Capsaicin or Plant Oxysterol 28-Homobrassinolide (28-HB) - Two Candidates for a Natty Test Booster that Works?

In am not sure if people got afraid that I rip their papers apart by pointing with a figure at the non-existent real-world significance of their revolutionary findings about the testosterone boosting effects of herb X from the deepest jungle in Y. What I do know however, is that for whatever reason studies like these have become rare as of late. I have still been able to pick up two of them, to do what Carl usually calls the SuppVersity Sniff Test on Capsaicin *achoo!* ... sorry! And the oxysterol 28-Homobrassinolide, which is present in miniscule amounts in Chinese cabbage, for example.

Capsaicin: The hotter, the better?

The first of the two studies we are going to tackle, today, comes right from the Department of Histology & Embryology at the Faculty of Veterinary Medicine of the University of Uludag in Turkey... and yes, the fact that it comes from the "Department of Histology & Embryology at the Faculty  of Veterinary Medicine" is in fact a first indicator that some of the initially mentioned "sniffing" and an appropriate amount of healthy skepticism are probably indicated. But let's not make any hasty judgments; after all, this study is not about herb X from the deepest jungle in Y, but a simple investigation into the effects of capsaicin on the morphology of rodent testes.

While capsaicin seems to be better used topical as a fat burner, here is a serious warning: Don't rub any capsaicin based fat burner onto your scrotum  in the false hope to turn it into a test booster ;-)

As a SuppVersity student you will be aware that capsaicin, the "hot stuff" in hot peppers, is quite a remarkable substance (e.g. "Capsaicin Cream for Topical Fat loss?").

Aside from topical (and at least in rodents) systemic effects on fat loss and the metabolic syndrome, there have also been several reports linking capsaicin to improvements in testicular morphology in diabetic and otherwise sick animals. Others report direct stimulative effects of capsaicin on testicular development and modulatory effects on the local and systemic expression of ghrelin, which has been shown to exert inhibitory effects of testosterone secretion in the testes (Tena-Sempere. 2005).

The latter, i.e. the connection between capsaicin, ghrelin and testicular morphology, development and function was obviously what Ilhan and Erdost must have had in mind, when they devised an experiment in the course of which they treated adolescent and adult mice with capsaicin (CAP) hoping to observe a change in the local expression ghrelin and subsequent changes in gonadal testosterone production.

"The animals were divided into two age groups: puberty and adult. Control groups for both age groups were fed with standard diet and experimental groups were fed with a diet containing 0.02% CAP. Testes were collected quickly after sacrifice. After dehydration, the specimens were embedded in paraffin and 5 μm sections were cut, and Crossman's triple staining and immunohistochemical staining for ghrelin were applied." (Ilhan. 2012)

The immunohistochemical stains of the testicular tissue the scientists conducted revealed that ghrelin was present in the testosterone producing Leydig and Sertoli cells of all animals. It was yet not expressed in any of the spermatogenic cells of either the adolescent or adult rodents.

The capsaicin treatment, on the other hand, reduced the immunoreaction in both groups - a clear sign of a local reduction in ghrelin.

Against that background and the previously cited findings by Tena-Sempera (as well as similar studies), it is not surprising that these local reductions in ghrelin went hand in hand with statistically significant increases in serum testosterone levels in both experimental groups, yet especially in adults (see figure 1).

Figure 1: Ghrelin and testosterone levels in response to control or capsaicin supplemented diet (base on Ilhan. 2012)

Since the increase in circulating testosterone took place in presence of an increase in systemic ghrelin levels, it is obvious that capsaicin does not block the release of ghrelin, but rather it's local effects - the exact mechanism, however has still to be elucidated.

The same goes for the beneficial effects of which is probably a "side effect" of the increase in testosterone, since any amelioration of the local inhibition of spermatogenesis in the the spermatogenic cells would require the presence of the "hunger hormone" in this cells. And, as mentioned above, the immunostaining did not reveal any significant amounts of ghrelin in the testes of both the treated and untreated animals.

Right, right, I don't bother about mechanisms as long as it works - So how much do I need?

Figure 2:  Capsaicin content (mg/100g) of different varieties of pepper fruits (Supalkova. 2007)

In view of all of these "may bes" and "could bes" the researchers conclusion that capsaicin "appears to enhance testicular cell proliferation and can affect the release of ghrelin and testosterone directly or indirectly" (Ilhan. 2012) is not very satisfying. If we do yet simply discard that we don't know why capsaicin boosts testosterone and further assume that the results will translate to human beings, capsaicin certainly sounds like an easy and cost-effective way to boost both testosterone and fertility, after all, the human equivalent of those 0.02% capsaicin amounts to no more than 200-300mg per day!

What may yet sound like a very reasonable for a good reason not achievable by eating peppers alone and could in fact burn right through your stomach lining. 

It stands out of question 200mg , that does not sound much, but if you take a closer look at the data in figure 2 you will be able to estimate that it will "taste" or rather "burn" like too much, already. After all, you would have to consume at least 100g of the ovaries  of the hottest variety of peppers the group of Czech researchers could find, when they did the analysis on which the data in figure 2 is based

Ovaries in a pepper? Are you serious? The "ovaries" are the parts inside a pepper on which the seeds are sitting... yeah, the stuffy you usually throw away, because you can't stand how "hot" it is (the illustration on the left a slightly modified version of figure 2 in Supalkova. 2007).

That said, milder varieties are obviously even less suitable, after all, you would need 1kg or even 10kg of the ovaries of those... Not exactly something anybody would expect to yield great health benefits, anyways, right?
So what about those  28-homobrassinolides, then? Those must be great, right?

I guess most normal people will immediately think of their touted cholesterol lowering effects, when they hear about "plant sterols". Not the average muscle-head, though for him (and mostly it's just "him" who falls for this idea) their structural resemblance to steroid hormones is what counts and their ability to totally mess up your own endocrine system is what is ignored as soon as the "Big T" is mentioned (click here to read all about the role of testosterone in building muscle). No wonder the "T-word" is also at the heart of the bro-scientific sales pitches the companies who are bottling respective products will have their reps propagate on the bulletin boards of the bodybuilding and fitness world. The scientific perspective is slightly different, though and the truth is probably, as so often, anywhere in the middle. And in this regards the recent study on possible pro-androgenic effects of 28-homobrassinolides (28-HB) that was founded on the rationale that 28-HB has been shown to ameliorate high blood glucose levels, while the latter have been shown to compromise testicular function and testosterone production is no exception.

Figure 3: Effect of 28-HB on lipid peroxidation, superoxide dismutase activity and catalase activity in rat testis (based on Premalata. 2012)

"Studies investigating the effects of 28-homobrassinolide (28-HB) on diabetic male rats indicated antihyperglycemic potency in this phytohormone. Since hyperglycemia was known to suppress testicular and ovarian steroidogenesis in the rat, it provided a basis for evaluating the biopotency of this oxysterol in rat testicular steroidogenesis. The present study was designed to elucidate the effects of 28-HB on testicular steroidogenesis in normal and streptozotocin (STZ)-induced diabetic rats." (Premalath. 2012)

Fortunately, though the researchers had a normal control group which received the same dose of 50µg of 28-HB in 50mL of 50% ethanol per day in their study. This gives the otherwise very artificial data at least some significance for the average, hopefully non-diabetic trainee as well.

A plant sterol that's obviously not for diabetics only

As the data in figure 3 shows all the expected beneficial effects on the streptozotocin-induced downregulation of superoxide dismutase (SOD) and catalase activity (CAT, as well as a reduction in reduced glutathione; not shown in figure 3) and partial reversal of the increase in lipid peroxidation were present in the diabetic rodents. And even in the healthy control, the ratio of anti- to pro-oxidant factors improved significicantly.

Figure 4: Changes in the levels of ABP and StAR protein, as well as testosterone in the testis of 28-homobrassinolide-treated rats (Premalatha. 2012)

The corresponding, or I should say "corollary" changes in steroidogenic acute regulatory protein (StAR), and androgen-binding protein (ABP) expression, but even more so increase in intratesticular (not(!) serum!) testosterone levels you see in figure 4 do however raise the question, whether what we are seeing here - specifically in the diabetic rodents - is actually (still) healthy or not (see figure 4).

To potent to be healthy?

In this regard it may also be worthwile to take into account what the scientists say about the enzymatic conversion of cholesterol to testosterone and how it may and does figure in this context:

"It is known that the synthesis of T in animal tissues is under the influence of 3b- and 17b-hydroxy steroid dehydrogenases. Increase in the activities of 3b- and 17b-HSD observed in the present study was suggestive of the active involvement of these enzymes in rat testicular steriodogenesis. Elevated 17b-HSD activity due to 28-HB was noted in relation to the elevated StAR content in normal rat testicular tissue. However, elevated 17b-HSD activity did not correlate with the StAR content of diabetic rat testis, suggestive of a disproportionate link between HSD activity and StAR content in the diabetic rat testis probably influenced by 28-HB. [...] It is reported that androgens reduced T biosynthesis in adult Leydig cells and in Leydig cell lines in an autoregulatory man-ner through receptor-mediated inhibition of StAR expression under normal physiological conditions. On the contrary, the increase in StAR protein level along with the relatively high level of T (figure 4) detected in the testis of male rats used in this study is due to the specific effect of the phytooxysterol 28-HB. Even though StAR and ABP were positively regulated by administered 28-HB, the observed increase in testicular
T content in diabetic rat is to be considered excessive." (Premalatha. 2012)

My gut feeling is that the attribute "excessive" Premalatha et al. use in their paper is absolutely spot on. And this goes despite the fact that similar yet way less pronounced effects effects have been observed in the absence of 28-HB administration simply as a result of streptozotocin administration in previous studies in both male and female rodents (Ho. 1991; Leaming 1982). These short term effects are probably a result of a skewed negative feedback at the level of the hypothalamus, where the increased circulating testosterone levels should actually lead to a corresponding decrease in gonadotropin-releasing hormone (GnRH). This regulatory mechanism, however does not work correctly in the early phase of STZ-induced diabetes, so that it take up to 120-140 days until a new "normal" and in this case supra-physological (= low testosterone) steady state is achieved.

Both, the questionable mechanism, as well as the "overshoot" in testicular testosterone levels and the absence of respective information on the levels of circulating testosterone -- what if it simply accumulated in the testis (remember the difference in systemic and local ghrelin in the capsaicin study!)? -- make the usefulness and even the safety of 28-HB as a test booster more than questionable.

Looking for more promising alternatives? Check out my previous post on "+180% Testosterone w/ Taurine"

Bottom line: If we go back to the original question whether one of the two supps could be the long-awaited breakthrough "natural" testosterone booster everyone expect me appears to be waiting for (what is "natural" about eating 100g+ of red pepper ovaries or using plant sterol extracts, by the way?), it appears as if none of the two would qualify.

Whether dihydrocapsiate, which has been pimped by Ajinomoto as a more potent, and safer fat burner than capsaicin and could be a more tolerable alternative to capsaicin, would even have the same effects on the testis is about as questionable as its value as a fat burner, of which Galgani and Ravussin found in 2010, already, that the <50kcal/day increase in energy expenditure in response to 1 month of supplementation with 9mg/day of the said capsiate "is in the range of day-to-day RMR variability" (Galgani. 2012) and therefore negligible.

Anyhow, in the unlikley case that some mad or sane scientists find non-negligible effects of supplementation with either dihydrocapsiate (or another more tolerable variety of capsaicin, such as a nano-encapsulated  for example) or 28-homobrassinolide in a future human trial, you know that the SuppVersity is the place to go to read about those results first, right?

References:

• Galgani JE, Ravussin E. Effect of dihydrocapsiate on resting metabolic rate in humans. Am J Clin Nutr. 2010 Nov;92(5):1089-93.
• Ho SM. Prostatic androgen receptor and plasma testosterone levels in streptozotocin-induced diabetic rats. J Steroid Biochem Mol Biol. 1991;38(1):67-72.
• Ilhan T, Erdost H. Effects of capsaicin on testis ghrelin expression in mice. Biotech Histochem. 2012 Sep 27.
• Kwon DY, Kim YS, Ryu SY, Cha MR, Yon GH, Yang HJ, Kim MJ, Kang S, Park S. Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats. J Nutr Biochem. 2012 Sep 28. pii: S0955-2863(12)00213-6.
• Leaming AB, Mathur RS, Levine JH. Increased plasma testoster-one in streptozotocin-diabetic female rats.Endocrinology.1982; 111(4):1329-1333.
• Premalatha R, Jubendradass R, Rani SJ, Srikumar K, Mathur PP. A Phytooxysterol, 28-Homobrassinolide Modulates Rat Testicular Steroidogenesis in Normal and Diabetic Rats. Reprod Sci. 2012 Sep 25.
• Supalkova V, Stavelikova H, Krizkova S, Adam V, Horna A, Havel L, Ryant P, Babula P, Kizek R. Study of Capsaicin Content in Various Parts of Pepper Fruit by Liquid Chromatography with Electrochemical Detection. Acta Chim. Slov. 2007, 54, 55–59.
• Tena-Sempere M. Ghrelin: novel regulator of gonadal function. J Endocrinol Invest. 2005;28(5 Suppl):26-9.

When Hype Meets Reality: D-Aspartic Acid Turns Out to Be Another Supplemental Nonstarter in First Human Trial With Any Relevance for Healthy Young Men

Training "on" D-Aspartic Acid is like training on guar gum.

Busted! D-Aspartic acid aka DAA is another "natural anabolic agent" that turns out to be more of a revenue- than a hormone-booster with muscle building prowess. And you know what? It took Darryn S. Willoughby and Brian Leutholtz from the  Exercise and Biochemical Nutrition Lab, Human Performance, and Recreation at Baylor University exactly 28 days and 20 apparently healthy, recreationally active, resistance trained (3x per week or more in the past year) men with an average age of 22.8 ± 4.67 years (BMI 24.65 kg/m²) to prove that d-aspartic acid (DAA) supplements belong to this never-ending list of supplemental non-starters.

Things that work: 28 days, 4x per week heavy resistance training; things that don't work DAA capsules

Willoughby and Leutholtz assigned their participants in a random, double-blinded fashion to one of the two study arms. Subjects in both arms of the study followed a standardized periodized 28-day resistance training program split into 2 upper-extremity (A1, A2) and 2 lower-extremity (B1, B2) exercise sessions each week. With an overall training volume of 16 exercises sessions with 9x upper- and 8x lower-body exercises

• A1, A2 - upper body: bench press, lat pull, shoulder press, seated rows, shoulder shrugs, chest flies, biceps curl, triceps press down, and abdominal curls
• B1, B2 - lower body: leg press, or squat, back extension, step ups, leg curls, leg extension,heel raises, and abdominal crunches

the same workout hat shown to elicit significant improvements in body composition in two previous studies on VPX' preworkout products (learn more; cf. Shelmadine. 2009; Spillane. 2011). The participants performed 3 sets of 10 repetitions at 70% - 80% of the previously established 1-RM for all exercises and had 2 minutes of passive rest between the sets. Contrary to the said VPX studies, the participants had to refrain from taking any kitchen-sink pre-/post-workout supplements, as well as the obvious roids, prohormones or other ergogenic substances that would compromise the study results. Instead, they received either...

• 4 capsules containing 3 g of guar gum (PLA), or
• 4 capsules containing 3 g of D-ASP (Better Body Sports, Ventura, CA, USA)

The dosing was identical to the manufacturers recommendation and based on the previous study by Topo et al. (2009) that caused the whole DAA hype back ~5 years ago (see figure 2, as well).

Figure 1: Endocrine and body composition changes with placebo or DAA supplementation (Willoughby. 2013)

That fact the whole hoopla was exactly that: All hype! is difficult to refute, if you take a look at the study outcomes in figure 1 or the researchers' conclusion:

"[...] 28 days of D-ASP of supplementation at a daily dose of 3 g is ineffective in upregulating the activity of the HPG axis and has no preferential effects in which to increase skeletal muscle mass and strength in resistance-trained men." (Willoughby. 2013)

In their discussion of what might be the physiological reasons for the non-existent effects on the gonadal production of testosterone the researchers state:

Figure 2: Comparison of the hormonal effect of DAA in sedentary men with low testosterone levels (Topo. 2009) vs. trainees with normal to high levels of testosterone (Willoughby. 2013)

"Based on our data presented herein, this [=the fact that the serum levels of DAA were higher than normal, but nothing happened] may indicate another potential mechanistic reason why the HPG [hypothalamus > pituitary > gonads] axis was not affected by D-ASP supplementation. Although we observed nonsignificant increases in serum D-ASP in the DAA group, we showed significant increases in DDO levels in response to D-ASP supplementation. The degradative role of DDO is to catalyze the oxidative deamination of D-amino acids to generate the corresponding 2-oxo acids, along with hydrogen peroxide and ammonia (or methylamine).

In rodents, the administration of D-ASP was shown to increase DDO activity (Nagasaki. 1994; Yamada.1989), suggesting that DDO activity is induced by increased levels of D-ASP. Based on this information, in the present study, it is possible that because of the higher baseline levels of testosterone, as a means of androgen-regulated feedback of the HPG axis, the level of serum D-ASP induced by supplementation was conceivably being degraded by DDO at a rate that rendered it unable to effectively activate the HPG axis." (Willoughy. 2013)

Or to put is simply: If DAA works at all, it works only in guys like the participants of the 2009 study by Topo et al. who had baseline testosterone levels at the lower end of the normal range (4.5ng/ml) at the beginning of the study and average levels (6.4ng/ml) at the end of the study period. In trained athletes with testosterone levels in the range of 8ng/ml such as the guys in the Willoughby study the negative feedback will prevent any further increase in testosterone.

---

Does testosterone actually build muscle and are natty test boosters worth your money? (learn more)

Bottom line: Before we have counter-evidence (this is science guys, you can't say something definitive based on one study) there is no good reason for someone with normal testosterone levels to spend money on D-Aspartic acid supplements.

Whether the same would be true for guys on post-cycle therapy or those who want to combat diet- / overtraining induced reductions in testosterone would certainly be worth investigating. Other aspects that could make a difference are the form of delivery (although this did not seem to be a problem; after all the DAA levels rose) and the provision of adjuvants to block the negative feedback on the HPG (see explanation above).

References:

• Nagasaki H. Gender-related differences of mouse liver-D-aspartate oxidase in the activity and response to administration of D-aspartate and peroxisome proliferators. Int J Biochem 1994;26:415–23.
• Shelmadine B, Cooke M, Buford T, Hudson G, Redd L, Leutholtz B, et al. Effects of 28 days of resistance exercise and consuming a commercially available pre-workout supplement, NO-shotgun, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers in males. J Int Soc Sports Nutr
  2009;6:16.
• Spillane M, Schwarz N, Leddy S, Correa T, Minter M, Longoria V, et al. Effects of 28 days of resistance exercise while consuming commercially available pre- and post-workout supplements, NO-shotgun and NO-synthesize on body com position, muscle strength and mass, markers of protein synthesis, and clinical safety markers in males. Nutr Metab (Lond) 2011;8:78
• Topo E, Soricelli A, D'Aniello A, Ronsini S, D'Aniello G. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. Reprod Biol Endocrinol 2009;7:120
• Willoughby DS, Leutholtz B.  d-Aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men.  Nutrition Research, Available online 15 August 2013. 
• Yamada R, Nagasaki H, Nagata Y, Wakabayashi Y, Iwashima A. Administration ofD-aspartate increasesD-aspartate oxidase activity in mouse liver. Biochim Biophys Acta 1989;990:325–8.

Brocebo? Add 10kg to Your Bench in Days with Sugar-Based "Anabolic Steroids". Old Study Shows, Many "Natural Anabolics" Could Work Solely via Placebo Effects

Image 1: If you start thinking about whether or not the product you just bought at your local supplement store works, it is - for a non-negligible amount of supplements - unlikely that you will see any results (photo Scientific American)

I guess, I don't have to tell you what the term "placebo effect" stands for, right? It is the occurrence of an effect that - assuming the effect could speak - would say of itself "placebo", i.e. "I am pleasing" (1st person singular, presence active from lat. "placere", i.e."to please" ). And while the medical establishment is still arguing, whether it was feasible, and, in view of the fact that this must obviously happen unbeknown to the patient, even ethical, to deliberately exploit the placebo as a "medical" treatment strategy, there are certain supplement companies that generate up to 90% of their revenue from a allegedly muscle-packed cousin of the placebo effect, the brocebo effect. And while public statements in "logs" (mostly in form of customer diaries on bulletin boards) like "I felt f*** great on product XYZ" are usually subject to a healthy amount of skepticism, it is quite amazing how willingly people make buying decisions on non-verifiable strength and size gains (the latter are rarely supported by diagnostically convincing photos) from men and women, they have never met before.

Your testbooster works, but mainly on your brain

About 12 years ago, Constantinos N. Maganaris, Dave Collins and Martin Sharp from the Universities of Manchester and Edinburgh tried to elucidate how potent these pla- or brocebo effects (whatever you want to call them) really are (Constantinos. 2000). In a well-controlled, yet relatively small-scale trial, the supplied a group of 11 national level powerlifters, who had been training in a team that was coached by the lead author of the study for two years. The latter may initially sound insignificant, the level of trust the previously non-using athletes had in their coaches must yet be considered one of the determinants of the strength of the placebo effect - specifically in view of the fact that the lifters who were selected for the trial had previously "approached the coach as a group and asked him for advice on effective use of AS", which, by the way, had instigated the whole investigation.

How to Spot a Nutraceutical Rip-Off - I want to use this chance for a shout-out, not just because I owe it to my friend Sean Casey from CasePerformance that I originally took notice of this study, but also because Sean has a nice compilation of tips on how to spot a neutraceutical rip-off on his website... a compilation, by the way, you should better not read too carefully, if you like to use test-boosters, pump-supplements and the like. After all, this could totally compromise their brocebo-powered muscle building, fat burning effects ;-)

To test the hypothesis that the mere belief in taking an anabolic steroid would already elicit profound effects on the performance of the lifters, Constantinos and his colleagues came up with a two-part testing + supplementation regimen that looked as follows:

• Trial 1: Bench press, deadlift, squat and 1-RM test after the ingestion of a capsule of which all participants were told that it contained a powerful anabolic steroid
• Two training weeks: In the subsequent two training weeks the subjects were instructed to take the rest of the steroids they had been given at the first trial.
• Trial 2: Half of the subjects were informed that the tablets they had taken contained nothing but sugar, while the others performed the 2nd trial in the belief that they had been taking steroids for two weeks now.

Before the second trial, the subjects had been questioned about their past training experiences and what they would expect from the second trial. At this point all subjects still believed that they had been ingesting anabolic steroids over the past two weeks and reported that they had experienced an "increased vigor during training" and had been able to lift "either heavier weights or complete more repetitions than their previous bests" (What? That sounds like the bro on "Brobolic 2000" from your favorite bulletin board?). Only afterwards were 5 of the 11 subjects told that the "anabolic steroids" they had been taking were nothing but sugar pills - it's probably not astonishing that the majority thusly refused to take their last pill right before the test and, ...

Figure 1: Increase in bench press, deadlift and squat 1-RM (in kg) in trial I and trial I of the study; lifters who still believed they were taking steroids on the left, lifters who were informed about the placebo nature of their "steroids" before the second trial on the right (data adapted from Constantinos. 2000)

... as the data in figure 1 clearly indicates, lost all their "steroid induced" strength gains. The six participants who still believed they were juicing, on the other hand, maintained, and in the case of the bench press, even upped their strength gains in the second session. With a 2x3 (Group x Trial) ANOVA test revealing "significant main effects for Trial: Bench Press (p<.001); Dead Lift (p<.001) and a significant interaction between Group and Trial [for] Bench press, Deadlift and Squat (p<.001)".

Increase your bench, deadlift and squat by 5% within days!

With baseline bench press, deadlift and squat 1-RMs, of 205kg, 260kg and 240kg, the relative placebo-induced increases amounted to ~5% - pretty impressive for an "all-natural" anabolic like sugar, right?

Image 2: Those pills don't look legit. They must be red and labeled *-bol or *-drol if they are supposed to work.

Now, if we, obviously purely hypothetically, assume that the aforementioned likewise hypothetical product "Brobolic 2000" contained nothing but sugar, and if we further assume that the bro was not lying, when he posted on your favorite board that his strength "[...]went through the roof within the first days already! +10kg on my bench!" Wouldn't it be fair to say that the supp-company that produces "Brobolic 2000" did not lie, when they promised "immediate results"? I guess it would, right? And wouldn't it also be fair to say that not only the production of sugar pills, but more importantly the marketing, which is the fundamental determinant of the products effectiveness, did cost money?

I will leave it to you to complete this train of thought, and rather remind you that you as an educated reader of the SuppVersity are at a definite disadvantage compared to people like the bro on your board - you simply know too much, to take "advantage" of the bulk of effectively useless supplements on the market.

Ursolic Acid and The Narrow Line Between Anabolism and Myotoxicity: +25% Increased Protein Accretion in In-Vitro Study, But Cell Death With 2x "Effective" Dose

Image 1: "An apple a day keeps the doctor away!" And though the ursolic acid in its peel may be part of the underlying mechanism, this does not make it a "natural anabolic", but rather another item on the list of "healthy stuff from real food"

The number of purported natural anabolics increases year by year. Against the background that most of these products are nothing but supplemental nonstarters in shiny bottles and boxes with "non-FDA approved" promises of "unparalleled muscle growth" on them, the recent release of a broad range of ursolic acid supplements must already be considered a "highlight". With a peer-reviewed rodent studies backing its anti-catabolic, pro-anabolic properties (Kunkel. 2011), it appears as if ursolic acid could be more than another potent placebo. And if we put things into perspective, in the end its potential beneficial effects on skeletal muscle hypertrophy are rather negligible compared to its previously proposed role as a therapeutic compound in various conditions such as Alzheimer’s diseases (Wilkinson. 2011), cancer (Kim. 2000; De Angel. 2010; Pinon. 2011), and diabetes (Zhang. 2006; Jayaprakasam. 2006).

More ain't more, but toxic! And even less is probably more than you can get.

Only recently, Vandré Casagrande Figueiredo and Gustavo A. Nader were able to confirm the muscle building effects in an in-vitro study using C2C12 myoblasts which were incubated with different concentrations of ursolic acid for 72h (Figueiredo. 2012).

Figure 1: Protein content and cell viability after 72h incubation with different concentrations of ursolic acid (in µM); light bars p > 0.05, statistically non-significant (data calculated based on Figueiredo. 2012)

As you can see in figure 1, this treatment lead to dose-dependent increases in protein accretion in the muscle cells. These increases reached statistical signficance only in the 10µM group (their real-world significance is even more questionable, as we don't know if similar concentrations can even be achieved by oral administration of ursolic acid).

The profound loss of protein in the higher dose groups and the subsequent decrease in cell viability, on the other hand, are statistically highly significant. Their real world significance does yet appear to be even more questionable, after all, it is rarely possible to double the serum concentration of a given substance by just ingesting twice as much. At the dosages that are present in the currently available supplements myotoxicity, as it was observed in this in-vitro study, is thusly probably not a real concern.

No reason to be afraid, but no reason to expect grandiose results, either

Image 2: These muscles were not build on ursolic acid - that's for sure.

In other words, while the study at hand did help us to elucidate the underlying mechanism of previously reported benefits under mostly atrophic (=muscle loss) conditions, its overall real-world significance in view of the negative, but also in view of the positive effects appears to be more than limited. If you also take into consideration that the scientists were able to rule out that ursolic acid exerts hyperplastic (cell proliferation) effects on skeletal muscle tissue, that its "muscle building" effects (referring to the increased protein accretion observed in the study at hant) was highly dependent on the presence of additional growth factors in the culture medium and that ursolic acid did not increase the myocyte RNA levels, it remains questionable whether the ingestion of respective (most certainly underdosed) supplements will produce any significant improvements in training and diet induced skeletal muscle hypertrophy.

In the end, the new data stand in line with the observations of Kunkel et al. who identified an increase in skeletal muscle insulin sensitivity and subsequent upregulation of the IGF-1 induced growth response as the underlying cause of the atrophy-inhibiting effects or ursolic acid. What can be said for sure, however, is that the currently available OTC supplements are in no way "muscle builders". According to the currently available research, they should rather be filed under "health supplements", along with alpha lipoic acid and the like. Now, that does obviously not exclude that the health improvements - above all the improvements in insulin sensitivity could not help you build muscle - the label "natural anabolic" does yet still appear largely misplaced.