Phenibut, Addictive Sleep Aid With Unhealthy Hangover? Dosages, Effects, Side Effects and Safety Concerns

Some say phenibut has addictive potential, others say it stops working after only a week and a third group of people will tell you that it's highly toxic and should not be used anyway... What's true? What's bogus? And how likely is it that phenibut helps / hurts you?

In a way today's SuppVersity article is part of the reverberations of the last installment of the Science Round Up, where Carl and I have been talking about the non-existent or surprisingly excitatory effects of GABA in certain individuals. I also presented a list of GABA alternatives that ranged from valerian to melatonin - a list of natural alternatives which did for that very reason not include phenibut (also "phenybut"; I will refer to it as "PB" for convenience reasons), a γ-aminobutyric acid (GABA) molecule with an additional phenyl group in the β-position.

It is this small, but important structural difference that allows the phenibut molecules to pass through the blood brain barrier (Shulgina. 1989) and allows them to do everything GABA should, but oftentimes cannot do, because it does not reach its destination in the brain.

What effects are we talking about here? 

According to Lapin phenibut can relieve tension, anxiety, and fear, and improve the sleep quality - specifically in psychosomatic or neurotic patients (Lapin. 2001). It is however important to remember that the effects are dose- and in some cases also patient-specific. Systemically administered phenibut produces a great variety of central effects:

• At doses that do not affect motor activity (e.g., 20 mg /kg; HED 1.6mg/kg) PB inhibits food conditioned reflexes in mice. 
• At doses higher than 70 mg kg i.p. (HED 5.7mg/kg) PB reduces motor and exploratory activities, rearings, muscle tone, coordination and body temperature.

Moroever, PB has been shown to potentiates the central effects of the anesthetics ether, chloral hydrate, and barbiturates - so you better be careful with PB supplements if you are scheduled to be exposed to any of those.

PB does not take much for the nootropic effects

In contrast to its anxiolytic and narcotic effects, PB's nootropic effects have been observed in rodent models at dosages as low as 5 to 10 mg/kg. In human beings this would equal ~0.4-0.8mg/kg and thus less than 75mg for the vast majority of us. Interestingly, ...

Table 1: Pharmacological effect of phenibut, diazepam, and piracetam based (Lapin. 2001)

"[t]he anxiolytic effect of PB appears to be dependent on the emotional reactivity of the animals. In anxious and passive cats, PB abolished or suppressed fear and brought about an aggressive reaction to provocation. In aggressive cats PB had no effect on aggression. In non-aggressive cats without obvious fear, PB expanded the scope of positive emotional symptoms." (Lapin. 2001)

In view of the fact that similar observations have been made in rabbits by Zyablitseva et al. in 2008, we may - not without the necessary healthy skepticism, though - assume that a similar influence of the baseline mental state can be observed in human beings, as well. This would imply that the often described calming effects will be most pronounced in those of us who are already chillin'. To effectively blunt aggression, on the other hand, dosages in the 2g+ range would be necessary (estimate based on rodent studies) and I hope I don't have to warn you that this amount of PB will leave you paralyzed if not worse!

GABA & dopamine, the phenibut double-whammy

Despite the fact that the majority of its effects are probably mediated by the interaction between the PB molecules and the GABA receptors, the existing research, the majority of which happens to be in Russian, suggests that PB may also stimulate dopaminergic processes and that this effect may be important for the sedative and tranquilizing effects of the drug (Goldblat. 1986; Mehilane. 1990).

Warning: Compounding phenibut with succinate, malate, nicotinate or glutamic acid can modify not just the potency, but also the expressiveness of some particular effects (Tiurenkov. 2011). These PB + organic acid combinations are thus not necessarily save and their effects are difficult to predict - you better stay away!

The antagonistim between PB and PEA (β-phenethylamine), on the other hand, could explain the anxiolytic (=anti-anxiety) effects of this compound, of which you should by now have realized that it PB is somewhat of a diva.

If the timing and dosing are right, it does however have some pretty interesting effect that do in fact reach far beyond the psychological effects that come with the changes in neurotransmitter levels.

• This is what WebMD will tell you about the current usage (of phenibut) - "Used for: Anxiety. Alcoholism. Irregular heartbeat. Fear. Insomnia. Tension. Stress. Fatigue. Post-traumatic stress disorder (PTSD). Depression. Improving memory, learning, and thinking. Other conditions."
  Researchers from the Volgograd State Medical Academy, for example, report that the use of PB can help ameliorate stress induced overload of the heart (Perfilova. 2007), protect the heart against the damaging effects of alcoholism (Perfilova. 2006).
• In a similar vein phenibut has been shown to protect against the phsychological side effects of chronic stress. In rodent models, it reduced the intensity of emotional disorders in the open-field test and elevated plus maze test, ameliorated cognitive disorders in the tests for conditioned avoidance response and extrapolatory deliverance and limited stress reaction due to a decrease in the intensity of adrenal hypertrophy, thymus involution, and stomach mucous membrane ulceration (Tiurenkov. 2012).

Moroever, data from 2011 suggests that phenibut (at a relatively high HED of 325mg) and other GABA-ergic agents can protect against lipopolysacharide(LPS)-induced immune stress as it would be produced by a leaky gut (Samotrueva. 2011) 

There is still one problem: Rumors have it phenibut is not save!

Let's be honest, what would the best nootropic, tranquilizing, sleep booster be worth, if using it would pose a serious health risk? How serious? Well about as serious as this:

• 

  In case I am not around, when you read the results of study, it may come handy to be able to calculate the human equivalent doses for mice, rats, rabbits, pigs and other animals, wouldn't it? If you'd agree I'd suggest you head over and read my previous article on "Human Equivalent Dosages" | read more

  PB has relatively a low lethal dose 50 of 900mg/kg in mice (HED: 73mg/kg) and 700mg/kg in rats (HED: 113mg/kg; the LD50 is the amount of a substance that has to be administered so that 50% of the lab animals die). It should be said, though, that I do have a case report here informing me that a former drug addict went up to 20g per day (Högberg. 2013), when he noticed that his new "dope" lost its efficiacy after only one week and survived - not without a serious psychosis, though!
  
• PB has some addictive potential. The previously case report of the drug addict makes it quite clear: For susceptible individuals the tranquilizing effect of PB will definitely have addictive potential (Samokhvalov. 2013). Plus, the fact that it loses its effect pretty rapidly is not going to help to stay within the "no danger zone", either

Ok, I know what you are thinking now: "Where is the rest of the side effects, the addictions and the psychoses?" And yes, that's basically what I have been asking myself as well, when I started searching for studies to confirm the horror stories you hear about phenibut on the Internet. A single ex-substance-abuser who overdoses on 20g(!) of phenibut is not exactly what I was thinking of, when I started researching the often-touted health hazards of an OTC supplement, of which the next best user report on reddit will tell you that "after 7 days on 4 grams/day" the corresponding user became "addicted" and "decided to go cold turkey" (google it up, if you want the source). The purported results of not following any of the Three Simple Rules of Sensible Supplementation were:

"[L]iterally no sleep, not being able to eat anything, severe depression/serious contemplation of suicide, loud tinnitus, pissing/shitting(barely anything) every 30 minutes and overall mild body pain" (I will leave it with "Anonymous")

If we look at the results of the rodent studies 2,000g/d would equal a rodent dosage of ~300mg/kg which is, as you probably realize, already 1/3 of the dosage that will kill (!) more than 50 in 100 mice who received a 300mg/kg dose of phenibut via intraperitoneal injection (~orally; the injection is used to avoid that the animals regurgitate the drugs, the pharmacology is however similar to regular oral consumption).

So if 20g is insane and 2g already too much how much would be sane? As much as I would like to provide you with a scientifically verified dosing recommendation, I can't. The necessary evidence from human studies is simply non-existent and even if it was, it would probably be suspect to high inter-individual variability and vary from one desired outcome to another. What I can tell you, though is this:

• 

  Listen to the Science Round-Up and read the corresponding article to learn more about GABA and potential PB alternatives | go ahead!

  Based on rodent studies, you should feel nootropic effects with dosages as low as 75mg.
• Based on what I read on "the boards", dosages in the 125-500mg range appear to produce relaxation effects that help you sleep.
• Moreover, common sense tells you that the (allegedly) inevitable "phenibut resistance" will occur faster with higher dosages, therefore it appears reasonable to soft-paddle and cycle β-Phenyl-GABA (PB).

In view of the non-existent scientific evidence with regards to its long-term safety, I would strongly caution against taking it each and every night. The mere fact that there is an accommodation effect and that PB holds the potential for dose-depended withdrawal symptoms should tell you that it messes with the neurotransmitter levels in your brain and that's nothing you would want to risk, if practicing sleep hygiene, stress reduction and - if all that does not help - the use of safer alternatives should actually suffice to alleviate your sleep problems. Used irregularly and as a "quick fix", it is however unlikely to be "worse" than the average FDA regulated sleeping pill.

References:

• Danilin VP, Krylov EN, Magalif AIu, Rait ML. [Effect of fenibut on the nocturnal sleep of patients with the alcoholic abstinence syndrome]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1986;86(2):251-4. 
• Goldblat YuV, Lapin IP. Potentiation of the therapeutic effect of antiparkinsonian drugs by phenibut.Zh Nevropatol Psikhiatrii1986;86:1146–1148 (in Russian with English summary).
• Högberg L, Szabó I, Ruusa J. [Phenibut yielded withdrawal symptoms and psychosis. Drugs for cosmonauts--now marketed as dietary supplements online]. Lakartidningen. 2013 Apr 17-23;110(16):825-7. 
• Tiurenkov IN, Bagmetova VV, Krivitskaia AN, Berestovitskaia VM, Vasil'eva OS. [Psychotropic effect of phenibut salts and their compositions with organic acids]. Eksp Klin Farmakol. 2011;74(2):3-7.
• Lapin I. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. CNS Drug Rev. 2001 Winter;7(4):471-81.
• Samotrueva MA, Magomedov MM, Khlebtsova EB, Tiurenkov IN. [Influence of GABA derivatives on some indices of lipid peroxidation in immunocompetent organs under experimental immunopathology conditions]. Eksp Klin Farmakol. 2011;74(8):32-6.
• Mehilane LS, Rago LK, Allikmets LH.Pharmacology and clinic of phenibut.Tartu: Izd. TGU, 1990 (in Russian with English summary). 
• Perfilova VN, Tiurenkov IN, Berestovitskaia VM, Vasil'eva OS. [Cardioprotective effect of GABA derivatives in acute alcohol intoxication]. Eksp Klin Farmakol. 2006 Jul-Aug;69(4):23-7.
• Perfilova VN, Tyurenkov IN, Lebedeva SA, Volotova EV, Berestovitskaya VM, Vasil'eva OS. Effect of citrocard on functional reserves of the heart under conditions of chronic stress. Bull Exp Biol Med. 2007 Jul;144(1):21-5.
• Shulgina GI. On neurotransmitter mechanisms of reinforcement and internal inhibition. Pavlov J Biol Sci. 1986 Oct-Dec;21(4):129-40.
• Tiurenkov IN, Bagmetova VV, Borodkina LE, Berestovitskaia VM, Vasil'eva OS. [Fenibut and its citrate prevent psychoneurological disorders caused by chronic stress (paradoxical sleep deprivation)]. Eksp Klin Farmakol. 2012;75(6):8-13.
• Zyablitseva EA, Pavlova IV. Effects of the GABA receptor agonist phenibut on behavior and respiration in rabbits in emotionally negative situations. Neurosci Behav Physiol. 2008 Jul;38(6):555-62.

Science Round-Up Seconds - GABA & Exercise: Both Can Improve and Mess With Your Sleep. Plus: Natural GABA Alternatives and Sleep As An Overtraining-Gauge

Don't forget that and prioritize proper sleep hygiene over pills and powders.

Let me make get this straight, yesterday's episode (please note that at the minute I post this article, the download is not yet working, should go up within the next hour, though) of the Science Round-Up on Super Human Radio was not only ultra-long (120min+), it was also largely speculative. If you already listened to the show, you will know that Carl and I took up on a discussion Dan Rollins triggered on his, Carl's and my Facebook page(s). Contrary to what you would expects Dan felt that gamma-Aminobutyric acid aka GABA would not help him calm down and let him sleep. For him GABA turned out to have stimulative rather than sedative effects.

I am not going to repeat all the potential explanations I went through in the first ~40min of the show here. Instead, I'd suggest you simply download the podcast and listen to the various hypothesis which range from (a) the general issue of whether or not GABA even crosses the blood-brain-barrier, over (b) the possibility that the GH spike, the sedative (low blood glucose) and the agitating effect (catecholamine + cortisol release with very low blood glucose) could all be brought about by a GABA induced increase in insulin production and a corresponding reduction in blood glucose levels to (c) potential confounding factors such as caffeine consumption (Roca. 1988; Desaulles. 1991; Mukhopadhyay. 1995), interactions with beta alanine, taurine or glycine (Tiedje. 2010; El Idrissi. 2013; Kletke. 2013), (d) genetic differences as with the tingling for beta alanine (Macphee. 2013) or (e) the influence of exercise on the density of GABA receptors in the brain (Dishman. 1990).

Enough of the speculations: What are proven alternatives

Against the background that we still don't really know why Dan and others don't seem to benefit from GABA supplementation the way Carl and Alisa do, we do know that there are other natural alternatives:

• Valerian [dosage: 400-900mg] - inhibits breakdown of GABA in the brain; assuming that GABA makes it across the blood-brain-barrier, valerian would thus work synergistically with oral GABA 

• 

  Due to its anti-PPAR-gamma effect ginseng also made it into the list of "agents that may help you to stay lean" I posted earlier this year. Want to know about the other "20 Anti-Obesity Agents Have the Potential to Inhibit Fat Gain Right at the Cellular Level"? Here you go!

  Ginseng [1-2g crude root extract or 200-600mg of extract] - ginsenoids compete with GABA on both the GABA-A & GABA-B receptor and are thus thought to exert their calming (only in low! doses) effects on the CNS via direct GABA-ergic effects; sedative effects have been observed for Panax ginseng (Korean or Asian ginseng), Panax quinquefolius (American ginseng), and Panax vietnamensis (Vietnamese ginseng); if you feel agitated, reduce the dosage
• Kava kava [180-210mg of kava lactones] - the active agents in Kava kava belong to a group of resinous compounds known as kava lactones or kava pyrones, they bind to the benzodiazepine binding site of the GABA receptor, which could reduce the risk of unwanted excitatory effects
• Passion flower (Passiflora incarnata) [4-8g as a tea] - has been used as a sleeping aid for centuries; chrysin, a mild anti-estrogen appears to be the active ingredient (GABA-A binding; cf. Zhai. 2008); warning: must not be consumed by pregnant women (!) PI can initiate uterine contractions

• 

  I know you don't want to hear that, but(!) don't forget that it could also be your BCAA product that keeps you you from falling asleep and makes you wake up several times during the night by blocking the uptake of tryptophan and thus depleting your brain of the raw material for serotonin (read more).

  Hops (Humulus lupus) [0.5g of dried herb] - has binding affinities to both the melatonin and serotonine receptor (Abourashed. 2004) and can increase GABA in the brain (Franco. 2012); warning: must not be consumed by women with a (family) history of breast cancer (!) hobs has mild, but distinct pro-estrogenic activity (Hajirahimkhan. 2013)
• L-tryptophan [1g] / 5-HTP [100mg] - both will increase serotonin and could thus be stacked with agents that act on GABA; incidentally, there is paucity of research on the efficacy of either of the two as sleep aid
• Melatonin [1-10mg] - as both Carl and I pointed out on the show, melatonin is not an acute sedative, but a signal that it's time to "shut down", don't expect it to actively "send you into sleep", like a sleeping pill

Aside from these agents, Carl and I talked about accupuncture and low energy emission therapy (LEET), as well. While the mechanisms of the former are still not fully understood (e.g. Kwok. 2013), the amplitude modulated high frequency fields the LEET mouthpiece emits right into your brain have been shown to modify the release of GABA and the concentration of benzodiazepine receptors in the rat brain. In addition, low level electromagnetic fields can directly induce the release of melatonin in mammals (Reiter. 1993).

If you are sprinting because of the increase in EPOC, you are a fool.

Read more about exercise and energy expenditure tomorrow! With the info on energy expenditure also crammed into this article it would have been too packed. Therefore you will have to live with a 24h deleay until you learn about the energetic costs of bench pressing, the laughable EPOC effects of HIIT and the evidence that exercise does not just make you hungry. If you feel that's not tolerable, you can already learn about the pathetic EPOC effects of HIIT and exercise & hunger in previous articles.

I already hinted at the physiological (side?) effects of chronic endurance training on the expression of the GABA receptors in rodent brains early in the show (and this article). It should thus not surprise you that exercise can have major impacts on the onset, quality and duration of your sleep - both positive and negative ones, obviously [based on data from Youngstedt (1997; published online 2003)]:

• 

  "90 Min Sleep Restriction Changes in Insulin Resistance Last For One Week"

  Timing of your workouts: While working out 4-8h before bed will have you fall asleep easily, you may experience problems if you have to ignore the onset of tiredness, because you have been exercising more than 8h before you go to bed or to close to hitting the hay. Incidentally, working out 4-8h before bed another advantage: It will help you to sleep through.
• Working out outdoors: The light exposure, the fresh air all that makes working out outdoors so healthy for you (as long as you are not living in Beijing ;-) will energize you and could keep you from falling asleep.
• Duration of your workout: There is a U-shaped dose-response curve for the negative effects of working out on your REM sleep. As Carl rightly pointed out during the show the negative effects of short exercise durations (<1h) is probably in as much a question of intensity / exhaustion (you train intense, when you train short) as the cumulative effects of "exercising" for more than 2h straight (which is by the way more than twice as detrimental for your sleep quality than the <1h exercise)
  
  Aside from its effect on the workout duration will also affect your overall sleep needs with both exercises in the 1-2h and exercises in the >2h range having a major impact on the amount of time you got to spend in bed to recover.
• Exercise intensity*: With a high propensity of low intensity exercise to help you sleep through, a walk on a treadmill in the evening is not going to compromise a good nights sleep, the HIIT workout that would improve your postprandial triglyceride response on the next day (I used this SuppVersity Facebook News as a discussion starter in the live-show), on the other hand may have you wake up several times during the night (*note: I used the studies on the post-exercise heat load in Youngstedt et al. as a proxy for intensity).

If you wanted to distill some practical advice on how you can / should exercise to avoid that your workouts will interfere with your sleep, you should (a) leave at least 4h between any intense workout and hitting the hay (HIIT, weight lifting, etc.) and (b) make use of the beneficial effects of moderate duration (20-40min) light intensity workouts (walking on an incline treadmill, cycling etc.) on sleep onset and quality.

Did you know that...

there are other agents that can "spike" GH temporarily?

• intravenous (iv) insulin 0.2 IU/kg - 50x increase
• intramuscular (im) glucagon 1 mg - 21x incr.
• iv. arginine 20 g/m² as an infusion over 30 minutes - 11x incr.

All observed in a human study involving 18 perfectly healthy young men(Rahim. 1996).

In view of the effect GABA has on the release of insulin from the pancreas, it is not unlikely that my previously voiced hypothesis that the "relaxation" and the "agitation" are responses to low and very low glucose levels would also explain the increase in GH as a response to the hypoglycemic effects of insulin.

What can you take away from the first part of this installment of the Science Round-Up Seconds?

• GABA does not work for everyone
• esp. in higher doses GABA can have excitatory, instead of calming effects
• the exact reasons that this happens is not clear; temporary hypogylcemia is albeit not the least likely candidate
• the hypoglycemia would also explain the GH release which is yet very unlikely to have beneficial effects on muscle growth (GH & gains don't correlate) or fat loss
• among the GABA alternatives, those with a specificity for the benzo docking site on the GABA receptor could work for people for whom GABA itself is excitatory
• working out too late / too intense can compromise sleep
• being "tired but wired" indicates sympathetic overtraining (too much intensity)
• constant fatigue + an increased sleep demand, but light and ineffective sleep is more indicative  parasympathetic overtraining (too much volume)

References:

• Abourashed EA, Koetter U, Brattström A. In vitro binding experiments with a Valerian, hops and their fixed combination extract (Ze91019) to selected central nervous system receptors. Phytomedicine. 2004 Nov;11(7-8):633-8.
• Desaulles E, Boux O, Feltz P. Caffeine-induced Ca2+ release inhibits GABAA responsiveness in rat identified native primary afferents. Eur J Pharmacol. 1991 Oct 2;203(1):137-40. 
• Dishman RK, Dunn AL, Youngstedt SD, Davis JM, Burgess ML, Wilson SP, Wilson MA. Increased open field locomotion and decreased striatal GABAA binding after activity wheel running. Physiol Behav. 1996 Sep;60(3):699-705.
• El Idrissi A, Shen CH, L'amoreaux WJ. Neuroprotective role of taurine during aging. Amino Acids. 2013 Oct;45(4):735-50. doi: 10.1007/s00726-013-1544-7. Epub 2013 Aug 21.
• Kletke O, Gisselmann G, May A, Hatt H, A Sergeeva O. Partial agonism of taurine at gamma-containing native and recombinant GABAA receptors. PLoS One. 2013 Apr 30;8(4):e61733.
• Kwok T, Leung PC, Wing YK, Ip I, Wong B, Ho DW, Wong WM, Ho F. The effectiveness of acupuncture on the sleep quality of elderly with dementia: a within-subjects trial. Clin Interv Aging. 2013;8:923-9.
• Macphee S, Weaver IN, Weaver DF. An Evaluation of Interindividual Responses to the Orally Administered Neurotransmitter β -Alanine. J Amino Acids. 2013;2013:429847.
• Mukhopadhyay S, Poddar MK. Caffeine-induced locomotor activity: possible involvement of GABAergic-dopaminergic-adenosinergic interaction. Neurochem Res. 1995 Jan;20(1):39-44.
• Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf). 1996 Nov;45(5):557-62.
• Reiter RJ. Electromagnetic fields and melatonin production. Biomed Pharmacother. 1993;47(10):439-44.
• Roca DJ, Schiller GD, Farb DH. Chronic caffeine or theophylline exposure reduces gamma-aminobutyric acid/benzodiazepine receptor site interactions. Mol Pharmacol. 1988 May;33(5):481-5.
• Tiedje KE, Stevens K, Barnes S, Weaver DF. Beta-alanine as a small molecule neurotransmitter. Neurochem Int. 2010 Oct;57(3):177-88.
• Youngstedt SD, O'Connor PJ, Dishman RK. The effects of acute exercise on sleep: a quantitative synthesis. Sleep. 1997 Mar;20(3):203-14.
• Zhai K, Hu L, Chen J, Fu CY, Chen Q. Chrysin induces hyperalgesia via the GABAA receptor in mice. Planta Med. 2008 Aug;74(10):1229-34.

Low Dose GABA for Diabesity Treatment? Dose Dependent Conservation of Lean Muscle Mass & Reductions in Oxid. Stress + Weight Gain + Fasting Blood Glucose & Co.

GABA tea contains comparably low amounts of GABA (180mg/100g; Wang. 2006) and still or, as the results of the study at hand suggest, rather thus helps with sleep (Cheng. 2009).

As a SuppVersity reader you know that GABA has been used successfully to revive the pancreas of diabetic animals (Soltani. 2011). As a conspiracy theorist, you believe that it's the pharma business that's paying researchers not to follow up on the results of Soltani et al. and other researchers. And as a physical culturist, you are obviously attracted by the idea that GABA supplements may help you achieve a leaner and more muscular physique... right?

I don't care if everything or anything of what I wrote before is accurate. What I do care about, though, are the results Xie et al. present in their latest paper in the Journal of Animal Physiology and Animal Nutrition.

Learn more about the effects of your diet on your body composition at the SuppVersity

Ladies, Beware! Dieting Makes Gymnasts Fat.

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Dairy Protein Satiety Shoot-Out: Casein vs. Whey

How Much Carbs Before Fat is Unhealthy?

5 Tips to Improve & Maintain Insulin Sensitivity

Carbohydrate Shortage in Paleo Land

The name of the journal gives it away: We are - again - dealing with animal data, but there is no reason to assume that the effect the researchers observed in obese mice would be completely irrelevant for human beings. The previously cited beneficial effects on the pancreas of diabetic animals have after all been confirmed in in vitro studies with human cells, already.

High amino acid levels in the blood of obese indiv. are not a result of their high protein intake, they're caused by low uptake and + high protein breakdown.

As Xie et al. point out the process of becoming obese goes hand in and with disturbances of the plasma free amino acids (pFAAs) pool. In fact, there is reason to believe that these disturbance are causally related to the increase in insulin resistance in obese patients and patients with diabetes mellitus and metabolic syndrome.

Now, contrary to what some "anti protein" gurus are going to tell you, the increased amounts of amino acids are not of dietary origin. Rather than that they are released as a consequence of the increase in protein breakdown - specifically muscle protein breakdown - in obese and diabetic individuals.

Xie et al did now speculate that the previously cited ability fo gamma-aminobutyric acid (GABA) to reduce high-fat diet (HFD)-induced hyperglycaemia could be brought about by the effects GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system exerts on peripheral organ tissue, like skeletal muscle.

Figure 1: GABA ameliorates / reverses the HFD-induced increase in markers of ox. damage in skeletal muscle (Xie. 2014)

To elucidate, whether that's the case the scientists from the Jiangnan University randomly assigned one hundred male C57BL/6 mice to one out of the following five groups

• CONTROL: rodents on control diet
• HFD: rodents on high fat diet (high fat + high energy; HFD) 
• GL: rodents on HFD supplied with 0.2%, 
• GM: rodents on HFD supplied with 0.12%, and
• GH: rodents on HFD supplied with 0.2% GABA in drinking water 

The animals remained on the respective diets for 20 weeks.

What else can GABA do for you? 80 mg of GABA reduce blood pressure in adults with mild hypertension (Matsubara. 2002). It can speed up the recovery of an alcohol intoxicated liver (Soh. 2003). And it will trigger an acute increase in growth hormone (with no proven benefit on muscle gains; Powers. 2013). The often-cited beneficial effects on sleep, on the other hand, are far from being confirmed - results of the study at hand suggest that this may be a result of the fact that you really have to hit the sweet spot to maximize specific effects and minimize the metabolism of GABA in the liver - taking high doses may thus trigger its excretion, while taking very low doses may not be enough get the GABA across the blood brain barrier (Kakee. 2001).

During and after the trial, the scientists observed significant increases in muscular oxidative stress (see Figure 1), protein oxidation, hyperglycaemia, as well as the previously cited plasma free amino acid disorders that included an augmented level of GABA in the blood

Figure 2: Body weight, rel. muscle weight and blood glucose expressed relative to control (Xie. 2014)

Interestingly, the provision of extra GABA was still able to restore normal fasting blood glucose levels and to dose-dependently inhibit body weight gains, muscular oxidation and protein degradation.

So what's the right dose, then? If we use the data from the study at hand and the regular HED calculations, the optimal, i.e. the medium dosage would be ~80mg per day, which is significantly less than most supplements provide and does not compare to the 5g of GABA that have been used by Cavagnini et al. in 1980 to elicit a growth hormone response GABA to which owes much of its fame in the bodybuilding community.

It's all about the right dosage! While medium and low doses of GABA mitigated HFD-induced pFAA disorders, the high dose of GABA deteriorated the pFAA disorders while reducing the level of GABA in the blood and increasing the activity of succinic semialdehyde dehydrogenase which is - you guessed it - responsible for the breakdown of GABA in the liver.

As Xie et al. point out, it is would thus be important to determine the optimal dose in human beings before any recommendations with respect to its use as an anti-diabesity supplement can be made. To do so, it would also be necessary to have a better grasp of its interactions with leptin of which Kahn & Minokoshi recently wrote that they me be interacting on a receptor level in the brain (Kahn. 2013) | Comment on Facebook.

References:

• Cavagnini, F., et al. "Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man." Acta endocrinologica 93.2 (1980): 149-154. 
• Cheng, Tsun-Chi, and Jui-Feng Tsai. "GABA tea helps sleep." The Journal of Alternative and Complementary Medicine 15.7 (2009): 697-698.
• Kahn, Barbara B., and Yasuhiko Minokoshi. "Leptin, GABA, and Glucose Control." Cell metabolism 18.3 (2013): 304-306.
• Kakee, Atsuyuki, et al. "Efflux of a suppressive neurotransmitter, GABA, across the blood–brain barrier." Journal of neurochemistry 79.1 (2001): 110-118.
• Matsubara, Futoshi, Et Al. "Effects Of Gaba Supplementation On Blood Pressure And Safety In Adults With Mild Hypertension." Japanese Pharmacology And Therapeutics 30.11 (2002): 963-972. 
• Powers, Michael. "GABA supplementation and growth hormone response." (2012): 36-46.
• Soh, Ju-Ryoun, Tokuo T. Yamamoto, And Youn-Soo Cha. "The Effects Of Carnitine And/Or Gamma-Aminobutyric Acid (Gaba) Supplementation On The Recovery Of Chronic Ethanol Administered Rats." Nutraceuticals And Food 8.2 (2003): 119-123.
• Soltani, Nepton, et al. "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes." Proceedings of the National Academy of Sciences 108.28 (2011): 11692-11697.
• Wang, Hsueh Fang, et al. "Comparison of bioactive components in GABA tea and green tea produced in Taiwan." Food chemistry 96.4 (2006): 648-653. 
• Xie, et al. "Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet." Journal of Animal Physiology and Animal Nutrition (2014).

Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek. Plus: Metformin the No.1 Drug? Supplements to Improve and Restore Insulin Sensitivity - Serving #1

Don't forget, those caps and pills are not worth a penny without you committing to the all the lifestyle changes I outlined in episode one of this series.

I am well aware that you had to wait for a full week for this 2nd part of the "Restore & Maintain Insulin Sensitivity" Series (read part I), so I am going to make no words about it and get straight to the annotated list of useful supplements.

Just a reminder for the lazy asses: Don't even think about starting any of the supplements on the list, if you have not already cut your carbs to a low, but not very low level, got rid of all plain sugar in your diet, started to work out frequently, get enough sleep, avoid stims and control (not totally eradicate) your linoleic acid (omega-6) intake.

Here we go, for serving #1

In order to give you at least some guidance on where you may want to start, I will classify the supplements in 4 very broad categories with

• [A] for supplements that are almost certainly useful,
• [B] for supplements that are potentially useful and definitely worth trying,
• [C] for supplements that are marginally useful and probably worth trying, and
• [D] for supplements that are simply bullocks and not even worth trying

Whenever I feel confident to do so, I will also suggest a concrete dosage - in some cases, such as GABA, I can however neither do the former, nor the latter, because there simply is too little quality research out there.

• Did you know that continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction in women with PCOS who have long been advised to stop metformin during pregnancy (cf. Nawaz. 2008)?
  Metformin [A]: Technically it is not a supplement, but let's be honest, who except for the FDA cares? Many supplements work as effectively as pharmacological drugs, but as far as real insulin sensitizers are concerned metformin still appears to have the edge on the rest of the pack (supplement or drug): It has an excellent safety profile (even in gestational diabetes, which has long been thought of being the one area of application, where metformin was not the first line intervention of choice; cf. Lautatzis. 2013). It works via a similar mechanisms as dieting and exercise does (→ AMPK; this is actually imho it's main advantage - an advantage it shares with lipoic acid btw.). And metformin has only recently been shown not to inhibit the benefits of exercise on glycaemic control or fitness (Boulé. 2013).
  
  Moreover, hundreds of studies support the preventive effects of metformin against the manifestation of tumors of pancreas, breast, colorectum, liver, endometrium and ovary. The prognosis of diabetic cancer patients on metformin therapy seems be better, than in diabetics without metformin treatment (Anděl. 2013).
  
  So, if you belong those people who have real issues and not just slightly elevated blood glucose levels, have your metformin prescription filled - it's unquestionable an [A] among the agents that can help you restore your insulin sensitivity [I don't have to tell you that this is not an agent you would use simply to stay insulin sensitive, right?].
  
  One thing you should keep in mind though, is that it may lower your B12 levels. While this could be a simply results of increased usage and more recent studies question previous reports according to which metformin radically depletes B12 levels have been questioned lately, it probably won't hurt to take 500-1,000mg of methylcobolamine alongside your metformin.
• Alpha lipoic acid (ALA) [A]: In a way lipoic acid, a naturally occuring organosulfur compound derived from octanoic acid, is a cousin of metformin. Unfortunately (for the future of alpha lipoic acid as an anti-diabetes agent and the diabetics who have ever since been treated with pro-obesogenic PPAR-agonists) the pharma industry realized that selling a natural and thus non-patentable anti-diabetes drug would not only generate a lower revenue, it would also hamper the sales of patentable and thus more profitable drugs.
  
  
  Don't take lipoic acid instead of working out. Why? Well, alpha lipoic acid has been shown to increase the arthesclerosis risk in a human trial by McNeilly et al. In the said study, 1g of alpha lipoic acid per day increased the cardiovascular disease risk, in 24 obese individuals with impaired glucose tolerance who participated in the experiment (McNeilly. 2012); the underlying mechanism was an increase in LDL oxidation that did albeit occur only in the "ALA only" but not the "ALA + exercise" group.
  Luckily, there are still more than enough animal and human studies (Jacob. 1999; Xiang. 2011; Porasuphatana. 2012) to support the beneficial effects lipoic acid will have on glucose management and hyperglycemic damage in (pre-)diabetics.
  
  In view of the fact that it could contribute to the development of heart disease precipitate hypoglycemic episodes (Khamaisi. 1990), has negative effects on appetite (which is the main mechanism by which it reduces weight gain in rodents) and appears to mess with lean mass gains - suggested reads ("You Could be Just as Lean, but More Muscular Without a Nutrient Repartitioner" (learn more); "Further Evidence Against Anti-Oxidant Supplementation: Vitamin E + Alpha Lipoic Acid Reduce Skeletal Muscle Mitochondrial Biogenesis" (read more) I would still not suggest you take high doses (>100-200mg) if you don't have problems with keeping your blood sugar levels in check.
  
  For those of you, who have established problems with managing their glucose levels, taking 2x250mg-600mg (with meals) would yet be a good point to start from (keep an eye on how it affects your glucose levels and adjust the dosage appropriately).
  
  With respect to the purported superiority of R-ALA vs. the regular (=racemic mixture) version of lipoic acid, I can only repeat that I am still waiting for someone to show me a study that would prove that R-ALA is more potent than regular the cheap racemic mixture that's been used in the vast majority of the currently available (mostly beneficial) studies.

• 

  Figure 1: GABA does effectively restore "almost" normal glucose levels in severly diabetic mice; the dosage is not mentioned in the FT or the supplemental material (Soltani. 2011)

  GABA [?]: No, the reason GABA (Gama-aminobutyric acid) is on the list is not that it will make you sleep better (although this may - for some(!) people, actually be the case). It's rather its direct protective and even restorative effect on pancreatic beta-cells (Soltani. 2011; Tian. 2013).
  
  Despite the fact that we have known about these effects for decades, up to now nobody seems to be interested to do or finance the research that would be necessary to make concrete and reliable dosage-recommendations. In fact, the evidence is still so scarce that we cannot even say: "Yes, GABA is definitely going to help" - if the prelminary evidence we have translates from the petri dish to the rodent cage and into the real world, it could however be the #1 agent on this list. Why? Well, this would basically mean that it could cure diabetes even when you have progressed from being insulin resistant to being a full-blown diabetic.
  
  The best evidence we have that this could in fact be the case does probably come from a 2011 study by Soltani, who have actually taken the important step from the petri dish to the rodent model and were able to show that  GABA restores β-cell mass and reverses diabetes in severely diabetic mice.
  
  
  Warning: Don't start out with 5g of GABA in one serving - esp. not on an empty stomach. This is not only going to give you parestesia (tingles), but could also have you gasp for air and have problems keeping on your feet, due to the profound actions on peripheral GABA receptors.
  Furthermore, human studies from the eighties have shown that 5g and 10g of GABA (consumed orally) exert direct insulinotropic effects (remember insulin resistance is not about too much insulin, but about the latter having no / too little effect on glucose uptake) and since oral GABA does not cross the blood-brain-barrier it's safe to be consumed by humans in relatively high doses (cf. Cavagnini. 1982). Still, as in the case of lipoic acid, GABA is not patentable and the stocks of the big players in the anti-diabetes drug business would certainly take a tumble, when someone actually proved that you could reverse diabetes by simply taking X grams of GABA everyday.
• Taurine [B]: You will remember that I mentioned Taurine only 2 days ago in the context of the anti-diabetic effects of whey protein (read more). You will probably also remember the numerous previous posts on the beneficial effects of taurine specifically for people with diabetes or pre-diabetes (learn more about taurine). I will therefore stick to a brief overview of the direct and indirect (protection against negative effects of high blood glucose) benefits taurine has to offer for people with insulin resistance and high glucose levels.

  • 

    Figure 2: The effects of taurine supplementation on glucose and insulin (top, left & right) 0, 6, and 12 weeks after beginning the taurine-supplemention in OLEFT rats (rodent model of diet induced diabesity), as well as the reaction to an insulin tolerance test and corresponding changes in insulin sensitivity (bottom, left & right; adapted from Kim. 2012).

    Taurine shows "independent of hypoglycemic effect in several animal model" (Ito. 2012)
  • It ameliorates both high glucose and lipid levels (Kim. 2012)
  • Taurine improves NO mediated blood glow in the corpus cavernosum (=battles erectile dysfunction) due to diabetes (Dalaklioglu. 2013)
  • Taurine exerts cardio-protective effects, partly via direct effects on the angiotensin II type2 receptor expression (Li. 2005)
  • It restores normal platelet aggregation in diabetics (Franconi. 1995)
  • Taurine protects the kidneys (Yao. 2009)
  • Taurine reduces mortality risk upon long-term administratio (rodent model; Franconi. 2004) 
  • It has a higher ability to reduce insulin resistance and stronger antioxidant properties than the diabetes drug glibenclamide (El Zahraa. 2012)
  • It protects the eye from diabetes induced damage (Hansen. 2001 Kim. 2007)
  • Taurine has protective effects against all components of the metablic syndrom (Hansen. 2001; Imae. 2012)
  • It increase the levels of conjugated tRNA, restore respiratory chain activity, and increase the synthesis of ATP at the expense of superoxide anion production (Schaffer. 2009)
  Beta alanine is the taurine antagonist #1: SuppVersity readers should know that (read more), but I guess I better repeat it: The "best" way to deplete taurine levels is the ingestion of copious amounts of beta alanine 24/7 (the side effects are similar to those of diabetes related taurine depletion, eg. Waterfield. 1993 → lowered protection against CCL induced liver damage). From a performance perspective there is as of now no evidence that you would need more than 2.5g of beta alanine per day, anyway. So why would you want to waste money and cellular taurine on additional beta alanine ;-)
  It should be mentioned thought that there are also studies which did not support the beneficial results reported above - they are not numerous, but may yield some insights into effective vs. uneffective dosage regimen.
  
  The 1.5g/day the overweight subjects with a predisposition for developing diabetes the subjects in a 2004 study by Brøns et al. received, may for example simply have been too little to exert any effects (Brøns. 2004). Based on the human equivalents of rodent studies, it appears most promising to distribute a daily taurine intake of 3g to max. 6g over your three main meals.
  
  Since taurine does also act as a gaba-ergic small molecule neurotransmitter (Albrecht. 2005), I would yet suggest you keep a close eye on (a) initial sedative effects and (b) longer term increases in anxiety - both of which have been reported in animal studies with allegedly higher and / or intracerebral administration of taurine.
  
  The effects on neurotransmitters, the diarrhea some users experience (esp. when they take it without food) and the fact that many, but by far not all studies confirmed direct inusulin sensitizing effects of taurine are the reason I'd still classify it as [B] level supplement - certainly one of the better ones, but still only "possibly beneficial".

• 

  Table 1: Within group changes in randomized controlled GTE supplementation study involving 20-65 year old type 2 diabetics with BMI > 25 kg/m² (Hsu. 2012)

  Green tea extract [C]: GTE can help with insulin sensitivity in two different ways. Firstly, it will help control the inflammatory processes that are (partly) responsible for the development of insulin resistance and it will secondly help you to "cut carbs" by simply blocking their digestion and assimilation (Forester. 2012; Williamson. 2013).
  
  And while the real world benefits of GTE supplementation in a 2012 study by Hsu et al. were not statistically significant, it may still be worth trialling a dose of 3x 200-500mg per day. That being said, unless you are specifically looking for the stimulant effects of GTE, you should consider using a decaffeinated extract because you do not really need the additional caffeine (cf. part I of this series). 
  
  The reason I still classified GTE as [C] as in "marginally useful" is that the study by Hsu is not the only human trial that did not find significant effects on insulin sensitivity. It is rather one of the few where you could actually argue that - though not significant - it may have had an independent effect on glucose management. In the majority of studies "green tea exhibited limited benefits in reducing FBS or HbA1c levels" and as Ruitang Deng puts it in his recent review: "Should not be recommended for managing hyperglycemia." (Deng. 2012) This does not mean that it cannot help ameliorate the side effects, but we are looking for agents that will actually help you lower your blood glucose levels and in this regard green tea extracts are only marginally useful.

• 

  Amla, gooseberry, or Emblica Officinalis call it whatever you want, but don't expect too much - it may work, but it's no comparison to the [A]-class supplements. Moreover, the results from the available human study could be distorted by additional ingredients in the supplement formulas the scientists used.

  Gooseberry (emblica officinalis) [C]: Studies by Mitra (2007), Faizal (2009), Iyer (2009) and Chen (2011) all provide evidence that the ingestion of extracts from Indian gooseberry (=Amla), an edible fruit from trees of the phyllanthaceae family can effectively improve blood glucose management.
  
  Due to the fact that the Gooseberry extract was administered in conjunction with other agents, it is however difficult to suggest an effective dosage, but it appears as if 100-150mg per day of gooseberry extract would be enough.
  
  In Iyer et al. even a single serving of fresh amla (~35g) got the job done, but the overall effect size is rather mediocre, thus Gooseberry is only "possibly useful" [C]. 
• Fenugreek [B]: Also known as trigonella foenum-graecum L., fenugreek belongs to the plant family fabaceae (or leguminosae).
  
  

  

  Figure 3: Relative changes in response to glucose challenge (glucose AUC, glucose half-life and metabolic clearance rate) in 5 non-insulin dependent diabetic patients after consuming a diet supplemented with 25 g fenugreek seeds daily for 15 days; the data is expressed relative to the values the scientists measured in five likewise diabetic control subjects (Raghuram. 1994)

  Fenugreek seeds and extracts from the leaves have a decent amount of studies to support its anti-hyperglycemic effects - including clinical studies with human volunteers showing that dosage of only 500 mg of seed or leaf extracts given once or twice daily either alone or in combination with standard, synthetic anti-diabetic drugs such as metformin and glipizide provided beneficial effects on controlling plasma glucose levels (Deng. 2012).
  
  The reason I'd still classify it as [B] are (a) the fact that it takes a huge amount of the seeds (e.g. 25g; see figure 3) to elicit significant effects and (b) the fact that studies using extracts yielded ambiguous results. Contrary to the whole seeds, of which it seems that they exert their beneficial effects by similar mechanisms as dietary fiber, leaf extracs appear to exert a direct insulin sensitizing effect.
  
  In a study by Abdel-Barry et al. from the year 2000, 40 mg/kg aqueous extract powder from fenugreek leaves(!) in 10 mL distilled water lowered the glucose levels of 20 healthy male volunteers aged 20-30 years by 13.4% 4h after ingestion. Unfortunately, the hunger, frequent urination and dizziness one third of the subjects complained about, was not the only side effect - the subjects also had significantly reduces serum potassium levels; an observation of which the researchers rightly state that it warrants further investigation to ensure the long-term safety of fenugreek leaf extracts.
  
  Bottom line? Well, once again "possibly useful", but only if you actually have problems with insulin resistance and high blood sugar.

"What? Where is there rest?" In case this is pretty much what you are thinking right now, I can calm you down, there will be at least another serving of pro-insulin sensitivity supplements. I simply don't have the time to write more today, but did not want to go back on my promise from last Sunday. So, be patient, there is going to be more: Promising supps such as cinnamon, vinegar, or grape seed extract, for example but also questionable stuff such as bitter melon or legume extracts.

References: 

• Abdel-Barry JA, Abdel-Hassan IA, Jawad AM, al-Hakiem MH. Hypoglycaemic effect of aqueous extract of the leaves of Trigonella foenum-graecum in healthy volunteers. East Mediterr Health J. 2000 Jan;6(1):83-8.
• Anděl M, Skrha P, Trnka J. [Metformin: the overlap of diabetology and oncology]. Vnitr Lek. 2013 Aug;59(8):738-42. 
• Boulé NG, Kenny GP, Larose J, Khandwala F, Kuzik N, Sigal RJ. Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both? Diabetologia. 2013 Aug 23. 
• Brøns C, Spohr C, Storgaard H, Dyerberg J, Vaag A. Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus. Eur J Clin Nutr. 2004 Sep;58(9):1239-47.
• Cavagnini F, et al. Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.Metabolism. 1982; 31:73–77. 
• Chen TS, Liou SY, Wu HC, Tsai FJ, Tsai CH, Huang CY, et al. Efficacy of epigallocatechin-3-gallate and amla (Emblica officinalis) extract for the treatment of diabetic-uremic patients. J Medicinal Food. 2011;14:718–23.
• Dalaklioglu S, Kuscu N, Celik-Ozenci C, Bayram Z, Nacitarhan C, Ozdem SS. Chronic treatment with taurine ameliorates diabetes-induced dysfunction of nitric oxide-mediated neurogenic and endothelium-dependent corpus cavernosum relaxation in rats. Fundam Clin Pharmacol. 2013 Jun 14. 
• Deng R. A review of the hypoglycemic effects of five commonly used herbal food supplements. Recent Pat Food Nutr Agric. 2012 Apr 1;4(1):50-60.
• El Zahraa Z El Ashry F, Mahmoud MF, El Maraghy NN, Ahmed AF. Effect of Cordyceps sinensis and taurine either alone or in combination on streptozotocin induced diabetes. Food Chem Toxicol. 2012 Mar;50(3-4):1159-65. 
• Faizal P, Suresh S, Satheesh Kumar R, Augusti KT. A study on the hypoglycemic and hypolipidemic effects of an ayurvedic drug Ra-janyamalakadi in diabetic patients. Indian J Clinical Biochem. 2009;24:82–7.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• Forester SC, Gu Y, Lambert JD. Inhibition of starch digestion by the green tea polyphenol, (-)-epigallocatechin-3-gallate. Mol Nutr Food Res. 2012 Nov;56(11):1647-54.
• Franconi F, Bennardini F, Mattana A, Miceli M, Ciuti M, Mian M, Gironi A, Anichini R, Seghieri G. Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation. Am J Clin Nutr. 1995 May;61(5):1115-9.
• Franconi F, Di Leo MA, Bennardini F, Ghirlanda G. Is taurine beneficial in reducing risk factors for diabetes mellitus? Neurochem Res. 2004 Jan;29(1):143-50.
• Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.
• Hansen SH. The role of taurine in diabetes and the development of diabetic complications. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. 
• Hsu CH, Liao YL, Lin SC, Tsai TH, Huang CJ, Chou P. Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial. Altern Med Rev. 2011 Jun;16(2):157-63.
• Imae M, Asano T, Murakami S. Potential role of taurine in the prevention of diabetes and metabolic syndrome. Amino Acids. 2012 Dec 8.
• Ito T, Schaffer SW, Azuma J. The potential usefulness of taurine on diabetes mellitus and its complications. Amino Acids. 2012 May;42(5):1529-39. doi: 10.1007/s00726-011-0883-5. Epub 2011 Mar 25.
• Iyer U, Joshi A, Dhruv S. Impact of Amla (Embilica Officinalis) supplementation on the glycemic and lipidemic status of type 2 diabetic subjects. J Herbal Medicine and Toxicol. 2009;3:15–21.
• Khamaisi M, Rudich A, Potashnik R, Tritschler HJ, Gutman A, Bashan N. Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats. Metabolism. 1999 Apr;48(4):504-10.
• Kim SJ, Ramesh C, Gupta H, Lee W. Taurine-diabetes interaction: from involvement to protection. J Biol Regul Homeost Agents. 2007;21(3-4):63-77.
• Kim KS, Oh da H, Kim JY, Lee BG, You JS, Chang KJ, Chung HJ, Yoo MC, Yang HI, Kang JH, Hwang YC, Ahn KJ, Chung HY, Jeong IK. Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes. Exp Mol Med. 2012 Nov 30;44(11):665-73.
• Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism. 2013 Jul 22. 
• Li C, Cao L, Zeng Q, Liu X, Zhang Y, Dai T, Hu D, Huang K, Wang Y, Wang X, Li D, Chen Z, Zhang J, Li Y, Sharma R. Taurine may prevent diabetic rats from developing cardiomyopathy also by downregulating angiotensin II type2 receptor expression. Cardiovasc Drugs Ther. 2005 Mar;19(2):105-12.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• McNeilly AM, Davison GW, Murphy MH, Nadeem N, Trinick T, Duly E, Novials A, McEneny J. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Health Dis. 2011 Nov 22;10:217.
• Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res. 2008 Oct;34(5):832-7. 
• Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac J Clin Nutr. 2012;21(1):12-21. 
• Raghuram TC, Sharma RD, Sivakumar B, Sahay BK. Effect of fenugreek seeds on intravenous glucose disposition in non-insulin dependent diabetic patients. Phytotherapy Research. 1994;8:83–6.
• Schaffer SW, Azuma J, Mozaffari M. Role of antioxidant activity of taurine in diabetes. Can J Physiol Pharmacol. 2009 Feb;87(2):91-9.
• Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7.
• Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL. GABA regulates both the survival and replication of human ss-cells. Diabetes. 2013 Aug 30. 
• Williamson G. Possible effects of dietary polyphenols on sugar absorption and digestion. Mol Nutr Food Res. 2013 Jan;57(1):48-57.
• Xiang G, Pu J, Yue L, Hou J, Sun H. α-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. Metabolism. 2011 Apr;60(4):480-5.
• Yao HT, Lin P, Chang YW,Chen CT, Chiang MT, Chang L, Kuo YC, Tsai HT, Yeh TK. Effect of taurine supplementation on cytochrome P450 2E1 and oxidative stress in the liver and kidneys of rats with streptozotocin-induced diabetes. Food Chem Toxicol. 2009 Jul;47(7):1703-9

Amino Acids for Super Humans, Part IV - Purported Ergogenics (1/3): Beta Alanine, The New Creatine?

Image 1: Despite its presence in meat,
fish and dairy, it is near impossible to
achieve supra-physiological and thus
ergogenic carnosine levels without
supplemental beta alanine.

Beta alanine, unlike l-alanine is one of the "beta-amino acids", indicating that it is neither essential nor proteinogenic, i.e. it is not built into proteins or used in the synthesis of major enzymes. Nevertheless, beta alanine plays a major role with regard to health in general and brain health and muscular performance, particular.

Taken orally, as a supplement, beta alanine (BA) has a slight sweet taste to it (the artificial sweetener suosan is derived from BA). It is highly water soluble and the funny tingles, which can be avoided by either taking it with food or by taking smaller servings (e.g. 5x 800mg for a total of 4g, which would be a reasonable amount for carnosine "loading") multiple times a day, aside, it is virtually side effects free (some people also develop benign allergic skin or mucosal reactions and/or diarrhea). 

According to Jeffrey R. Stout from the University of Oklahoma, who is one of the scientists behind many of the the commonly cited studies on beta-alanine and exercise performance, humans, in contrast to other mammals, cannot synthesize beta alanine (PerfNut. June, 2006). Humans get their beta-alanine directly from BA-containing dipeptides in our food:

• Carnosine (beta-Alanyl-L-histidine), 
• Anserine (beta-Alanyl-N(pi)-methyl-L-histidine) and 
• Balenine (beta-alanyl-N tau-methyl histidine)

are dietary sources of beta alanine. All three are particularly high in meat, eggs, dairy, which is why vegetarians tend to have significantly lower beta alanine intakes. With beta alanine being a non-essential amino acid, low intakes of beta alanine would not be a problem, if it were not the rate limiting substrate in muscular (and cerebral) carnosine synthesis.

Note: This is the detailed transcript of my show notes to "Amino Acids for Super Humans Part IV"
click here to download the podcast if you want to listen before / during / after you read the rest of the notes

Beta alanine, the rate-limiting substrate in carnosine synthesis

Carnosine, i.e. beta-Alanyl-L-histidine (C9H14N4O3), is a dipeptide which was first isolated by Gulewitsch and Amiradzhibi at the dawn of the 20th century. Yet, science begins only recently to grasp all the remarkable health and performance benefits, its presence in muscle, nerve and other tissues may provide. In the following I will summarize the most relevant facts and findings:

• carnosine levels are particularly high in brain tissue and fast-twitch muscle fibers (Harris. 1998)
• mean concentrations are 17.5 ± 4.8 mmol kg−1 dm in females and 21.3 ± 4.2 mmol kg−1 dm in males (Mannion. 1992),
• interestingly muscle carnosine levels of sprinters and other sports with short bursts of high intensity work are elevated compared to non-athletes and athletes from endurance-oriented sports such as marathon runners
  
  carnosine & the brain
  
• carnosinemia (a rare condition of low carnosine levels) effects almost exclusively the brain, which indicates that it is of utmost importance to brain health
• carnosine levels (in all tissues) decline with age; scientists speculate about the role of low carnosine levels in dementia and other age-related neurological diseases
• carnosine's antiglycation effect makes it a promising therapeutic agent in the treatment of AGE-related (AGE = advanced-glycation-end-products) pathologies such as Alzheimer's (Reddy. 2006)
  
  carnosine & athletic performance



Figure 1: In one of the most recent studies
beta alanine supplementation @ 4g/day
significantly improved performance and
body composition in trained football
players and wrestlers (Jun 13, 2011)



• carnosine appears to have general anti-oxidant capacity and could thus protect athletes from exercise induced oxidative stress
• carnosine has a PH of 6.9-7.0, which is identical with the normal intracellular PH level of 7.0 (cf. blood PH is higher: 7.4); similar to bicarbonate (PH ~8.0) which is an excellent extra-cellular buffer, carnosine can act as a buffer on the cellular level
• by buffering H+ ions which are produced in the course of strenuous exercise sessions, it reduces the buildup of lactic acid, which other than its base, lactate cannot be readily "recycled" as fuel (Catham. 2002), but contributes to exercise induced and acidosis and consecutive performance decrements (Böning. 2008)

Increasing carnosine levels by beta alanine supplementation

I has been shown, that oral beta alanine supplementation can elevate carnosine levels (in muscle) by up to 80% (Derawe. 2010). The beneficial effects of the practice of what I would like to call carnosine loading (via BA supplementation) have been confirmed by numerous studies in the course of the last decade. In a 2010 review of the literature Sale et al. conclude:

β-Alanine supplementation has consistently been shown to augment muscle carnosine concentrations in man [...] There is now a growing body of evidence to show that β-alanine supplementation of 4 weeks or longer evokes significant improvements to exercise capacity, especially when that performance is likely to be limited by the accumulation of H+ ions in the skeletal muscle (i.e. in high-intensity exercise tests lasting between 1.5 and 4 min)

In that, it is important to note that the immediate effects, many fitness enthusiasts report on the health and body building boards on the Internet, are probably placebo and/or psychological effects related to the tingling sensation, most people get from beta alanine intakes in the range of 1g+.

Muscle carnosine levels rise gradually, a sensible supplementation regimen would thus span 4-6 weeks with a daily intake of 3-5g of beta alanine per day - preferably in divided doses to avoid the tingling and ensure proper absorption.

Studies show that after a certain time-frame, which varies according to interpersonal differences and training modalities, carnosine levels saturate. Whether or to which extent continuous supplementation makes sense in these circumstances has not yet been elucidated and would certainly depend on the individual athletic demands.

Tingles, flushing and myocardial suffocation

Regardless of whether they enjoy or hate the tingling sensation that comes with higher doses of beta alanine, neither the "lovers" nor the "haters" can provide a 100% scientifically proven explanation for their occurrence. A common theory relates to the process of carnosine synthesis, of which you have already learned that it involves two amino acids: beta alanine and l-histidine. The latter is abundant in muscle tissue and the generally accepted hypothesis is that it is released in the presence of beta alanine in order to form carnosine. If a sudden spike in serum beta alanine levels occurs, the amount of histidine that is released from the muscle tissue could either surpass the amount of beta alanine that is actually there to recombine to carnosine, which would subsequently be stored within the muscle (or other tissue), or there is simply not enough carnosine synthetase (the enzyme which catalyzes the reaction of beta alanine + l-histidine to carnosine) available. In both instances there would be a net increase in "free floating" l-histidine in the blood stream, which in turn could undergo decarboxylase by the respective enzyme, L-histidine decarboxylase. The histamine produced in this reaction could then activate histamine receptors at the tissue level and provoke an "allergic" reaction that feels like a tingling sensation. Both, the non-occurrence of the tingling as well as the few reported instances, where the latter are accompanied by a rash on the tingling body parts, would support the histamine-hypothesis.

In Joe Antonio's Performance Nutrition Podcast, back in 2006, however, Jeffrey R. Stout suggested another possible mechanism (PerfNut. June, 2006). According to Stout, a direct interaction of the beta-alanine molecules with neurons in the respective tissue would be responsible for the (un-?)comfortable sensation. 

And, to make things even more complicated, I would like to suggest a third hypothesis: Those of you who have had thequestionable experience of (over-)consuming GABA orally, may have noticed that, the shortness of breath aside, the activation of peripheral GABA receptors can provoke a feeling which is not all too different from the BA-tingles. With beta alanine being a GABA-A & GABA-C agonist, this would be another, yet possibly the least likely, explanation.

Beta Alanine & Taurine - archenemies or synergists?

Figure 3: The structural difference in their
molecular structure is the outward sign of
the very different biological functions of
alanine (left) and beta-alanine (right);
one part of the energy supply chain,
the other a potent H+ buffer

Whatever the reasons for the tingles are, they are just as benign as oral beta alanine supplementation in general. In this respect, any possible concerns, my report on the hypoxic consequences of beta alanine induced taurine depletion in isolated cardiomyocytes might have brought up, would be inappropriate. Other than cells in a petri dish, your heart, or rather your whole body can very well take counter-measures against overtly high beta alanine levels and consequent cellular taurine depletion. The latter could at worst become an issue, if you decided do lace all your foods, drinking water and whatever else you consume with tons of beta alanine for weeks to deliberately deplete your taurine stores.

In the aforementioned study the scientists found that "buffering" (remember these experiments were done in a petri dish) the beta alanine with equal amounts of taurine, i.e. one taurine molecule for each beta-alanine molecule. If you wanted to mimic this equilibrium state in your supplemental regimen, the higher molecular weight of taurine (125.15 g mol−1), as opposed to beta alanine (89.09 g mol−1), would dictate a ratio of about 3:5. A reasonable way of achieving this could be 1.5g of beta alanine upon waking, 1.5g before workout, 2.5g taurine post-workout and another 2.5g before bed. 

Personally, I do not think that supplementary taurine intake would be necessary (assuming you keep your beta alanine intake in the suggested range of 3-6g per day), but since both amino acids appear to have ergogenic potential (and taurine is also involved in many other metabolic processes) it may make sense to supplement both, anyway. Whether would be necessary or even beneficial to take them one at a time in order to avoid competitive absorption is yet questionable. Under the assumption that the ratio is not totally off - like 15g of bet alanine and 500mg of taurine - I assume that you will absorb reasonable amounts of both, even when you take them together.

Beta alanine, does it have endocrine effects as well?

Aside from the neurological effects of beta alanine (Tiedje. 2010) there is yet another hitherto hardly recognized effect of 3-Aminopropanoic acid (BA) in mammals: Beta alanine appears to modulate estrogen metabolism. A 2010 study by Yang et al. (Yang. 2010) found that beta alanine significantly (-18%) decreased estradiol levels in adult rats. This is an interesting observation, especially if one takes into account the results of Walter et al. (Walter. 2010) who recorded a significant weight gain in 44 women supplemented with 1.5g of beta alanine for 8 weeks. In contrast to other studies on male subjects, the weight gain was not due to superior increases in lean mass (measured, unfortunately, by air displacement instead of DEXA), as the latter increased similarly in the control group.

Note: The study by Yang et al. does not conflict with existing human data from Hoffman 2006 and Hoffman. 2008, who found no increase in testosterone, growth hormone or cortisol response to exercise in football players and experienced resistance trainers after 10, respectively 4 weeks of beta alanine supplementation. Those endocrine parameters remained unchanged in the Yang study, as well.

It is common knowledge that the reduced estrogen production at the onset of menopause is partly responsible for the weight gain women experience at that age. That the opposite, i.e. weight loss, and more specifically, fat loss, is a consequence of lower estradiol levels in men is yet less well known. And despite the fact that this hypothesis warrants experimental verification, it may be possible that small, yet statistically significant endocrine modulations due to beta alanine supplementation may in part explain both, the weight gain the women in the Walter study experienced (Walter. 2010), as well as the improvements in fat loss and retention of lean mass in dieting wrestlers in the recently published study by Kern et al. (Kern. 2011).

Bottom line: Although beta alanine is the next "big thing" since protein and creatine supplements, it probably is a way smaller "big thing". If you got to chose and are no athlete competing in weight classes, creatine will probably provide greater benefits in view of performance increases and body recomposition or muscle building. If you can afford taking both, however, do not hesitate! Studies like Hoffman 2006 make it quite clear that the combination of creatine and beta alanine, which work via distinct mechanisms of action, is the way to go for the non-drug taking athlete who is looking for the slight edge which so often decides on victory or defeat.