Forskolin: Friend or Foe? Stories and Studies About Fat Loss, Lean Gains, Topical Cellulite Treatment, Testosterone, Cancer, Hepatotoxicity, Drug Interactions & More

There is a single human study that would suggest that forskolin would make you get closer to this classic physique w/out tons of salad (who said that's necessary anyway?).

Since Maxim asked in one of his more recent comments about the usefulness and/or downsides of forskolin, I dediced to dedicate this Sunday (finally again?) to answering a user question and am going to briefly sum up some older and the few novel findings on forskolin I am aware of.

For those of you who find that boring: Don't blame Maxim alone, another reason for this decision was that I have seen discussions on forskolin resurface elsewhere on the Internet. By the way, I write re-surfaced, because forskolin has once been hailed as a testbooster and fat loss adjuvant, but as the prices increased and people came out with faked or low-quality products that did not yield results, the market collapsed.

What is forskolin and where does it originate from?

As usually there is more than a single answer to this question. The most straight forward general ones are probably (a) it is a white to white with yellow cast powder, or (b) a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory and adenylate cyclase activating properties. Moreover, forskolin is able to activate the adenylate cyclase and thus increase the intracellular cyclic AMP levels in most tissues and cells. And hat  it's called forskolin, because it is derived from the Indiant plan Coleus forskohlii is probably something 99% of you knew already.

The reason I suppose that Maxim got interested in it, is that it is commonly used in cell studies to raise the levels of cyclic AMP (cAMP; cf. Alasbahi. 2013) and did a pretty impressive job in the recently discussed PGC-1a study. On the other hand, it did also increase the expression of the aromatase enzyme in the Yang study mentioned in the "Natural Sildenafil & Testosterone Alternative" post on which Maxim replied with the initially mentioned comment.

"Wait, wasn't it supposed to be a testbooster and now it also inhibits myostatin and increases estrogen? What does this stuff not do?" - Well, forskolin is, above all, a cAMP modulator

Forskolins chemical structure. Sometimes it's also referred to as Colforsin; 7-beta-acetoxy-8, 13-epoxy-1-alpha, 6-beta, 9-alpha-trihydroxylabd-14-en-11-one; or Coleonol (img. from Sigma-Aldrich's product database)

I know that sounds confusing, but in essence forskolin does nothing but increasing cAMP levels in almost all types of cells. cAMP a breakdown product of ATP (=> cAMP => AMP) in turn is one of those molecules which exert most their effects as intracellular signal transducer. In that, it is involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. It also modulates the calcium channels and contributes to growth hormone release; unfortunately, cAMP has also been implicated in the proliferation of not very beneficial cell growth aka cancer. The same ion-flux mediation has recently been implicated in the etiology of ADHD, as well (Arnsten. 2013).

Still, it's not all about c-AMP. Probably cAMP unrelated downsides of coleus forkohlii are for example:

• forskolin induces hepatic CYP2C enzymes and coleus forskohlii extract and thus attenuates the anticoagulant action of warfarin. (Yokotan. 2013) 
• even more than isolated forskolin, coleus forskohlii  messes with the hepatic enzyme cascade (P450) and has even been shown to be hepatoxic in a study published in the July issue of the Journal of Toxicology (Virgona. 2013)

On the other hand there are a handful of benefits, e.g.

• 

  Figure 1: Effects of 12 weeks on 2x250mg (10%) forskolin on testosterone (free and total) and lean & fat mass (Godard. 2005)

  In a 2005 study (Godard. 2005), which caused quite a stir in the health and fitness community back then, Godard et al. observed profound beneficial effects of testosterone and body composition (cf. figure 1) after the ingestion of 2x250mg of a 10% standardized forskolin (Forslean).
  
  Now, the unfortunate truth is that the15 subjects (average age, BMI, and body fat percent were 24.4 +/- 5.9 years, 32.5 +/- 4.1 kg/m2 , and 35.2 +/- 8.3%) who had been randomized to the active arm of the study, and the 15 participants in the placebo arm (28.7 +/- 8.6 years, 32.6 +/- 3.8 kg/m2 , and 35.0 +/- 7.3%) were non-active sedentary overweight/obese (BMI 26 kg/m2 or more) individuals. Add the funding by Sabinsa (Forslean producer) to the equation and decide for yourself how relevant you think the results are going to be for you...

• In several in-vitro studies, forskolin has been used as a positive control to compare the effects of other compounds on the testosterone release in leydig cells. Lin et al. for example used it in 2001 as a comparison for lactate and found a ~3x increase in testosterone release in incubated leydig cells (Lin. 2001). A similar study by Yu et al. showed that the addition of green tea catechins lead to an additional stimulation of forskolin induced testosterone production in cell cultures (Yu. 2010).

• 

  Figure 2: Results of 12-week intervention w/ forskolin containing topical cream (Roure. 2011)

  As part of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, retinol and, obviously, forskolin it has shown some promise as a topical anti-cellulite and toning agent (Roure. 2011). The clinical study was however financed by Johnson & Johnson and I am not sure how much of the effects were actually brought about by forskolin (the placebo was a basic gel with the same texture containing mainly water, gelifying and preservative systems). So take the data in figure 2 with a grain of salt, ladies - I bet 12 weeks on this product are not going to be exactly inexpensive.

• The administration of forskolin in conjunction with rutin (the glycoside between the flavonol quercetin and the disaccharide rutinose), vitamin B1 & B2 in a 2010 study by Pescosolido et. al. lead to a significant reduction in intra-ocular pressure in 15 glaucoma patients after 40 days (Pescosolido. 2010). Similar results were observed in a 2013 study for forskolin and rutin alone (Vetrugno. 2013)

• An in-vitro study by Cristobal et al. provides first evidence for the ability of forskolin to restore PPA2 in acute myeloid leukemia. That would make it a potential candidate for the treatment of this type of cancer, but to my knowledge there is as of yet not even a rodent study that would support these in-vitro results. Moreover, previous studies have suggested that Forskolin may even favor the proliferation of other types of leukemia (Kobayashi. 1994)

Time to weigh the "established" benefits and downsides

Figure 3: Effect of different doses of forskolin with and w/out epinephrine on FFA release from rat adipocytes - watch out this is from yet another in-vitro study with rodent cells (Litosch. 1982)

 In view of the fact that the aforementioned study by Godard is the only human study is only backed up by in-vitro data from rodent studies (Litosch. 1982, cf. figure 3), the fat loss benefits are as  Jeukendrup et al. point out in their 2011 review of purported fat burners...

"[...] promising, there is [yet] only one study at the present time and more work is required before forskolin can be recommended as a fat metabolism-enhancing substance." (Jeukendrup. 2011)

If you add to this the host of wanted and unwanted, known and unknown side effects that occur in response to the coleus foskohlii induced cytochrome P450 modulation (e.g. the mice in the aforementioned study by Virgona lost some visceral fat, but the costs were increased fat deposition in the liver and elevated transaminase levels).

With the questionable "fat loss" benefits (remember stress is also a powerful lypolitic and the problem is not to get the fat out of the cell, but rather to burn it), and the almost non-existant human data on the purported testosterone boosting effects, this should be reason enough not to buy more than one bottle for a test-run. After which I highly suggest to do some lab work to see if whatever good or bad you believe you are feeling is an actual boost in T (check T-levels) or hepatic side effects (check ALT, AST & ALP).

Note (update in response to comments): As far as the hepatoxicity is concerned the suggested dosage of 2x 250mg coleus forskholii most supplements come with may be higher than the medium dose in the study by Virgona, but is still probably "liver save" if you double dose on that, you are however landing in the no-man's land (=not tested for) gray zone between the medium dosage and the "danger zone" of  ~49mg/kg per day (human dose equivalent) that was tested in the study. Don't freak out, if you did that in the past, the levels return to normal afterwards and temporarily elevated ALT + AST or ALP levels do not necessarily mean that your liver is whacked forever ;-)

References:

• Alasbahi RH, Melzig MF. Forskolin and derivatives as tools for studying the role of cAMP. Pharmazie. 2013 Jan;67(1):5-13.
• Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2013 Mar;85(1):45-58. Epub 2013 Mar 29.
• Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res. 2005 Aug;13(8):1335-43. 
• Jeukendrup AE, Randell R. Fat burners: nutrition supplements that increase fat metabolism. Obes Rev. 2011 Oct;12(10):841-51. 
• Kobayashi K, Nishikawa M, Omay SB, Toyoda H, Deguchi K, Shirakawa S. Forskolin potentiates G-CSF-induced proliferation of a murine myeloblastic leukemia cell line. Leuk Res. 1994 Feb;18(2):111-7.
• Lin H, Wang SW, Wang RY, Wang PS. Stimulatory effect of lactate on testosterone production by rat Leydig cells. J Cell Biochem. 2001 Jun 26-Jul 25;83(1):147-54.
• Pescosolido N, Librando A. Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients. Clin Ter. 2010;161(3):e81-5. 
• Roure R, Oddos T, Rossi A, Vial F, Bertin C. Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies. Int J Cosmet Sci. 2011 Dec;33(6):519-26.
• Vetrugno M, Uva MG, Russo V, Iester M, Ciancaglini M, Brusini P, Centofanti M, Rossetti LM. Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther. 2013 Oct;28(5):536-41.
• Virgona N, Taki Y, Yamada S, Umegaki K. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. J Appl Toxicol. 2013 Jun 22.
• Yokotani K, Chiba T, Sato Y, Taki Y, Yamada S, Shinozuka K, Murata M, Umegaki K. Hepatic cytochrome P450 mediates interaction between warfarin and Coleus forskohlii extract in vivo and in vitro. J Pharm Pharmacol. 2013 Dec;64(12):1793-801.
• Yu PL, Pu HF, Chen SY, Wang SW, Wang PS. Effects of catechin, epicatechin and epigallocatechin gallate on testosterone production in rat leydig cells. J Cell Biochem. 2010 May 15;110(2):333-42.

Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved

Tired, exhausted, had to cut your workout short today? Is it the flu, or just too much BCAAs?

When some is good and more is better, even more is not necessarily going to be 'betterer' - and that's not simply due to the fact that there is no comparative to an adjective that's already in the comparative. Therefore it is actually not surprising that a team of researchers from the Department of Food and Experimental Nutrition at the Faculty of Pharmaceutical Sciences, the Department of Nutrition at the School of Public Health and the Department of Physiology and Biophysics at the Institute of Biomedical Sciences of the University of Sã o Paulo in Brazil has just published the results of a study (Falavigna. 2013) which demonstrates that there is an upper limit to the benefits of BCAA supplementation. What I guess will be surprising at least for some not so regular SuppVersity visitors, is that there is more than just a saturation effect: Too much BCAAs can actually have ergolytic (= anti-ergogenic) effects - at least under certain circumstances.

Another chapter in the book of good things that turn against you, when taken in excess

In their latest paper that has just been published in nutrients, Gina Falavigna and her colleagues analyzed effects of chronic BCAA supplementation on exercise performance in male Wistar rats. Based on previous animal and human data and the still widely supported, though actually experimentally non-validated (cf. Meeusen. 2007) theory that BCAAs would work their non-hypertrophy specific, endurance enhancing magic via the blockade of exercise induced 5-HT (serotonin) accumulation in the brain, the researchers speculated that ...

"[...] chronic BCAA supplementation (through the diet, using different BCAA  concentrations) would increase performance in rats subjected to a swimming exhaustion  test." (Falavigna. 2013)

To verify this hypothesis, Flavigna et al. randomized their rats to three different groups receiving either the standard AIN-93M diet for the maintenance of adult rodents (control group) or the same diet with additional additional 3.57% (group S1) and 4.76% (group S2) BCAAs at a ~2:1:1 ratio of lecine : valine : isoleucine (the BCAAs were manufactured by the Brazilian branch of Ajinomoto). The rodents in the S1 and S2 groups did thus receive 50% and 100% more branched-chain amino acids than the rodents in the control group which had to contend themselves with the BCAAs in the casein fraction of their diets (see figure 1, right). In order to assure that the diets would be isocaloric, an amount of starch equivalent to the amoung of BCCAs that had been added to the chow was removed from the supplemented diets.

Overall, the study lasted for six weeks. During this time the rodents were subjected to a 1h/day weight bearing swimming protocol five times a week. In the first two weeks, the rats were ...

"[...] adapted to the water medium and exercised with increasing overloads attached to the tail until an overload corresponding to 5% of total body weight was reached. This final overload was used until the end of the training protocol [...] The overloads were corrected weekly according to the variations in animal weight.  The efficiency of the training protocol was assessed on the basis of maximum activity of the enzyme citrate synthase in the soleus muscle, with a group of sedentary animals being used as the control for this parameter." (Falavigna. 2013)

Neither the overall amount of food nor the body weight gain of the rodents in the control, and the two exercise groups showed any statistically significant difference. The latter cannot be said about the exercise performance, as well as the accumulation of ammonia, though (see figure 1):

Figure 1: Exercise duration and plasma ammonia levels during / after swmming test (left) and macronutrient composition of the experimental diets (right; based on Falavigna.. 2013)

While the rodents in the +50% BCAA group (S1) do show the expected increase in endurance (+37%) their peers in the high dose (+100%) BCAA group (S2) experienced an even more pronounced drop in endurance performance (-43% vs. control), which went hand in hand with a profound increase in blood ammonia (+34%).

"Ammonia is a ubiquitous metabolic product producing multiple effects on physiological and biochemical systems. Its concentration in several body compartments is elevated during exercise, predominantly by the increased activity of the purine nucleotide cycle in skeletal muscle. Depending on the intensity and duration of exercise, muscle ammonia may be elevated to the extent that it leaks (diffuses) from muscle to blood, and thereby can be carried to other organs. The direction of movement of ammonia or the ammonium ion is dependent on concentration and pH gradients between tissues. As such, ammonia can also cross the blood-brain barrier, although the rate of diffusion of ammonia from blood to brain during exercise is unknown. It seems reasonable to assume that exhaustive exercise may induce a state of acute ammonia toxicity which, although transient and reversible relative to disease states, may be severe enough in critical regions of the central nervous system (CNS) to affect continuing coordinated activity. Regional differences in brain ammonia content, detoxification capacity, and specific sensitivity may account for the variability of precipitating factors and latency of response in CNS-mediated dysfunction arising from an exercise" stimulus, e.g., motor incoordination, ataxia and stupor. There have been numerous suggestions that elevated ammonia is associated with, or perhaps is responsible for, exercise fatigue, although evidence for this relies extensively on temporal relationships." (Falvigna. 2013; my emphasis)

Mark the last words of the previously cited paragraph: "[E]vidence for [the role of ammonia] in exercise fatigue relies extensively on temporal relationships". It is thus - as for now - a solely corollary, not yet a causative association, of which I do however feel that it would be very likely to turn into a causal one if someone actually measured the influx of ammonia into the brain during a workout.

Wait, ammonia? But ain't it more likely that the BCAAs block the uptake of tryptophan?

What's for sure is that another hypothesis, which relates to the blockade of tryptophan uptake can be ruled out as an underlying reason of the differences. After all the scientists who argue that ...

"[t]he increased synthesis of serotonin during exercise may be related to the development of central fatigue, because this neurotransmitter has several physiological functions, since it operates by  mood, lethargy, individual behavior, regulation of sleep, body temperature and blood  pressure, appetite suppression and changes in perceived exertion." (Falavigna. 2013)

...actually measure the 5-HT levels and observed no differences between the dietary groups. Overall, the study results to thus clearly indicate that both, medium nor high dose "chronic BCAA supplementation was not effective in improving the main parameters indicative of central fatigue" (Falavigna. 2013) - well, at least as long as we still stick to the hypothesis that the latter is induced by the accumulation of 5-HT in the brain.

Forget about tryptophan and serotonin, focus on ammonia

The fact that neither the high, nor medium dose of BCAAs did exert any effects on the serotonin levels in the brain does yet not explain why the medium dose supplementation regimen produced ergogenic, while the high dose regimen induced ergolytic effects.

The occurrence of direct toxic effects due to (too) high amounts of branched-chain amino acids can be ruled out based on previous studies in which the administration of more than 10g/kg body weight of BCAAs (the human equivalent would be 130g+ per day), as well as dosages of 2.5g/kg body weight chronically did not entail any toxic side effects (Shimomura.  2004). The same is true for other confounding variables, such as the citrate synthase activity, a measure of the general efficiency of the training protocol, bood glucose, insulin,free fatty acids, and lactate levels, as well as liver and muscle glycogen content, which were virtually identical in both groups. This leaves us with the increase in plasma ammonia as our 'last resort' to explain the -58% shorter swimming time in the high (S2) vs. medium (S1) dose BCAA group (-43% lower vs. non-supplemented control).

Figure 2: The reduced performance of the high BCAA group could well be related to peripheral and/or central ammonia build-up as a results of increased BCAA oxidation, camparably low glutamine intakes and the rate-limited enzymantic conversion and recycling of gluatmine (illustration originally from Earrante. 2003). Studies by Snow (2000) and Carvalho-Peixoto (2007) suggest: Both carbohydrate & glutamine supplements could help.

Based on what we know about the mammalian body, the increased build-up of ammonia in the high BCAA group could be a result of the unfortunate combination of temporary energy shortage and learned wastefulness' in a situation, where the otherwise sparse BCAAs are available in abundance. Furthermore, with a glutamine content of only 9-13% in the casein fraction of their diets (Swails. 1992), the rodents in the high BCAA group did ingest more than 2.6-3.8 times more BCAAs than glutamine; a fact which may have contributed to a temporary glutamine deficiency as a result of its increased use in the detoxification of the ammonia that's generated when the BCAAs are oxidized. The resulting peripheral and possibly central ammonia build-up (see figure 2) could then have begun to intoxicate liver and brains of the rodents and thus hampered gluconeogensis (normal levels stimulate, high levels of ammonia hamper gluconeogensis; cf. Fritz. 1988) and induced central fatigue (Wagenmakers. 1990; Nybo. 2004) -- and that not despite, but rather due to the chronic "high dose" BCAA supplementation (HED ~50g/day).

So do I have to drop my BCAAs now or what? Whether these results are relevant for you will probably depend on a whole host of parameters, which include

• the type, intensity and duration of exercise you do, 
• the ratio of BCAAs to glutamine in your diet,
• the amount of arginine, which acts as a substrate for the urea cycle and is therefore necessary to for the excretion of ammonia by the kindeys (Schaefer. 2002),
• the amount of carbohydrates in your diet (with more = less amino acid oxidation = lower ammonia and very low carb = you are in trouble; e.g. Czarnowski. 1995; Snow. 2000; Carvalho-Peixoto. 2007), 

... and those factors I will probably have forgotten to mention now. Unless you don't forget that you can neither lifve from BCCAs and protein alone, but accept the neflglected truth that too much protein is about as bad a too little protein, you can file this post under "show your stupid friends" and get back out, when they complain about feeling sick, bloated and fat "despite" eating a BCAA supplemented high protein, low carb (and often even low fat) diets.

References:

• Carvalho-Peixoto J, Alves RC, Cameron LC. Glutamine and carbohydrate supplements reduce ammonemia increase during endurance field exercise. Appl Physiol Nutr Metab. 2007 Dec;32(6):1186-90.
• Errante LD, Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure. 2003 Jul;12(5):300-6.
• Falavigna G, de Araú jo Junior JA, Rogero MM, de Oliveira Pires IS, rio Graç a Pedrosa R, Martins Junior E, Alves de Castro I, Tirapegui J. Effects of Diets Supplemented with Branched-Chain Amino Acids on the Performance and Fatigue Mechanisms of Rats Submitted to Prolonged Physical Exercise. Nutrients 2013. 4; 1767-1780.
• Fritz S, Bohnensack R. Stimulation of alanine metabolism in rat liver by ammonia. Biomed Biochim Acta. 1988;47(12):923-32.
• Meeusen R, Watson P. Amino acids and the brain: do they play a role in "central fatigue"? Int J Sport Nutr Exerc Metab. 2007 Aug;17 Suppl:S37-46.
• Nybo L, Dalsgaard MK, Steensberg A, Møller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol. 2005 Feb 15;563(Pt 1):285-90. Epub 2004 Dec 20. 
• Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J. L-arginine reduces exercise-induced increase in plasma lactate and ammonia. Int J Sports Med. 2002 Aug;23(6):403-7.
• Shimomura, Y.; Murakami, T.; Nakai, N.; Nagasaki, M.; Harris, R.A. Exercise promotes BCAA catabolism:  Effects  of BCAA supplementation on skeletal muscle during exercise.  J. Nutr.  2004, 134, 1583S–1587S.
• Snow RJ, Carey MF, Stathis CG, Febbraio MA, Hargreaves M. Effect of carbohydrate ingestion on ammonia metabolism during exercise in humans. J Appl Physiol. 2000 May;88(5):1576-80.
• Swails WS, Bell SJ, Borlase BC, Forse RA, Blackburn GL. Glutamine content of whole proteins: implications for enteral formulas. Nutr Clin Pract. 1992 Apr;7(2):77-80.
• Wagenmakers AJ, Coakley JH, Edwards RH. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease. Int J Sports Med. 1990 May;11 Suppl 2:S101-13.

Carnitine as Repartitioning Agent? IGF-1, p-AKT & mTOR Up, Catabolic Proteins Down + 7% Improvement in Lean- to Total Mass Ratio W/ HED of 1-1.5 of Carnitine/Day

It won't spare you the sweat, but carnitine could make it even more worthwhile by ramping up the anabolic and shutting down the catabolic signals.

Until 2006 l-carnitine has been known as a fat-burner, an in-effective fat-burner and an expensive and pretty useless supplement (depending on whom you were asking). Then, in July 2006, Kraemer et al. published a paper (a human study, above all!) in the journal Medicine & Science in Sports and Exercise a consequential paper so to say; a paper in which the authors report that l-carnitine l-tartrate supplementation at a dosage of 2.933g/day (this amount of LCLT contains 2g of pure carnitine) led to a statistically significant increase in androgen receptors in the vastus lateralis after a heavy resistance training protocol in previously strength trained male subjects (Kraemer. 2006).

Still, the evidence has always been inconclusive to say the least

Despite the fact that the concomitantly elevated post-workout luteinizing hormone levels (+19%) Kreamer et al. observed would tell you that the testosterone that would have been necessary to activate those receptors was already on its way, I have never considered this study as convincing evidence of the anabolic prowess of l-carnitine. Plus, let's be honest, differences in whatever serum markers in response to an acute bout of resistance training have failed us way too often, not to look at studies like these with appropriate skepticism.

Do you remember the Ratames study from 2005? The one that showed that high volume training lowers the no. of androgen receptors on the trained muscles? This certainly makes l-carnitine sound like the perfect addition to high volume routines, right? (learn more)

That the same principle of "calm down and don't get too excited over the results of a single trial" does all the more apply to rodent studies should be self-evident and still, science is all about taking each and every experimental result into account to form a theory that can explain all of them, or, alternatively, is able to bust short-comings in previous studies that don't comply with the predictions of the respective theory.

Now, the soon-to-be-published paper by Janine Keller and her colleagues from the University of Giessen (Germany) certainly qualifies as part of the evidence we simply cannot ignore, when we are looking for evidence in support of the theory that l-carnitine could be an overlooked muscle builder or repartitioning agent.

After all, their observation of decreased levels of the proteolytic (=catabolic) MuRF1 protein, as well as the ubiquitin-protein conjugates, which are increased in catabolic states such as starvation and atrophy denervation (cf. Wing. 1995) , alone, would signify that l-carnitine could make a valuable addition to everybody's supplementation regimen.

Lower catabolism + increased anabolism = ???

There is more, however, the addition of 1250 mg L-carnitine/kg to a basally "low carnitine" vegetarian diet also led to significant increases in systemic IGF-1 concentrations in plasma and a local increase in the activity of the PI3K/Akt/FoXO-1 signalling pathway (see figure 1)

Figure 1: IGF-1 mRNA and serum levels, as well as the muscle specific expression and phosphorylation (ph) Akt, mTOR & co after four weeks on the low or high carnitine diets (Keller. 2013)

These results do yet not stand in isolation as the ones by Kraemer et al. still do. Other recent studies by the same research group in Giessen, as well as colleagues from the University of Barcelona have already confirmed the anti-catabolic effects of l-carnitine in piglets and a cancer cachexia model in rodents, respectively (Keller. 2013; Busquets. 2013).

"And you are telling me that works in humans, as well? "

What's the best form of carnitine to take to elicit these effects: I knew you would ask this, so I react to two facebook questions by adding this red box willingly admitting that I just cannot tell you what the best form of carnitine is. There simply is no study that would compare e.g. acetyl-l-carnitine (ALCAR) and l-carnitine l-tartrate (LCLT) in a scenario that would be relevant to the above question. What I can tell you though, is that it appears as if you were better off with LCLT than with ALCAR, if your goal is to top off your intra-muscular carnitine levels. That being said, even normal creatine can do that - you will just have to take more of it. If you are looking for more information you can check out the part of the Amino Acids for Super Humans Series that's dealing with "the carnitines", here.

In this context it does yet also have to be mentioned that the effects of l-carnitine are at least in part species specific. How we know that? Well, in contrast to the said study by Basquets et al. the provision of an carnitine to piglets (Keller. 2013) did not only reduce the MuRF-1 expression, but also the level of its likewise catabolic E3 ligase cousin atrogin-1.

"It has been shown that myofibrillar proteins, like myosin light chain proteins are the main targets of MuRF1for ubiquitination. Thus, carnitine might suppress particularly the degradation of myofibrillar proteins, which under physiological conditions comprise around 60% of total muscle proteins. In contrast to MuRF1, atrogin-1 tags primarily proteins for degradation which are important for controlling protein synthesis and myoblast differentiation, like myogenic factor MyoD, myogenin and the eukaryotic initiation factor of protein synthesis eIF3-f." (Keller. 2013)

With pigs usually being a superior model of the human physiology, this would suggest that the anti-catabolic effects l-carnitine could have on humans are probably more, not less pronounced than those that were observed in previous rodent studies.

Whether the same goes for the IGF-1 response cannot be said, but just like the anticatabolic effects, the pro-anabolic increase in IGF-1 has been observed in previous trials, including a human trial by Di Marzio et al. who observed a significant increase in IGF-1 in HIV patients in response to the provision of 3g/day of acetyl-l-carnitine (Di Marzio. 1999). In the absence of the existing evidence from animal studies, these results would yet have little significance for healthy human beings, whose growth hormone and IGF-1 levels are not rock bottom to begin with (Viganò. 2003).

---

Bottom line: Irrespective of the absence of human data on the IGF-1 boosting effects from non-HIV patients - or even better in training scenarios - it would warrant future studies if an adequate amount of carnitine in the diet can exert beneficial effects in non-obese human beings. For the "sedentary", or let's rather say non-exercised rodents in the study at hand, the latter was a mere fat loss effect - despite the elevations in p-AKT, m-TOR, IGF-1 and the overall more "anabolic" state the rodents were in their lean body mass was not increased compared to their peers on the low carnitine diet.

"Just another set!" ... "I don't know man, we've already pumped away 100,000kg today... do you really believe that's productive, I mean, yeah, we are cuttin', but still" ...learn what this dialog is all about and whether and if / when "another set" is / isn't a good idea (read more)

The lean-to-total mass ratio of the rodents, on the other hand was ~7% higher in the rodents in the high carnitine group. If we do however take into consideration that most of you will not be vegetarians and thus not similarly carnitine deprived as the rodents in the control group on the <1mg/kg carnitine diets, it is highly questionable if the addition of the human equivalent of the 1.25g/kg chow, i.e. 15mg/kg body weight (HED) would actually yield any measurable benefit to non-vegetarians - irrespective of whether they train or not. After all, even the average omnivore human being consumes 100-300mg of carnitine per day (Broquist. 1994), so that the difference between your basal carnitine intake and the supplemental equivalent dose of 1050-1500mg/day is more than 100x lower than the exorbitant difference between the low (if not deficient) carnitine diet in Keller's rodent study at hand (remember: the basal diet had less than 1mg/kg chow; the supplemented diet hat 1250mg/kg diet!).

So what's the verdict then? I guess, I will leave the final words to Burke et al. who reviewed the usefulness of carnitine as an ergogenic aid in one of the first installments of the "A-Z Supplement Review" in the British Journal of Sports Medicine and wrote "future work with l-carnitine may also find some useful outcomes" (Burke. 2009) - needless, to say that the SuppVersity is going to be the place, where you will read about it first ;-)


References:

• Broquist HP. Carnitine. In Shils ME, Olson JA, Shike M (eds): "Modern Nutrition in Health and Disease." Malvern, PA: Lea & Febiger, 1994. 459– 465.
• 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.
• Busquets S, Serpe R, Toledo M, Betancourt A, Marmonti E, Orpí M, Pin F, Capdevila E, Madeddu C, López-Soriano FJ, Mantovani G, Macciò A, Argilés JM:  l-Carnitine: An adequate supplement for a multi-targeted anti-wasting therapy in cancer.  Clin Nutr. 2013;31:889–895.
• Di Marzio L, Moretti S, D'Alò S, Zazzeroni F, Marcellini S, Smacchia C, Alesse E, Cifone MG, De Simone C. Acetyl-L-carnitine administration increases insulin-like growth factor 1 levels in asymptomatic HIV-1-infected subjects: correlation with its suppressive effect on lymphocyte apoptosis and ceramide generation. Clin Immunol. 1999 Jul;92(1):103-10.
• Glass DJ:  Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol. 2003; 5:87–90 .
• Kraemer WJ, Spiering BA, Volek JS, Ratamess NA, Sharman MJ, Rubin MR, French DN, Silvestre R, Hatfield DL, Van Heest JL, Vingren JL, Judelson DA, Deschenes MR, Maresh CM. Androgenic responses to resistance exercise: effects of feeding and L-carnitine. Med Sci Sports Exerc. 2006 Jul;38(7):1288-96.
• Keller J, Ringseis R, Koc A, Lukas I, Kluge H, Eder K:  Supplementation with l-carnitine downregulates genes of the ubiquitin proteasome system in the skeletal muscle and liver of piglets. Animal. 2013;6:70–78.  
• Keller J, Couturie A, Haferkamp M, Most E, Eder K. Supplementation of carnitine leads to an activation of the IGF-1/PI3K/Akt signalling pathway and down regulates the E3 ligase MuRF1 in skeletal muscle of rats. Nutrition & Metabolism. 2013; 10:28. 
• Lösel D, Rehfeldt C. Effects of l-carnitine supplementation to suckling piglets on carcass and meat quality at market age. Animal. 2013 Mar 11:1-8.
• Salama AF, Kasem SM, Tousson E, Elsisy MK. Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats. Toxicol Ind Health. 2013 Feb 13.
• Viganò A, Mora S, Brambilla P, Schneider L, Merlo M, Monti LD, Manzoni P. Impaired growth hormone secretion correlates with visceral adiposity in highly active antiretroviral treated HIV-infected adolescents. AIDS. 2003 Jul 4;17(10):1435-41.
• Wing SS, Haas AL, Goldberg AL. Increase in ubiquitin-protein conjugates concomitant with the increase in proteolysis in rat skeletal muscle during starvation and atrophy denervation. Biochem J. 1995 May 1;307 ( Pt 3):639-45.

Optimal Carnosine Loading: Taking Beta Alanine With Food Renders the Cheap Bulk Stuff more Potent Than Fancy Time-Released Preparations. Preview: Science Round-Up: Daylight Saving, Stevia Toxicity, Protein Excess & More

Since it's Thursday my voice is back and I am already looking forward to today's SuppVersity Science Round-Up in which Carl Lenore an I are going to "attack" the following topics (tune in live at 1PM EST),

That pills can rarely compete with whole foods is something you've heard on SHR and read on the SuppVersity often, but that pills - in this case beta alanine pills - are better, when the content is mixed into the food instead of being prepared in form of time-released or whatever else caps may be news to some of you.

• Summer time and the jet-lag is there... the effects and idiocy of daylight saving.
• Stevia an anti-fertility sweetener, carcinogen and yet another welcome root of all evil?
• Dairy & weight loss revisited, when even the abstract contradicts the conclusion.
• Does too much protein make you fat? Yes it does - at least that's what the latest epidemiological data says.
• Fish oil makes women hungry, exercise satisfies their cravings and improves gut hormone signalling.
• High dietary restraint makes women lose their nocturnal progesterone surge

I decided to pick a fast, put practically relevant topic as the SuppVersity news of the day: Beta Alanine Supplementation; or, to be even more precise: "Optimal" beta alanine supplementation.

The less tingles the better!?

What type of food did the subjects eat? In the acute test the data in figure 1 (left + right) is based on, the subjects consumed a standardized breakfast consisting of 4 slices of white bread with chocolate-hazelnut paste, 200ml semi-skimmed milk, 1 banana and 125gr fruit yogurt, and a second meal with 150gr baguette topped w/ 40gr young cheese, 30gr mayonaise and vegetables with a 33cl orange juice (data not shown in figure 1). In the chronic ingestion study (figure 1, middle) participants in the w/ meal groups had 1x800mg cap with their three regular main meals and the fourth with a snack.

As a diligent student of the SuppVersity you will know that a major problem with beta alanine  in scientific studies is that even the "time-released" tabs, the scientists usually use can produce this tingling sensation in all sorts of the body (I can tell you about that, from my more is more days back in the day; you really won't believe in which places you can "tingle" ;-) After my initial excitement and putting some thought into the hitherto still not 100% understood origin of the tingles, I did yet realize that they are not just unnecessary for the BA to work but could in fact be a negative (also physiologically negative) side effect of too much of the potentially toxic substance floating around in your blood stream (cf. Beta Alanine Suffocates Cardiomyocytes; other previous posts on BA).

Don't worry, it is totally unlikely that you will ever achieve serum concentrations that could do any harm, but one thing you should remember is that what you are striving for is not a high amount of beta alanine (BA) in your body. Your goal is to ramp up the intramuscular carnosine stores and that works only if the BA does recombine with the essential amino acid histidine and is subsequently stored within the skeletal muscle.

Food as an "advanced delivery formula"

The recombination / incorporation process is likely to be rate limited, so that it is only logical that any "overshoot" of beta alanine (again nothing your body likes to  have floating around in the system) is going to be cleared before it can do its carnosine loading job. A job that is therefore facilitated by "packaging" the BA molecules with fillers & co in tabs, or - much cheaper and obviously way more natural - by simply ingesting it with food.

Figure 1: Selected time-frame of 8h blood profile of plasma insulin and beta-alanine (BA) after ingestion of 800mg of BA after meal in between meals or with meal (left and right). Effect of chronic ingestion of 4x800mg/day BA for five weeks with or w/out food in regular and sustained released form  ( Stegen. 2013)

As the data in figure 1 that's based on the results of a soon-to-be-published study by Stegen et al. goes to show you, the "food advantage" is (as usual ;-) the 34 male and female subjects (age 19.4y; weight 66kg, daily BA intake at baseline ~230mg/day) derived from ingesting the BA with meals may not be earth shattering.

Still, the subjects who took the BA with a meal did not just have higher muscular carnosine levels than those who took the pure powder, at least in the slow-twitch fibers of the soleus, which are actually not that beta alanine affine as their counterparts in the gastrocnemius, the cheap and ingeniously simple "take it with food" solution to BA supplementation also outperformed the obviously pricier pre-prepared slow-release formula.

Where does the beta alanine go to, if not into the carnosine stores? 

The scientists did yet also make another interesting observation, while only 1.6% of the beta alanine was excreted in the urine (slow release formula) the muscular uptake and the incorporation efficiency of exogenous BA into carnosine is actually so low that "the vast majority (~160g or 95-96%) of the ingested BA is neither going into muscle carnosine nor into the urine" (Stegen. 2013).

While respective scientific studies would still have to be conducted, the most likely hypothesis to explain the "disappearance" of beta alanine are:

• Oxidation and use for energy production: While the contribution of alpha-amino acids to energy delivery in muscle and other tissues is usually quite low, as compared to carbohydrates and fat, their usage increases (up to 10% of total energy usage) with increasing amounts of the AA in the bloodstream. Evidence suggests that this is also the case for beta-amino acids, where and "excess" would obviously be achieved with dosages as they were used in most of the previous research on beta alanine supplementation (Harris. 2006, Hill. 2007; Baguet. 2009).
  
  This hypothesis is also supported by the recent revelation that GABA transaminase activity, the enzyme that's required to initiate the oxidation of beta alanine increases upon  BA supplementation (Everaert.2013)

• Alternative pathways including uptake and incorporation into carnosine in other tissues: While it is not impossible that other organs (e.g. the kidney, liver or brain) avail themselves of small quantities of BA to up their own carnosine levels it is, as the scientists point out " unlikely that the conversion of BA into carnosine in other (non-muscle) tissues is of any quantitative significance, because presence of carnosine and carnosine synthase in non-muscle tissues is several orders of magnitude lower than in muscle" (Stegen. 2013)

Now that we have gotten that straight, the one question that remains is actually pretty simple, unlike the answer unfortuntately....

How does the meal improve the the bioavailability of BA

Personally I still feel that the main effect is the prolonged elevation of beta alanine, the scientists themselves however propose another (at least confounding) factor, which would also explain why simply taking the slow release formula won't work even if it is released just as slow as regular BA with food:

While BA still is often named in the same breath with creatine, the effect size and the likelihood that athletes will see any benefits at all is much smaller than in the case of the supplemental top dog (learn more in  "Beta-Alanine Does not Make it From Bench to Pool Side: Are the Effects Too Short-Lived? Is Swimming the Wrong Sport? Or Was the Dosage of 3.2g/day Simply Too Low?")

"Clausen et al.showed that Na+/K+ pumps in skeletal muscle are stimulated by insulin over a range of concentrations down to low physiological levels (Clausen. 2003). Therefore, it is possible that meal-induced elevations in serum insulin are capable of triggering the sodium-dependent transporter TauT. In our study, a meal-induced effect could only be confirmed in soleus muscle. Considering the fact that this is a more insulin-sensitive muscle, it is not unlikely that the soleus responds better on insulin induced BA uptake. In addition Lavoie et al. demonstrated that insulin-induced translocation of Na+/K+ ATPase subunits to the plasma membrane (Lavoie. 1996), one of the two possibilities to increase Na+/K+ ATPase activity, is restricted to oxidative fiber-type skeletal muscles which are predominantly present in soleus."

Sounds more than logical and can also explain the differential effect on the oxidative = slow twitch fibers of the soleus (cf. figure 1, middle). With the insulin enhanced "pump activity" you have a mechanistic increase in BA uptake, no wonder that this improves the bioavailability, right?

---

Bottom line: From now on you buy your beta alanine in bulk and spoon-feed yourself with your 4x800mg of BA (the dosage used in the study at hand) after your preferably carb-containing meals and snacks. Don't worry BA is one of the few amino acid supplements that don't have a disgusting taste to them. You can actually add it directly to the food, but I would refrain from doing that before you prepare your meal. As simple as the BA molecule may be, we still don't know what kind of chemical reaction it may be exposed to if you actually cook it or do whatever other "nasty" things to it ;-)

References:

• Baguet A, Reyngoudt H, Pottier A, Everaert I, Callens S, Achten E, and Derave W. Carnosine loading and washout in human skeletal muscles. J.Appl.Physiol. 2009; 106:837-42.
• Clausen T. Na+-K+ pump regulation and skeletal muscle contractility. Physiol Rev. 2003; 83:1269-324.
• Everaert I, De Naeyer H, Taes Y, Derave W. Gene expression of carnosine-related enzymes and transporters in skeletal muscle. Eur J Appl Physiol. 2013 Nov 4.
• Harris RC, Tallon MJ, Dunnett M, Boobis L, Coakley J, Kim HJ, Fallowfield JL, Hill CA, Sale C, and Wise JA. The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis. Amino.Acids. 2006; 30:279-89.
• Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, and Wise JA. Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity. Amino.Acids. 2007; 32:225-33. 
• Lavoie L, Roy D, Ramlal T, Dombrowski L, Martin-Vasallo P, Marette A, Carpentier JL, and Klip A. Insulin-induced translocation of Na+-K+-ATPase subunits to the plasma membrane is muscle fiber type specific. Am.J.Physiol. 1996; 270:C1421-C1429.
• Stegen S, Blancquaert L, Everaert I, Bex T, Taes Y, Calders P, Achten E, Derave W. Meal and Beta-Alanine Coingestion Enhances Muscle Carnosine Loading. Med Sci Sports Exerc. 2013 Mar 5.

Review Claims: CLA & Fish Oil Improve "Anabolic" Effects of Exercise - What Does the SuppVersity Sniff Test Say?

A bigger biceps and less body fat to cover your precious gains? At least for CLA this has in fact been observed in a human study (see figure 1).

About two weeks ago, I stumbled across an interesting paper that had just been published in the peer-reviewed journal Nutrients, filed it and got so much to do that I would almost have forgotten about it. When I was just thinking about which topic to address next, I did yet remember the auspicious conclusion to the abstract, which says "we can hypothesize that fat supplements may improve the anabolic effect of exercise." (Macaluso. 2013). "May" and "hypothesis", those are terms I like and since fish oil and CLA were implicated in the previous lines, I suppose you are going to like it as well. So what would be more obvious than to apply the "SuppVersity Sniff Test" (I am beginning to like this term, Carl often uses on the Science Round-Up) to this ostensibly well-researched review of the literature?

"May improve the anabolic effect of exercise"

Usually things that "may" do just that, namely "improve the anabolic effect of exercise" end up in a pricey and useless testosterone booster.

Check out the overview of the Intermittent Thoughts on Building Muscle and learn how testosterone, growth hormone, IGF-1, mTOR and the rest of the pack orchestrate skeletal muscle hypertrophy and why boosting your testosterone levels from mid will not translate into visible muscle gains (read more)

Personally, I don't know of any test booster though, which boasts that fish oil or CLA were it's main ingredients and without taking away too much of the results of this sniff test, I can already tell you that there is a good reason for why this is the case: It's even less likely to produce significant effects than the next best herb that "grows but in one place" in the Amazonian rain forest, where the CEO of company X harvests it at the hazard of his own life... ah, you know that spiel, so I don't have to repeat it here.

If you take a look at the tables the researchers provide as part of their review and have basic mathematical and reading skills, it's not difficult to count the number of which would remotely support the notion that fish  or CLA supplementation have any effects at all: It's 5 out of 9 for fish oil and 4 out of 7 for CLA. Certainly reason enough to "hypothesize" a bit.

Fish oil is good for your heart, but not for your physique

In the next step we need a little more than to identify those studies with the "no effect" label from the tables and take a the ones we were left with after our initial glance at the data. If we do just that the number of studies we have to look at decreases from 9 to 4 studies, as none of the fish oil studies survives the "Sniff Test", after all, neither

• 

  They probably ain't anabolic either, but could help you to stay lean on a bulk: DHA-phospholipid, as you would find them in krill vs. common fish oil supplements (learn more).

  improved cardiovascular function in the absence of increased endurance performance or recovery in football players (Buckley. 2009)

• a minimal reduction in O2 cost in the absence of effects on the endurance performance in cyclists (Peoples. 2008), 

• improvements in VO2max in previously sedentary men a non-placebo-controlled study (Brilla. 1990)

• a reduced acute phase inflammatory response in a non-randomized non-placebo controlled intervention with average Joes (Ernst. 1991) 

would qualify as convincing evidence for any "anabolic effects" - in fact, even if we were talking about ergognenic effects in general, only the study by Guezennec would survive 2nd phase of the Sniff Test.

Now, what's interesting about the Guezennec study, though, is that the "beneficial" effects (a profound decrease red blood cell deformability; RCD) were hypoxia specific and could easily turn against you. After all, one of the reasons athlete "train high and compete low" (meaning they train at high altitudes with less oxygen in the air and thus hypoxic conditions to outperform the competition at sea level) is that this will increase the production of red blood cells. Now guess why that happens!? Correct! It's a result of the hemolytic effect of hypoxic training... now, what will happens if you copy the 6g /day EPA-max supplementation regimen of the 19-38 years old guys in the Guezennec study? Right, this effect will be absent. I wouldn't go so far and call this "ergolytic", but you could certainly make a point that huge amounts of EPA are - at least in this scenario - anti-ergogenic.

So what about CLA, then? Isn't that simply a fat burner

So, if even the widely hailed fish oil has little data to support its usefulness as an ergogenic supplement for athletes and aspiring physical culturists, what about CLA, then? I mean, we all know that the benefits researchers observed in human trials were miles apart from what they had expected to happen based on previous experiments in rodents (click on the image to the right to be redirected to a study, where the CLA treated ice dropped 77% body fat and did nevertheless display statistically significant increases in endurance capacity).

Adequate dosing still remains an issue

These discrepancy in terms of the body fat reducing effects of conjugated linoleic acid supplementation, as Dilzer and Park pointed out only recently, at least in parts a result of insufficient doses:

In July 2013 I wrote about what I believe is the unquestionably most impressive study on the fat burning and endurance enhancing effects of conjugated linolic acid. 77% body fat reduction - that's bordering lipodystrophy. The dosage used in this study would be roughly equivalent to 30g/day for human being and supports the notion that profound effects are only observed with amounts of CLA that have yet not been administered to humans in controlled trials (learn more)!

"Studies with mice used diets containing 0.5 w/w%* CLA, which is equivalent to about 56 g CLA/day/70 kg (Malpuech-Bruger. 2004). Most human studies used CLA doses ranging between 0.7 g and 6.8 g per day, which is lower than doses used in mice." (Dilzer. 2013)

*Addendum: Anonymous pointed out correctly, that the figures in the above quotation (which is dirertly from the FT) are inconsistent. 0.5% would be only 5.6g. I guess that's a typo in the Dilzer study, because the Malpuech-Bruger study they reference says "a daily intake of 0.70 g/kg body mass was effective in mice". (Malpuech-Bruger. 2004) - sloppily as they are, they don't say that this is already in human equivalents, though. That becomes clear in the next sentence only, which says "A value of 0.70 g/kg body mass in humans would correspond to a daily intake of 56 g of CLA." (ibid.) The July 2013 study I reference under the image to the right used a HED of ~30g (learn more), so even if the exact figures are questionable, the argument obviously still holds.

Since the same goes for studies investigating the "anabolic" effects the abstract to Macaluso et al.'s review explicitly mentions, chances are that increases in endurance performance, as they were observed in the previously mentioned rodent study (read the full story, here), were likewise species or at least dosage specific.

Is CLA "anabolic" or at least ergogenic?

If we take a look at the 7 studies the researchers included in their review (I guess you will be hard-pressed to find more than those seven, as CLA is not exactly the typical supplement researchers use as an ergogenic), we can easily exclude three of them. In these studies that were conducted on healthy young women, trained male bodybuilders and physically active men and women, supplementation with 3g, 6g and 3.9g/day of CLA did exactly nothing.

This leaves us with a set four studies to take a closer look at - three of them report improvements in body composition, two of them also observed increases in endurance performance and a single one even found "slight increases in testosterone":

• Improvements in body composition were observed by Thom (2001), Colakoglu (2006) and Pinkonski (2006); all studies were placebo controlled and the participants were physically active or at least healthy men (only in the Thom study) and women who consumed 1.8, 3.6 and 5g of CLA per day.
  
  While the former two studies by Tho and Colakoglu used exhaustive and medium intensity endurance programs, the study by Pinkonski et al. used a stardardized full-body workout with 12 exercises ranging from leg presses, bench and shoulder presses, to lat pull downs, biceps curls, and some core exercises. Each exercise was performed three times per week consisting of 3–4 sets of 4–10 repetitions at approximately 75–90% of one-repetition maximum (1RM).

  

  Figure 1: Relative changes in body composition biceps and quadriceps size and strength parameters after 7 weeks of serious strength training with or without 5g of CLA per day (Pinkoski. 2006)

  This protocol and the high number of study participants (76 men and women) and their training status - the majority had more than 2 years of weight training experience under their belts - make the results of the Pinkoski study so interesting for us. The results, on the other hand (cf. figure 1), are not exactly earth shattering, especially in view of the fact that only the fat loss and the increase in biceps size reached statistical significance and that despite a pretty high number of participants. Whether or not CLA really is "anabolic" and not "just" a mediocre fat burner has thus still to be determined.

Figure 2: Increases in cortisol (top) and testosterone (bottom) and respective increases in lean body mass in response to a 12-week hypertrophy oriented resistance training program (West. 2013)

• Increases in testosterone, as Macaluso et al. observed them in 10 "physically active" male subjects (age, 27.4) in a previous study in response to 6g CLA per day, on the other hand, would probably qualify as "anabolic" if the latter had not been measure right the workouts, as part of a short 3-week study with no corresponding effects on body composition (Macaluso. 2013).
  
  The latter should actually not come as a surprise to any seasoned SuppVersity student. After all you've learned that (1) endocrine induced changes in body composition take their time in the Intermittent Thoughts on Building Muscle, that (2) the role of  testosterone levels in the normal range in the whole process is fundamentally overrated and (3) that the seminal paper by West & Phillips, on which the data in figure 2 is based, clearly refutes the notion that post-workout increases in testosterone have any impact on skeletal muscle hypertrophy.

If we also take into account that numerous rodent studies do in fact support the notion that CLA posses "ergogenic",  yet not necessarily "anabolic" qualities. Macaluso et al. are certainly correct, when they conclude their paper with the scientific equivalent to "And they lived happily ever after" stating that "additional research".

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Milk from pastured cows has a relatively high amounts of both, CLA and DHA + EPA. The absolute amounts are however so low that you would probably have to drink more than the notorious gallon of milk per day to see any effect - and let's be honest, even if CLA + DHA make a good fat burner, the gallon of milk certainly makes a better weight gainer ;-)

Bottom line: I guess, you'd like to hear a supplement recommendation now, right? Well, as far as ergogenic and/or anabolic effects are concerned, CLA is unquestionably the more promising fatty acid off the "two" (actually we are talking about four fatty acids, here: DHA + EPA = fish oil and cis-9,trans-11 and trans-10,cis-12 CLA). CLA's anti-PPAR-gamma effect, which is probably responsible for the reductions in insulin sensitivity and detoriations of the lipid metabolism that have been observed in numerous studies (only trans-10,cis-12 CLA), is probably not so much of a problem for lean, physically active people and the upside of the PPAR-gamma blockade is a reduced rate of fat storage....

Ah, you see I am diverting to the fat loss effects again. And if we are honest, the results of this review do actually only confirm that what you've read here at the SuppVersity roughly 3 months ago the combination of CLA + DHA could turn out to be a safe and effective fat burner (learn more), if we would finally see adequately doses, long(er) term supplementation trials in humans.

As ar as the "anabolic" nature of either of them, i.e. EPA + DHA or cis-9,trans-11 and trans-10,cis-12 CLA. The jury may still be out there, but the verdict is - at least in the case of regular fish oil almost certainly "not guilty", .. ah I mean, "not anabolic".

References:

• Brilla, L.R.; Landerholm, T.E. Effect of fish oil supplementation and exercise on serum lipids and aerobic fitness. J. Sports Med. Phys. Fitness 1990, 30, 173–180.
• Buckley, J.D.; Burgess, S.; Murphy, K.J.; Howe, P.R. DHA-rich fish oil lowers heart rate during
  submaximal exercise in elite Australian Rules footballers. J. Sci. Med. Sport 2009, 12, 503–507. 
• Colakoglu, S.; Colakoglu, M.; Taneli, F.; Cetinoz, F.; Turkmen, M. Cumulative effects of conjugated linoleic acid and exercise on endurance development, body composition, serum leptin and insulin levels. J. Sports Med. Phys. Fitness 2006, 46, 570–577.
• Dilzer A, Park Y. Implication of conjugated linoleic acid (CLA) in human health. Crit Rev Food Sci Nutr. 2013;52(6):488-513.
• Ernst, E.; Saradeth, T.; Achhammer, G.  n-3 fatty acids and acute-phase proteins.  Eur.  J.  Clin.
  Invest. 1991, 21, 77–82.
• Guezennec, C.Y.; Nadaud, J.F.; Satabin, P.; Leger, F.; Lafargue, P. Influence of polyunsaturated fatty acid diet on the hemorrheological response to physical exercise in hypoxia.  Int.  J.  Sports Med. 1989, 10, 286–291.
• Lenn, J.; Uhl, T.; Mattacola, C.; Boissonneault, G.; Yates, J.; Ibrahim, W.; Bruckner, G. The effects of fish oil and isoflavones on delayed onset muscle soreness. Med. Sci. Sports Exerc. 2002, 34, 1605–1613. 
• Macaluso, F.M.;  Catanese, P.; Ardizzone N.M.; Marino Gammazza, A.; Bonsignore, G.; Lo Giudice, G.; Stampone, T.; Barone, R.; Farina, F.; Di Felice,  V. Effect of conjugated linoleic acid on testosterone levels in vitro and in vivo. J. Strength Cond. Res. 2013, 26, 1667–1674. 
• Macaluso F, Barone T, Catanese P, Carini F, Rizzuto L, Farina F, Di Felice V. Do Fat Supplements Increase Physical Performance? Nutrients 2013; 5:509-524.
• Malpuech-Brugère C, Verboeket-van de Venne WP, Mensink RP, Arnal MA, Morio B, Brandolini M, Saebo A, Lassel TS, Chardigny JM, Sébédio JL, Beaufrère B. Effects of two conjugated linoleic Acid isomers on body fat mass in overweight humans. Obes Res. 2004 Apr;12(4):591-8.
• Oostenbrug, G.S.; Mensink, R.P.; Hardeman, M.R.; De Vries, T.; Brouns, F.; Hornstra, G. Exercise performance, red blood cell deformability, and lipid peroxidation: Effects of fish oil and vitamin E. J. Appl. Physiol. 1997, 83, 746–752.
• Peoples,  G.E.;  McLennan,  P.L.;  Howe,  P.R.;  Groeller,  H. Fish oil reduces heart rate and oxygen consumption during exercise. J. Cardiovasc. Pharmacol. 2008, 52, 540–547..
• Peoples,  G.E.;  McLennan,  P.L.;  Howe,  P.R.;  Groeller,  H. Fish oil reduces heart rate and oxygen consumption during exercise. J. Cardiovasc. Pharmacol. 2008, 52, 540–547. 
• Pinkoski, C.; Chilibeck, P.D.; Candow, D.G.; Esliger, D.; Ewaschuk, J.B.; Facci, M.; Farthing, J.P.; Zello, G.A. The effects of conjugated linoleic acid supplementation during resistance training. Med. Sci. Sports Exerc. 2006, 38, 339–348.
• Thom, E.; Wadstein, J.; Gudmundsen, O. Conjugated linoleic acid reduces body fat in healthy exercising humans. J. Int. Med. Res. 2001, 29, 392–396.
• Toft, A.D.; Thorn, M.; Ostrowski, K.; Asp, S.; Moller, K.; Iversen, S.; Hermann, C.;  Sondergaard, S.R.; Pedersen, B.K. N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise. J. Appl. Physiol. 2000, 89, 2401–2406.
• West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2013 Jul;112(7):2693-702.