Magnesium Round-Up: Know If You Are Deficient, Whether You Need More, Where to Find It, How Dietary Mg Contents Changed & How Magnesium Interacts W/ Vitamin D

24%, 23% and 22% of the DV for magnesium that's what you can find in one serving of sunflower seeds (0.25cup), halibut (4oz) and a large(r) banana - now you tell me it was impossible to get your magnesium from dietary sources.

After having handled half of the Science Round-Up from Thursday yesterday, yesterday, there is still something left to serve: seconds to the seconds, if you will and probably not so "new" as the average SuppVersity news. In order not to bore you, I will yet refrain from telling you how important magnesium is and how it is involved in thousands of enzymatic reactions ... you know the whole magnesium-guru-spiel all too well, anyway. I mean, anyone doing a cursory Google search will have to conclude that there is nothing magnesium cannot cure, right?. Whatever you may suffer from, someone has already found out that it must be related to magnesium deficiency or, even more profitable, taking the wrong form of magnesium supplements.

Apropos deficiency: How do you even know you are deficient?

What sounds like a question that could be answered in one, at best two sentences turns out to be one of the root causes of the whole confusion about magnesium. Based on a standard blood test you can only exclude that your levels are (a) so high or (b) so low that you better head straight to the emergency room. Magnesium is, just as the other electrolytes, simply too important for your body to have them drop below a certain margin in which your heart works optimally. So if there is not enough magnesium around, your body will tap into tissue stores the status of which is obviously not identical to the serum levels on a standard lab test.

Table 1:The lion's share of magnesium to replete your serum levels is not coming from your red blood cells and therefore RBC levels are only a proxy and not a 100% reliable marker of total body mg status (data based on Elin. 1987)

According to Maurice J. Arnaud who wrote a review with the telling title "Update on the assessment of magnesium status" in 2008, the most reliable method to assess the whole body magnesium status would be a metabolic ward study in the course of which a so-called "loading test" would be performed, But...

"[b]alance studies are time consuming, labour intensive and need well trained staff. They are often performed in a metabolic unit and require complete urine and faecal collections; therefore it is not a method that can be applied as a routine test for the evaluation of Mg status. Loading tests are simplified balance studies where absorption is supposed not to be disturbed when Mg is given orally so that body retention is calculated from urine elimination. Mg administration during a loading test can be either oral or intravenous and it is important that the subjects have normal kidney function. Urine is collected for 24 hours following administration of the Mg load as Mg excretion by the kidney has been shown to have a circadian rhythm . Under these conditions, the loading test is supposed to be a reliable indicator of Mg status." (Arnaud. 2008)

With the erythrocyte (red blood cell) test for magnesium, there is however an alternative available, which may not be just as reliable but appears to show a relatively high correlation with whole body magnesium levels in many, but not all studies (Malon. 2004).

How likely is it that you are deficient?

Honestly, I would hope that it is unlikely, because if that is the case for someone who is not taking supplemental magnesium you can almost be sure that her or she is following a healthy whole foods diet.

Table 2: Overview of age groups with more than 5 % of intakes below the lowest recommended intake levels in 7 European countries; T, toddlers (1–3 years (both sexes)); C, children (4–10 years); Y, youth (11–17 years); A, adults (18–60 years); S, seniors (.60 years); capitals, both sexes; lower case, women only; lower case italic, men only (Mensik. 2013)

If you take a look at table 2 you will see that even the average German gets enough magnesium in his diet, irrespective of his age, and much contrary to our neighbors in the East, West and Northwest (I could not resist to mark zinc another of those purported minerals of which conventional wisdom tells you that you simply cannot get enough from your diet).

Knowing that most of you are probably Americans, I can calm you down. You are not worse than your British friends. In fact, the NHANES data from 1999-2000 suggests that the average American Caucasian and Mexican man below 50 gets enough magnesium from his food only! Unfortunately, the same cannot be said for the women, and both male and female African Americans who have trouble meeting their requirements even if one accounts for the additional magnesium from supplements (NHANES).

Magnesium and the athlete

A note on magnesium and cramps: While there is evidence that altered serum osmolality and altered serum electrolyte concentrations, notably hypochloraemia, hyponatraemia, and hypocalcaemia (=not hypomagnesaemia) can cause generalized skeletal muscle cramping at rest in specific clinical settings, "data from well-conducted prospective cohort studies show that athletes with acute EAMC are not hyponatraemic, hypochloraemic, or hypocalcaemic and do not have an abnormal serum osmolality." (Schwellnus. 2008).

For the average athlete, a low magnesium intake is yet rather the exception and can even be problematic for athletes with a high anaerobic-to-aerobic ratio who suffer from increases in blood mg due to an overall reduction on blood volume after intense workouts, anyway (Cordova. 1992; Joborn. 1985; Monteiro. 2005; Monteiro. 2006). It is thus no wonder that not magnesium deficiencies, but high magensium levels are a problem that is commonly observed in athletes. I mean, what are you supposed to do, when even your mother "lies" to you about cramps being caused by magnesium deficiency?

"The most common alterations were higher serum phosphate (29/61, 47%) and magnesium concentrations (28/61, 46%). Abnormalities of serum phosphorus and magnesium concentrations were detected in almost half of the athletes. Hyperphosphataemia and hypermagnesaemia were the most common abnormalities." (Malliaropoulos. 2012)

The data Malliaropoulos et al. analyzed came from 130 elite track and field athletes (65 males and 65 females, age range 20-30 years) from the National Athletics Sports Medicine Center database in Thessaloniki, Greece. And maybe some of them were even on the proven non-ergogenic ZMA (zinc + magnesium + vitamin B6; cf. Wilborn. 2004).

So where do you get your supplemental magnesium from and how much?

I am not going to tell you to stop supplementing with magnesium if you feel that this has done you good in the past. It is after all an important mineral. What I want to remind you of is yet the fact that taking 100% of the RDA is imho the absolute maximum. Even if you don't end up with high levels due to supplementing more and don't care about wasting money, there is one thing that's commonly overlooked about human physiology and that is how the intake and excretion of nutrients are highly inter-related. In other words, if your body switches into a "get rid of magnesium" mode it is likely you are loosing other electrolytes you do not supplement in copious amounts (e.g. salt ;-), as well.

Figure 1: Plasma an bone (primary axis) as well as red blood cell (RBC; 2ndary axis(!)) content after 14 days of supplementation with identical amounts of magnesium in different organic and inorganic forms (Coudray. 2005)

As far as the best forms are concerned the number of studies comparing multiple forms to each other is limited and the inter-comparison of different studies not really legit. Therefore I have simply copied + pasted the figure that went with a previous article on the matter - as you can see, you can generally use whatever form of magnesium you want - even the cheap oxides, which worked wonders for anxiety ridden ladies in a study by De Souza et al. that was published in the Journal of Women's Health & Gender-Based Medicine in March 2000. As long as you take your magnesium supplements in reasonably low doses - the dose in the De Souza study for example was 200mg + 50mg B6 - and over a long enough period, they are going to bring your levels back up - if not sooner, then later.

Magnesium depletion of our foods

A note on topical Epsom salt from the early 20th century: While I did tell you on the show that I could not find peer-reviewed adequately powered studies on the topical absorption of magnesium in the for of mg oil or Epsom salt, I found a comment in a 1915 paper on the potential harm caused by cosmetics quite enlightening, esp. the part on the economic value of respective products, where Martin I. Wilber writes that the ability of respective products to penetrate the "unbroken skin has as yet not been demonstrated" and cautions against the sue "of the now widely advertised lotions containing magnesium sulphate or Epsom salt", of which "the latter preparations serve very well to show the gullability of that portion of the public that is desirous of improving its facial appearance. As Epsom salt, magnesium sulphate can usually be purchased for 5 cents a pound, while in the form of any one of the popular skin or wrinkle lotions it is sold at the rate of from $2 to $4 a pound." (Wilbert. 1915) You see, there were snake,... ah I mean mg oil vendors all over the place even 100 years ago ;-)

Aside from the almost cult-like worship of epsom salt baths and topical ng oils, the notion of a general depletion of mg in the foods we eat is one of the favorites among the bazillion of websites run by people who hoax you to believe they were concerned with your physical health, when all they are concerned with is their own financial health.

Figure 2: Changes in mineral content of selected food types from 1940-2002 (Thomas. 2007)

It is, as the data in figure 2 goes to show you true that the amount of magnesium in many of the foods we consume is lower these days than it was amidst WW2. The mg loss in meats, for example, is  driven by the processing, while corned beef has lost almost 50% of its "original" mg content, the amount of mg in roast beef and steaks is still the same, the one in turkey is even up by ~30% and for chicken it remained 100% stable (Thomas. 2007). It is also a very intriguing coincidence that the same websites will usually also tell you how we are all not just magnesium deficient, but also copper toxic. Strange in view of the fact that the average reduction in copper is -62% and thus >2x higher than that of magnesium.

Magnesium supplementation for special conditions

Before closing this round-up with a bottom line, I am briefly listing a couple of things related to magnesium or rather a deficiency in this important mineral that could be solved by simply upping your dietary and/or supplemental magnesium intake.

• 

  Higher vitamin D levels increase MG uptake from the gut and supplementation with VD has been shown to increase mg in obese, yet not in normal individuals (Farhanghi. 2009). On the other hand, mg has recently been found to be necessary for the production of calcitriol from 25OHD (Matsuzaki. 2013)

  anxiety - mg is the gate-keeper at the NMDA receptor and interacts with the GABA receptors; a deficiency can cause anxiety, the use of extra magnesium will yet not automatically solve the problem if you are not low to begin with
• depression - low cellular mg levels can precipitate if not cause depression(-like) symptoms, 150-300mg of magnesium glycinate or better taurinate can help (Eby. 2006)
• low vitamin D - while it is not yet sure if it helps with upping the storage form of vitamin D (25OHD), it has been recently established that magnesium is necessary for the production of calcitriol the active form of vitamin D; adequate levels of D also facilitate mg absorption very high levels of vitamin D, on the other hand, have been associated with low / imbalanced mg levels - probably due to their effects on calcium homestasis
• constant stress / burnout - initially low mg levels will lead to a hyper activity of the stress-axis within the HPTA; the constantly overtaxed CNS will then give in and you will end up totally burned out (Sartori. 2011); this state cannot be reversed by magnesium supplementation, alone, but it can aid the recovery process which is largely based on taking off of everything that stresses you

Whether or not simply eating more high magnesium foods will be enough or whether you actually have to buy supplements to work on these and other issues will also depend on whether

• you can digest / absorb it, which would be hampered due to vomiting, diarrhea, bowel resection, intestinal and biliary fistulas or hemorrhagic pancreatitis
• lose too much mg over the kidneys, due to chronic parental fluid therapy, osmotic diuiresis, hypercalcemia, diuretics, aminoglycosides, amphotericin B, pentamidine, cisplatin, cyclosporine, alcohol metabolic acidosis (ketosis, starvation, alcoholism), renal diseases, or
• suffer from endocrine disorders like primary or secondary aldosteronism, diabetes, hyperthyroidism or hyperparathyroidism

If anything of these sounds familiar, I would certainly consider testing my mg levels (erythrocyte test) before and while I was supplementing and that's not about wasting money on potentially unnecessary supplements, but much more about making sure that you actually get, absorb and retain enough magnesium.

---

Bottom line: Magnesium is certainly an important mineral, but its effects must not be seen in isolation, it should not be supplemented in copious amounts in isolation without medical indication and it may not be misunderstood as a natural pharmacological agent - it works by (a) replacing a deficiency or (b) countering an imbalance. Plus: It is not generally impossible to get your 300-400mg of magnesium from your diet.

References:

• Arnaud MJ. Update on the assessment of magnesium status. Br J Nutr. 2008 Jun;99 Suppl 3:S24-36.  
• Bohl CH, Volpe SL. Magnesium and exercise. Crit Rev Food Sci Nutr. 2002;42(6):533-63. Review.
• Cordova A. Changes on plasmatic and erythrocytic magnesium levels after high-intensity exercises in men. Physiol Behav1992; 52: 819-21.
• Eby GA, Eby KL. Rapid recovery from major depression using magnesium treatment. Med Hypotheses. 2006;67(2):362-70. 
• Elin RJ. Assessment of magnesium status. Clin Chem. 1987 Nov;33(11):1965-70. Review.
• Farhanghi MA, Mahboob S, Ostadrahimi A. Obesity induced magnesium deficiency can be treated by vitamin D supplementation. J Pak Med Assoc. 2009 Apr;59(4):258-61. 
• Joborn H, Akerstrom G, Ljunghall S. Effects of exogenous catecholamines and exercise on plasma magnesium concentrations. Clin Endocrinol (Oxf)1985; 23: 219-26; (Oxf).
• Malliaropoulos N, Tsitas K, Porfiriadou A, Papalada A, R Ames P, Del Buono A, Lippi G, Maffulli N. Blood phosphorus and magnesium levels in 130 elite track and field athletes. Asian J Sports Med. 2013 Mar;4(1):49-53.
• Malon A, Brockmann C, Fijalkowska-Morawska J, Rob P, Maj-Zurawska M. Ionized magnesium in erythrocytes--the best magnesium parameter to observe hypo- or hypermagnesemia. Clin Chim Acta. 2004 Nov;349(1-2):67-73.  
• Matsuzaki H, Katsumata S, Kajita Y, Miwa M. Magnesium deficiency regulates vitamin D metabolizing enzymes and type II sodium-phosphate cotransporter mRNA expression in rats. Magnes Res. 2013 May 1;26(2):83-6.
• Mensink GB, Fletcher R, Gurinovic M, Huybrechts I, Lafay L, Serra-Majem L, Szponar L, Tetens I, Verkaik-Kloosterman J, Baka A, Stephen AM. Mapping low intake of micronutrients across Europe. Br J Nutr. 2013 Aug;110(4):755-73.   
• Miriam C. De Souza, Ann F. Walker, Paul A. Robinson, and Kim Bolland. Journal of Women's Health & Gender-Based Medicine. March 2000, 9(2): 131-139.  
• Monteiro CP. Equilíbrio Oxirredutor: um estudo em nadadores e em não atletas, em repouso e em resposta ao exercício [PhD]. Lisboa: Faculdade de Motricidada Humana, Universidade Técnica de Lisboa, 2005.
• Monteiro CP, Santa Clara H, Raposo MF,et al. Effect of training and exercise intensity on magnesium status. In: Alpoim C, Vasconcelos Morais P, Santos MA, Cristóvão AJ,
  Centeno JA, Collery P, eds.Metal Ions in Biology and Medicine. Paris: John Libbey Eurotext, 2006: 546-52 
• Sartori SB, Whittle N, Hetzenauer A, Singewald N. Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology. 2012 Jan;62(1):304-12. doi: 10.1016/j.neuropharm.2011.07.027. Epub 2011 Aug 4.
• Schwellnus MP. Cause of exercise associated muscle cramps (EAMC)--altered neuromuscular control, dehydration or electrolyte depletion? Br J Sports Med. 2009 Jun;43(6):401-8. 
• Thomas D. The mineral depletion of foods available to us as a nation (1940-2002)--a review of the 6th Edition of McCance and Widdowson. Nutr Health. 2007;19(1-2):21-55. Review.
• Wilbert MI. Cosmetics as Drugs: A Review of Some of the Reported Harmful Effects of the Ordinary
  Constituents of Widely Used Cosmetics. Public Health Reports. 1896-1970; 30(42): Oct. 15, 1915. 3059-3066.
• Wilborn CD, Kerksick CM, Campbell BI, Taylor LW, Marcello BM, Rasmussen CJ, Greenwood MC, Almada A, Kreider RB. Effects of Zinc Magnesium Aspartate (ZMA) Supplementation on Training Adaptations and Markers of Anabolism and Catabolism. J Int Soc Sports Nutr. 2004 Dec 31;1(2):12-20.

The Neurotransmitter Depleting Effects of Branched Chain Amino Acids (BCAAs) and Their Potential Ergolytic, Anxiogenic & Depressive Downstream Effects

Oh yes, this will happen despite if not because you've taken large amounts of BCAA before the workout.

Usually you don't put the cart before the horse, but I guess you won't mind if I do so and postpone a summary of the information on magnesium from yesterday's installment of the Science Round-Up to tomorrow, when this means that we are going to take care of the "BCAA crisis" today.

Ok, maybe "crisis" is not the best word to describe the reverberations the recent publication of a study by SuJean Choi et al. should be having (=nobody buys BCAAs anymore), but I was looking for something better than the usual "the truth about..." Science, and I am not going to tire repeating that, is after all not about truth (that's what the confessional box is about), but about experimentally verifiable/verified and non-verifiable/non-verified hypothesis (Popper. 1994).

BCAAs can have ergolytic effects - A verifiable hypotheses?

Based on the observations Choi et al. made in by then decapitated lab animals (so much about the "why don't they prove this works in humans"-argument), the administration of a solution that contained either a BCAA + Arginine + Glutamine mix, or one out of two different EAA mixtures, it is safe to say that the hypothesis formulated in the subheading of this paragraph could belong to the former, i.e. the verifiable, hypothesis; and that despite the fact that the addition of glutamine and arginine to the human equivalent of 19:12:12 mg/kg body weight of leucine:isoleucine:valine (less than most BCAA products offer) would at least buffer the previously discussed performance decrements due to the accumulation of ammonia (learn more)

Table 1: Amino acid composition (mg/kg body weight) of the AA supplements tested (Choi. 2013)

In the end, the results Choi et al. present contradict both, the promises on the labels of the countless BCAA products and Newsholme's and Blomstrand's hypothesis that the inhibitory effect the BCAAs exert on the uptake of tryptophan from the blood into the brain and the way this forestalls the subsequent conversion of tryptophan to serotonin would lead to a reduction of central fatigue during exercise (Newsholme. 1996).

Figure 1: Effects of BCAA and BCAA + 100mg/kg l-tyrosine supplementation on serum and brain amino acid and neurotransmitter levels in sedentary rats; data expressed relative to vehicle (Choi. 2013)

Now, the data in figure 1 does confirm the first part of the Newsholme + Blomstrand hypothesis: The adminstration of BCAAs in an amount similar to many low dose BCAA supplements that are currently being marketed as ergogenic agents does blunt the increase in serotonin by competitively inhibiting the uptake of l-tryptophan from the bloodstream. The latter is a necessary consequence of the fact that both the BCAAs and the said 5-HTP (=serotonin) precursor are being transported by the same large amino acid transporter (think of it like a taxi that is allowed to pass the blood brain barrier) as l-tryptophan.

A note on the pro-obesity effects mentioned during the show: While some scientists invoke the increased BCAA levels in obese individuals and the subsequent blockade of serotonin (and dopamine) production in the brain to the constant insatiable cravings, anxiety and depression in these individuals (Breum. 2003; She. 2007; Coppola. 2013) a more fundemental contribution to the obesity pandemic has been proposed by Newgard et al. (2009). Their hypothesis is that a continuous presence of BCAAs in the blood will lead to a continuous overexpression of mTOR that increases the susceptibility to diet induced obesity and insulin resistance.

Now, it is also true that this will blunt the increase in 5-HTP synthesis in the brain (-48%; in the absence of exercise; see figure 1), but with the concomitant -25% decline in hypothalamic DOPA (=dopamine, the "get going neurotransmitter") in the brain after ~30min, the net ergogenic effect will, just as it was the case in the majority of pertinent rodent and human studies, be negligible, at best!

Modulatory Effects of Different Macronutrient & Stress Compositions on Serotonin (read more)

"Following oral intubation with the ‘‘BCAA’’ mixture to sedentary rats (see Table1; n=3/group), serum TRP and TYR concentrations showed non-significant reductions; the serum TRP and TYR ratios, and cortical TRP and TYR concentrations dropped markedly at 30 min. Cortical TRP and TYR concentrations remained low for the duration of the study (120 min), while the ratios began to recover at 90–120 min. DOPA and 5HTP synthesis dropped to nadir values at 60 min; DOPA synthesis remained low, while 5HTP synthesis had rebounded by 120 min (bottom panels, Fig.2).

Inasmuch as the maximal effects on DOPA and 5HTP synthesis occurred 60 min following intubation, all subsequent studies used 60 min as the experimental endpoint." (Choi. 2013)

In fact, the overall and as you've just read persistent drop in neurotransmitter levels can not only make you tired, previous research even suggests that it may be invoked in the etiology of depression / central fatigue (see previous SuppVersity post "Study Investigates Modulatory Effects of Different Macronutrient Compositions on Serotonin in the Presence and Absence of Stress" | read more).

Balancing leucine with tyrosine at a ~1:1 ratio helps

The data in figure 1 does however also tell you that you can mitigate the problem by the addition of 100mg/kg body weight of l-tyrosine to the supplement. With that being roughly equivalent to the amount of leucine in the BCAA formula (cf. table 1), this is yet far more of the dopamine precursor than your average BCAA product is going to have... after all it's a maximal leucine concentration that sells and is propagated as being "modern" and "maximal anabolic".

Figure 2: Hypthalamic DOPA and 5HTP levels after BCAA or BCAA + 100mg/kg tyrosine ingestion with / without exercise, left (Choi. 2013); effects of BCAA or l-tyrosine supplementation on time to exhaustion (Strüder. 1998)

With the addition of 100mg/kg l-tyrosine, you may yet in fact expect to see some benefits. Unfortunately, the currently available literature will put you right in a study that was conducted by Strüder et al. for example neither 21g of BCAAs nor the whopping dose of 20g of pure l-tyrosine resulted in the expected increase in the time-to-exhaustion during time trials in trained cyclists (see figure 2, right; Strüder. 1998) and Blomstrand concludes in his review for the British Journal of Sports Medicine's A-Z Supplement Review Series:

"Under certain conditions, BCAA supplementation can also improve physical performance, although the majority of studies have found no effect of BCAA on performance when supplied together with carbohydrates." (Blomstrand in Burke. 2009)

This, on the other hand, tells you that the performance enhancing effects are a mere result of the oxidation of BCAAs of which both Blomstrand, who is by the way defending his own hypothesis here, and the recently discussed by Falavigna et al. (see SuppVersity News) indicate that the ensuing increased release in ammonia production "may be detrimental to performance" (Blomstrand in Burke. 2009). If you also take into consideration that a study by van Hall et al. from 1995, i.e. before Newsholme & Blomstrand came up with the hypothesis the whole BCAA myth was built on, basically falsified the tryptophan hypothesis of fatigue, In the pertinent study the scientists were after all able to show that the provision of BCAAs as workout fuel is not superior to that of tryptophan and that despite a 8-12% reduction in brain tryptophan uptake at exhaustion with BCAAs and a 7- to 20-fold increase in response to the ingestion of a tryptophan supplement (van Hall. 1995).

Milk protein EAAs: An option, but a logical one?

If you finally take a look at the data in figure 3  you will notice that the head-to-head comparison would place an amino acid pattern as the one you can find in milk proteins, would probably be the best amino acid supplement source to resort to (don't ask me what exactly it is that makes the difference, I can't tell, but suspect it could be related to lysine which is also going to block the same small AA channel into the brain + the inclusion of non-essential amino acids in milk protein vs. pure EAAs).

Figure 3: Comparison of the the effects of BCAA, regular EAAs and an EAA amino acid mix from milk protein; composition of the mixtures see table 1 (Choi. 2013)

But let's be honest, does it really make sense to buy an additional supplement, when you already have a pouch of cheap and tasty whey and/or another fast digesting high BCAA protein such as pea protein lying around at home?

---

So what's the verdict then? As you've heard on the Science Round-Up, yesterday, I personally think that this does not make sense, because ...

1. .

   

   Suggested Read: "Spiking Whey W/ EAA Will Provide Inferior Results" (read more)

   .. neither the total amount of amino acids that are obsorbed within 1h from free form EAAs, nor the the utilization speak in favor of EEAs - both have been shown to be +7% and +92% higher with slightly hydrolized whey vs. EAAs (Monchi. 1993),
2. ... nor is there any anabolic benefit to the addition of EAAs or leucine to whey, in fact "25 g of whey is better suited to increase resistance exercise-induced muscle anabolism" compared to lower amount of whey that has been pimped with additional EAAs and leucine to offer the same amount of the purpoted "anabolics" as the 25g dose of plain whey protein (click on the picture to the right to learn more; Churchward-Venne. 2012)

Contrary to Carl's jovial suggestion to simply throw away your BCAA supplements, I would suggest you keep them (unless you already have problems with anxiety, etc.), cut back on the dosage and monitor your response closely. The latter is especially true, when you take them on an empty stomach. After you've run out, train a month with nothing but cheap protein and decide afterwards whether or not your past "great training experience", "superior intensity" and whatever else the ads tell you the respective products will do was more than just another instance of the brocebo effect (learn more about brocebos).

References:

• Breum L, Rasmussen MH, Hilsted J, Fernstrom JD. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr. 2003 May;77(5):1112-8. 
• Burke LM, Castell LM, Stear SJ, Rogers PJ, Blomstrand E, Gurr S, Mitchell N, Stephens FB, Greenhaff PL. BJSM reviews: A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 4. Br J Sports Med. 2009 Dec;43(14):1088-90.
• Choi S, Disilvio B, Fernstrom MH, Fernstrom JD. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids. 2013 Aug 1. [Epub ahead of print] 
• Coppola A, Wenner BR, Ilkayeva O, Stevens RD, Maggioni M, Slotkin TA, Levin ED, Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E405-13.
  
• Churchward-Venne TA, Burd NA, Mitchell CJ, West DW, Philp A, Marcotte GR, Baker SK, Baar K, Phillips SM. Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Physiol. 2012 Jun 1;590(Pt 11):2751-65.
• Monchi M, Rérat AA. Comparison of net protein utilization of milk protein mild enzymatic hydrolysates and free amino acid mixtures with a close pattern in the rat. JPEN J Parenter Enteral Nutr. 1993 Jul-Aug;17(4):355-63. 
• Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009 Apr;9(4):311-26.
• Newsholme EA, Blomstrand E. The plasma level of some amino acids and physical and mental fatigue. Experientia. 1996 May 15;52(5):413-5. Review.
• Popper, KR. Zwei Bedeutungen von Falsifizierbarkeit [Two meanings of falsifiability]. In Seiffert, H.; Radnitzky, G. Handlexikon der Wissenschaftstheorie. München: Deutscher Taschenbuch Verlag. 1994.  
• She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1552-63. Epub 2007 Oct 9.
• Strüder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res. 1998 Apr;30(4):188-94.  
• van Hall G, Raaymakers JS, Saris WH, Wagenmakers AJ. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol. 1995 Aug 1;486 ( Pt 3):789-94.

Dopamine, Serotonine, Creatine: Creatine Supplementation Modulates Post-Exercise Neurotransmitter Levels in Man

Can creatine beneficially influence your neurotransmitter so that you can run longer?

I guess, some of you will remember, while others will still ignore the discussion revolving around the serotonin (5-HT) depleting effects of high doses of BCAA (see news item "BCAAs inhibit serotonin metabolism"). To those who remember and may even have followed the ensuing discussion it is probably no news that the acute ingestion of ~60g of BCAAs suppresses 5-HT, raises prolactin and lowers dopamine to such a degree that it has a direct negative impact on emotional decision making in human beings (Sevy. 2006). Against that background you may probably be assuming the worst, when I am now telling you that every gymrat's darling, creatine monohydrate, does also exhibit non-negligible effects on the levels of the two important neurotransmitters.

All clear: Creatine probably won't make you depressed

Contrary to BCAAs which exert their effect irrespective of whether you do or don't exercise. The current evidence suggests that creatine does the same only in the context exhaustive aerobic exercise (I would bet it does the same with high volume training, though). In their recently published paper, Moghadasi et al. describe the dopamine, serotonin and prolactin response of 20 healthy, but sedentary male volunteers (BMI 23.5; body fat %: 20.5%) who received 4x5g creatine (standard loading protocol) for 7 days before they underwent an exhaustive aerobic exercise test, the so-called Bruce protocol, in the course of which participants are made to run on a treadmill to exhaustion, while incline and speed are increased every three minutes.

Figure 1: Dopamine and serotonin levels of the healthy, but sedentary volunteers before, immediately, 10 min and 20 min after the Bruce protocol (Moghadasi. 2012)

As you can see in figure 1 the preloading protocol  resulted in significantly different 5-HT responses to the exercise protocol and a trend towards higher, more stable dopamine levels. But this is not the only interesting observation the scientists made. Contrary to the common believe that creatine supplementation will make you look bloated in response to an increase in extra-cellular water, the participants in the creatine group of the Moghadasi study who gained a whopping 1.6kg of total mass in the course of the study period exhibited lower extracellular water levels than their peers in the control group.

Figure 2: Effect of creatine supplementation on BMI and intra- and extracellular water (Moghadasi. 2012)

The relative figures in figure 2 do obviously not exclude that the subjects in the creatine group still had a slight increase in total extra-cellular water. What's yet more important though is the more pronounced increase in the intra-cellular compartment, which has, as Moghadasi et al. rightly point out, "been identified as a universal anabolic signal, stimulating protein synthesis and net protein deposition." (Moghadasi. 2012)

Figure 3: Especially immediately after the workout the dopamine to serotonin ratio seems to suggest that there should be a significant effect. As far as the time on the treadmill was concerned there were yet no statistically significant intergroup differences in the study at hand (Moghadasi. 2012).

But all that is not new to you, I guess, so let's get back to the modified neurotransmitter response. Is that something we won't or something we don't won't? Well, from a performance perspective it turned out to be useless (just as the 5-HT blockade by BCAAs, by the way). Participants from both groups flagged after roughly 15.5-16.0 minutes on the treadmill - how accurate the Bruce Test is, specifically as a measure of central fatigue, is yet still a matter of ongoing scientific debate. Machado et al. for example have pointed out that peripheral fatigue in the legs may set in well before the purportedly 5-HT mediated central fatigues forces the study participants to jump off the treadmill (Machado. 2008), so that we cannot really tell whether the supplementation had an effect on central fatigue. After all, the leg musculature of sedentary subjects is obviously tiring faster than the fortified quads, glutes and hams of trained athletes.

The same is unfortunately true for the actual effects of the modified neurotransmitter response, while the authors are right to point out that 5-HT has been imlicated as a factor that induces mental and subsequently central fatigue, whereas dopamine is known as the "motivational neurotransmitter", previous studies by Wantanabe et al. suggested that respective cognitive benefits from creatine supplementation were facilitated by an increased oxygen utilization in the brain - not via changes in the neurotransmitter levels. And though these changes may not have reached statistical significance in the study at hand, there is actually better evidence for potential pro-dopaminergic effects of creatine, which has been shown to increase DA synthesis in the substantia nigra of mice by protecting against striata DA depletion (Klivenyi. 2003) and / or by enhancing the tyrosine hydroxylase activity and thus increasing the production of dopamine from its precursoe tyrosine (Matthews. 1999).

Much ado about nothing?

Is there a connection between creatine and prolactin: While the prolactin levels were not measured in the study at hand. The results of a 1996 study, in which Prysor-Jones et al. were able to show that the "creatine analogue" beta-guanidinopropionic acid (GPA) which is in fact a competitive inhibitor of creatine, increased the TRH induced release of prolactin. By implication this could mean that creatine will do the exact opposite. This hypothesis would also be supported by the increased dopamine levels after the workout - after all, dopamine is a natural prolactin antagonist (and vice versa).

There is however one study, by Hadjicharalambous et al. that appears to support the hypothesis that the modified 5HT-to-DA ratio may in fact figure large. The authors found that 7 days of creatine supplementation effectively reduced the central fatigue index of subjects who had to exercise in the heat. In that, they observed that the additional creatine blunted the increase in the free tryptophan-to-tyrosine ratio, which suggests that the brain 5-HT and DA levels were modulated by the supplementation protocol, as well. According to Hadjicharalambous et al. this effect was yet single-sided and related to an overall reduction in serotonin levels, while there were no significant difference between two groups as far as their dopamine levels were concerned.

Bottom  line: As it is the case in so many of the complex processes underlying human performance and the effects of proven and purported ergogenics, these insights into the effects of creatine as a potential mediator of the exercise induced neurotransmitter-response are still very preliminary. That may be surprising if you take into accaunt that millions of consumers are currently using creatine monohydrate or supplements that contain it, but in the end it's not much different from the way the same people use to train: Things that work will prevail - irrespective of whether or not the mechanisms have already been fully understood. 


References:

• Machado M, Sampaio-Jorge F, Dias, N, Knifis FW. Effect of oral creatine supplementation in soccer players metabolism. Revista Internacional de Ciencias del Deporte. 2008; 4:44-58. 
• Moghadasi M, Rahimi E, Mahani MS, Molaee, AA. Effect Of Creatine Supplementation On Brain Neurotransmitters After An Exhaustive Aerobic Exercise. Brazilian Journal of Biomotricity. 2012; 6(3):213-221. 
• Sevy S, Hassoun Y, Bechara A, Yechiam E, Napolitano B, Burdick K, Delman H, Malhotra A. Emotion-based decision-making in healthy subjects: short-term effects of reducing dopamine levels. Psychopharmacology (Berl). 2006 Oct;188(2):228-35.