated with protection against stroke (a mechanism related to opening potassium channels) a modulatory effect was proposed.[40]

Has been noted to cause neuronal excitation, which may be related to the reported psychostimulatory effect; beyond this limited evidence there is not too much assessment of the stimulatory effect of Noopept


Inflammation and Immunology

4.1. Mechanisms

One study has noted that Noopept injections (0.5-10mg/kg) is able to augment the phagocytic index of macrophages and increased splenocyte proliferation (70.4%) relative to control; enhanced T-cell proliferation was noted only with chronic dosing for seven days and to the degree of 16.2%.[43]

Noopept was noted to reduce immunosuppression induce by cyclophosphamide,[43] which was thought by the authors to possibly be related to protective effects against stroke due to a stroke inducing apoptosis of some immune cells.[44]

Some interactions with the immune system, fairly unexplored, and may interact with protective effects on cognition


Safety and Toxicity

5.1. General

In a comparative study, although both treatments were generally well tolerated there was a reported 1.8-fold less side-effects associated with 20mg Noopept relative to 1200mg Piracetam despite both treatments being effective in reducing symptoms of cognitive injury.[3]


Scientific Support & Reference Citations

Source @


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