Tuesday, January 8, 2013

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. 

  • 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.