A variety of medications have been developed and prescribed to anxious/depressed individuals over the years; however, these “solutions” can also produce a variety of adverse effects (including ones affecting your sexual health and performance).[1,2,3,4]
This can result in stopping treatment and leaving individuals right back where they started (or in worse condition).
Natural therapies for anxiety and depression have existed for centuries, and modern science has begun to uncover the various mechanisms behind these age-old remedies.
Today we’re looking at one of the most common calming agents on the market, with a spotlight feature on its key active ingredient -- chamomile and apigenin.
Chamomile is one of the most popular herbal remedies around the world and can be found in the pharmacopeia of 26 countries.[5] Traditionally, it is brewed as an herbal tea to help relieve feelings of stress and set the stage for a peaceful night’s rest.
Various extracts of the herb have also been used for quite some time in relaxation supplements and sleep aids. Previous research has demonstrated that using chamomile may help to reduce worrying as well as depression.[6,7,8]
At the heart of chamomile’s calming effects are a slew of bioactive compounds, including flavanoids, with anxiogenic and anxiolytic properties. One, in particular, has skyrocketed in popularity and usage in the industry, thanks in part to being mentioned on Andrew Huberman’s podcast (though, truth be told, I first came across the ingredient in Glaxon’s Tranquility).
The alkaloid to which I am referring is none other than apigenin.
Apigenin is a flavonoid structurally similar to other well-known botanical bioactives, including quercetin, luteolin, and kaempferol.
It’s primarily found in celery, parsley and chamomile, but it can also be synthesized in the body from the amino acids phenylalanine and tyrosine.[9]
Pay attention to this last point, because it will be of interest later on.
Researchers have shown that apigenin possesses a wide range of noteworthy effects, including[9,14]:
Despite the structural similarities, apigenin offers some rather intriguing benefits in regard to mood, mental well-being, and cognitive function.
Apigenin exerts its calming effects due to its ability to cross the blood-brain barrier (BBB), a highly selective, semi-permeable membrane that allows certain compounds to enter while restricting other ones, thereby offering neuroprotection.
Research indicates that apigenin possesses a greater ability to cross the blood-brain barrier than other popular flavonoids/antioxidants, including quercetin, rutin, and hesperidin. The only two flavonoids that were superior to apigenin (as found in this study) were genistein (a phytoestrogen found in soybeans) and isoliquiritigenin (a component of licorice).[10]
After crossing the blood-brain barrier, apigenin has an affinity for the GABAA-receptor.
GABA is the primary inhibitory neurotransmitter, and GABAA receptors are a major target for drugs used to treat anxiety and other neuropsychiatric disorders.[11]
Researchers also posit that apigenin may possibly improve mood and reduce feelings of anxiety via modulation of dopamine, serotonin, and noradrenaline.[9,12]
Additionally, apigenin can inhibit both MAO-A and MAO-B -- an enzyme that metabolizes certain neurotransmitters, including dopamine.
Lastly, studies demonstrate that apigenin stimulates the uptake of L-tyrosine, a dopamine and noradrenaline precursor.[13]
Research on direct supplementation with apigenin in humans is severely lacking. That being said, apigenin has a low toxicity and is considered by researchers to be safe, even when consumed in larger amounts that what is commonly seen in dietary supplements.
Speaking of dietary supplements, the typical apigenin dosage included in most products ranges between 25-50mg.
Studies finding a reduction in anxiety from chamomile supplementation used chamomile extracts standardized to a content of 1.2% apigenin.[6,7,8]
Participants in those studies received between 1,100-1,500mg of chamomile extract (std. to 1.2% apigenin), yielding 13.2-18mg apigenin.[6,7,8]
Earlier studies in mice that initially documented apignenin’s anxiolytic effects used much higher dosages (10-100mg/kg).[15]
To convert the dose from mouse to human equivalent dose, divide it by 12.3, and then multiply by your weight in kilograms.[16]
Converting to a Human Equivalent Dose for an 80kg male (176lbs), you would need to consume between 65-650mg.[16]
Keep in mind that at the upper end range of dosing (30-100mg/kg in mice), apigenin was noted to exert a strong sedative action.[16]
Apigenin has low toxicity, and both apigenin and chamomile are considered safe, even when consumed long-term.
Apigenin is a biopharmaceutics classification system (BCS) class II substance, which means it has very low solubility in water coupled with a high permeability.[17]
This essentially means that apigenin has low bioavailability due to not dissolving very well in water, BUT it is readily absorbed in the gut.
As a result, various delivery-enhancing techniques (phytosomes, liposomes, polymeric micelles, nanosuspension, etc.) may be a superior option vs isolated apigenin.[18,19,20,21]
That being said, few (if any) products on the market include an “enhanced” form of apigenin.
Like many supplements, apigenin (mechanistically) is very intriguing, lacks adequate research in humans, and has been overhyped by many outlets.
Nevertheless, it does have a high safety profile, and could be worth trying.
When introducing any new supplement into your regimen, keep everything else constant (diet, exercise, daily supplement intake, etc.) to eliminate as many variables as possible, buy from a reputable supplier, and start on the lower end of the dosing range.
Would apigenin be on my “top 5” for stress-relieving supplements?
No, but if you’ve already tried (are using) the likes of ashwagandha, theanine, bacopa monnieri, magnolia bark extract, lemon balm extract, and/or saffron, then apigenin is worth consideration.
What’s your opinion on apigenin?
Are you using it for stress management, testosterone support, or another reason?
Regular readers and savvy supplement connoisseurs are well-acquainted with AstraGin, the flagship ingredient of NuLiv Science, that improves the absorption of amino acids and promotes gut health by reducing inflammation. I’ve previously discussed the ingredient on various podcasts, and, a few months back, I wrote an in-depth review of the first human clinical trial showing that 50mg of AstraGin significantly increased arginine absorption.[1]
NuLiv recently published the findings of its most recent human clinical trial on AstraGin showing that not only does it increase arginine levels, but it may support cardiovascular health from a lesser-known avenue.
Let’s see what’s cooking!
30 healthy volunteers (20-80 years of age) participated in the randomized, double-blind, placebo-controlled, crossover trial.[2] The benefit of a crossover trial is that each subject serves as their own “control.”
Subjects were given 50mg of AstraGin or placebo (maltodextrin) capsule at 9 p.m., and then fasted for 12 hours (water was allowed). At 9 a.m. the following morning, the first blood sample was collected, and immediately, all subjects ingested the AstraGin (50mg) or placebo capsule along with 5g of arginine mixed with 250 mL (8.8-oz) of water.
Additional blood samples were collected at 15, 30, 45, 60, 90, 120, 150, and 180 minutes for the purpose of analyzing the plasma concentration of arginine. After a one-week washout period, the test product was replaced with the placebo (or vice versa) to repeat the experiment.
Six subjects were excluded due to incomplete data or large individual variabilities in the blood sample results. Therefore, the data of 24 subjects were ultimately included in the final results.
Researchers found that (on average) the area under the curve (AUC) of arginine significantly increased by 17.3%, and the maximum concentration rose by 11.1%. Moreover, AstraGin supplementation reduced ADMA levels by 42.5% and increased the Arginine/ADMA ratio by an astounding 167.1%![2]
Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO production by competing with arginine for binding to nitric oxide synthase (eNOS) -- the enzyme that catalyzes NO synthesis in blood vessels. Reduced NO production impairs endothelial function and contributes to the development/progression of atherosclerosis (narrowing of the arteries).
Based on these facts, researchers are beginning to consider the ratio of arginine/ADMA as a better predictor of nitric oxide production (and thus cardiovascular health) compared to focusing solely on levels of arginine or ADMA.[2,3]
Additional cell studies have shown that elevated ADMA levels in skeletal muscle inhibit glucose uptake and may serve as a biomarker for insulin resistance.[4]
This most recent clinical study further adds to the body of evidence that AstraGin is a no-brainer for pre workout supplements and other amino acid supplements (EAA formulas, protein powders, etc.), especially if they include L-arginine (which suffers from poor bioavailability).
It also can’t be overlooked that, despite the number of studies already conducted on AstraGin, NuLiv continues to support on-going research efforts to further establish the credibility of AstraGin (which can't be said of many other popular trademarked/branded ingredients).
From a formulator or brand owner’s perspective, AstraGin is an ideal inclusion in products -- it’s economical, backed by multiple studies, and offers a range of benefits across multiple product categories (pre workouts, pump enhancers, intra workouts, EAA supplements, BCAA supplements, nighttime recovery aids, cardiovascular support supplements, gut health supplements, etc.).
Going forward, I’d personally like to see companies include 50mg as the minimum dose and/or NuLiv make it a part of their license agreement that any brand using AstraGin must use a minimum of 50mg of AstraGin per full serving.
What do you think of the new findings?
Hi-Tech Pharmaceuticals (“Hi-Tech”) has been around for over 25 years (longer than many of you reading this, as well as yours truly, have been using sports nutrition products). When I first started writing in the industry, Hi-Tech was one of the biggest ad-buyers/sponsors for the website, and I got to try quite a bit of different product offerings from “Papa Jared” (Jared Wheat, President & CEO of Hi-Tech), including their DMAA-laden pre workout behemoth…MESOMORPH!
My first encounter with Mesomorph was other-wordly. Until that first magical, PR-shattering scoop, I had only ever used low-to-moderate stim pre workouts, of which caffeine was the only stimulant included in it. Gains were made with the “entry-level” pre workouts, but holy mother of Edison, my first scoop of Mesomorph was an experience I have not had since then (that may have to do with the fact that DMAA is an amphetamine-like compound, not found in nature…)
Truth be told, DMAA was a beast, and Hi-Tech/Papa Jared championed the fight against the FDA that DMAA was a “naturally occurring constituent” of various botanicals, including geranium. Despite some salacious reporting and poorly-executed research, DMAA (consumed is a responsible amount by an otherwise healthy individual) doesn’t present any life-threatening risks (unless you perceive tunnel-vision focus and run-through-the-wall intensity as a “risk”). For better or worse, DMAA has been excluded from pre workouts for several years.
Nevertheless, Hi-Tech has evolved past DMAA (as have many other brands), using other aggressive stimulants, including DMHA (2-aminoisoheptane), acacia rigidula extract, Senegalia Berlandieri extract (contains various PEA-relatives), theophylline, and isoproplynorsynephrine (isopropyloctopamine).[1,2,3]
As of July 16, 2023, Mesomorph is no longer offered on Hi-Tech’s website, but a new(ish) pre-workout has been unveiled…Krank3D.
Upon seeing the newsletter blast land in my inbox announcing the arrival of Krank3D, my curiosity was piqued, and I decided to check it out.
As you’ll see, I was vastly underwhelmed by the ingredients panel, but let’s start with the “good.”
Beta alanine is the preeminent tingle-inducing endurance supplement that’s been a staple inclusion in pre workouts for well over a decade. It binds with the amino acid histidine to form carnosine -- a powerful intracellular buffer that helps clear acidic (H+ ions) which delays the onset of fatigue.
Beta alanine has been studied across various daily dosages from 3.2-6.4 grams per day, usually consumed in multiple 1.6 gram dosages. Something to keep in mind is that beta alanine doesn’t offer any acute performance benefit, unless you consider your lips and ears tingling ergogenic.
Depending on your daily dose and consistency of consuming beta alanine, you’ll generally reach saturation between 4-8 weeks, at which point your muscles will benefit from increased buffering capacity.
More often than not though, beta alanine is included to lead uninformed consumers to believe the product is hitting “harder.”
Make no mistake, this is where the actual nitric oxide amplification resides in Krank3D…not the following “N.O. Amplification Matrix.”
Citrulline is well-known to you all -- it is more effective at raising plasma arginine levels than L-arginine. It improves nitric oxide production, boosts athletic performance, delays the onset of fatigue, and supports cardiovascular health.
Citrulline has been studied across a range of dosages, from as low as 2.4 grams up to 10 grams.
Citrulline silicate is a “novel” form of citrulline, that Hi-Tech is likely including to “riff” on Nitrosigine (inositol-stabilized arginine silicate). While arginine suffers from poor bioavailability, citrulline does not. So, I can’t really see the point of including citrulline silicate other than window dressing and to dupe consumers into thinking there is some other benefit to be had from the silicate component (which there isn’t).
I swear we must be back in the 1990s if L-Arginine HCL (or AAKG) is leading off your pump blend. Arginine HCl has terrible bioavailability (as you well know), which is why most reputable sports nutrition companies have switched over to Citrulline/Citrulline Malate or Nitrosigine for boosting plasma arginine levels.
Yes, there are a couple of studies showing that a combination of citrulline + arginine (1.2 grams of each) is effective[5], but those studies were funded by Kyowa Hakko -- a provider of amino acids and patent holder of Setria L-glutathione. But, a March 2023 narrative review concluded that:
“both recreational and trained athletes did not see improved physical performance or increased nitric oxide (NO) synthesis with 0.075 g or 6 g doses of Arg [arginine] supplement per body weight. However, 2.4 to 6 g of Cit per day for 7 to 16 days of various NSs had a positive impact, increasing NO synthesis, enhancing athletic performance indicators, and reducing feelings of exertion.”[6]
Given that Krank3D already has a quality dose of citrulline (from Citrulline silicate and L-Citrulline), the additional L-Arginine, at worst, offers no benefit. At best, it may further support NO production.
Given the 1,525mg prop blend, and that Arginine HCL is first, I’d guess there’s between 750-1000mg of L-Arginine HCL.
Well, well, well.
We finally have something interesting to sink our teeth into!
Viewing the Krank3D product label as well as reading the product write-up, you’ll see that it’s very heavily emphasizing arginase inhibition. Arginase is the enzyme that breaks down arginine (the “fuel” for NO production). By limiting arginase activity, arginine levels will remain higher for longer, which supports greater nitric oxide production, blood flow, nutrient delivery, exercise performance, and pumps.
Conventional arginase inhibitors found in pre workouts supplements include the likes of norvaline and agmatine. Norvaline is seen infrequently these days thanks to a cell study that was published a few years back finding it was toxic to brain cells. I’ve covered that study before on the SuppEngr.com blog. Suffice it to say that the headlines greatly exaggerated the actual study and its findings.
But, when you dig into the literature on norvaline, you’ll see that it’s really not a very effective arginase inhibitor.
Krank3D brings something new to the table…(S)-(2-boronethyl)-L-cysteine HCl (BEC).
I was unfamiliar with this ingredient…it’s been years since I’ve used a Hi-Tech pre workout, and while it may have been included in other formulations, including Plasmagen (which was renamed after Gaspari separated from Hi-Tech and took PlasmaJet, their capsule pump pre workout, with them).
While there isn’t much human research on BEC, various animal and cell culture studies have shown it to be an effective arginase inhibitor.[7,8,9]
The human equivalent dose reported in the study that investigated BEC administered via inhalation was 8mg.
A major limitation of effective arginase inhibitors, though, is the cost. A 2009 study stated that based on catalog prices at the time that a mere 50mg of BEC costs $1300![8]
Checking a few other suppliers, the current day cost for 50mg of BEC is between $924-2800![10,11]
Using current day prices, that means the cost of including 8mg of BEC in a single serving of Krank3D is between $148-448. Again, that’s per serving…never mind the other ingredients that are included in the product.
Given that an entire tub of Krank3D costs $70 (likely less with a discount code), Krank3D either has such a trivial amount of BEC that it offers no real world effects or doesn’t include any BEC at all. Personally, I’d be very curious to have this product tested by a 3rd party…
Furthermore, on the product page of Krank3D, Hi-Tech states, “no other supplement company has figured out how to tackle the arginase problem head-on... to take arginase out of the NO equation!”
Hi-Tech may have “figured out how to tackle the arginase problem head-on…” but they have actually solved it since they don’t put an efficacious dose of BEC in Krank3D, in my opinion.
No, that’s not a typo…Krank3D (as well as other previous pre workouts from Hi-Tech) include a red wine extract standardized for 30% glycerol.
An immediate thought that jumped to mind as well as an industry colleague who I reached out to was, “Why would you extract glycerol from red wine grapes?!”
To put things into perspective, research notes that the average concentrations of the major constituents of red wine are[12]:
Typically, grape skins or grape seeds are standardized for polyphenols, not glycerol…just imagine how expensive (and unnecessary) that process would. A more cost-effective and beneficial solution would be to just use a high-yield glycerol supplement (HydroMax, GlycerPump, 3DPump-Breakthrough, etc.) + red wine (grape skin) extract for your polyphenols.
Taurine is a versatile amino acid that is part cell-hydrator (osmolyte), part antioxidant, and part ergogenic. It’s stored, primarily, in the heart, brain, and skeletal muscle tissue, and has been the subject of previous Patreon articles.
When included in pre workouts, taurine is usually dosed between 500-2,000mg (though there are outliers). A 2021 systematic review concluded that “taurine supplementation (2 g three times daily) with exercise can decrease DNA damage…1 g of acute taurine administration before or after exercise can decrease lactate levels.”[13]
Personally, I like taurine, not only for its ergogenic and hydrating potential but also its antioxidant and organ support qualities (namely for the heart and liver). I’d guess that Krank3D includes 1,000mg of L-Taurine, which is one of the few appropriately-dosed ingredients in the product.
Creatine is awesome. It’s the most studied, consistently demonstrated effective supplement in the history of sports nutrition. As I’ve said in other articles, creatine is the standard against which all other sports nutrition supplements are compared.
In combination with proper nutrition and training, creatine offers numerous benefits, including increased performance, improved energy production, greater lean mass gains, enhanced recovery, and better hydration. Creatine has even been found to offer cognitive benefits.
To get these benefits, creatine needs to be taken consistently between a dose of 3-5 grams.
In Krank3D, creatine is the second of four ingredients in a 2,980mg prop blend, which means you’re not getting anywhere close to 3g of creatine monohydrate. My guess is that you’re getting about 1g of creatine here.
Having an extra gram of creatine in a pre workout certainly isn’t a bad thing, but it’s also misleading to consumers to advertise the benefits of creatine in your pre workout when it doesn’t offer a clinically-backed amount.
Agmatine is a fascinating compound, and I’ve discussed at length the nootropic/neuroprotective potential of this multi-faceted supplement. Pre workout veterans will recognize agmatine as a popular component of the pump matrix. Typically, it’s included for its ability to stimulate eNOS and possibly limit arginase activity.
The usual form of agmatine found in supplements is agmatine sulfate. Hi-Tech includes agmatine silicate.
Now, you may be wondering why you use the silicate form. Well, there are no studies that I can find (cell cultures, rats, humans, etc.) using the silicate form of agmatine. Scouring the internet for any reference to this ingredient, I came upon an older Bodybuilding.com thread, and apparently this variation of agmatine surfaced shortly after the first several studies on Nitrosigine (inositol arginine silicate) were published, demonstrating improved bioavailability.
The thinking (I’m assuming) is that “bonding arginine to silicate yielded better results, so we should do the same with agmatine” and instead of actually performing studies on this particular form of agmatine, the creators/marketers of agmatine silicate will use “borrowed” science.
Here’s the issue though…
Arginine has terrible bioavailability. Agmatine does not…neither does citrulline, for that matter (citrulline silicate, as discussed above is included in Krank3D).
Until some actual research is carried out using silicate-bonded forms of agmatine and/or citrulline, I can’t see any reason to include these other than to try to differentiate your product and dupe customers into thinking they’re getting something “superior” to the actual supplement forms more commonly used in pre workouts (as well as studied and shown to be beneficial in humans).
There’s also this gem from the Wicked Pre Workout product page explaining the benefits of agmatine silicate:
“Supplementing with agmatine silicate will yield a metabolic cascade that provides the benefits above and importantly promotes leanness and muscle building. Agmatine Silicate increases appetite even when full, making it easier for underweight individuals to gain weight and muscle.”
No, no, no…
There is no study in humans to confirm increased appetite. There is a rat study from 1996 which found that acute agmatine administration increased caloric intake and dietary carbohydrate preference in satiated rats. “However, agmatine does not modulate caloric intake in hungry rats. Furthermore, repeated administration of high doses of agmatine does not decrease its ability to stimulate appetite.”[14]
A separate 2011 rat study found that injections of agmatine increased appetite via the supplement’s effects on neuropeptide Y.[15] However, researchers found that combining agmatine with yohimbine reduced the appetite-stimulating potency of agmatine. Krank3D includes both agmatine and yohimbine…which pretty much negates the product page hype stating “Agmatine Silicate increases appetite even when full, making it easier for underweight individuals to gain weight and muscle.”
Suffice it to say that, this is hardly a ringing endorsement for agmatine as an appetite stimulator and/or mass-gaining aid.
As discussed in my other article about agmatine. It’s typically dosed in pre workouts between 500-1,500mg. Human studies investigating its effects on pain-relief use doses over 2,000mg.
Given that agmatine silicate is the third ingredient out of four included in a prop blend totaling 2,980mg, you might be lucky to have 500-750mg agmatine silicate.
ATP is the cellular currency of energy production. Muscle cells have a very small supply of ATP, after which it turns to creatine-phosphate stores, glucose, and then fatty acids to sustain performance.
Oral ATP supplements, by and large, have been shown to be ineffective, even when using doses up to 5,000mg. You’re not getting anywhere near that amount here.
While including ATP on the supplement facts panel looks good, it’s not offering any tangible or performative benefits here. Superior options would be elevATP, Peak ATP, or even Senactiv (which upregulates an enzyme that boosts endogenous ATP production).
Yet again we have another prop blend. This time it’s a cocktail of various stimulants, including:
No doubt this will provide a formidable kick in the ass to crank through your workout. The blend is 590mg. I’d venture a guess you’re getting 250-275mg caffeine, 75-100mg DMHA, 75-100mg theobromine, and a touch of PEA + yohimbine.
Speaking of yohimbine, there’s a typo on the label…yohimbine is what you standardize yohimbe extract for…you don’t have a yohimbine extract. The label should read yohimbe extract (standardized for X% yohimbine).
Like most other Hi-Tech stimulant-inclusive supplements, there’s a high probability that Krank3D will ignite your senses and make you feel upbeat, energetic, and highly motivated to train. For a lot of people, that’s all they’ll ever want or need.
But, when spending $70 on a pre workout, I expect a hell of a lot more to be included, such as an open label, every ingredient being dosed in a research-backed range, etc. Also, don’t be surprised if there’s a “crash” a few hours after taking this pre workout as there are no sources of neurotransmitter precursors (tyrosine, mucuna pruriens, cdp-choline, etc.) to support the added biosynthesis demands of the various stimulants included in Krank3D.
In my opinion, this could be interesting to try as a one-off (e.g. your friend buys a tub, and you want to try it), but I can’t endorse or recommend this product for purchase.
What do you think?
3DPump-Breakthrough emerged as a novel pre workout pump supplement a few years ago. Engineered by seasoned supplement industry veterans, Bruce Kneller, Dr. Hector Lopez, and Dr. Tim Ziegenfuss, 3DPump-Breakthrough garnered considerable attention, and I’ve had the pleasure of discussing the ingredient several times with both Bruce and Dr. Lopez.
In full transparency, I was skeptical. At first glance, every 6 gram serving of 3DPump-Breakthrough appears to be just a collection of three common pre workout supplements, including:
After several conversations with the creators of 3DPump-Breakthrough and NutraShure (the ingredient house that distributes 3DPump) as well as putting the ingredient through the paces with my own training, my opinion has shifted from skeptical to favorable.
Newly published research (with more in the works) demonstrates that 6g of 3DPump-Breakthrough is as effective as 8g L-Citrulline (not 8g citrulline malate).[1] Before we get to the recently released results, let’s discuss the individual ingredients contained in 3DPUMP-Breakthrough.
L-Citrulline (as well as Citrulline Malate) is a well-known ergogenic and pre workout supplement that increases levels of arginine (the “fuel” for nitric oxide production) more effectively than L-arginine. While L-arginine can boost nitric oxide levels, it has poor bioavailability (~20%), and when consumed in large doses (10-20 grams), it results in considerable GI distress.[2,3]
Citrulline (as well as citrulline malate) is tolerated much better, even up to 10 grams, and has been shown to improve exercise performance with doses as low as 2.4 grams.[4,5] While an “arms race” has been going on in the supplement industry for a few years now with regard to citrulline (and before that it was caffeine amounts and before that it was the size of pre workout scoops), researchers have stated that the upper limit of citrulline that offers benefit is 10 grams. Specifically, “a 10 g dose should be the most appropriate for use in clinical practice.”[6]
The 3g dose of L-Citrulline provided in the full 6 gram serving of 3D Pump is sufficient and within the research-backed range of dosing. As mentioned above, Citrulline is merely the “foundation” of 3DPump-Breakthrough…the next ingredient may offer enhanced hydration and cell volumization (“the pump”) in a different, complementary manner.
Glycerol is an ingredient that I’m personally not a huge proponent of. I usually don’t recommend it for inclusion in pre workout formulas for a variety of reasons, including the facts that it leads to clumping and requires a significantly larger dose (in combination with a high volume of water intake) to create the state of “hyperhydration” and muscle fullness that so many pre workout supplements tout.
The reason that glycerol is typically included in pre-workouts is due to its osmolytic properties. Osmolytes are organic compounds that encourage cells to absorb water, thereby improving hydration, cellular swelling, and muscle fullness (aka “water-based pumps”). In addition to enhancing pumps, the hyper-hydrating potential of glycerol may also boost endurance, fatigue resistance, and thermoregulation (resistance to high temperatures and greater endurance in physical activities).
However, multiple studies have shown that the amount of glycerol required to achieve a state of hyperhydration and improve exercise performance far exceeds what is typically included in powder pre workout supplements. I’ve discussed this at length in the Engineer Insider, but to recap, research demonstrates that in order to obtain the “hyperhydration” effects of glycerol, it should be consumed between 0.5-1.5g/kg bodyweight.[7,8,9] The caveat is that if an individual is hyperhydrated before exercise, THEN they can supplement with an additional 0.125g/kg body weight of glycerol in a volume equal to 5 mL/kg body weight.[9]
A recently published study in Nutrients found that even supplementing with 1.4g/kg glycerol with 30 mL/kg fat-free mass (FFM) of water pre workout did not improve performance in athletes despite the additional body water and plasma volume gains provided by glycerol supplementation.[10]
The latest study published on 3DPump-Breakthrough may shed some new light though…but, before we get to the study…there’s still one component of 3DPump to cover…
Amla (Phyllanthus emblica, Emblica officinalis, or Indian gooseberry) is an Ayurvedic plant that has been used for centuries to improve vitality and cognition as well as promote longevity. The fruit is rife with phytoactive compounds and antioxidants that support cardiovascular, immune, and digestive health, including the ellagitannins -- pedunculagin, puniglucanin, emblicanin A, and emblicanin B) which stimulate endothelial nitric oxide synthase (eNOS), combat oxidative stress, and support cardiovascular health.
3DPump-Breakthrough® includes a premium amla fruit extract standardized to >68% low molecular weight tannins.
Animal and human studies indicate that amla extracts may reduce blood pressure and improve endothelial function.[11,12,13] Typically, amla extracts are dosed between 250-500mg[14,15,16], but again there may be more than meets the eye with the select combination contained in 3DPump-Breakthrough.
With the preamble concluded, let’s discuss the new study on 3DPump vs L-Citrulline in regards to pump and performance.
28 healthy, young, recreationally-trained individuals (6 women and 22 men, 29.4 ± 10.1yr, 174.3 ± 9.0cm, 78.7 ± 13.2kg, 25.7 ± 2.8kg/m2) were took part in the randomized, single-blind, positive-controlled study. Individuals were randomized so that half of the subjects started with citrulline first while the other half started with 3D PUMP BREAKTHROUGH®.[1]
Participants underwent 30 min of walking/jogging on a treadmill in a heated room (80-90°F) at a self-selected pace that would elicit 60-70% max heart rate. Participants entered the heated room 35 minutes after consuming their respective supplement so that they would have a 10-min acclimation period where they were fitted with a heart rate monitor and provided instructions for the upcoming exercise bout. Therefore, supplements had been consumed 45 minutes before exercise testing began, which is sufficient time for the ingredients to “load.”
Following the steady-state cardio workout, participants had 5 minutes to provide a urine sample to measure urine specific gravity (one marker of hydration tracked by the researchers).
After a 5-minute rest, participants performed bilateral leg extensions and Smith machine squats for 2 sets of 12 repetitions with 60s of rest in-between sets. Participants were instructed to choose a load they could lift for at least 12, but no more than 15, repetitions on each exercise. On the third set of each exercise participants were instructed to perform as many repetitions as possible (go to failure). Failure was defined as the inability to complete a full repetition.
Following the final set of Smith machine squats, the men and women took a 3-minute rest before having their thigh circumference measured to assess the pump-enhancing effects of 3DPump vs L-Citrulline.
After the measurements, the participants performed an arms superset consisting of dumbbell arm curls and triceps rope pushdowns under the same parameters as the lower body exercises discussed previously.
After the last set of pushdowns, a 3-minute rest break was taken followed by arm circumference measurements.
“Muscle girth” in the arms and legs increased after both supplement trials. Keep in mind that this isn’t all that surprising, to be honest, as higher-rep training with relatively short rest periods (30-60 seconds between sets) by itself will generate pretty decent muscle pumps, even in the absence of pre-workout supplements like 3D Pump and L-Citrulline.
What is interesting is that the combination of ingredients in 3DPump (3g Citrulline, 1.2 glycerol, and 165mg amla) delivered similar results in terms of pump and repetitions to failure as a considerably larger dose of pure L-Citrulline (8g).[1]
There was a slight trend to vascular tone improvement with 3DPump Breakthrough as denoted by follow-up post hocs from the interaction trends in systolic and diastolic blood pressure. Researchers commented that this is likely due to the “vasoactive effects” of the phytocompounds included in amla fruit.
A common complaint among select individuals is that large scoop pre workouts and/or higher doses of select ingredients (e.g. caffeine, citrulline, creatine, betaine, arginine, etc.) can lead to GI distress.
3D Pump can offer similar benefits to a much larger dose of L-Citrulline with fewer instances of GI-related complication. In this study, individuals reported fewer adverse effects with 3D Pump (5 out of 28) than when they took pure L-Citrulline (10 out of 28). Specifically, when supplementing with pure L-Citrulline those 10 individuals reported feeling “lightheaded, nauseous, had a headache, and even regurgitated during and/or after the workout, whereas during the 3D PUMP condition [subjects] felt lightheaded during and/or after the workout and had diarrhea 2 hours post workout.”
Keep in mind that how an individual reacts to a certain ingredient or pre workout formula is highly individual, meaning what is true for one person isn’t the same for another. If you find a particular ingredient at a certain dose doesn’t jive with your GI, then consider reducing the dose consumed and/or removing the ingredient altogether. You may also want to experiment with different combinations of ingredients to see what provides the greatest benefit in terms of energy, focus, performance, and pumps vs GI distress.
Brandon Sojka, Founder of NutraShure Distribution, LLC had the following to share regarding the new findings[17]:
“We are excited to deliver efficacy outcomes with 3DPump Breakthrough® compared to that of L-citrulline. The outcome of this study shows that over-engineering finished product formulations does not always equate to better results. 3DPump Breakthrough® was developed using proper synergy and provided comparable results at nearly half of the active ingredient dose. To those manufacturers looking to formulate with benefits that include muscle pump while also providing effects on aerobic and anaerobic exercise performance, 3DPump Breakthrough® delivers innovation to the next generation of sports and active nutrition."
It’s encouraging to see on-going research with new ingredients brought to market -- the vast majority of branded, “premium” ingredients have a lone study (or two, at most), after which no further research is conducted. The team behind 3DPump-Breakthrough has stated they have several studies in the works (with more potentially down the line), which is a win for the industry as a whole. Clearly, 3DPump-Breakthrough is effective for enhancing “the pump.” Hopefully, the future studies of 3DPump-Breakthrough delve into other metrics of athletic performance -- time to exhaustion, lean mass gains, vasodilation, etc. -- over a longer period of time (4, 8, or 12 weeks) and compare it to L-Citrulline/Citrulline Malate, Nitrosigine and/or nitrates (beetroot juice or NO3-T).
If you’re looking to experiment with other pump ingredients or pre workout supplements, 3DPump-Breakthrough is certainly worth a try. For supplement companies that are considering adding it to their pre workout formulations, it may come down to a matter of cost vs benefit vs optics (ingredient profile). With bulk L-Citrulline prices coming down ($9-10/kg as of May 2023), it may be more advantageous for those brands to explore a combination of individual ingredients. However, the ingredient supply-chain is in constant flux so formulation decisions will vary depending on the particular brand and consumer demands.
Nevertheless, I’m excited to see what lies ahead for 3DPump-Breakthrough and the other ingredients that NutraShure has to offer.
This idea for this article comes from a recent Stack3D post in which Shane announced that Costco is now offering a 5-lb bag of Ascent Native Whey protein for $55.99 (as of April 2023). Given the hundreds of protein powders I’ve tried over the years, I don’t think I’ve ever tried (or can’t remember) one that included “native whey.” Still, with the ever-increasing prices of whey (and other) protein powders, seeing a product that wasn’t Optimum Nutrition (ON) or Dymatize delivering 20+ grams of high-quality protein/serving for under $1 is bound to attract attention.
So, I purchased a 5-lb bag of Ascent Native Whey protein (chocolate), since I wanted to try a different protein powder from our usual assortment. Best case, we have a great value protein that offers a delicious flavor, easy mixability, and pleasant mouthfeel. Worst case, it’s relatively cheap and can be covered up in the multi-ingredient smoothie I make for Sandy every morning before work (and, if you want the recipe, send me an email. I'm happy to share it!).
Nevertheless, my curiosity was piqued regarding the potential advantages/benefits of native whey vs whey protein (the primary ones being “better quality whey” and “higher leucine content”) , and I thought it would make a great topic for discussion. So, if you’ve been a long-time imbiber of whey protein powder (whey concentrate or whey isolate) or blended proteins and wondered how they stack up against native whey, you’re in luck!
We’re going to discuss everything about native whey and whether it’s worth the hype (and potentially) increased cost vs whey protein concentrate. Let’s begin by first discussing…
Any long-time consumer of whey protein knows that whey is one of the two protein sources naturally found in cow’s milk (the other being casein). Whey is a by-product of the cheese-making process, with casein (the “curds”) being used to make a panoply of delicious cheese. Once callously discarded by cheese-makers, the benefits of whey were eventually realized, and, subsequently, the thin milky-looking liquid was collected, processed, and dehydrated into the delicious, muscle-building powder we’ve known and loved for decades.
“Conventional” whey protein begins as fresh milk collected from dairy cows. The unpasteurized milk is then cooled and transported (under refrigeration) to a cheese-making plant, where it is pasteurized (heated) and then cooled (again). At this point, the milk still retains its natural 80% casein/20% whey ratio.
Now, the curds are separated using a complex set of enzymes known as rennet (and used to make cheese) while the liquidy whey is collected and transported to various filtration/separation units (microfiltration, ultrafiltration, etc.) to remove extraneous fats, carbohydrates (lactose) and other impurities. Here’s a fun fact: It takes 720 pounds of the raw liquid to produce one 5 lb bag of whey.[3]
Whey protein concentrate (WPC) typically results from microfiltration, and whey protein isolate (WPI) usually results from ultrafiltration. Keep in mind that whey concentrate can vary in protein content between 30-80%, and whey isolate “must” be a minimum of 90% protein.[4]
Once the liquid whey has been filtered to its desired protein yield, it is then spray-dried into a powder. From here, it can be shipped to manufacturing facilities for formulation purposes. Flavors, thickeners, inclusions, and/or other “bonus” ingredients (e.g. Velositol) can also be added to the powder at this point to create a brand’s desired whey protein product.
So, where does “native whey” fit in?
Whereas regular whey protein is created using pasteurized milk, native whey is produced via filtration of unprocessed raw milk.[5] Other sources state they use “skimmed milk” as the basis of their native whey as opposed to “unprocessed raw milk.”[2]
Using unprocessed “raw milk” (that may or may not be pasteurized depending on which source) leaves milk proteins intact, limits the amount of “chemicals” (enzymes, acids, and salts used during cheese-making), and gives native whey a higher leucine content than conventional whey protein concentrate (WPC-80).[2,5]
This graphic (from a supplier of native whey) helps illustrate the differences[2]:
Again, take this with a grain of salt (or a scoop of whey) as it was created by a company who has a primary interest in selling native whey protein powder.
A leading talking point of native whey protein is that it undergoes less processing and is subjected to fewer additives/processing components, thereby making it more “natural.” While it is true that native whey undergoes fewer steps of refinement to yield a high quality protein powder, that doesn’t inherently mean those added steps of processing are “bad” or lead to a poorer quality product, as we’ll discuss below.
For instance, whey derived from acid-casein (which is similar to whey obtained after the production of cottage cheese) contains higher concentrations of certain minerals, in particular phosphate and calcium (the latter of which is known to support bone health). Furthermore, cheese production represents the greatest resource of whey available for processing and protein recover.[4]
So, while native whey may be more “natural” in that there are less steps in the manufacturing process, that doesn’t necessarily mean it contains more key micronutrients or health-promoting compounds (more on that in a moment).
Another key commentary from native whey protein providers is…
As mentioned above, native whey production yields a protein powder that is higher in leucine than whey protein concentrate (WPC-80). Leucine is regarded as the “king” of amino acids as it is the most potent stimulator of mTOR (mechanistic target of rapamycin) -- the biological switch that activates muscle protein synthesis (MPS). As a result of having higher leucine levels, brands using native whey tout the notion that native whey is “more anabolic” and/or can support greater muscle recovery and growth.
However, research shows that the filtration process used in the production of native whey that yields higher leucine levels may also remove beneficial whey microfractions, including glycomacropeptides, immunoglobulins and lactoferrin -- which are known to confer various physiological benefits, such as immune support.[6,7,8,9]
In fact, a whey protein review from 2000 concluded that (albeit slightly more expensive), whey proteins rich in immunoglobulins are superior to those not containing immunoglobulins (e.g. native whey).[8]
“Undenatured” refers to a protein that has not deviated from its most natural form, and it’s frequently used interchangeably with other marketing terms, including “non-denatured whey protein” or “whole protein” or “undamaged protein.”
Companies that produce and sell native whey claim their whey protein is undenatured and imply that somehow all other types of whey protein are denatured, which is to imply they are “damaged” or somehow of a lesser quality.
“Denaturing” itself is influenced by several factors, including[10]:
Something to keep in mind, though, is that just because a protein is “denatured” doesn’t render it ineffective or harmful. For instance, many of us enjoy a grilled burger or steak…high heat is applied to raw beef protein -- the result is an incredibly delicious and highly bioavailable protein (red meat) full of beneficial micronutrients. The original product could also be considered “denatured” due to the means of cooking it. Keep in mind that digestion also requires the breakdown and denaturing of proteins via mechanical and chemical means (i.e. chewing, saliva, digestive enzymes, and stomach acid).
Whey is often considered a “delicate” protein, which has led to many fears by fitness enthusiasts and much misinformation spewed by influencers and sponsored athletes that protein powder will somehow become less effective if it’s heated. Nothing could really be further from the truth and there’s no considerable body of evidence to show that denatured whey protein is ineffective in humans.
For example, hydrolyzed whey (whey protein that has been “pre-digested” via the application of chemical enzymes) has been investigated numerous times and shown to be safe (even in infants!), efficiently digested and utilized by the body, resulting in increased muscle growth and recovery.[11,12,13,17]
Another protein that’s considered “delicate” are eggs. Consuming liquid egg whites or adding raw whole eggs to blenders (a la Rocky) was a popular fad and was thought to be the superior way to obtain nature’s “perfect” protein. However, a landmark 1998 study demonstrated that cooked eggs are more bioavailable than raw eggs.[14]
One last thing to consider is that native whey being sold is produced from milk that has been pasteurized. It may not be treated with the acid or rennet used to generate curds to make cheese, but it has been heated and cold-pressed through filters, much in the same way conventional whey protein is cold-filtered to remove impurities (lactose, milk fats, etc.).
Now that we’ve discussed the major talking points of native whey vs whey protein powder, let’s now see how they stack up head-to-head in research trials.
A 2017 double-blinded, RCT appearing in the IJournal of the International Society of Sports Nutrition (JISSN) compared two 20g doses of different proteins in 24 healthy, young resistance trained men and women.[5] Subjects were randomized to receive either:
Participants received one 20g shake immediately after a lower body workout and a second 20g shake two hours post-workout.[5] Researchers also collected blood samples and muscle biopsies to track changes in the subjects as a result of their supplement.
As expected, native whey increased blood concentrations of leucine more than WPC-80 and milk. However, after five hours post-exercise, there were no significant differences in muscle protein synthesis between native whey or WPC-80. In other words, “regular” whey protein concentrate was just as effective as native whey.[5]
Figure 7: Isometric knee extensor force-generating capacity relative to resting values following intake of milk, WPC-80 or native whey immediately and two hours after a bout of heavy leg resistance exercise.[5]
Native whey increased MPS rates in the 5-hours post workout more than milk protein; however, after 24 hours of recovery, there were no no tangible differences in muscle recovery amon either native whey, whey protein or milk protein.[5] This suggests that consuming enough high quality protein is more important that getting mired in the differences of native whey vs whey protein vs milk protein concentrate.
A follow-up 2019 RCT appearing in Medicine and Science in Sports and Exercise, Hamarland and colleagues conducted another investigation comparing native whey vs powdered milk. 40 healthy untrained young men and women participated in a 12-week resistance training program and supplemented twice daily with 20 grams of protein from native whey or powdered milk.[15]
Table 2: Amino acid and macronutrient content of supplements.
At the end of the 12-week study, there were no significant differences between the groups in terms of muscle strength or muscle mass. In other words, supplementing with milk protein powder was as effective as native whey protein powder.[15]
While whey protein is commonly thought of as a “young person’s supplement” (e.g. college/pro athletes, bodybuilders, high school students looking to bulk up, soccer mom’s looking to “tone”, etc.), it can also be incredibly beneficial for the elderly, a population at risk for sarcopenia (muscle wasting). The elderly human body is anabolically stunted, which is to say it is less sensitive to the anabolic effects of protein ingestion and resistance training. Older individuals typically are also less physically active and have poorer appetites. All of this can contribute to accelerated muscle wasting, which also accelerates aging.
Whey protein offers a palatable solution for elderly individuals to up their protein intake that is also easy to digest. A third study from the Hamarsland lab, this one appearing in The Journal of Nutrition, Health & Aging, investigated the muscle-sparing prowess of native whey vs whey protein vs skim milk in elderly folks combined with a structured resistance training program.[16]
21 healthy men and women (≥70 years) received either 20 grams of native whey or WPC-80 on separate days in a crossover design (which means every individual served as their own control), or milk. The men and women consumed their respective supplements immediately and two hours after a bout of lower body heavy-load resistance exercise.[16]
Similar to previous findings, native whey resulted in higher MPS rates than whey and milk during the initial stages (1-3 hours and 1-5 hours, post workout).[5] However, over the duration of the study, no discernible (“real world”) differences were observed between native whey vs WPC-80 in their respective ability to stimulate MPS or build lean muscle.[16]
Published in Nutrients, yet another study from Hamarsland (these guys must really love their whey protein!) investigated the the effects of two daily servings of 20 grams of protein from either native whey or milk protein in 30 healthy, elderly men and women during an 11-week strength training intervention.[18]
Similar to previous findings, no significant differences in muscle or strength gains we documented native whey or milk protein or native whey, when supplemented as 2 × 20g daily in conjunction with resistance-training.[18]
Native whey protein is made from pasteurized, skimmed milk instead of the liquid by-product resulting from cheese production. This may remove some of the “chemicals” and transportation consequences common to whey protein production as well as increase the total leucine and essential amino acid content per 100g.
However, these effects are more significant in marketing and advertising campaigns than in terms of real-world results. Human studies find no significant long-term differences between the intakes of native whey vs whey protein powder (WPC-80) in terms of muscle or strength gain, despite the greater short-term spikes in leucine found when supplementing with native whey. It would be interesting to see the short-term blood leucine increases comparing native whey to whey protein isolate (which is closer to the protein content -- >90% protein -- of native whey than WPC).
Something else to consider is that, due to the production processes, native whey is lacking the beneficial, immune-boosting subfractions of whey, including immunoglobulins.
Regarding the taste difference between native whey and regular whey, that will depend on several factors, not the least of which is the final additions to the whey protein powder (stabilizers, thickeners, sweeteners, inclusions, etc.).
Both types of protein can be effective for supplementing your daily protein intake to build muscle, aid recovery, and improve body composition. Stay tuned for our Ascent Native Whey protein review (when it arrives) and we’ll compare it to other chocolate whey protein powders we enjoy.
What do you think?
Is Native Whey worth the hype?
Let us know!
Serious Nutrition Solutions (SNS) has been around for a long time. I’ve used and recommended a number of their products over the years, including Joint Support XT and GlycoPhase. Their best-selling nootropic powder, Focus XT, was among the first “real” nootropic supplements I tried. In fact, I previously tried my hand at “hacking” the original formula:
At the time, my guess at the individual ingredient dosages was:
Grand total: 9800mg
SNS never confirmed or denied my guess, but alas, the brand overhauled the OG formula for a new and improved one.
As you may have noticed, the brand has been on a tear recently releasing a steady stream of premium-quality formulas, but not ones solely relegated to sports nutrition. Notable additions to the SNS lineup the past few months include Cardiovascular Support XT, Phosphatidic Acid XT, Anabolic XT, and the focus of today’s article -- Kidney Assist XT.
The kidneys serve as one of the body’s primary filtration/defense organs. Current estimates indicate that ~50% of US adults have hypertension (high blood pressure).[23] Elevated blood pressure can constrict and narrow the blood vessels (reducing blood flow, oxygen & nutrient delivery), which can eventually damage and weaken the cardiovascular system, adversely affecting the kidneys.
Impaired kidney function reduces your body’s ability to remove waste and extra fluid. As a result, extra fluid in the blood vessels can further raise your blood pressure, creating a vicious cycle that leads to even greater damage and (ultimately) kidney failure.
In addition to living a healthy lifestyle (diet, exercise, stress management, sleep, etc.), certain supplements are also known to support renal health, the best of which are included in Kidney Assist XT.
Astragalus is one of the fundamental plants of Traditional Chinese Medicine (TCM). It contains various bioactives (collectively referred to as astragalus polysaccharides) that are known to possess a wide range of beneficial biological activities including[1,2,3,4]:
Hypertension (high blood pressure) is one of the primary contributors to kidney damage. Astragalus polysaccharides may reduce the increase in blood pressure (and resulting renal damage), and these effects may may be related to its anti-inflammatory and antifibrotic effects.[1] It may also decrease the expression of transforming growth factor-β (TGF-β) and Integrin-linked kinase (ILK), which are involved in the growth and production of fibroblasts and cell migration. Furthermore, TGF-β is one of the most important regulatory molecules in the development of renal fibrosis
Additional research indicates that astragalus may increase the kidney’s estimated glomerular filtration rate (eGFR), which is a measure of how well a person’s kidneys are working.[5] It has also been shown in multiple studies to improve proteinuria[6], a condition in which excessive levels of protein are found in the urine. Normally, protein levels in urine are low, when elevated, it is a sign that the kidneys may be damaged or not functioning optimally. To cap it off, astragalus has also been found to limit infections in people with reduced kidney function.[7]
Commonly regarded for its cardiovascular support benefits (usually in the 300-600mg range), a number of studies have also examined the effects of high-dose grape seed extract on kidney health.
Grape seed extracts are rich in a variety of antioxidants and polyphenols, including proanthocyanidins and other flavanoids.
Studies in individuals with chronic kidney disease (CKD) find that high doses of grape seed extract (upwards of 2,000mg per day), enhances GFR and significantly lower proteinuria.[8]
Additional benefits of grape seed extract may be mediated via its antioxidant and anti-inflammatory properties. Following 6 months of daily usage (2100mg/day), grape seed extract supplementation counteracts both plasma lipoperoxidation and carbonylation as well as c-reactive protein (CRP) and lactate dehydrogenase (LDH) -- two markers that check for inflammation and tissue damage. Grape seed extract was also found to significantly increase plasma catalase (CAT) and superoxide dismutase (SOD).[8]
Animal studies have also shown that grape seed extract can combat the deleterious effects of high-fat diet-induced obesity and lipotoxicity.[9,10] These effects added to the blood pressure-reducing effects of grape seed extract make it great addition to Kidney Assist XT that supports renal health across multiple fronts.
Cranberries have a long history of use in supporting the kidneys and urinary health. In fact, the bioactives in cranberries inhibit the adherence of E. coli to the urinary tract[11,12], among other assorted benefits. Cranberry and its various assorted extracts have also been investigated for its benefits concerning cardiovascular health, oncology diseases, type 2 diabetes, metabolic syndrome, obesity, tooth decay and periodontitis.[13] Similar to grape seed extract, it contains a panoply of polyphenols, including phenolic acids, anthocyanins, flavonoids, and proanthocyanidins.
Additionally, chronic kidney disease has also been associated with gut dysbiosis and increased gut barrier permeability, due to CKD-associated factors such as uremia, prescription pharmaceuticals, and certain dietary restrictions. Research finds that cranberries promote GI health, reduce inflammation and decrease cholesterol levels.[13] Specifically regarding gut health, polyphenols in cranberry combat oxidative stress and inflammation in the gut while improving mitochondrial dysfunction by quenching reactive oxygen species.
Most often associated with liver health (which indirectly supports kidney health and it’s a supplement I take daily), milk thistle extract also has a long history of use for supporting the kidneys and gallbladder.
The primary phytoconstituent present in milk thistle is silymarin, which owes its beneficial actions to a potent flavonoid complex called silybin that acts as a potent antioxidant, neutralizing harmful free radicals. Research notes that silymarin is at least 10x as powerful as vitamin E. PLUS, it also helps increase levels of two additional, “master” antioxidants -- glutathione and superoxide dismutase (SOD).[15]
Beyond offering liver/kidney defense/protection, silymarin can help the liver to repair injured cells and generate new ones via stimulating protein synthesis. Finally, milk thistle extract’s regenerative qualities have been investigated in cases of toxic fatty deposits in the liver, cirrhosis and chronic hepatitis.[16,17]
Curcumin awareness and usage has exploded in recent years. It not only offers anti-inflammatory benefits (which promotes joint health and immune support), but also neuroprotective ones (a topic I’ve discussed at length for Engineer Insiders).
The role of curcumin in kidney health and CKD has been studied quite a bit. A 2021 meta-analysis, including five RCTs involving 290 participants with diabetic kidney disease, concluded that curcumin may offer significant potential benefits as the researchers found that curcumin supplementation improved levels of serum creatinine, total cholesterol, systolic blood pressure, and fasting blood glucose.[18]
A prior 2014 study in Molecules found that despite poor bioavailability, curcumin improves tight junction proteins and corrects gut permeability, which reduces the levels of circulatory inflammatory biomolecules and may benefit individuals with CKD.[19]
Recently published research in Cell, investigating the role of oxidative stress and mitochondrial dysfunction in kidney diseased, noted that curcumin supplementation “decreases 5/6Nx-induced alterations early in mitochondrial dynamics, bioenergetics, and oxidative stress, which may be associated with the preservation of renal function.”[20]
Various studies also have found that curcumin supplementation improves renal function, lipid profile, blood pressure, and fasting blood glucose levels in individuals with kidney disease.[21,22]
Like many phytochemicals, curcumin suffers from poor bioavailability, which either requires large dosages or assorted absorption enhances (a la AstraGin or BioPerine…both of which are included in Kidney Assist XT).
Brought to you by the same company that offers BioPerine (Sabinsa), Curcumin C3 Complex is a patented and clinically-evaluated composition containing three curcuminoids (hence the “C3” moniker). Those three curcuminoids are:
Yet another botanical rife with bioactives as well as a favorite inclusion in nootropic supplements and pump pre workouts, pine bark extract contains high levels of proanthocyanidins. These bioactives promote increased blood flow throughout the body via its effects on reactive oxygen species and inflammatory substances as well as their ability to stimulate eNOS (the enzyme that catalyzes nitric oxide, NO, production) and promote vasodilation.
Additional research also suggests that pine bark supports kidney function, prostate health and urinary flow.[25]
Developed by NuLiv Science, AstraGin has established a formidable foothold in the supplement industry largely due to its ability to enhance the bioavailability/uptake of various amino acids, vitamins, and polyphenols, including L-Citrulline, Creatine, and curcumin, via increasing the activities of certain absorption-specific mRNA and transporters, including SGLT1, CAT1, and GLUT4.
AstraGin contains a novel and patented mixture of dried extracts of Astragalus membranaceus (10:1 hydroethanolic extract) and Panax notoginseng (50:1 aqueous extract) roots, standardized to contain ≥1.5% saponins.
The OG absorption enhancer in dietary supplements, BioPerine is the premier black pepper extract (standardized for piperine) offered by Sabinsa, the same ingredient house behind Curcumin C3 Complex. There’s also research to show that combining BioPerine with curcumin enhances bioavailability upwards of 2000% (20x)![25]
I reached out to the owner/founder of SNS for some insight into the creation behind the product:
"I love helping people and I love supplements, and that’s what SNS is about – helping people reach their health and fitness goals and to help improve their quality of life through providing top quality products at prices that people can afford.
...building out the Health Series of products is something that I’m very passionate about because we want to be able to provide products that can help improve quality of life and address different issues.
Kidney Assist XT was intentionally released in sequence very shortly after Cardiovascular Support XT because cardiovascular disease is the number one cause of death in the United States and it, along with diabetes contributes a lot to kidney damage. Kidney disease is the ninth leading cause of death in the US and a lot of people don’t even realize they have it or that it is happening until a lot of damage has taken place.
We are going to be continuing to build out the Health Series to address a lot of different issues, including getting restocked on Blood Pressure Support XT soon and the upcoming releases of Cholesterol Support XT, Prostate Support XT, and hopefully several other new additions this year. "
A lot of the hype around supplements is centered on pre workouts, protein powders, and other sports nutrition offerings. As wonderful as those products can be, there are countless other options available that deserve equal, if not greater attention.
Renal health (kidney function) isn’t the sexiest topic to discuss, but it’s something that is pertinent to every individual walking the planet. SNS Kidney Assist XT offers a great formula at a very reasonable price, making it a viable option for anyone seeking renal and cardiovascular support.
My first experience with Olympus Labs was their Conqu3r Unleashed pre workout supplement, which I enjoyed immensely and I honestly wish it still existed. The last time I tried a product from the brand was their Re1gn pre workout, which looked good on paper; however, there were some production delays/delivery difficulties and after trying multiple flavors of the product, both CJ and I had rather unpleasant (“awful”) experiences with the product. Keep that in mind, as there is a particular ingredient in Re1gn that also finds a home in Oracle.
As for the reason why Re1gn was not a good fit for me, it could be any number of issues, including the overdosing of certain ingredients that were not explicitly labeled.
Anyway, after a multi-year hiatus, Olympus Labs has re-emerged in sports nutrition, offering a pre workout supplement — Oracle.
Per Stack3D, Olympus Labs says:
“the upcoming Oracle pre-workout will provide impressive euphoria, energy, and focus, as well as enhanced pumps, all rolling together for a balanced experience.”[1]
Looking at the supplement facts panel, I have several thoughts…
Right off the bat, the multiple proprietary blends should be a red flag to consumers. You have no idea of the dosages, and after my experience with RE1GN, I’m not likely to trust OL’s prop blends (fool me once…) — what you choose to purchase and experiment with is your choice.
There’s also another issue upon first inspection of the Oracle pre workout label, specifically regarding the QA/QC of the supplement facts panel (SFP):
“The Caffeine Matrix” lists a total of 405mg of three different caffeine sources:
Adding those three up, that results in a total of 410mg…not 405mg.
While this isn’t a massive difference in terms of how much caffeine consumers will end up getting from a full serving of Oracle, it is a glaring QA/QC oversight. For a brand that has largely been off the radar/on hiatus from the mainstream, you’d think they would have double and triple-checked every facet of the product to make their re-emergence impeccable.
Of course, any individual or company can make mistakes (including your friendly, neighborhood Supplement Engineer), but there are other concerns I have regarding the ingredients profile...
Since Oracle contains a partially-proprietary/partially-open label/partially correctly (or incorrectly) printed supplement fact panel, I am not able to speak with 100% certainty as to the dosages of each and every ingredient. However, I can offer insight into efficacious dosages of the selected ingredients as well as what the scientific literature reports.
Let’s start with the first semi-prop blend…
Oracle’s “Innovative Performance Matrix” (which really isn’t all that innovative, if we’re being honest) is combination of three ingredients:
Of the three, only S7 is open-labeled at a dose of 50mg in a full (2-scoop) serving. Assuming what is stated on the label is actually in the tub, that leaves a remaining 3,310mg split between beta-alanine and ligustrazine.
Renowned as the pre-eminent endurance-enhancing ergogenic, beta-alanine is pretty much a “must-have” in pre workouts for most companies today. Understand that the primary manner in which beta-alanine boosts endurance is via its enhancement of carnosine levels in the body. Carnosine serves as an intracellular buffer that reduces H+ ions, ultimately enabling muscles to contract for longer periods of time before succumbing to metabolic fatigue.
Despite a considerable body of evidence showing its benefits (particularly for prolonged exertion), if we’re being honest, the real reason supplement companies include beta alanine in pre workouts is for its tingle-inducing effects (paresthesia) — essentially, consumers think a supplement “hits harder” if they’re experiencing tingles, flushing, etc. FYI, …the “tingles” are harmless and a mere by-product of consuming relatively “high” doses of the supplement in isolation. Anecdotally, the tingles subside with regular/daily supplementation of beta-alanine and/or taking it in combination with a meal.
Keep in mind that beta alanine is a saturation-based ingredient (a la creatine monohydate, PeakO2, etc.). Supplementing with beta-alanine (even in high doses) does not offer immediate benefits — it only causes the tingles. To realistically obtain the benefits of beta-alanine, it needs to be taken consistently (preferably daily).
The saturation amount of beta-alanine is ~179 grams. This means that if you’re taking a pre workout that contains 3.2g beta-alanine daily, it will take about 8 weeks to reach saturation, at which point you will actually realize the ergogenic properties of beta-alanine. Consuming 6.4g/day will allow you to reach saturation in 4 weeks. Keep in mind, the studies in which individuals consume 6.4g beta-alanine per day ingest the supplement in divided dosages (e.g 1.6g BA 4x/daily).
With the understanding that most pre workouts contain between 1.6-3.2g beta-alanine per full serving and that the average individual only trains three maybe four times per week, and the average individual’s only beta-alanine supplementation occurs via pre workout supplements, it’s highly unlikely the average consumer using Oracle (or any other pre workout supplement) is actually maximizing the potential ergogenic properties of beta-alanine. It also warrants mention that this is a tactic employed by the vast majority of supplement companies on the market who claim to include beta-alanine to “boost endurance/performance” but really include it to make the products seem like they “hit harder.”
Also, keep in mind that beta-alanine really only benefits performance when engaged in repeated bouts of effort interspersed with brief periods of rest (e.g. HIIT, boxers, martial artists, football players, etc.) or those engaged in endurance exercise. Furthermore, a position stand issued by the ISSN (International Society of Sports Nutrition) stated that :
“Daily supplementation with 4 to 6 g of beta-alanine for at least 2 to 4 weeks has been shown to improve exercise performance, with more pronounced effects in open end-point tasks/time trials lasting 1 to 4 min in duration.”[2]
Given that Oracle supplies 50mg S7 (which leaves a remaining 3,310mg divided between two ingredients), my guess is that Oracle includes approximately 2.4-3.2g per serving.
Let’s now look at the other significant player in the “innovative performance matrix”…
As mentioned at the outset, Olympus Labs is a company that has always prided itself as a company committed to R&D, and as a result of their efforts, they’ve introduced several unique ingredients to the market. That tradition continues with the inclusion of ligustrazine, which supports blood flow and pumps.
Also known as Tetramethylpyrazine, Ligustrazine is a chemical found in cocoa beans as well as Ligusticum striatum (syn. L. wallichii), which is native to India, Nepal, and Kashmir. It is considered one of the 50 fundamental herbs of traditional Chinese medicine (TCM) and has been used in Chinese clinics for the prevention and treatment of cardiovascular and cerebrovascular diseases, inlcuding coronary heart disease, cerebral thrombosis, and vasculitis.[3]
While humans studies in which ligustrazine is consumed orally are sparse, there is a randomized control study from 2019 including 120 individuals with pulmonary hypertension.[3] The disease involves oxidative stress, vascular inflammation, and and imbalance of intracellular calcium homeostasis.
Individuals in the ligustrazine group received 100mg three times per day for four weeks in addition to “routine therapy” that included phosphodiesterase type 5 (PDE5) inhibitors, sildenafil and tadalafil. The control group only received “routine therapy.”
Researchers noted that “oral intake of TMP is safe, without obvious adverse reactions.”[3]
An update/correction was published in 2020 stating that “Treatment with TMP will be finished in March 2020.[4] Since then, there have been no published results.
Previous research from the same lab found that ligustrazine injections (100mg/kg/day) prevented rats from developing pulmonary hypertension and ameliorated three models of established pulmonary hypertension.[5]
A 2014 study using isolate human arteries found that Suxiao Jiuxin, a popular patented drug in Chinese medicine that is a combination of ligustrazine and borneol, demonstrated “potent vasorelaxant effect on various vasoconstrictor-mediated vasoconstriction.[6] Its benefits were mediated by endothelium-dependent and -independent mechanisms.
Numerous other trials have been conducted using the Suxiao Jiuxin pills and noted reductions in major adverse cardiovascular events (MACE), improved heart function, electrocardiogram (ECG) readings, and lipid profiles.[7]
A 2016 meta-analysis of 16 RCTs investigating the utility of ligustrazine for the treatment of unstable angina concluded that “combined with conventional medicine [ligustrazine] was associated with an increased rate of marked improvement in symptoms and an increased rate of marked improvement of ECG compared with conventional Western medicine alone.”[10]
Researchers also noted a reduction in the consumption of nitroglycerin and the level of fibrinogen (a glycoprotein complex produced in the liver that assists with blood clotting).
The dosage included in the meta-analysis was 80 ligustrazine 99% purity.[10]
Other cell culture and animal studies indicate that ligustrazine may help reduce kidney and brain damage induced by ischemia perfusion in rats via scavenging oxygen-free radicals as well as inhibit the process of inflammation. For example, ligustrazine has been shown reverse the activation of NLRP3 inflammasome and caspase-1 and inhibit the expression and secretion of IL-1β in LPS-treated LO2 hepatocytes.[8,9]
Regarding the dosage, each Suxiao Jiuxin pill is 40mg (split between ligustrazine and borneol). Most dosing protocols recommend individuals consume 5-6 pills 3x/day. That’s a total of ~720mg (18 pills x 40mg/pill).
As mentioned above, the lone human study orally dosing ligustrazine used 300mg/day (100mg thrice daily).
Regarding Olympus Labs Oracle, I would estimate there is between 100-300mg ligustrazine in every full serving. If a “full” 3,200mg (3.2g) beta-alanine is included, that would mean consumers are getting 110mg Ligustrazine in every serving.
I’ve discussed S7 at length as well as my disdain for companies that try to promote it as this “game-changing” nitric oxide booster. Check out this podcast where Dr. Scott Stevenson and I go in-depth into the truth about S7.
S7 is a proprietary combination of seven plant-based ingredients developed by FutureCeuticals that has been clinically shown to increase nitric oxide (NO) by 230% in humans.[11] Researchers noted that S7 enhanes NO production by modifying the “redox signaling” process in humans and significantly inhibiting the production of mitochondrial and cellular reactive oxygen species. This resultedin a 2.3-fold increase (230%) of bioavailable nitric oxide.[11]
As a cellular health and tertiary pump ingredient, S7 is a decent option and is backed by two (small) human clinical trials. Keep in mind that it has not been studied yet in regards to intense exercise (resistance training, powerlifting, MMA, etc.) and won’t deliver increased pumps and vascularity like L-Citrulline, Nitrosigine, or NO3-T (nitrates).
I’m not exactly sure why the ED was capitalized in “FocusED”…when I see ED, I automatically think of erectile dysfunction (not that I’ve ever had that problem). However, there is a phenomenon known as “stim d***” and results from a man’s inability to “stand tall and strong” after consuming certain gray-area stimulants (e.g. DMAA, DMHA, etc."). So, could this be Oracle warning users what may happen after taking this combustible concoction of stimulants?
Anyway…let’s take a look at the blend:
Eria Jarensis emerged several years ago as a successor/alternative to the “aggressive” stims of years past that are no longer allowed to be used in dietary supplements (DMAA, DMHA, AMP Citrate, etc.). The reason for its inclusion is that the plant contains a number of bioactive compounds that deliver phenylethylamine (PEA)-type substances. The two most prominent ones identified in Eria Jarensis are N-methyl-phenethylamine (N-methyl-PEA) and N,N-dimethyl-phenethylamine (N,N-dimethyl-PEA).
PEA is a natural monoamine alkaloid that acts as a CNS stimulant. It acts fast, boosts mood, energy, and euphoria, and its effects are fast-fleeting…usually subsiding ~15min or so (at most).
The “enhanced” forms of PEA found in Eria Jarensis offer the prospect of longer-lasting energy and euphoria.
Likely dose here is 300mg, this estimate is based off the total prop blend (887mg) and the published dose of the next ingredient...
Developed by OmniActive (the same company behind LuteMax 2020 and CapsiMax), EnXtra is an award-winning caffeine-free extract of alpinia galanga shown in human clinical studies to enhance alertness and focus for up to 5 hours with and without caffeine.[12,13,14]
Pairing it alongside caffeine, EnXtra® helps to prolong the energy and focus-boosting effects of caffeine as well as offset any potential crash that certain caffeine consumers (usually those more caffeine-sensitive individuals) may experience when taking higher amounts of the stimulant.
As to how EnXtra increases energy and pairs well with caffeine, studies demonstrate the active components present withing enXtra can block dopamine reuptake, which increases dopamine levels — further enhancing mood, motivation, focus, decision-making, etc. It also has a pronounced effect on acetylcholinesterase — the enzyme that break down the “learning neurotransmitter”, acetylcholine.[15]
EnXtra has been shown to be without significant adverse effects, and it does NOT impact heart rate, blood pressure, and sleep, even when consuming 600mg of enXtra — 2x the dose in Olympus Labs Oracle.
Briefly touched on above when discussing Eria Jarensis, PEA is a mood-enhancing CNS sitmulant with a very short half-life (~5-10 minutes).[16] PEA is great for providing the initial impetus (which is a euphemism for “kick in the ass”) to get amped-up for your training session, after which the other stimulants in Olympus Labs Oracle can take the reins and power you through the end of your workout. Combining Eria jarensis with PEA and the next ingredient in Oracle could make for some long-lasting "feel-good" vibes.
Another under-the-radar ingredient that’s likely never been encountered by most consumers, genistein is an incredibly well-researched isoflavone found in soy as well as the Japanese pagoda tree (sophora japonica).
Isoflavones, including genistein, that possesses anticarcinogenic (specifically hormone-related cancers) and antioxidant properties.
Its anti-cancer benefits are attributed to the[17]:
It also warrants mentioning that genistein has 4% binding affinity for estragen receptor ER-α and 87% for ER-β.[18] As an added benefit, injections of genistein may also protect rat testicular cells from radiation.[19]
What does all of this have to do with a pre-workout?
Well, genistein also has been investigated for its mood-enhancing and anti-depressive benefits.[20] Specifically, researchers note that “genistein might improve major depression through suppressing miR-221/222 or increased the expression level of Cx43.”[20]
miR-221/222 are microRNA that regulate the expression of several genes, including oncogenic (cancer causing) genes.[21] Additionally, miR-221 and miR-222 have to associated with depression. On the flip side, Cx43 has been identified as a noteworthy suppressor of depression. Seeing as genistein both suppresses miR-221/222 and/or boost Cx43 expression, it promotes greater mood.
Other research notes that Genistein may function as a reversible MAO-inhibitor. MAO (monoamine oxidase) is a group of enzymes that metabolize catacholimes, including dopamine, noradrenaline, and PEA. Inhibiting MAO promotes stronger, longer-lasting levels of these neurotranmsitters/catecholamines, supporting more powerful and sustained enregy, mood, and motivation. Previous MAO inhibitors seen in pre workouts supplements include hordenine and garcinol.[25]
However, a major limitation of genistein is its poor bioavailability. Studies investigating its bioavailability have noted it varies as low as 6.8% to 50%.[17] There are no absorption enhancers included in Oracle, such as BioPerine or AstraGin.
One other cause for (potential) concern are the research findings[24]:
Researchers report that genstein may interfere with thyroid function, testosterone production, and allergies (hypersensitivity), as well as increase the risk of cancer proliferation.[24] Keep in mind, that the majority of research paints genistein in a positive light, with multiple potential benefits; however, these potentially serious side effects warrant mentioning. As always, the dose makes the poison, but…we have no idea how much genistein is in this product.
Previously appearing in RE1GN, KannaEase is an extract of kanna (Sceletium tortuosum) standardized for total alkaloids >= 0.5% alkaloids and 0.2% mesembrine.
Personally, I really enjoy this ingredient, especially in nootropics or sleep supplements. KannaEase as well as the other popular branded kanna extract on the market (Zembrin) are typically included for the mood-enhancing properties as well as their anxiogenic (anxiety-reducing) properties.
The reason for this is that the bioactives present in KannaEase and Zembrin function as a dual serotonin transporter blocker (selective serotonin reuptake inhibitor, SSRI) and selective inhibitor of phosphodiesterase-4 (PDE4).[22,23]
Research using Zembrin indicates that it may be a promising nutraceutical for cognitive disorders, as it has been found to significantly enhance executive function and cognitive flexibility (via PDE4 inhibition).[22]
As for why KannaEase is included in RE1GN, we can reference a RE1GN-related forum post from Olympus Labs HQ:
Essentially, KannaEase can help “tame the beast” of stimulants by providing a strong, yet controlled and “productive”, boost in energy, mood, and focus, while also combatting the crash, jitters and edginess that some users experience with high-stim products.
As I mentioned before, this ingredient was included in OL’s previous pre-workout, Re1gn, and its overdosing led to a product recall, specifically of the “Dragon’s Mist” flavor. While there has been much speculation as to what’s STIM-X actually is standardized for, I have it on good authority (from a previous consultant of OL) that it is extremely similar to alpha-yohimbine or a chemical cousin of it. This is likely the cause of the adverse reactions experienced from the original run of RE1GN.
For many individuals, yohimbine and alpha-yohimbine are a great stimulant that is fast-acting all the while boosting mood and motivation while also suppressing appetite and boosting fat burning. However, as I (and many other pre workout consumers) can attest, consuming too much yohimbine/alpha-yohimbine can result in rather unpleasant side effects.
Hopefully, the QA/QC is dialed in for this relaunch (fingers crossed…I’ve already discussed the issue with the SFP above).
Touched on earlier, the caffeine matrix is a blend of fast-acting and sustained-release caffeine sources to provide rapid and long-lasting energy, focus, and motivation, helping to power you during your training and for hours afterwards. Based on the numbers listed on the SFP, Oracle should deliver a caffeine payload yield of 300mg per full serving -- divided across the three forms included in the product.
This is a great dose of caffeine, on par with OL’s previous pre workout offerings as well as many other pre workout supplements and energy drinks on the market.
Something else that doesn’t exactly jive with me. An independent, highly-trusted source in the industry informed me that the first “review” published on StrongSupplements.com (the primary retailer offering Oracle) was written by the OWNER of Olympus Labs:
I’ll leave it to you to decide whether the first review of a product written by the owner of the company producing the supplement counts as “unbiased”…
Olympus Labs has delivered some phenomenal supplements over the years during which they’ve introduced numerous novel nutraceuticals and botanical extracts. Oracle looks primed to deliver a lot of energy and focus, but is lacking in pumps (unless ligustrazine is some ultra-effective NO-booster/pump-enhancer).
We need supplements companies to continue to delve deep into the research and innovate with their formulas. It’s exceedingly tiring (and boring) to see the same formulas (essentially -- 300mg caffeine, 6g L-Citruline, 3.2 beta alanine, etc.) show up on the market with the only difference being the flavors or company selling it.
For that, I appreciate what Olympus Labs is doing. At the same time, previous experiences and a history of delivering products on time to consumers who pre-order products (not to mention the aforementioned SFP errors) give me pause.
What do you think?
Are you interested in trying Olympus Labs Oracle? Have you tried any of OL’s previous supplements over the year?
Pregnenolone is a “master” precursor for numerous other important hormones in the body, including dehydroepiandrosterone (DHEA), progesterone, testosterone, estrogen, and cortisol. It is synthesized from cholesterol, and peaks around age 30, after which there is a steady decline until ~age 55 at which point it significantly declines.[1] In fact, one study reported that pregnenolone levels were as much as 60% lower for individuals in their mid-70s compared with those in their mid-30s.[2]
Following diminished pregnenolone production, there is a subsequent (and expected) decline in its downstream hormones -- DHEA, testosterone, and estrogen, in particular. Consequences of these low hormone levels include:
To combat declining hormone levels (particularly sex hormones), hormone replacement therapy (HRT) has become incredibly popular, not only with aging adults but younger adults looking to resist the effects of aging (“biohackers”), build more muscle, and optimize body composition. Typical hormones used in HRT protocols include testosterone, estrogen, and progesterone. While these are beneficial, prolonged used of them has been known to lead to various complications, including (but not limited to)[2]:
Pregnenolone is often overlooked by hormone/anti-aging clinics, yet researchers posit that utilizing a combination of pregnenolone with “relatively small amounts of sex steroids might give the same physiological effects as would administration of larger amounts of the latter alone.”[2] This, in turn, could achieve the same end result/benefits with less risk of adverse side effects.
As a result, pregnenolone supplements may be an option to support optimal hormone levels and promote healthy aging, as it is the “mother” hormone. In fact, the anti-inflammatory and anti-fatigability properties of pregnenolone have been recognized since the 1930s.[20,21]
Here are some of the top benefits of pregnenolone supplements:
Stress is inherent to the human condition, which means there’s no getting around it -- there will be instances (physical, emotional, psychological, etc.) that stress your mind and/or body. Now, it’s important to realize that not all stress is bad. In fact, some stress is not only beneficial (e.g. resistance training, HIIT, etc.) but necessary as it serves as a powerful signal to our physiology that it needs to “batten down the hatches” after which it will become stronger and more resilient.
Where stress goes “bad” is when the volume and/or magnitude of stress exceeds the body’s ability to recover. This leads to chronically elevated of cortisol (the body’s primary stress hormone), which has numerous deleterious effects, including:
In addition to making the requisite lifestyle changes (diet, sleep, exercise, stress management, breaking up with a batshit crazy girlfriend, leaving a job that makes you miserable, etc.), certain supplements may also help alleviate feelings of stress and anxiety. Common ones I’ve discussed before include L-Theanine, Ashwagandha, Lemon Balm, and Magnolia Bark.
Pregnenolone is another stress-relief supplement that doesn’t get the attention it deserves but does offer some interesting stress-relief benefits.
Up top, I mentioned that pregnenolone is a precursor to cortisol, and this might make you think that supplementing with pregnenolone might increase baseline cortisol levels, but that’s a bit of an oversimplification.
Pregnenolone, in addition to facilitating steroid hormone synthesis, also exerts a number of other effects throughout the body. One of those many actions is as a neurosteroid.
Research notes the pregnenolone sulfate (the primary form of pregnenolone found in the body as well as that which is included in dietary supplements) acts as both a negative modulator of GABA and a positive modulator of the N-Methyl-D-Aspartate (NMDA).[2,3,4,5]
Note: GABA is the body’s primary inhibitory neurotransmitter, and NMDA is an excitatory neurotransmitter (and NMDA receptors are a binding site for glutamate -- another major excitatory neurotransmitter).
Due to this dual-action on opposing neurotransmitter systems, researchers note that “PREG-S (pregnenolone sulfate) could exert a remarkable synergistic amplification of excitatory transmission at much lower concentrations than would be expected from effects of PREG on either the inhibitory or excitatory system alone.”[2]
Additional studies investigating doses ranging from 25-75mg pregnenolone found improvements in performance under stressful conditions (i.e. greater productivity), less fatigue, and improved feelings of well-being.[2] Research also noted that the effects seemed to compound with time with no adverse side effects.
Another thing to note is that pregnenolone may also be converted to allopregnanolone, and researchers have found it may offer some interesting results based on the dosage used in animal studies. In particular, low doses of allopregnanolone may have an adverse, anxiogenic effect. This effect decreases with increasing doses of allopregnanolone and the beneficial and calming property occurs.[6,7]
These calming properties are, in part, due to the way allopregnanolone interacts with GABA-A receptors.[8]
As is the case with natural hormone production, many other aspects of life decline with age (let alone the other lifestyle factors -- drinking, smoking, stress, sleep deprivation, etc. -- that can accelerate said degradation).
Two such critical components of daily life that decline with age are memory and cognitive function. Chronic stress and sex steroids are also known to adversely impact memory and are also linked to the development of dementia.[9]
My fascination (“obsession”) with brain health/performance has led me to explore numerous nootropics over the years that not only improve cognitive function in the short term, but also help combat cognitive decline and support healthy aging. I’ve covered many of these over the years, but it wasn’t until doing research for this article (courtesy of long-time listener/reader Devin) that I was aware of the brain-boosting benefits of pregnenolone.
In addition to modulating GABA, pregnenolone Other research indicates that GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices.[10]
Research has shown that Alzheimer’s patients have lower levels of pregnenolone, allopregnanolone (a pregnenolone metabolite) and DHEA-sulfate in all key memory-related areas of their brains, compared to individuals without Alzheimer’s.[11,12,13]
Supplementing with pregnenolone is a viable option to help increase the body’s pregnenolone “reservoir” which can then be used to produce the downstream hormones.
Additionally, pregnenolone has also been shown to increase acetylcholine levels.[14] Acetylcholine (dubbed the “learning neurotransmitter”) is heavily involved in memory, learning, muscle contractions, and the mind-muscle connection.
Animal studies have also found that infusions of pregnenolone sulfate stimulate neurogenesis -- the process by which new neurons are produced.[15]
To top it off, pregnenolone (as well as allopregnanolone) are considered by researchers to have “immense neuroprotective potential.”[16]
Previous studies conducted in mouse hippocampus cells noted that allopregnanolone offered neuroprotective properties against glutamate and amyloid beta protein neurotoxicity.[17]
A recent 2022 animal study found that pregnenolone also reduced the neurological impairments via reducing mitochondrial reactive oxygen species (ROS).[18] In case you weren’t aware, ROS are a contributing factor towards inflammation (including neuroinflammation) as well as cognitive decline.
Research has found that cocaine-using individuals supplementing with 500 mg/day of pregnenolone demonstrated lower stress-induced heart rate and blood pressure.[22] Furthermore, pregnenolone supplementation also may help decrease cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.
Animal studies have shown that pregnenolone sulfate injections may attenuate memory impairment caused by alcohol and nicotine.[23,24] Remember that chronic excessive alcohol intake downregulates GABAergic transmission and reduces levels of neuroactive steroids.
Newly published research, appearing in the January 2023 edition of Psychopharmacology, found that humans with alcohol use disorder consuming 300mg/day pregnenolone decreased stress- and alcohol cue-induced craving and reduced stress-induced anxiety.[25]
Pregnenolone may also protect the brain against the intoxicating effects of marijuana.[27] Cannabinoid drugs, including marijuana, modulate brain activity and behavior principally by activating cannabinoid-1 (CB1) receptors. This, in turn, inhibits the release of several neurotransmitters, in particular GABA and glutamate.[28] Animal studies found that injections of pregnenolone inhibited the increase in food-intake and memory impairment, commonly seen with marijuana use.[27]
Interestingly, marijuana increases levels of pregnenolone. This naturally made researchers curious as to why pregnenolone injections demonstrated protective effects. They surmised that:
“Pregnenolone then, acting as a signaling specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals an unknown paracrine/autocrine loop protecting the brain from CB1 receptor over-activation that could open an unforeseen novel approach for the treatment of cannabis intoxication and addiction.”
In addition to serving as a precursor for steroid (including neurosteroid) hormones, pregnenolone is also a precursor for hormones involved with lymphocytes (white blood cells).[19] Researchers have also shown that chronic stress, sleep deprivation, systemic inflammation, and a whole host of other factors contribute to increased infection and reduced immune function.
Cell studies indicate that pregnenolone, allopregnanolone, and progesterone (a derivative of pregnenolone) may significantly suppress LPS- or Pam3CSK4-induced TNF-α (an inflammatory cytokine) in macrophages.[19]
Pregnenolone may also help reduce feelings of stress and chronically elevated cortisol levels (two factors known to impair immune function and increase risk of infection).
Early research on pregnenolone suggests it may also benefit individuals with arthritis.[2,26] This is likely due, at least in part, to its anti-inflammatory effects discussed above. Doses varied quite wildly in arthritic research from 100-300mg per day (as pregnenolone acetate) all the way up to 12,000mg (12 grams)![29]
Researchers noted that “Clinically, it is apparent that some patients who eventually respond well may not exhibit any change at all during the first few weeks of treatment. It seems advisable, therefore, for treatment to be continued for three to four weeks before final evaluation is attempted in any one patient.”
Animal studies indicate that pregnenolone sulfate may increase REM sleep without affecting slow-wave sleep or wakefulness.[30]
A wide range of dosages of pregnenolone have been investigated in humans over the past several decades, from as low as 50mg all the way up to 12,000mg per day.
Pregnenolone supplementation, as described in research, is generally well-tolerated and without significant side effects for the majority of individuals. A 1950 review on pregnenolone concluded that, “The substance has an extraordinarily low order of toxicity…It appears, moreover, that very large doses can be employed without danger of side-effects.”
Pregenonolone supplements also appear to be most beneficial when taken consistently ("daily" for several weeks at a time) as opposed to occasionally.
Most supplements on the market today include between 50-100mg pregnenolone sulfate.
Pregnenolone is a neurosteroid naturally produced by the body that serves as the “mother” hormones for numerous other hormones in the body that exert a multitude of effects. Based on the current body of research, pregnenolone possesses a high safety profile and seems like a viable option to support mood, mental energy, stress levels, and brain health.
There’s no shortage of mass market supplement offerings that are constantly plastered across media outlets (e.g. Nugenix, Force Factor, etc.). Despite the haughty claims and fancy ad-speak, the vast majority of these products are woefully underdosed.
Along these lines, Sandy asked me the other day about a product she saw an advertisement for called Superbeets Heart Chews. With the understanding that she learned of the product on a TV/radio spot, I quickly made the flippant remark, “it’s probably underdosed garbage that includes 500mg of beet root extract and not much more.”
When I finally pulled up the ingredients panel for Superbeets Heart Chews, I wasn’t far off:
The question remains though -- are Superbeets Heart Chews a “scam” or are they just another underdosed, mass market supplement?
Let’s discuss.
Beetroot is rich in dietary nitrate (NO3-), and consuming nitrate-rich foods has been shown to increase nitric oxide (NO) levels, improve blood flow, reduce blood pressure, and boost exercise performance.
The dose of dietary nitrate found to benefit cardiovascular health and athletic performance is at least 300-600mg (~4.8-9.8 mmol) nitrate.[1,2,3,4]
Regarding beetroot, specifically, most studies have individuals consume 500mL of beetroot juice (delivering an average of ~5-8mmol nitrate per serving). In addition to nitrates, beetroot juice also contains other bioactive compounds that act independently or synergistically with nitrate to improve NO production and blood flow, including polyphenols such as quercetin and resveratrol as well as antioxidants.
However, the form of beetroot juice commonly included in most dietary supplements, including Superbeets Heart Chews, is 500mg beet root powder. There is no standardization for nitrate contents, it’s just dried, ground up beetroot. Average nitrate contents of beetroot powder, according to research, is between 1-5%.[5,6] It also should be stated that 500mg of beet root powder is NOT equivalent to 500mL of beetroot juice.
Interestingly, Superbeets (and their parent company HumanN) have had their “nitrate-rich” beetroot powders tested by 3rd party researchers. You can see the results below[6]…
As you can see, the amount of nitrates delivered per 5,000mg serving of Superbeets beetroot powder is only ~1.03mmol (63.86mg) nitrates…This is ~4-5x less than the efficacious amount of nitrate noted in research to offer cardiovascular and athletic performance benefits.
Furthermore, the amount of beetroot powder included in a serving of Superbeets Heart Chews is 500mg, which means you’re probably only getting about 30-35mg of actual nitrates in a serving of the supplement -- 10x less than the minimal dose shown in research to improve NO levels and blood flow.
The takeaway here is that (at best) you’re getting some polyphenols that may support healthy blood flow and nitric oxide production, but in terms of getting any profound boost in nitrate concentrations or NO from the beet component of Superbeets Heart Chews, it doesn’t look promising.
The other ingredient included in Superbeets Heart Chews is doing the real work, which we’ll get to in a moment.
One thing to keep in mind concerning nitrate supplementation, particularly in regards to athletic performance, is that it takes between 1-2 hours after ingestion for plasma nitrate levels to peak , and plasma nitrite levels peak after 2–3 hours following ingestion.[8] Research also indicates that both nitrate and nitrite levels gradually return to baseline after about 24 hours.[11]
Additionally, it’s best to avoid excessive use of mouthwash with beetroot juice supplementation as it can limit the effects of nitrate ingestion.[12]
Enovita is a trademarked, proprietary grape seed extract standardized to provide[22]:
A number of studies have been conducted over the years on grape seed extract and its effects on various markers of cardiometabolic health, including blood pressure, cholesterol, and blood glucose.
Grape seed extract is a rich source of polyphenols and antioxidants, especially proanthocyanidins which have been investigated for their health-promoting effects. Proanthocyanidins are products of the flavonoid pathway and are related to anthocyanins (the “fun” bioactive compounds in blueberries and other dark berries that aid cardiovascular and cognitive health).[13]
Proanthocyanidins support healthy blood pressure by modulating angiotensin-converting enzyme (ACE) and stimulating endothelial nitrogen oxide synthase (eNOS).[14,15,16]
Compounds that limit or blunt the activity of are referred to as ACE inhibitors, and they are one of the major targets of researchers for combating high blood pressure. ACE inhibitors block the conversion of angiotensin I to the vasoconstrictor compound, angiotensin II. By inhibiting ACE, there will be lower levels of angiotensin II, which helps reduce vasopressor activity and decreased aldosterone secretion.
The end result is increased vasodilation, which helps blood vessels to stay open and flexible -- aiding blood flow, circulation, nutrient delivery, and more.
A 2020 meta-analysis concluded that supplementing with grape seed extract decreased LDL (“bad”) cholesterol, total cholesterol, and triglycerides[17]. A prior 2016 meta-analysis by Zhang et al. concluded that grape seed extracts can help decrease systolic and diastolic blood pressure, with effects being significantly more pronounced in subjects with metabolic syndrome and in pre-hypertensive individuals.[18]
A 2021 meta-analysis, including 13 studies analyzing the potential BP-lowering effects of grape seed extract supplementation, found an average systolic blood pressure decrease of 9.3 mmHg which is equivalent to a 10% risk reduction for stroke.[19]
Apart from the other studies referenced above, there are two human studies (to date) specifically investigating the benefits of Enovita.[20,21]
The first human trial published on Enovita was a controlled registry study involving 119 healthy, pre- and mildly hypertensive subjects. Two dosages of Enovita were evaluated (150mg and 300mg/day.[20]
Researchers concluded, “After four months of treatment, a statistically significant higher, and dose-dependent, improvement in all endpoints was observed in the treatment groups compared to that of the control, with blood pressure normalizing in 93% of the higher dosage (300 mg) treatment group.”
In other words, 150mg Enovita was helpful, but 300mg offered greater benefits for blood pressure.
A 2021 double-blind, randomized, placebo-controlled parallel group study was conducted in 80 men and women with mild hypertension.[21] Participants consumed either placebo or 150mg Enovita grape seed extract twice daily (for a total of 300mg/day) for 16 weeks.
Significant reductions of systolic blood pressure of −4.6 mmHg and diastolic blood pressure of −3.2 mmHg was observed in men after 16 weeks of Enovita supplementation. Interestingly, researchers also noticed a trend toward lower feelings of self-perceived stress by the men and women after the study.
The takeaway here is that 300mg Enovita supports reductions in elevated blood pressure -- 150mg was not investigated.
Despite the slew of advertisements, Superbeets Heart Chews are really just a sprinkle of beet root powder and the lesser-beneficial dose of grape seed extract (150mg).
As shown above, beetroot powder is more hype than substance since it contains negligible amounts of actual dietary nitrates. If you’re actually interested in the NO-boosting, BP-lowering effects of nitrates, then it would be better to consume a nitrate-rich diet (dark leafy greens, beets, beetroot juice) and/or supplement with nitrates (NO3-T).
As for grape seed extract, there are a wide variety of high-quality grape seed extracts available in both powder and capsule forms that are better dosed (300-600 mg/serving) and more affordable.
For my money, I’d look to a bulk grape seed extract supplement and focus on consuming enough other high-quality foods throughout the day/week.
Are Superbeets Heart Chews “bad”?
No.
Are they overhyped and potentially misbranded?
In my opinion, yes.
The real workhorse in Superbeets Heart Chews is the grape seed extract. Even then, to get the maximum benefit of Enovita (per the published research), you’d need to consume two servings of soft chews per day…OR you could just purchase a grape seed extract supplement and take one each day and be done with it.
Bang RTD has been one of the top-selling energy drinks, alongside Red Bull and Monster, for several years. Originally launched in 2012 as “Bang 357” (due to it containing 357mg of caffeine) by Vital Pharmaceutical, Inc. (aka VPX)[1], Jack Owoc, founder & CEO of VPX, created the beverage in response to his displeasure with the options available at the time.
Initially, Bang was slow to catch on with the general population, but persistence paid off and Bang experienced 80% growth from 2019 to 2020, resulting in sales over $780 million.[2] The brand’s success even thrived during the global hysteria of 2020 with Bang sales totaling $1.2 billion between June 2020-June 2021.[3] Bang’s success can be attributed to a combination of its branding, advertising, and expansive number of flavors (Note: At present, Bang Energy has over 30 flavors!).
Aside from higher caffeine content, Bang also brought several previously-unused ingredients to the energy drink sphere, namely “Super Creatine.”
Chemical structure of creatyl-l-leucine ("Super Creatine") (A) and creatine (B).[7]
In fact, Jack Owoc was granted a patent by the USPTO for his creatine-amino acid peptides, including creatyl-l-leucine, a creatine-amino acid peptide (AKA “Super Creatine”). The proposed benefits of this “Super Creatine” were that it was:
The massive marketing hype that propelled Bang to the forefront of the increasingly competitive energy drink market is admirable, so much so that when having conversations with average Bang imbibers, I have been told (on multiple occasions) that he/she “feels” the BCAAs and/or Super Creatine “working”.
Now, you and I know (as well as other well-informed supplement enthusiasts) that the amounts of these buzzword ingredients in Bang (as well as most other energy drinks) is so pitifully low amount that to even approach an efficacious dosage would entail ingesting an amount of caffeine which many individuals will not respond well to.
To further deflate any potential enthusiasm around “Super Creatine,” consider the following:
Therefore, the only real upside to Super Creatine is that it remains stable in solution. However, as I just mentioned, Bang energy drinks contain such a paltry amount of Super Creatine (25mg/16oz can), you’re better off not even factoring it into your daily creatine supplementation.
Now, this isn’t to dissuade you from enjoying Bang or any other energy drink, as they do offer a number of delicious flavors, but to assume that you can meet the dosage recommendations for most supplements from drinking an energy drink or two (bearing a few exceptions) is a futile endeavor.
All of this background underscores the recent story published by Stack3D[5] which stated that VPX has to pay $293 million to Monster after losing a false advertising lawsuit. This comes after VPX was ordered to pay $175 million to Monster and Orange Bang, a California juice maker, for breach of contract and trademark infringement in April 2022. The ruling also required VPX to pay a 5% royalty on all future US sales of Bang Energy to Monster and Orange Bang. Previously, ThermoLife International, LLC (providers of NO3-T amino-bound nitrates, including creatine nitrate) filed suit against VPX in Arizona for false advertising.
ThermoLife’s founder, Ron Kramer, also said in a statement to PR Newswire[10]:
"ThermoLife cannot stand by while VPX and Jack Owoc falsely tout 'Super Creatine' as superior to all other forms of creatine. First, as detailed in the complaint Super Creatine is NOT creatine, nor is it a source of creatine, and despite their intentional false advertising, VPX and Owoc know this. Second, ThermoLife has the exclusive rights to the 'Super Creatine' compounds in the USA and we already had the USPTO cancel ALL of Jack Owoc's patent claims to the 'Super Creatine' compounds, because contrary to what Owoc tells people, Jack Owoc is NOT the inventor of the 'Super Creatine' compounds. Now, in filing this lawsuit, we seek to have the court hold VPX and Owoc responsible, and punish them for the lies they are intentionally telling to consumers."
Two other factors to keep in mind:
Despite this grim reality, Jack Owoc has asserted VPX will endure and emerge stronger. Time will tell if this actually transpires. In the interim, we can discuss some of the contributing factors that led to VPX paying Monster $293 million.
It just so happens that Monster funded a pair of studies to be conducted on “Super Creatine.”[7,8] The manuscripts have recently been published, which is where I’ll now shift the focus of this article.
Appearing in Nutrients, the first study we’ll review is an animal study which investigated if creatyl-l-leucine (“super creatine”) is a bioavailable compound, and if it can supply creatine if efficacious amounts to the brain, plasma, or skeletal muscle tissue.[7]
24 rats were given a creatine-free diet for 14 days at which point they were divided into one of three groups and fed a 7-day diet containing:
Note: In terms of a human equivalent dose, the above dosages for a 70kg (154lb) individual would equate to a dose of 17.6 g/day of creatine monohydrate and 28.9 g/day of Super Creatine (based on the molecular weight of creatine if Super Creatine degraded into creatine).[7] You don’t need me to tell you that you’re not getting anywhere near this amount of Super Creatine in a single can (let alone two, five, or TEN cans of BANG).
Creatine content of quadricep muscle. The open bar represents rats fed creatine-free diet, light gray bar represents rats fed 0.4% w/w creatine monohydrate-supplemented diet, dark gray bar represents rats fed 0.656% CLL supplemented diet.[7]
As you would expect, rats given creatine monohydrate-enriched diets experienced significant increases in creatine concentrations in plasma, brain, and muscle tissue. However, rats given Super Creatine did NOT increase blood, muscle, and brain creatine content above and beyond rats fed the control diet.[7]
Based on these results, the researchers concluded that creatyl-l-leucine does NOT increase creatine bioaccumulation, meaning it is not a bioavailable source of creatine.[7]
The second study (conducted in a randomized, double-blind, placebo-controlled, parallel design) investigated the effects of 2 weeks of dietary supplementation with creatine monohydrate, Super Creatine or placebo on muscle creatine content in 29 healthy men and women (the authors did not stipulate if participants had to be resistance-trained or not).[8] Despite the much-ballyhooed Super Creatine, this was the first human study conducted to see if Super Creatine actually increased body stores of creatine.
Participants completed baseline strength testing. At least 72 hours post-preliminary testing, test subjects had a muscle biopsy where researchers harvested a plug of muscle tissue from the quads. Following the baseline test, individuals began their 14-day supplementation of either:
During the 2 week supplementation period, subjects completed three supervised resistance exercise sessions per week following an A/B split which included:
Note: While this training program is far from comprehensive, at least there was a decent amount of lower body work (though they skipped calf training). There also wasn’t much work for the back muscles and NO direct arm work (curls, pushdowns, etc.)…the gym bros would be up-in-arms (pun intended).
If participants were unable to complete 10 repetitions at the given intensity, the load was reduced by 2.5%–5% until 10 repetitions were completed. Exercise sessions were separated by at least 48 hours.
After the 14-day supplementation & training period, subjects underwent another muscle biopsy. If you’ve ever had a biopsy, it’s certainly not the most pleasant experience (especially if it’s in your hip and they “miss” the bone marrow on the first two attempts!)
Mean ± SD muscle creatine content before and after 14 days of supplementation. Cr = creatine; WW = wet weight; CLL = creatyl-L-leucine; CrM = creatine monohydrate; PLA = placebo. *Significantly greater than the presupplementation time point within group. †Significantly greater than PLA and CLL post-supplementation.[8]
At the conclusion of the study, researchers documented a 24% average increase in muscle creatine content for the creatine monohydrate group. There was NO increase in muscle creatine content for the Super Creatine group.[8]
Based on these findings, researchers stated:
“As such, this work does not support the use of CLL (“super creatine”) as an alternative dietary supplementation strategy to CrM (creatine monohydrate) to increase muscle Cr content in healthy males and females.”[8]
Suffice it to say that relying on Super Creatine to fulfill your daily creatine requirements, let alone improve any aspect of physical or cognitive performance is a no-go. In fact, Dr. Richard Kreider, professor and director of the Exercise & Sport Nutrition Lab at Texas A&M University as well as an expert witness for Monster Energy Co., testified in court that:
Therefore, if you want to gain the benefits of creatine supplementation, then opt for plain, ol’ creatine monohydrate. It’s stood the test of time and has been shown (repeatedly) to not only be effective and safe, but affordable.
Again the above two studies were funded by Monster Energy Company, but they did not participate in the execution, analysis, or documentation of the trials.
So, if you want to drink Bang or any other energy drinks for the taste, caffeine content, or as a replacement for sodas or other sugar-containing beverages, go ahead. I enjoy the occasional energy drink, and at the same time realize I’m not consuming it to satisfy any of my daily supplement protocols (creatine, ALCAR, CDP-Choline, NAC, etc.).
While Jack Owoc publicly states that VPX and Bang are going to emerge stronger, only time will tell as they have to deal with considerable payments (over half a billion dollars and counting) and an increasingly crowded and competitive market.
What do you think the final outcome of Bang energy will be?
Will they recover, persevere, and grow going forward? Will they “survive” as just another energy drink offering, or is this the sign of a slow decline of a once-strong brand?
Leave a comment below along with your favorite energy drink!
Following are three short research recaps I've written over the past few weeks for Stack3D. If you enjoy this kind of supplement ingredient analysis, don't forget to hop over to the Supplement Engineer Insider where I go into greater detail about individual ingredients as well as new pieces of research.
So, without further adieu...
Sabroxy® is a little-known nootropic from Sabinsa Corp., distributors of the widely used absorption-enhancer BioPerine®.
The first human clinical trial investigating Sabroxy® documented the unique extract’s cognitive-enhancing effects, particularly in the areas of memory, concentration, focus and recall.[1]
Published in Frontiers in Aging Neuroscience, the 12-week randomized, double-blind, placebo-controlled study included 82 men and women aged 60–85 years, with self-reported impairments in memory or cognitive skills.
Participants were randomly assigned to receive either Sabroxy® (500mg) or placebo. They were instructed to take one capsule, twice daily (morning and evening), with or without food, for 12 weeks.
Effectiveness of Sabroxy® was assessed via the Computerized Mental Performance Assessment System (COMPASS) -- a software application that helps assess episodic memory and speed of response. The men and women completed the COMPASS test at day 0 and at the end of the 12-week study.
Men and women who used Sabroxy® experienced significant improvements in the areas of:
Researchers also found that Sabroxy® supplementation increased BDNF levels in the serum by 27.13%, compared to 22.6% in placebo. BDNF (brain-derived neurotrophic factor) is an important protein in the brain that impacts the growth, development, and differentiation of neurons. It also plays a crucial role in long-term memory and neuronal plasticity -- how the nervous system processes, changes, and adapts to things it encounters.
Sabroxy was well-tolerated by the study participants and no serious adverse effects were reported with its use.
Sabroxy is a standardized extract of Oroxylum indicum, which is standardized to contain:
Oroxylum indicum is found predominantly in China, Japan, and India, and it has a long history of use in traditional herbal medicine where it was used in the treatment of multiple disorders.
Animal studies indicate that Sabroxy confers neuroprotection by[2]:
Other research conducted on oroxylin-A (one of the main actives in Sabroxy demonstrates that it can inhibit dopamine reuptake, and has an antagonistic effect on the GABA-A receptor.[3,4] GABA is the body’s primary inhibitory (“downer”) neurotransmitter).
Sabroxy has a high safety profile with pre-clinical studies finding it safe and not associated with any toxic effects even at doses as high as 500mg/kg (equivalent to a 2,500mg human dose).
Joint health is an often-overlooked aspect of sports nutrition…at least until it’s too late (i.e. after suffering an injury).
That’s a shame because there are a number of well-formulated joint support products specifically catered to hard-training individuals.
Boswellia serrata is a long-standing favorite for formulators. The tree grows in the dry mountainous regions of India, Northern Africa and the Middle East. Its resin is loaded with bioactives, the most well-known being boswellic acids, and has been used in folk medicine for centuries to treat various chronic inflammatory diseases.
ApresFlex (aka Aflapin) is a clinically-backed extract of boswellia serrata extract, from PLT Health Solutions, the same company behind Zynamite, Zembrin, and RipFactor. Compared to generic boswellia extracts, which may not list a standardization, ApresFlex is standardized to 20% 3-O-acetyl-11-keto-β-boswellic acid.
A new clinical study was recently published in the Journal of the American Nutrition Association finding significant improvements in pain scores after just 5 days of use.[5]
70 individuals with knee osteoarthritis participated in the trial and were randomized to either receive placebo or 100mg ApresFlex daily for 30 days.
Researchers collected data on a host of metrics including WOMAC pain and physical function measurements. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) is one of the premier assessments used in assessing pain, stiffness, and function in individuals with osteoarthritis.
Several other notable inflammatory and cartilage biomarkers were also documented, including c-reactive protein (CRP), tumor necrosis factor-α (TNFα), and MMP-3. FYI, the expression of MMP-3 protein is closely related to the cause of osteoarthritis.
65 individuals completed the trial, and researchers noted that ApresFlex provided pain-relief benefits beginning just 5 days after starting supplementation!
At the end of the 30-day study, significant reductions were also noted in joint stiffness as well as circulating levels of CRP, T (TNFα), and MMP-3. Individuals receiving ApresFlex also experienced pronounced improvements in joint mobility and function.
This is the third double-blind, placebo-controlled study investigating AprèsFlex and the second study to confirm significant improvements in joint comfort beginning after just five days of use.
InnoSlim is a stimulant-free body recomposition ingredient developed by Nuliv Science, the same ingredient house behind the popular absorption enhancer, AstraGin, as well as the ATP enhancing, Senactiv.
InnoSlim is comprised of a unique blend of Panax notoginseng and Astragalus membranaceus, and early research on the ingredient highlighted a number of alluring benefits for those seeking to lose weight and improve body composition, including:
Recently, the first human clinical study on InnoSlim was published, where a number of other notable health benefits were documented, particularly regarding cardiovascular health.[6]
12 individuals (>20 years old) took part in the 16-week randomized, double-blinded crossover trial and met the following eligibility criteria:
Since this was a crossover trial that means each subject was able to serve as their own control. The 16-week trial was broken out as follows:
During the 6-week phase each participant would consume either placebo or 250mg InnoSlim.
At the end of the study, researchers found that (compared to placebo) 6 weeks of InnoSlim significantly reduced[6]:
Researchers also noted significant improvements in HDL-Cholesterol (11.78%), adiponectin (22.07%), and AMPK (12.72%). Note: Adiponectin is a hormone secreted by fat cells that activates AMPK, which subsequently inhibits gluconeogenesis and maintains the balance of blood glucose and lipids. Decreased adiponectin leads to reduced insulin sensitivity and a greater risk of obesity.
Based on these results, the team of researchers concluded that InnoSlim can be effective for reducing hyperglycemia (high blood sugar) and hypercholesterolemia (high cholesterol).
Have you used Sabroxy, ApresFlex, or InnoSlim before?
If so, do you think these ingredients are beneficial?
Drop a comment below!
And, if you enjoy this kind of supplement ingredient analysis, don't forget to check out the Supplement Engineer Insider, where I go into greater detail about individual ingredients, including CDP-Choline, enfinity Paraxanthin, and more, as well as new pieces of research.
The ingredient in question?
The arginase inhibitor, and nitric oxide extender, L-Norvaline.
Let’s take a look beyond the attention-grabbing headlines, dive deep into the study and see what’s really going on here.
First off….
L-Norvaline is a derivative of the branched-chain amino acid (BCAA) valine that has been noted in research to be a mixed arginase inhibitor.[1,2,6] Arginase is the enzyme in the body that degrades arginine -- the primary substrate used to generate nitric oxide, increase blood flow, and boost muscle pumps. It also plays a role in many inflammatory disorders by reducing nitric oxide synthesis and inducing fibrosis and tissue regeneration.
The theory goes that by limiting the actions of arginase, you’re removing the “governor” plate in your body allowing for unrestricted nitric oxide production, yielding stronger, longer-lasting pumps.
L-Norvaline isn’t the only arginase inhibitor commonly used in pre workout supplements either. Many pre workouts use Agmatine Sulfate
Now, as we mentioned L-Norvaline is a mixed arginase inhibitor, which means that it both degrades arginase in the liver as well as in the lumen of the GI tract and endothelium of blood vessels.
In regards to enhancing blood flow and pumps, arginase inhibition in the endothelium and lumen would be beneficial, in theory as it would lead to greater arginine availability. However, you would only benefit from the increased arginine if there was a subsequent enhancement in eNOS expression -- the enzyme that actually generates nitric oxide.
Furthermore, all studies using L-Norvaline are in unhealthy individuals, there is no substantial body of evidence in otherwise healthy individuals that L-norvaline exerts the same anti-arginase / anti-inflammatory activity.
Continuing on, arginase inhibition in the liver is a bit of a concern, as arginsase is a critical component of nitrogenous waste removal where it catalyzes the final step in the production of urea.
By inhibiting arginase in the liver to a large enough extent, there is the potential for an excess of ammonia in the body (hyperammonemia), which is often seen in individuals with congenital arginase deficiency, and may lead to brain injury and death.
And this brings us to the current study.
Researchers took SH-SY5Y brain cells, placed them in petri dishes, and exposed them to 500-2000uM l-norvaline.[3]
FYI, this verges on injecting yourself with upwards of 1g of L-Norvaline. The typical pre workout supplement contains between 100-300mg of L-Norvaline.
Researchers noted that brain cells die when exposed to L-Norvaline, and the longer they were exposed to it, the more toxic it was.
The method in which L-Norvaline caused neuronal cell death may be due to its starving the brain cells of energy, as tests showed it did not reduce the amount of mitochondria, but decreased their size.
Interestingly, researchers found that by increasing the concentration of the three BCAAs (Leucine, Isoleucine, and Valine), it was possible to fully protect against the toxic effects of L-Norvaline. It’s worth mentioning that the BCAAs are also the amino acids most closely related in structure to L-Norvaline. As a result, the BCAAs may limit L-Norvaline’s uptake into the cell by blocking system L transporters, the group responsible for transporting large, neutral amino acids into the cell.[3]
In a follow-up press release to the publication of the study, Kate Samardzic, lead author of the study said[4]:
“Protein requirements are higher in very active individuals and proteins are considered to improve and increase performance. The demand for amino acids in supplements has expanded but in addition to the normal protein-building amino acids other 'non-protein' amino acids are being taken.
Some non-protein amino acids are toxic because they can mimic protein amino acids and deceive the body into making faulty proteins; a property used by some plants to kill predators.
Some plants can even release non-protein amino acids into the soil to kill other plants so that they can have access to all the nutrients. Chemical warfare among plants is a well known phenomenon. Since there was evidence that L-norvaline has antimicrobial and herbicidal activity we examined its toxicity in human cells."
Shortly after publication, a rebuttal was published in the December 2019 issue of Brain Science aptly titled: “Reports of L-Norvaline Toxicity in Humans May Be Greatly Overstated.”
The authors point out several issues with the study suggesting norvaline’s cytotoxicity to neurons, namely that they used a cell culture model, no in vivo toxicity for norvaline has been established, and a few others I’ll discuss below.
The authors conclude[7]:
“In brief, the conclusions of the study by Samardzic and Rodgers are significantly overstated and omit the fact that L-norvaline toxicity is limited to specific in vitro assays at exceedingly high concentrations… the study at hand does not confirm any human toxicity of L-norvaline; however, it makes claims unsupported by actual data, which resonate in newspaper articles and interviews. For example, they claim that “Bodybuilding supplement could be bad for the brain”, which is a misleading and false statement.“
Despite these more recent findings, previous research actually finds that L-Norvaline may support cognitive function and brain health.
As an arginase inhibitor, L-norvaline can boost nitric oxide production as well as reduce urea production.[6]
Other research has shown that L-norvaline can inhibit the activity of ribosomal protein S6 kinase β-1 (S6K1) as well as offer anti-inflammatory properties.[2] Combined, these actions suggest that L-Norvaline could be an effective option for Alzheimer’s Disease extremely effective in AD. Animal models of Alzheimer’s Disease have found that decreasing expression of S6K1 improves spatial memory and synaptic plasticity.[7]
Now, it should be noted that the aforementioned “controversial” study on L-norvaline was conducted using cell cultures. It was not conducted with individuals ingesting L-Norvaline as they would in a pre workout supplement. Still, this does bring a bit of concern to the ingredient especially in regards to the amount and frequency of using it pre workout formulations.
In the end, low doses of L-Norvaline likely aren’t effective in healthy populations, high doses may be dangerous (and potentially toxic), and moderate doses may increase the bioavailability of co-ingested L-arginine.
Essentially, these neuro chemicals are what enable us to feel, interpret, act, and react to our surroundings.
Executives, students, bio-hackers, and even top-tier athletes are constantly seeking ways to optimize and balance these neurotransmitters to manifest the ideal neurological environment for next-level performance.
It’s rather common to use a stable of precursor compounds, such a L-Tyrosine or Alpha GPC, to optimize levels of important neurotransmitters like Acetylcholine, Dopamine, and Serotonin.
But, what if you could use just one supplement that impacted all of the major neurotransmitters to some degree, balancing them out to create the ultimate cognitive environment for mental energy, focus, and clarity while at the same time reducing feelings of stress and anxiety?
Today, we discuss a compound that’s been regularly used for thousands of years known as bacopa monnieri, and why it could be the supplement you need to get more done while feeling less stressed this year!
Bacopa monnieri is one of the oldest herbs of Ayurveda traditionally used in the treatment of neurological and behavioral defects. Some accounts indicate that the herb has been used as far back as 800 B.C.[1]
Given its prolonged history of use, the powerful herb has collected various monikers over the centuries, including[2]:
Bacopa derives its name from Brahma, the mythological “supreme ruler” and creator of the world as well as the science of Ayurveda.
In addition to its neuro-enhancing effects, bacopa was also routinely used as an adaptogen and natural medicine in the treatment of all manner of diseases ranging from depression to leprosy.
Like most medicinal plants, bacopa monnieri contains a whole host of biological compounds which are believed to be responsible for the plant’s therapeutic effects.
Of all the alkaloids, saponins, and other phytocompounds present in bacopa, the ones doing the real “heavy lifting” are a pair of steroidal saponins called bacosides A and B.
Bacosides are known to cross the blood-brain barrier (BBB) where they are able to modulate neurotransmitter levels in the brain.[3]
Included among the various neurotransmitters that bacopa’s bacosides are able to modulate are:
More specifically, bacopa is known to inhibit acetylcholinesterase –- the enzyme that breaks down acetylcholine, and stimulates choline acetyltransferase -- the enzyme that stimulates acetylcholine synthesis. choline acetyltransferase -– the enzyme that produces acetylcholine.[3]
Bacopa also boosts levels of serotonin and GABA in the hippocampus, heightening mood and promoting feelings of calm relaxation.
Research also indicates that bacosides can stimulate antioxidant enzymes (such as Superoxide Dismutase -- SOD), support synapse regeneration, and repair damaged neurons.[4]
Bacosides are even noted to help reduce “hippocampus devaluation” by removing aluminum from the cerebral cortex, which is especially important if you use mass-market deodorants & antiperspirants (which almost always include aluminum as a primary active ingredient).
Bacopa offers a number of alluring benefits, but it is perhaps best known for its ability to improve memory and cognition.
The main mechanism by which bacopa bolsters memory and cognition is via improving synaptic communication.
Specifically, the herb encourages the growth and proliferation of dendrites, which strengthens neural signaling.
Note: dendrites are branch-like nerve cell extensions that receive incoming signals. Reinforcing this “connection” through which the nervous system communicates ultimately boosts cognitive function.
Research finds that Bacoside-A stimulates nerve cells, which makes the synapses more receptive to the incoming nerve impulses.
But, there’s more...
Bacopa also has been shown to enhance memory and cognition through stimulation of hippocampal activity by increasing protein kinase activity in the body, which regulates various cellular pathways.[3,6]
Since the hippocampus is crucial to virtually all cognitive activity, researchers believe this is one of the main avenues through which bacopa dials up brain power.
Additional studies have shown that daily supplementation with bacopa monnieri at doses between 300-640mg per day) shows improvements in[4-9,27-30]:
Be it financial, social, physical, psychological, or emotional, stress is at the forefront of many individuals’ lives. Now, more than ever, individuals are looking for an escape by and all means, including drugs and alcohol.
However, substances like drugs and alcohol come with their own adverse affects to both a person’s mental and physical health.
You might be interested to know that bacopa has a long history of use as a tonic for the nervous system to alleviate feelings of anxiety, worrying, and stress.
This is due to bacopa’s adaptogenic properties wherein it enhances our body’s ability to encounter and interact with stress (mental, physical, and emotional) as well as recover from it.
Bacopa exerts these adaptogenic traits partly due to its modulation of neurotransmitters, but the age-old herb also affects cortisol levels. Cortisol, as you probably know, is the body’s primary stress hormone.
Chronic stress and elevated cortisol levels can damage your brain.
In fact, neuroscientists have found that chronic stress creates long-term change in the brain’s structure and function, resulting in the overexpression of certain proteins that damage neurons.[19]
Chronic stress can also result in oxidative damage to neurons which has several negative consequences including[20]:
Enter bacopa and its potent stress-relieving, neuron-protecting benefits.
Human studies document bacopa’s adaptogenic effects, including a reduction in cortisol.[8,21]
Lower cortisol leads to less feelings of stress which not only heightens mood but also pays dividends towards concentration and productivity (since you’re not worried all the time).
Additionally, since bacopa modulates dopamine and serotonin, it can attenuate stress-induced alterations in dopamine and serotonin in the hippocampus and prefrontal cortex, further underscoring the herb’s adaptogenic qualities.[22]
Bacopa also increases production of Tryptophan Hydroxylase (TPH2), an enzyme vital to numerous CNS activities, including serotonin synthesis.[23]
And to top it off, bacoside-A (one of the primary actives in bacopa) has been documented to encourage GABA activity.[24]
GABA, as you may recall from above, is a calming, inhibitory neurotransmitter. Bacopa is noted to both upregulate GABA activity and decrease glutamate activity[25], which may help reduce feelings of anxiety by decreasing activation of neurons that can get overstimulated.
The end result is reduced feelings of stress & anxiety, improved cognitive function, and more “feel good” vibes.
Thus far, we’ve mentioned that bacopa can help modulate and balance various neurotransmitters in the brain.
But, what does that mean exactly and how does bacopa do that?
Let’s discuss…
Studies show that bacopa monnieri may activate choline acetyltransferase (an enzyme involved in the production of acetylcholine -- the “learning” neurotransmitter) and inhibit acetylcholinesterase (the enzyme that breaks down acetylcholine).[3]
The result of these two actions increases levels of acetylcholine in the brain which promotes increased attention, memory, and learning.
Bacopa monnieri helps preserve dopamine synthesis by keeping the dopamine-releasing cells alive.[3]
This is particularly noteworthy when you realize that levels of dopamine (“the motivation molecule”) begin to decline with age. This is, in part, due to a decrease in dopaminergic function as well as a “dying off” of dopaminergic neurons.
Now, here’s where things get really interesting.
Dopamine and serotonin have a delicate balance in the body.
Over supplementation of one neurotransmitter precursor, such as 5-HTP or L-DOPA, can lead to an imbalance of the other, resulting in decreased efficacy and depletion of the other neurotransmitter.
In other words, if you’re only supplementing with 5-HTP while not using something to help balance dopamine (e.g. L-Tyrosine or L-Dopa), you may be risk for creating a massive dopamine deficiency.[18]
Bacopa is able to keep things on an even keel by balancing out dopamine and serotonin promoting optimal mood, motivation, and focus.
Cognitive decline is an inevitability we all will encounter to some degree or another as the years go by.
But, there might be some help in staving off the effects of Father Time.
Various studies show that the herb offers robust neuroprotective benefits.
Specifically, bacopa has been noted to[3,12-14]:
Bacopa also helps reduce β-amyloid deposition in the hippocampus and resulting stress-induced hippocampal damage and neuroinflammation, which may help resist aging and the onset of dementia.
Note: β-amyloid is a “sticky” microscopic brain protein that accumulates in the brain to form plaque. Researchers also use β-amyloid as a marker to track Alzheimer’s.[16]
As if that wasn’t enough, bacopa monnieri extracts also offer neuroprotection via nitric oxide-mediated cerebral vasodilation.
Basically, bacopa monnieri can increase blood flow in the brain via increasing in nitric oxide production.[17]
Greater blood flow means better oxygen and nutrient delivery (glucose, vitamins, minerals, amino acids, etc.) to the brain promoting both cognitive function and long-term brain health.
Cognitive health is something that we as a society really only tend to focus on the older we get. But, the truth is that it’s something that needs to be at the forefront of everyone’s minds from a much earlier age.
It just so happens that Bacopa has not only been studied in adults, but adolescents and children, too!
A 2016 systematic review included children from 4 to 18 years old and found that bacopa monnieri supplementation consistently yielded improvements in[10]:
Furthermore, the same review noted that children supplementing with bacopa demonstrated improvements in their spelling ability, vocabulary, ability to understand words, and sound processing![10]
Researchers even found that bacopa supplementation led to reductions in hyperactivity and attention-deficit domains.
A subsequent review analyzed nine studies in children and adolescents and found that supplements that contained bacopa monnieri (as well as other cognitive-enhancing ingredients such as ashwagandha and rhodiola) improved:
There are a wide variety of bacopa monnieri extracts available for purchase. And (like most things in life), some options are superior to others.
One of the best bacopa monnieri supplements on the market is Synapsa.
Synapsa, also known as KeenMind or CDRI-08, is a standardized extract of Bacopa monnieri developed by the Central Drug Research Institute (CDRI) in India and distributed by PLT Health Solutions.
Synapsa is backed by multiple human trials noting improvements in[5,7,29,30]:
Effective dose begins around 300mg per day up to 640mg per day.
Typically, bacopa is a nootropic that needs to be taken consistently (i.e. daily) to derive maximum benefits (particularly in regards to memory).
That being said, there is research noting that the herb can offer acute benefits, primarily in regards to improving performance in multi-tasking and reducing anxiety commonly experienced during cognitively-demanding work.[21]
Historically, the herb was consumed alongside ghee, the typical cooking fat of Indian cuisine.
Bacopa contains fat-soluble compounds, thus requiring a lipid transporter to be efficiently absorbed and utilized.
As such, it may be helpful to take your daily serving(s) of bacopa with a meal, or at least with some type of fat (fish oil, MCT oil, etc.).
Side effects are rarely experienced with bacopa, but there is the off-chance for mild GI distress or fatigue.
Bacopa has even been studied in children, and a 2016 review noted that “Bacopa monnieri has potential to thrive as a natural and safe option…”[10]
However, does adding Huperzine A to pre workout supplements actually enhance mental or physical performance?
After all, the purpose of a pre workout supplement is to supply the body and mind with the nutrients it needs to lift more weight for more reps, delay the onset of fatigue (both centrally and locally in the muscle), and perform better.
With that understanding, some recent research indicates that Huperzine A doesn’t really belong in a pre workout supplement.
Before we get to the study, though, let’s first discuss the methodology behind including Huperzine A in pre workouts.
Huperzine A is an alkaloid naturally occurring in toothed clubmoss (huperzia serrata).
It does a couple of interesting things in the body, but it is primarily known for its ability to inhibit acetylcholinesterase -- the enzyme that breaks down acetylcholine (“the learning neurotransmitter”).
In addition to learning, acetylcholine is involved in the mind-muscle connection and muscle contraction.[1]
Since acetylcholine is involved in muscle contractions, and other studies show that prolonged endurance exercise can deplete choline and acetylcholine[4], supplementing with an ingredient that sustains acetylcholine levels in the body makes sense (in theory).
With that in mind, let’s see what the new research has to say…
Published August 2021 in the International Journal of Exercise Science, researchers sought to investigate whether taking huperzine prior to exercise would improve mental or physical performance.
15 exercise-trained individuals between the ages of 18-60 participated in the double-blind, crossover trial. This means that each individual essentially served as their own control as they performed the exercise trial both under placebo and Huperzine A.
“Exercise-trained” in the context of this study meant that individuals need to engage in “moderate to vigorous intensity endurance exercise (i.e., brisk walking, running, cycling, etc.), at least three days per week, for at least 20-minutes per session, for at least six months prior to this study.”[2]
Interestingly, resistance training was not part of the definition of “exercise-trained” for the purposes of this study. (Personally, I find this a bit odd as the vast majority of people using pre workout supplements are engaged in at least a modicum of resistance training).
Individuals received 200mcg Huperzine A or placebo capsules 30–45 minutes before exercising.
Previous research indicated that orally ingested huperzine A appears in the blood within 15-minutes and reaches peak levels by 60-minutes.[3]
Participants performed a battery of mental and physical tests, including:
Here’s a diagram from the study for further clarification[2]:
Note: cognitive function tests were performed during the last 10-minutes of exercise.[2]
After the endurance exercise portion was complete, individuals then had their hand-grip strength and vertical jump height tested to assess muscular strength.
Up next, they performed a standardized push-up test after the grip strength and jump tests were over.
Rounding things out, participants completed a dart throwing test (three rounds of three throws) to measure hand-eye coordination following the muscular endurance task. Participants completed three rounds of three throws. Finally, they performed a “Sharpened Romberg test” to assess balance performance.
The Sharpened Romberg Test had participants remove their shoes and stand with their feet in tandem position (heel to toe), their arms crossed over their chest, and the palms of their hand on the opposite shoulder.
“They were first asked to stand quietly with their eyes open and then with their eyes closed. They were instructed to attempt to maintain this position for 60-seconds. If they were unable to do so, they were given up to three additional attempts. The sum of each trial was recorded. If a score of 60-seconds was reached at any attempt the subsequent attempts were forgone and given the score of 60.”[2]
After all the data was collected and analyzed, researchers found that Huperzine A supplementation offered no significant differences in cognitive function between study trials.[2]
Additional analysis revealed that the perceived difficulty of the endurance exercise was rated an average of 1.1 points (0–10 scale) higher during the huperzine A trial than the placebo trial.
When this data is combined with the rate of perceived exertion (RPE) and heart rate data that was collected, this indicates that huperzine A supplementation may actually have made exercise more difficult![2]
Additionally, there was no decline in cognitive function observed from baseline to exercise.[2]
Researchers concluded:
“...based on our data, it is not likely to provide such benefits. A practical implication of these findings is that athletes and other exercisers should be advised to seek other approaches for maintaining or enhancing cognitive function during exercise.”
This is the first study (albeit a very small study population) to investigate the potential performance-boosting effects of Huperzine A in an exercise setting. While a popular and powerful nootropic, the results of this study suggest that it does not make sense to include huperzine A in pre workout supplements.
Perhaps if the participants engaged in a longer and/or more rigorous exercise protocol (one that really taxed the cholinergic reserves of the body), huperzine A may have shown some benefit. But, more research in larger study groups is required.
Something else to consider is the relatively long half-life of huperzine A (about 12 hours).
What this means is that if you take 200mcg of huperzine at 10AM, there is still around 100mcg in your system at 10PM.
This becomes a cause for concern in healthy individuals absent cognitive decline because it could accumulate in your system and your body will adapt to it, thereby negating its potential benefits.
Chronic dosing isn’t a concern for those with cognitive decline or Alzheimer’s as they are expected to take it consistently, but for young, healthy individuals, it’s best to proceed with caution. This is all the more pertinent since so many brands are haphazardly throwing huperzine in products these days -- pre workouts, nootropics, energy drinks, sleep aids, etc.
If you want to use huperzine every once in a while (a couple of times per week on non-consecutive days) for when you have a lot of work to do or shrugging off sleep deprivation, that’s likely ok, but for an everyday use, I wouldn’t recommend it.
Do you like Huperzine A?
If so, do you like it in pre workouts?
If not, what do you prefer?
Leave me a comment below with your feedback, and if you want to be privy to the latest research reviews and in-depth ingredient discussions check out the Engineer Insider!
BrainBerry is a novel extract of Aronia Berry (aronia melanocarpa or chokeberry) standardized for cyanidin-3-O-galactoside -- an anthocyanin that can cross the blood-brain barrier and increase acetylcholine levels by lowering levels of acetylcholinesterase (the enzyme that breaks down acetylcholine).[6]
Animal studies have also found that cyanidin-3-O-galactoside may significantly ameliorate learning and memory impairment induced by amyloid-β neurotoxicity.[6]
In addition to being a rich source of anthocyanins, chokeberry also contains other prominent bioactives (albeit in relatively minor quantities) including, quercetin, quercetin glycosides and epicatechin.
Aronia berry (black chokeberry fruit) has a very high content of total polyphenols, estimated to be in the range of 690–2560 mg gallic acid equivalents (GAE) in 100 g fresh weight.[13,14,15,16,17]
To put this into perspective, aronia berries contain more total polyphenols that other more prominent “superfoods” including:
Black currant is similar in total polyphenol content to aronia, but both are 4x richer in total polyphenols that blueberries -- a berry viewed as one of the best for long-term cognitive health.[18,19]
The daily clinical dose of BrainBerry is 65mg.
Cognitive function increases rapidly during childhood and continues through early adulthood. However (as with most things in the human body), there comes a point where Father Time comes calling and there is a slow, steady decline.
In fact, roughly 15–20% of individuals over 60 years old present with mild cognitive impairment, a condition which alters their ability to learn new information or to recall stored information.[2]
Furthermore, it is estimated that over the next 30 years, the number of people 65 years and over is projected to double from 700 million to 1.5 billion worldwide, which makes it all the more imperative to identify ways to combat cognitive decline as there are currently no medications or treatments for neurodegenerative disorders.
Vascular function also declines with aging, which may be due, in part, to concomitant lifestyle-induced conditions, including high blood pressure, obesity, poor lipid profile, inflammation, etc.
Also contributing to the onset and progression of cognitive decline are lifestyle factors -- diet, exercise, sleep, stress, etc.
With the knowledge that what we put into our bodies can have profound effects on our long-term health and wellness, and that there is an ever-growing body of evidence that consuming a diet high in fruits and vegetables can help lower the risk of non-communicable disease as well as decrease the occurrence of age-associated diseases such as cardiovascular or neurodegenerative diseases[3,4], researchers are constantly on the lookout for promising foods, botanicals, extracts, etc. that can improve the human condition.
Join the Supplement Engineer Insider on Patreon and get access to exclusive, in-depth articles like this as well as other private content, including:
Concomitant with this surge in all things “plant strong,” the supplement industry has seen a steady influx of plant-based protein powders, which usually contain a mix of several plant proteins, including (but not limited to):
While there are more and more vegan protein powders entering the market, there has been one plant-based protein powder that has been a mainstay in the sports nutrition sphere for over 20 years -- soy.
Suffice it to say that soy protein is the OG vegan protein powder.
It’s been sold in bulk powder forms, and it’s included as an ingredient in many protein bars.
Moreover, soy is known to contain biologically active components that can help lower concentrations of total cholesterol, LDL cholesterol and triglycerides -- making it beneficial for cardiovascular health.
But, many concerns still abound as to whether it’s safe to consume, particularly for men due to presence of isoflavones -- phenolic compounds that are classified as both phytoestrogens and selective estrogen receptor modulators.
Are these concerns well-founded?
Should we be wary of consuming soy protein?
That’s what we’ll answer in this guide to all things soy protein.
Let’s first start by discussing what soy protein is, where it comes from, and how it stacks up compared to the grandmaster of all protein powders -- whey.
Soy protein is derived from the humble soybean, a type of legume indigenous to Asia. Some accounts note that soy was used in China as far back as 2838 B.C.[11]
Soy was introduced to Europe in the early 1700’s and North America around 1765, where it was initially used for animal feed. Humans didn’t start consuming soy in North America until the early 1900s.
The United States is the world's biggest soybean producer, generating about 73 million tons per year. However, the average American only consumes only 40 grams of soy per year. This is less than the amount eaten in a single day by the average Japanese person.[10]
Today, soy-inclusive foods are some of the most rigorously investigated foods on the market, with some 2000 soy-related peer-reviewed articles published each year![2]
Before the sudden interest in the protein content of soy, it’s primary use was for the production of soybean oil, which is high in polyunsaturated fats (PUFAs) and low in saturated fats, leading many to consider it a “heart healthy” fat.
As research expanded into soy, the focus began to shift towards its protein content...
Soybeans are higher in protein and fat compared to most other legumes.
Between 35-38% of the calories in a soybean are protein, about 40% of calories are fat (most legumes -- except peanuts -- contain between 2-14% percent fat), and the remainder are carbohydrates.
Soybeans also contain essential vitamins, such as calcium and iron, as well as fiber.
Soy is consumed in a wide range of forms, such as:
Unlike most plant protein sources, the protein in soy is considered a “complete” protein on account of it including sufficient amounts of all nine essential amino acids needed to stimulate and fuel muscle protein synthesis (MPS).
For example, leucine (the anabolic “trigger” of protein synthesis), methionine, and lysine contents are typically lower in plant-based proteins than animal-based proteins (whey, casein, beef, etc.).
This is one of the main reasons why plant-based proteins are known to possess lesser anabolic properties -- lower essential amino acid content and/or deficiency of specific amino acids (leucine, lysine, and/or methionine).
Soy, however, contains adequate amounts of all the essential amino acids.
In fact, research notes that the protein digestibility corrected amino acid scores (PDCAAS) for soy protein range from 0.9 to 1.0 depending upon the specific soyfood in question, which is on par with whey (1.0), casein (1.0), egg (1.0), milk (1.0), and beef (0.92).[11]
There are other methods for ranking the quality of various protein sources.
For instance, the biological value (BV) provides a measurement of how efficient the body utilizes a given protein.
Comparing the same protein sources above, the biological values are[11]:
For a closer comparison, here are the typical amino acid profiles of common protein sources in the diet:
Soy protein powder typically comes in one of three forms[11]:
Soy concentrate is typically used in protein bars, cereals, and yogurts.
Isolates are typically used in protein powders, since they contain the highest concentration of protein. (Note: isolate is also the most refined soy protein product, not that that’s necessarily a bad thing.)
Whey protein is the most popular form of protein powder on the market, routinely consumed by individuals looking to increase lean mass and support muscle recovery.
Given whey’s status as the leading protein powder on the market (plus the fact that it’s been shown in multiple studies to enhance resistance training adaptations -- gainz), and the fact that soy protein is a complete protein, researchers have compared the two proteins head-to-head to see how they impact performance, growth, and recovery.
Comparing the proteins side by side, soy protein contains a lower quantity of essential amino acids (EAAs) on a per gram basis as well as fewer branched-chain amino acids (BCAAs) compared to whey protein.[13]
Further comparing soy to whey, you’d need to consume ~40 grams of soy protein to the same amount of leucine (2.7g) and total amino acids (10.9g EAAs) as found in 25 grams of whey protein.[1]
Additional research has found evidence that consumption of soy protein does not stimulate acute post-exercise muscle protein synthesis to the same magnitude as whey or milk protein, either.[14,15]
Still, a 2018 meta-analysis including nine studies comparing soy protein supplements to animal-based protein supplements (with 5 of the 9 directly pitting soy against whey) found no significant differences in strength or lean mass gains between those who supplemented with whey vs those who supplemented with soy in conjunction with resistance training.[12]
Essentially, the authors of this meta-analysis concluded that soy was just as effective as whey protein in enhancing gains in strength and lean body mass when used in combination with resistance training.
A more recent 2020 study including 61, untrained men and women, again compared soy protein to whey protein in combination with a 12-week resistance training program. All participants performed supervised resistance training 3×/week and consumed either 19 grams of whey protein isolate or 26 grams of soy protein isolate, both containing 2 g (grams) of leucine.[16]
At the end of the 12-week study, researchers noted that both groups experienced similar increases in lean mass and strength when strength training and supplementing with soy or whey matched for leucine.[16]
Now, while soy may be a suitable option for supplementing your protein intake during the day, and supporting your quest to make gains in size and strength….the larger issue at hand is...
As we mentioned at the beginning of this article, isoflavones are phenolic compounds that are classified as both phytoestrogens and selective estrogen receptor modulators (SERMs). They are also noted to possess both estrogen-agonist and estrogen-antagonist properties, due to their structural similarity to 17-β-estradiol.[3]
Soy isoflavones can preferentially bind to and activate estrogen receptor-β (ER-β) — as opposed to ER-α — mimicking the effects of estrogen in certain tissues in the body and antagonizing (blocking) the effects of estrogen in other tissues.[4]
Furthering the concern over the intake of soy products are case studies noting an association between soy consumption and hypogonadism as well as erectile dysfunction.[5,6] Other research, though, disputes the potential feminizing effects of soy isoflavones.[7]
Additionally, a meta-analysis of 15 placebo-controlled studies concluded that soy protein nor isoflavones have no significant impact on[8]:
Still, concerns abound about soy protein, in large part due to consumer misconceptions stemming from fear-mongering articles that litter the internet.
So, let’s see what the latest research has to say regarding soy protein intake and men’s health.
Is it another quality source of protein that can be added to the diet, or...
Will consuming soy lead to rampant increases in estrogen levels, gyno, ED, and infertility?
Let’s find out!
The first study to investigate the effects of soy protein consumption on body composition and sex hormone profiles was published in 2007.
Out of the 41 participants screened for the study, 20 subjects took part and completed the 12 week trial.
Subjects supplemented their diets with one of the following protein powders:
On training days, subjects were instructed to consume one serving of their respective protein supplement within 1 hour post-workout, and a second dose was consumed at some other point during the day.
On non-training days, subjects consumed two doses of protein at different times throughout the day.
Resistance training during the study consisted of 3 full body workouts per week for 12 weeks, with individual instruction once per week by a qualified personal trainer to make sure subjects were using proper form, pushing themselves hard enough, etc.
At the end of the 12 weeks, researched documented similar gains in lean body mass in subjects consuming whey or soy protein, which at the time of this publication (2007) was quite surprising since it was believed that whey was “far superior” for building muscle than soy.
The researchers do note, though, that “the subjects enrolled in the study were relatively novice exercisers with little previous exposure to training program.”
Whether soy is effective for muscle building isn’t really the point here, what we’re really interested in is if consuming soy shrinks your balls and increases your cup size.
So, what did the study find concerning soy intake and male hormone profiles?
“There was no significant decrease in serum androgenic hormones following supplementation with any protein intervention. The biological significance of the sex hormone changes within the current study resulting from lower estradiol, and increased testosterone/estradiol ratio in response to soy and whey supplementation is unknown at this time.”[9]
Basically, consuming two soy protein shakes per day for 12 weeks (3 months) didn’t cause the male subjects to grow breasts or tank their testosterone.
But, one study isn’t enough.
Fortunately, there are several more studies investigating this same line of inquiry…
A 2018 study by Cody Haun and colleagues investigated the effects of different protein supplements on serum sex hormones, androgen signaling markers in muscle tissue, and estrogen signaling markers in subcutaneous adipose tissue.
47 untrained men took part in the twelve week study and were distributed into one of three groups:
Subjects performed three total body resistance training sessions per week for 12 weeks and consumed two servings of either soy protein, whey protein, or placebo every day during the 12-week study period.
At the end of the study, researchers documented no significant interactions of supplement and time on adipose tissue estrogen receptor α/β protein levels, muscle tissue androgen receptor protein levels, or mRNAs in either tissue indicative of altered estrogenic or androgenic activity.
Based on these findings, the researchers concluded:
“These data suggest that, while isoflavones were detected in SPC, chronic WPC or SPC supplementation did not appreciably affect biomarkers related to muscle androgenic signaling or SQ estrogenic signaling.”
Essentially, while soy protein contains isoflavones, their ingestion did not affect androgenic or estrogenic signaling in college-aged men, even when consumed twice a day, everyday for 12 weeks.
The European Food Safety Authority (EFSA) has also stated that isoflavones do not adversely affect the breast, thyroid or uterus of postmenopausal women.[2]
And, on a final note, a 2010 review of the literature by Messina (who has spent 20 years researching soy protein) concluded[18]:
“Finally, other than allergic reactions, there is almost no credible evidence to suggest traditional soyfoods exert clinically relevant adverse effects in healthy individuals when consumed in amounts consistent with Asian intake.”
Another meta-analysis from 2010 also found that:
“soy foods nor isoflavone supplements alter measures of bioavailable T concentrations in men.”[19]
At the end of the day, the current body of evidence indicates that soy protein supplements may not only be effective for enhancing gains in strength and lean body mass, but they are also safe for men to consume in reasonable doses.
Evidence to date shows that the consumption of soy protein does NOT raise estrogen levels in men, or adversely affect testosterone production.
So, if you happen to eat some protein bars that include soy protein, or have the occasional plant-based protein shake that includes soy protein, you can rest easy knowing that neither your gains (or manhood) is threatened.
Peak ATP® is a clinically-researched, patented form of adenosine 5’-triphosphate (ATP) disodium that is identical in structure to human ATP.
Research has shown that supplementation with Peak ATP may improve athletic performance and body composition by increasing muscular excitability, blood flow and recovery.[1]
Studies note that Peak ATP® is effective after a single dose (400mg) for increasing the ratio of muscle activation and power output during high-intensity exercise, and may also help prevent performance drop-off as training goes on..
ATP serves as the “cellular currency” of energy production in the body. It is constantly being used and regenerated in cells via cellular respiration.
Each day the human body creates and burns about as much ATP as its own body weight.[2]
Beyond its role in producing usable energy for cells, ATP also serves as an important extracellular signaling molecule, acting as a neurotransmitter in both the central and peripheral nervous systems.
Furthermore, ATP (and its derivative adenosine) are involved in:
ATP has three phosphate groups (hence the “tri-phosphate” name) in each molecule.
When one one of these phosphate groups is removed (“cleaved”), a tremendous amount of energy is released.
The body in turn uses this energy to perform a wide range of biological processes including:
As this energy is used up, the body must create more ATP to meet demand.
Under normal circumstances, this process happens seamlessly, meaning your body can easily produce enough ATP to keep up with the demands of regular tasks -- unloading groceries, walking the dog, folding laundry, etc.
However, intense physical activity (resistance-training, sprinting, etc.) creates a tremendous demand for ATP.
Since skeletal muscle tissue only stores a limited amount of ATP at any one time, and intense exercise consumes high amounts of it, your body has to rely on other substrates to generate ATP after a few seconds.
Research indicates that endogenous muscle stores of ATP are capable of supporting maximal work for a max of 1–2 seconds, after which intercellular phosphocreatine kicks in to supply additional “fast-acting” ATP, which lasts all of 2–7 seconds.[8]
Increasing muscle’s ability to rapidly regenerate ATP (and thereby stave off decrements in performance) is one of the primary reasons many individuals supplement with creatine monohydrate.
Many individuals also consume a carbohydrate-rich meal pre workout or sip on an intra workout supplement during training to make sure there is a steady supply of blood glucose to support energy production and delay the onset of fatigue.
However, these processes are varying orders of magnitude slower than pulling from a pool of already existing ATP due to the fact that extra reactions have to be performed in order to get what the cells need to keep performing at a high level -- ATP.
For instance, it is quicker to generate ATP from phosphocreatine than it is glucose, and it’s faster to create ATP from glucose than it is fatty acids.
This led sports scientists to examine whether or not it is possible to supplement with an exogenous (outside source) of ATP, which effectively cuts out the “middle man” in the energy production process (phosphocreatine, glucose, oxygen) by supplying the body with a bioidentical form of ATP.
Unfortunately, the vast majority of oral ATP supplements on the market have come up short in research (at least in humans anyway) due to a lack of bioavailability (even using doses as high as 5 grams).[3,4,5,6]
Peak ATP, however, is a form of orally supplemented ATP shown in human studies to increase ATP levels in the body and boost exercise performance.
Let’s now take a look at the work done on Peak ATP and see how it may benefit you during training.
The initial study investigating the potential ergogenic effects of Peak ATP sought to determine whether a 400mg dose of Peak ATP would improve force output and reduce fatigue in resistance-trained individuals.[7]
16 healthy participants (8 male and 8 female) ages 21–34 years enrolled in the double-blinded, placebo-controlled study using a crossover design.
Following is a graph showing the supplementation and training protocol used during the trial.[7]
For each of the trials, participants consumed their assigned capsules (placebo or Peak ATP) for 15 days (one in the morning before dinner and one at night before dinner). Subjects receiving the Peak ATP treatment were receiving 200mg Peak ATP per capsule for a daily total of 400mg.
After the supplementation period, the participants reported to the laboratory for testing following a 12-hour overnight fast.
The reason researchers used a 400 mg/d dose was that previous research using a dose of 225 mg Peak ATP per day failed to improve bench press strength compared with the placebo group [6]
During the course of each of the trials (placebo and Peak ATP), participants were instructed to refrain from vigorous exercise for three days before reporting to the laboratory in the morning after an overnight fast.
“Light” exercise (stretching and/or mild aerobic exercise lasting less than 45 minutes) was allowed during this pre-study period. At this time, a blood sample was obtained.
Weight and height were measured and BMI was calculated during the study, and researchers also tracked body composition for “research purposes only” using BodPod.
After an overnight fast, subjects were tested for strength and fatigue — consisting of three sets of 50 maximal knee extensions (talk about a muscle burn!) — at baseline and after 15 days of supplementation.
Following the 7-day washout period, the groups were crossed over (“switched”), so those who had been taking placebo now took PEAK ATP® and vice versa.
Researchers collected measurements of high peak torque, low peak torque, and torque fatigue of the leg muscles over the three exercise sets.
Supplementation with 400mg Peak ATP led to a significant increase in low peak torque and a trend toward a decrease in torque fatigue across the 3 working sets. Results are displayed in the following figure[7]:
What this means is that supplementation with Peak ATP (according to this study) may help you maintain a higher level of output for a longer duration during training and experience less of a dropoff in performance the deeper you get into a workout.
As we mentioned above, ATP can enhance vasodilation, and as a result, blood flow.
In addition to improving exercise performance, researchers wanted to know if supplementing with Peak ATP could increase blood flow above what is naturally obtained from exercise, since physical activity in and of itself increases blood flow to the working muscles.
To determine this, researchers conducted a batch of animal and human studies.
Animal models using a human equivalent dose of 1,000mg and 1,600mg exhibited the most pronounced increases in blood flow during exercise and into the recovery period.[9]
During this same study, humans were also studied using the previously researched dose of 400mg Peak ATP.
For the 12-week pilot study, 12 resistance-trained males (age 23.7 ± 3.6 years; height 179.0 ± 1.0 cm; weight 87.3 ± 6.1 kg) were given 400mg of Peak ATP daily 30 minutes before breakfast for 12 weeks.
To determine blood flow during in working muscles, subjects performed an exercise test consisting of 3 sets of 20 contractions at 50% of the subject’s 1-RM).[9]
Volumetric blood flow and vessel dilation in the brachial artery were measured using ultrasound at rest before taking the supplement, at rest 30 minutes after supplementation, and then at 0, 3, and 6 minutes after the exercise test.
On testing days, subjects ingested the Peak ATP supplement 30 minutes prior to the bicep curl tes.
Blood flow measurements were taken at weeks 0 (baseline), 1, 4, 8, and 12.
Major findings from the study were:
We all know that one by-product of greater blood flow is bigger muscle pumps (which increases cellular swelling and may promote muscle growth), but another by-product of this enhanced blood flow could improve removal of metabolic waste products (such as lactate and urea) generated from muscle contractions.
Additionally, improved circulation also facilitates greater delivery of nutrients (amino acids, glucose, etc.) as well as oxygen to exercising muscles, which can help sustain performance and promote recovery.
In the conclusion, researchers note that “the exact mechanism whereby ATP increases blood flow during post-exercise recovery periods remains unknown.”
As such, more studies are needed to elucidate this exact mechanism.
Additionally, some limitations of this study include the lack of control group (a group of people who only received a placebo during the 12 weeks) and a stronger control of other confounding variables such as potential differences in exercise habits outside of the trial or baseline dietary habits and dietary supplement use in male subjects participating in the trial.
The next study to be performed using Peak ATP was a randomized, double-blind, placebo- and diet-controlled, parallel groups with repeated measures study design.[10]
21 resistance-trained males were randomized to receive either 400 mg of PEAK ATP® per day or placebo for 12 weeks.
Both groups were assigned the same 12-week periodized resistance training protocol, consisting of:.
Researchers measured muscle mass, strength and power at baseline and at weeks 4, 8, and 12.
2 weeks before the start of the 12-week study, subjects met with a registered dietician and were placed on a diet consisting of 25% protein, 50% carbohydrates, and 25% fat.
Subjects followed their respective meal plan for the duration of the trial and continued diet counseling was on an individual basis as needed throughout the study.
The primary findings of this study were that the men consuming 400 mg of Peak ATP daily exhibited greater gains in muscle mass, lean body mass, strength and power when compared to the the placebo-matched control.[10]
More specifically, supplementation with Peak ATP led to improvements in:
Additionally, based on the results noted during the group’s overreaching cycles, supplementation with Peak ATP appeared to attenuate reductions in muscle power and strength common with periods of overreaching.
Now, we’re going to take these results with the proverbial “grain of salt.” The lead researcher on this study was Dr. Jacob Wilson, who has a “complicated” history with supplement research to say the least.
Fortunately, there are other studies involving Peak ATP that can be considered, like this next one!
The next double-blind, placebo-controlled, randomized study involved 42 healthy male individuals (age 18-30).[11]
To qualify for the study, subjects had to have prior resistance training experience (min. 3 times per week for the past 6 months and have a minimum of 1 year of training experience).
During the testing period, subjects were instructed not to train within 72 hours of the test in order to prevent any confounding variables (muscle damage, fatigue, etc.).
Subjects were given either 400 mg of Peak ATP or placebo for 2 weeks prior to testing.
Following the 14-day loading period (day 15), subjects consumed 400 mg of either Peak ATP or a placebo 30 minutes prior to repeating the same sprinting bout they had performed at baseline testing.
During the sprint bout (10 rounds of 6-second springs on an ergometer), muscle activation and excitability and Wingate test peak power were measured. Additionally, researchers also gathered measurements on ATP and exercise metabolites.
Primary findings of the study were that supplementation with Peak ATP prevented exercise-induced declines in ATP and its metabolite.
Additionally, Peak ATP supplementation also enhanced peak power and muscular excitability, which would be beneficial for sports requiring repeated high-intensity sprinting bouts (such as football, basketball, soccer, etc.).
Interestingly, while Peak ATP supplementation appears to improve performance, researchers still aren’t 100% sure how it does so:
“Though the exact mechanism of oral ATP absorption is still not fully understood, ATP and its metabolites may stimulate intracellular ATP by interacting with specific ATP and adeno- sine receptors on cell surfaces through a signaling effect.”[11]
However, the improvements in muscle excitability and metabolite clearance may have something to do with increased blood flow.[9]
One of the more recent studies investigating Peak ATP (that also didn’t involve Dr. Wilson) involved 11 resistance-trained men (age= 27.5±5.5 yrs, weight= 83.4±9.8 kg, height= 182±0.04 cm) who completed two randomized, double-blind trials.
Subjects received either 400mg Peak ATP or placebo 30 minutes prior to an exercise test consisting of 4 sets of half-squats until momentary muscular failure at 80% of the 1 repetition maximum with 2 minutes of recovery between sets.
Researchers collected data on the total number of repetitions performed as well as blood pressure, heart rate, blood lactate, and oxygen consumption.[12]
At the conclusion of the study, researchers noted that a one-time dose of Peak ATP improved performance, oxygen consumption and energy expenditure during lower body resistance exercise.
This study suggests that supplementing with Peak ATP prior to a fatiguing, high-volume leg day may help gym goers lift more weight.
Two possible mechanisms suggested for Peak ATP’s ability to improve performance are:
The final study, to date, conducted with Peak ATP sought to determine the autonomic modulation and blood pressure following supplementation with Peak ATP in hypertensive women.[13]
45% of adults in the US have hypertension and having hypertension is known to significantly increase your risk for heart disease and stroke, both of which are among the leading causes of death in the United States.[14]
The study utilized a randomized, double-blind design. Participants completed two exercise sessions in the lab, with each one being separated by seven days.
To ensure chronobiological control (and limit confounding factors), all experimental trials were performed at the same period of the day.
11 hypertensive women (age, 61.8 ± 5.0 years) completed the trial and received either 400mg of Peak ATP or placebo 30 minutes before performing 30 minutes of cardio (aerobic exercise at 70%–75% of maximum heart rate).[14]
Researchers assess autonomic modulation by tracking heart rate variability (HRV) during rest and recovery (immediately post exercise until 30 min of recovery). Blood pressure was recorded at rest, immediately post-exercise, post-10, post-20 and post-30 min after exercise.
The primary finding of the study was that a single dose of Peak ATP reduced systolic blood pressure after aerobic exercise compared to placebo.
At the conclusion of the study researchers also noted that ATP supplementation potentiated the parasympathetic recovery after exercise.[14]
Basically, ATP supplementation encouraged faster recovery of HRV following exercise by increasing parasympathetic modulation.
These findings bear importance not only for regular exercisers looking to improve recovery following training, but the average individual who may not train consistently, yet still wants to support cardiovascular health.
Peak ATP® is not a stimulant, and therefore, does not adversely affect heart rate or blood pressure.
The ingredient has been studied multiple times in humans and found to elucidate no adverse reactions.
Peak ATP is self-affirmed GRAS (Generally Recognized As Safe) for use in functional food, bars and powders.
The recommended dose of Peak ATP® is 400 mg, consumed once daily 30-60 minutes prior to exercise.
On non-training days, you may consume one serving of Peak ATP ~20-30 minutes prior to your first meal of the day.[15]
Peak ATP is an exogenous form of bioavailable ATP shown in research to:
The mitochondria in our cells generate ATP which is then used to do work (such as lifting weights).
The more ATP you have, the more efficiently you can create energy for your cells to do work. This is particularly important for individuals seeking to boost performance in the gym or on the field of competition and delay the onset of fatigue.
Furthermore, a number of studies have found that higher ATP levels are associated with improved health and performance.[7,8,9]
But, ATP’s role in the body extends beyond serving as a mere currency for exercising muscles.
It is also involved in hundreds of biochemical reactions and several extracellular functions, too.
To name a few, ATP is involved in:
As is the case with most things in life, natural ATP production declines as we age, which is a contributing factor to declining performance, reduced cognitive function, and low feelings of energy.
A number of ATP supplements have been developed over the years to increase ATP levels in the body, but most have come up short in testing.[1,2,3,4]
Today, we look at one of the more promising ATP-boosting supplements on the market in elevATP.
elevATP® is a patented ingredient from FutureCeuticals formed from a natural combination of ancient peat and apple extracts.
The polyphenols contained in the extract have been noted in several human studies to increase levels of endogenous ATP in the body as well as improve strength, power, and performance in resistance-trained athletes.[5,6,7,8]
As we mentioned above, a number of other exogenous ATP supplements have been tested over the years with mixed results.[5,6,7,8]
The primary reason previous exogenous ATP supplements have failed is due to poor bioavailability. Even using doses as high as 5 grams of oral ATP have failed to provide benefit.[5,6]
This has led researchers to wonder if it’s possible to attack the problem of increasing ATP levels by other means.
One potential solution to increasing ATP levels in the body is elevATP.
Unlike other oral ATP supplements that try to directly raise levels of ATP by providing an exogenous source of the compound, elevATP® helps our cells produce more ATP on their own.
The initial studies carried out on ATP were to ascertain what the bioactives present in the supplement were as well as if it actually did what it claimed to do -- increase ATP.
Researchers found a total of 66 minerals present in the ancient peat and apple extracts:
The main plant phenolic component of elevATP was chlorogenic acid (5-O-caffeoylquinic acid), having a concentration of 201±11 mg / 100g.
The second most prevalent phenolics in the supplement were procyanidins -- oligomeric compounds formed from catechin and epicatechin molecules.
Procyanidins are abundantly found in fruits, vegetables, nuts, legumes, and grains and have been noted to possess a wide range of beneficial biological effects.[9,10,11]
Let’s now take a look at the studies to see what else elevATP® has to offer.
The initial study involved 18 healthy individuals between the ages of 21 and 55 with a BMI between 21 and 30 kg/m2. Individuals participating in the study also could not be using any type of medication or supplements for a period of at least 15 days prior to the start of the study.
On the day of testing, subjects were instructed not to eat for 12 hours prior to the initial blood draw.
They were divided into two groups:
Both groups received 200 ml of water to swallow with their respective capsule.
Body temperature and blood samples were taken prior to and during the testing period.
Blood samples were immediately prior to capsule administration (T0) and at 60, 90 and 120 minutes following ingestion.
ATP levels obtained from samples collected at 60, 90, and 120 minutes were averaged and compared the effect of elevATP to placebo.
Compared to the placebo group, the participants receiving elevATP™ experienced an acute increase in blood levels of ATP by 64% (P=0.02).
Figure 1: Effect of elevATPTM on blood ATP levels. Whole blood was collected from placebo-treated or elevATPTM-treated subjects at T0 (baseline), T60, T90 and T120. ATP was detected by using a luciferase-based assay on 10μl of lysed whole blood.[5]
Researchers also noticed that levels of reactive oxygen species (ROS) were slightly lower in the elevATP group than those receiving placebo.[5]
The reason this is noteworthy is that previous research has found that increased ATP production is associated with greater concentrations of intracellular ROS, which can lead to oxidative stress and cellular dysfunction.[12,13]
Researchers attributed this to the polyphenolic compounds naturally present in elevATP, which could help reduce ROS, thereby decreasing their overall levels.
The follow-up study to the pilot sought to extend the work using a crossover design and a larger group of subjects.
For this second study, researchers also collected a biopsy of muscle tissue from one individual before and after a single dose of elevATP™ in order to determine intramuscular ATP levels.[6]
20 “generally healthy” subjects (12 female and 8 male) ranging in age from 22-35 years old and BMI ranging from 24.1 to 30 kg/m² were selected to participate.
To be considered “generally healthy”, subjects had to be free of infections, influenza, and diabetes mellitus. They also had to have no allergies to dietary products, use of anti-inflammatory drugs, analgesics, statins, diabetic drugs, anti-allergy medicines, multivitamins, and use of supplements within 15 days of the start of the study.
Similar to the pilot trial, participants were instructed not to eat for 12 hours prior to the initial blood draw.
Since this was a crossover design, all subjects received both treatments (placebo and elevATP).
On day 1, subjects received the placebo treatment, and on their second day reporting to the lab, they received 150mg elevATP.
Blood samples were collected immediately prior to test capsule ingestions and at 60 and 120 minutes post-ingestion.
After tabulating the data, researchers noted that administration of elevATP increased ATP levels by 40% at the 1-hour mark.
Additionally, researchers found no changes in plasma ATP levels after treatment with elevATP™, indicating elevATP™ likely does not affect extracellular ATP levels.[6]
While the first two studies showed that elevATP could enhance ATP levels, neither of them investigated the potential for the ingredient to improve exercise performance.
The 3rd and 4th studies on elevATP did.[7,15]
While these are two separate studies on paper, it’s really the same group of subjects being tested. The researchers collected a massive amount of data and wrote two separate papers based on their findings.
25 healthy resistance-trained men (age 27.7 ± 4.8 years) completed this study.[7,15]
To qualify as “resistance-trained”, each subject was required to be able to squat and deadlift 1.5× their body weight and bench press 1× body weight.
Note: Approval for research with human subjects was obtained from the MusclePharm Sports Science Institute IRB.
Subjects were randomly assigned to either the placebo or treatment groups and instructed to consume 1 serving of either placebo or elevATP® 45 minutes prior to training on training days or at a similar time of day on rest days.
Subjects were resistance trained under the supervision of a certified strength and conditioning specialist 3 days per week for 8 weeks followed by a 2 week overreach and 2 week taper phase corresponding to weeks 9–10 and 11–12
The first 8 weeks of training consisted of:
Participants rested 48–72 hours between each training day.
During the “overreaching phase” (weeks 9-10), participants performed high-volume workouts, similar to the hypertrophy-focused workouts performed during weeks 1–8, on Monday through Thursday.
Friday of week 9 was focused on a strength workout, and Friday Week 10 was performance testing.
The final two weeks (“taper weeks”) consisted of:
Exercises on these days included low volume back squats, bench press, and deadlifts only.
Additionally, subjects each consumed a eucaloric (“maintenance”) diet consisting of:
Eucaloric diets were used to offset the possibility that extra food was responsible for the gains in performance and size, instead of the supplement.
Researchers tracked each subject’s diet weekly via 3-day food logs.
Subjects also consumed one serving of a whey protein supplement supplying 25g of protein, 5g of carbohydrate, and 1.5g of fat immediately following their workout on training days.
During the 12 week trial, researchers assessed progress across a wide range of performance and body composition metrics, including peak power, average power, and average speed.
Measurements were taken at the beginning of the trial, and then repeated at the 4, 8, 10, and 12 week marks.
Both groups experienced increases in strength and size.
However, the individuals receiving elevATP experienced greater gains in size, strength, and power than the placebo group.
More specifically, subjects receiving elevATP increased their 1-RM squat and deadlift scores to a greater degree than those receiving placebo.[15]
Additionally, vertical jump peak velocity and vertical jump peak power increased more in the treatment (TRT) group compared to the control (placebo) group.
Unfortunately for you bench press fans, elevATP® supplementation did not seem to statistically impact bench press 1RM respective to placebo.
However, elevATP supplementation helped attenuate power loss during the overreaching phase.[15]
This suggests that elevATP supplementation may help you experience less of a decline in power output during higher volume and intensity phases of your training.
Researchers concluded, saying:
“This is the first study examining the ergogenic potential of endogenous ATP enhancement with supplementation. The proprietary blend of ancient peat and apple extracts were capable of increasing lower body and total strength as well as lower body power output compared at an equal-volume, visually-identical placebo.”[15]
Researchers used DEXA to assess body composition metrics, including:
Ultrasound was also used to measure muscle cross-sectional area (CSA), muscle thickness (MT), and fat thickness (FT).
After 12 weeks of supplementation with elevATP, both muscle cross-sectional area and muscle thickness increased while body fat content and body weight were unchanged.
In the placebo group, muscle cross-sectional area tended to decline following the overreaching and taper phases.
Researchers hypothesized that the elevATP supplement helped lessen (“attenuate”) performance decrements (i.e. “overtraining”) that can potentially go along with increased training volume and overreaching (or sometimes just not eating or sleeping enough to support the demands of training.)
Note: It should be mentioned that two authors involved in the study were at the time employees of VDF FutureCeuticals Inc. Additionally, several other authors on the paper (JJ, RV, PF, MM, MK, and JM) were employed by the grant recipient, MusclePharm Corp., at the time of data collection.
This doesn’t necessarily “negate” or nullify the quality or findings of the study, but just something to be aware of.
The next study on elevATP again measured its effects on athletic performance in resistance-trained men over the course of a 12-week training program.
However, instead of just testing elevATP on its own against placebo, researchers paired it with an extended-release caffeine supplement.[17]
This study was carried out by the same lab as the previous two studies (Jordan M. Joy and colleagues).
To be considered well trained, each male had to be able to lift 1.5x BW in the squat and deadlift and 1x bodyweight in the bench press.
Baseline assessments noted that the placebo group was able to:
Baseline metrics for the treatment group were:
Overall, it would appear that the placebo group started out being slightly stronger (on average) than the treatment group.
The resistance training program was very similar to that used in the previous two studies (8 weeks of training 3x per week with one training session each week devoted to hypertrophy, strength, and power training, 2 weeks of overreaching, and 2 weeks of tapering).
Body composition measurements of the subjects were gathered at weeks 0, 4, 8, 10, and 12, while blood draws and vital signs were collected at weeks 0, 8, and 12.
Similar to the previous two studies, researchers used a combination of DEXA and ultrasound to track changes in lean soft tissue, fat mass, body fat percentage, muscle thickness, and cross-sectional area.
21 subjects randomized to either the placebo (n = 11) or treatment (n = 10) groups.
The treatment for this study included the same 150mg dose of ElevATP used in previous studies, but added to it 38mg of B-vitamins along with a 180mg blend of caffeine anhydrous and PurEnergy™
PurEnergy™ is an extended-release caffeine composed of 43 % caffeine and 57% pterostilbene.
The total caffeine “payload” for the entire supplement was ~129 mg.
At the end of the study, ultrasound-based measurements of muscle thickness and cross-sectional area increased while fat mass and body fat percentage decreased in the lower body.
Researchers believe that the increases in muscle mass documented were likely produced by supplementation with elevATP. They also speculate that the modest reduction of body fat observed in the treatment group, versus a slight increase in body fat in the placebo group, is likely due to the caffeine component of the supplement.
The reason for this is that caffeine is known to promote lipolysis and enhance fat oxidation during exercise.
Though, they do not discount the possibility of a synergistic effect existing between caffeine and the polyphenols in elevATP.
Unfortunately, this study did not measure whole-blood or intramuscular ATP levels, but based on previous work, we do have evidence indicating that supplementation with 150mg elevATP does boost ATP levels.
And, it’s also hard to determine how much of the effect is really attributable due to the elevATP component of the supplement since the researchers did not have a “caffeine only” group run through the same training program.
Researchers justify this by noting that while caffeine has been noted to improve exercise performance, it largely does so by increasing the number of repetitions performed to failure while reducing perceptions of fatigue.[18]
In this study, however, there were no significant changes in training volume performed between groups over time according to the authors.
Still, the dose of caffeine used in this study is on the low end for performance enhancement (~129mg total) as the current body of evidence suggests that a dose of 3-6mg/kg caffeine is required to derive its ergogenic benefits.[19]
The final study to date on elevATP was led by the team of researchers who published the first two papers on the supplement -- Reyes-Izquierdo and colleagues.
In this study, researchers performed a blinded three-way crossover study in nine “healthy” subjects (4 female and 5 male) comparing the effects of placebo vs a single 150mg dose of elevATP before, during, and after 20 minutes of stepping exercise.[16]
Subjects in this study were not regular exercisers with an average age of 27.3 ± 5.0 years and BMI of 28.97 ± 6.6 kg/m2. The BMI of the group technically places them in the “overweight/mildly obese” category,
Subjects fasted for 12 hours prior to each of the three exercise study days.
Additionally, subjects took a 10-day “recovery” period between each exercise day.
On day 1, subjects were randomly given capsules containing:
Subjects were also given two Smucker’s Uncrustables® sandwiches to eat 15 minutes after taking a capsule.
Researchers gave subjects this meal to prevent hypoglycemia during exercise.
Each sandwich contained:
Researchers collected blood samples (via finger prick) before ingestion of capsule (T0) and, 35 min after the consumption of snacks (T50).
Afterwards, subjects were instructed to exercise.
Additionally blood samples were collected after completion of the 20-minute stepping exercise (T70) and after 30 minutes of rest following exercise (T100).
Total steps and calories burned were recorded by the stepper.
At the end of the study, researchers noted that when subjects received the elevATP supplement, they burned more calories and took more steps than subjects receiving placebo.
Analysis of the blood samples revealed there were significant differences in blood lactate or glucose levels between elevATP treatments and placebo.
elevATP is a combination of ancient peat and apple extracts that, when used in combination with a structured resistance-training program, may:
The studies have largely been funded by Futureceuticals and/or performed at research institutes run by supplement companies (i.e. MusclePharm).
Does this mean the studies are fraudulent and the data corrupted?
Not necessarily.
The researchers don't make any outlandish claims in their papers (such as HMB being as effective as anabolic steroids), and they openly note their conflicts of interest as well as their funding sources.
More research should be conducted to see how the ingredient works alongside caffeine and other common pre workout supplements, such as L-Citrulline, Betaine, and Beta Alanine to see if any possible synergistic effects exist.
Society runs on caffeine.
It’s in our coffee, pre workout, and energy drinks.
Caffeine is even working its way into other “functional foods” like protein powders and peanut butter.
And, make no mistake, I enjoy my caffeine (and in a multitude of ways).
But, not everyone reacts well to caffeine, or can handle the ever-increasing doses that are working their way into dietary supplements and energy drinks.
As a result, a number of caffeine alternatives have been investigated over the years, with some being a bit more “effective” than others.
Notable examples of these caffeine alternatives include TeaCrine and Dynamine, both of which you’ve heard me talk about before.
Today, we’re going to cover another intriguing new caffeine alternative/replacement/synergist is Zynamite®.
Zynamite® is a patent-pending proprietary extract of Mangifera indica (mango) standardized to 60% mangiferin.[1]
To date, Zynamite® has been the subject of seven clinical studies and noted for both its nootropic and sports performance benefits.
Image courtesy Nektium.
Mangifera indica has long been used in ayurvedic medicine for a wide variety of ailments due to its antiseptic, astringent, diaphoretic (inducing perspiration -- “sweat”), stomachic (improves appetite or digestion), vermifuge (anti-parasitic), tonic, diuretic, and laxative properties.[2]
As a result, various parts of the plant have been used as a remedy for anaemia, asthma, bronchitis, cough, dysentery, hypertension, insomnia, rheumatism, and toothache.
The plant have also been used to treat stings, snakebites, abscesses, blisters, wonds, diarrhea, colic, liver disorders, excessive urination, tetanus and asthma.[2]
Mangiferin is the primary active compound in mangifera indica, found in the leaves, bark, fruit and roots. It can also be found in several other plants, including Salacia chinensis, Swertia chirata, and Hypericum aucheri.[3]
Fig. 1: Structure of Mangiferin[24]
It is a xanthone glycoside, possessing strong antioxidant, antidiabetic, hypotensive, anti-lipid peroxidation, immunomodulatory, cardiotonic, wound healing, and anti-degenerative activities.[2]
Mangiferin is also considered to be a “super antioxidant” capable of specifically protecting against free radical production via the Fenton reaction due to its iron-chelating properties.
Moreover, mangiferin can cross the blood-brain barrier and modulate neurotransmission, K+ channels and nociception.
Zynamite® is a catechol-o-methyltransferase (COMT) inhibitor that activates brain waves and increases Long-Term Potentiation (LTP) in a manner similar to caffeine.[23]
COMT is the enzyme that metabolizes neurotransmitters and catecholamines, including dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). It also metabolizes levodopa (L-Dopa), the direct precursor to dopamine.
By inhibiting COMT, the bioavailability of L-Dopa is significantly increased, promoting stronger, longer-lasting dopamine and norepinephrine levels in the central nervous system.
FYI, pharmaceutical-grade COMT inhibitors are also used alongside carbidopa-levodopa therapy in the treatment of symptoms of Parkinson’s disease.
Long-Term Potentiation can be thought of as the “strengthening” of synaptic connections between neurons, which benefit both space and time dependent memory.
While caffeine boosts feelings of energy, mood, and alertness via antagonism of adenosine receptors, Zynamite® acts non-selectively to modulate various CNS targets and stimulate brain activity.[1]
Animal studies note that a dose of 25 mg/kg of Zynamite® attenuates alpha2 and beta1 spectral frequencies in the brain during the first hour after administration, indicating that Zynamite has a fairly quick onset of action (again, similar to caffeine).
Additionally the pattern of frequency changes induced by Zynamite administration mimics those observed following administration of caffeine.
Interestingly, you’ll notice that when Zynamite and caffeine are combined, there is a synergistic and additive effect on brain waves (but, more on that in a bit).
Based on the data, researchers suggest that at least part of Zynamite’s stimulating properties are due to activation of dopamine, since alpha2 waves are under the control of dopamine.
Researchers also noted a sustained attenuation of alpha1 spectral power during their testing, which can be interpreted as a higher state of wakefulness.
In case you were curious, Alpha1 waves are under the control of the neurotransmitter serotonin.
Since mangiferin is the main active compound that we’re interested in, you might be wondering why not find some generic mangiferin extract and leave the “designer” (read: more expensive) Zynamite® alone?
Well, studies show that while mangiferin can cross the blood-brain barrier, its bioavailability is greater as part of a polyherbal preparation in comparison to administration of pure, isolated Mangiferin.[4]
Based on this, researchers question whether Mangiferin alone is responsible for the stimulating effects of Zynamite®, or if it is the presence of the other “supporting cast members” present in the remaining 40% of the herbal preparation that potentiates its effects.
The primary reason people use caffeine is to increase their wakefulness, alertness, and/or feelings of mental energy. These wakefulness promoting properties of caffeine come as a result of adenosine antagonism.
Zynamite enhances mental energy is a “caffeine-like” manner, in that it yields similar effects on brain wave activity, but the manner in which it does this isn’t the same as caffeine, meaning it doesn’t antagonize adenosine.[1]
It works by inhibiting COMT (the enzyme that breaks down dopamine), thereby leading to sustained dopamine levels in the CNS.
A pair of randomized, double blind, placebo-controlled crossover pilot clinical trials involving 16 participant were carried out to assess potential nootropic benefits of Zynamite®.
Subjects received either a 500mg dose of Zynamite® or placebo.[23]
Researchers found that 500mg Zynamite significantly reduced fatigue after only 90 minutes, as demonstrated by a Profile of Mood States questionnaire (POMS).
Additionally, Zynamite® reduced stress during the Calculation Performance Tests and improved reaction time compared to placebo.[23]
During a Number Sequence Test (NST) and a Number Connection Test (NCT), subjects receiving 500mg Zynamite® had a significant activating effect on the brain compared to placebo as determined by frequency analysis of the changes in electrical activity across six brain wave frequency ranges (shown below) in the EEG of the association cortex.
Unfortunately, these two pilot studies are not accessible online save for the data published by Nektium in the White Paper on Zynamite, so it’s hard to really delve into the methods of the paper.
Fortunately, several other studies in humans have been published noting benefits with lower doses of Zynamite (more on that in a bit!)
As mentioned above, preliminary animal studies found that Zynamite increases long-term potentiation (LTP) in a manner similar to caffeine.
Interestingly, Zynamite® had a greater effect on LTP than caffeine, but the combination
of Zynamite® and caffeine demonstrated a remarkable synergy in increasing long-term potentiation.
LTP strengthens the connections between synapses, which can increase memory, learning, and attention.
Excessive production of reactive oxygen and nitrogen species (RONS) during exercise can damage cellular structures, leading to inflammation, fatigue, and impairment of executive and cognitive functions. It can also hinder adaptations to exercise (effectively undercutting your efforts in the gym to get better).
These reactive oxygen and nitrogen species are generated constantly during exercise by mitochondrial respiration.
However, two other enzymes, xanthine oxidase (or xanthine oxidoreductase; XO) and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase, also called NOX) are also contribute to the formation of RONS during exercise.
As a result, a number of antioxidants have been studied to limit the formation of RONS and improve athletic performance. However, some of these antioxidants offer a double-edged sword in that they might combat RONS and lower inflammation, but simultaneously blunt desired training adaptations (i.e. killing your gains).
Now, it’s worth mentioning that the dose of these antioxidants is important as is the form.
Lower dose, natural antioxidants (present in grape extracts, green tea, etc) seem to have less adverse effects on training adaptations than mega-doses of synthetically derived Vitamin C or E.
As we mentioned earlier, mangiferin is a natural polyphenol that also happens to be an antioxidant as well as an inhibitor of XO and NOX.[5,6]
Based on these activities, researchers were curious to see if supplementing with mangiferin (as Zynamite) might limit RONS production and improve athletic performance.
To date, a trio of human studies have been conducted using a range of Zynamite doses.
The first study sought to investigate the effects of Zynamite and either quercetin or luteolin, on sprint performance and recovery from ischemia-reperfusion.[7]
35 healthy subjects (18 men and 17 women) took part in the trial, but only 30 completed it (17 men and 13 women).
Participants were randomized into one of three treatments two days before the exercise test:
For the exercise test, after completing a warm-up, subjects performed two 30-second Wingate tests as well as a 60-second all-out sprint with 4-minute recovery periods.
At the end of the 60-second sprint, the circulation of both legs was instantaneously occluded for 20 seconds.
After the 20 second occlusion period ended, circulation was reopened and the subject then had to perform a 15-second sprint. This was then followed by 10 seconds of recovery with open circulation, and a final 15-second sprint.
(Sounds rather hellacious, doesn’t it?)
Fig. 1: Experimental protocol[7]
Both Zynamite treatments improved performance in the exercise trial, but a slight edge can be obtained from the combination of Zynamite + Quercetin + Tiger nut over the combination Zynamite + Luteolin.
Moreover, brain oxygenation during the sprints was greater after Zynamite combination supplements B and C compared to placebo.
This is noteworthy as previous studies show that decreased brain oxygenation is associated with fatigue.[8]
Zynamite supplements also enhanced peak (Wpeak) and mean (Wmean) power output by 5.0–7.0% and peak VO2 during the repeated sprints by 5.8%.
Researchers concluded that:
“In summary, this study shows that the MLE 60% mangiferin (Zynamite) has a remarkable ergogenic effect increasing muscle power in fatigued subjects, without increasing the consumption of oxygen, submaximal exercise efficiency or submaximal and maximal blood lactate concentrations. This type of response is expected for a compound acting on the central nervous system.”
Note: Nektium Pharma supplied the supplements for this study and partly financed the experiments. However, the experiment and interpretation of the results was carried out using a double-blind design in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.[7]
The next study investigating the effects of Zynamite® again tested it against placebo and in combination with peanut husk extract (supplying 95% luteolin) on various markers of exercise performance.[9]
12 healthy male P.E. students (age = 21.3 ± 2.1 years) took part in the double-blind, crossover design (meaning each subject spent time consuming one of the following treatments:
48 hours after beginning their supplementation regimen, subjects reported to the lab to have their body composition and RMR measured.
Exercise testing for this particular study included a warm-up consisting of 8-second isokinetic sprint on a cycle ergometer followed by a 5-minute “recovery period” during which the subjects pedaled at low speed (~40 rpm) with no load.
Next, the subjects performed an incremental exercise test to determine the maximal fat oxidation (MFO) capacity.
Afterwards, they then performed a 2-minute period of unloaded pedaling.
Then, each subject had the load increased to the same intensity reached at the end of their MFO test and increased 15 Watts every minute until exhaustion in order for researchers to determine the subject’s VO2max.
Upon reaching exhaustion, researchers clamped on the occlusion cuffs for 1-minute.
During this time, the subjects remained seated and silent on the cycle ergometer without pedaling.
At the 50th second of occlusion, a 10-second countdown was initiated while the subjects got ready to sprint as fast and hard as they possibly could for 15 seconds.
Following the one-minute ischemia, the occlusion cuff was deflated such that the men were sprinting with the circulation opened. At the end of the 15-second sprint, a second occlusion was started for 30 seconds, which was then followed by another 10 seconds of free circulation.
At the end of the 15-second sprint, a second occlusion was started for 30 seconds, then the cuff was released and the subjects pedaled slowly at 20 watts while a 10-second countdown towards another 15-second sprint was started.
Following this sprint, subjects performed 2.5 minutes of passive recovery on the bike. Researchers then collected a blood sample from the earlobe to measure blood lactate concentration
After this cycle, subjects rested for 30 minutes.
During the first 20 minutes of the rest period, they laid on a stretcher.
For the final 10 minutes, they moved back to the cycle ergometer for unloaded pedaling at low speed while the instruments were reconnected.
At the conclusion of the 30-minute rest period, subjects performed a 30-second Wingate test followed by 4 minutes of recovery during which they pedaled at low speed with the cycle ergometer unloaded.
At the end of this 4-minute block, subjects performed a second Wingate test.
This second Wingate was followed by a 10-minute recovery block whereby subjects pedaled at a low 20-watt rate.
2.5 minutes into this 10-minute block, researchers collected another blood sample to measure blood lactate concentration.
At the completion of the 10-minute recovery period, subjects performed a submaximal [(70% of the intensity reached in the incremental exercise test (Wmax)] constant-intensity time-trial to exhaustion.
Researchers noted that this last portion of the testing protocol was carried out to assess the effects of the Zynamite + Luteolin supplements on endurance capacity, since the test likely started with the subjects having very low glycogen levels -- a scenario which closely mimics conditions competitive athletes face during the final stages of endurance competitions.
At the end of the endurance test, subjects had occlusion cuffs placed on both legs for 60 seconds.
Again, at the 50-second mark of ischemia, researchers began a 10-second countdown which led into a final Wingate (30-second) sprint.
At the end of this sprint, the subjects remained seated on the bike while pedaling at low speed with the cycle ergometer unloaded.
After 2.5 minutes of recovery, another blood sample was obtained from the earlobe to measure blood lactate.
Then the subjects moved to the stretcher and rested for 30 minutes.
As if performing this whole thing wasn’t bad enough, subjects repeated this protocol after 15 days of supplementation to determine any potential effects due to prolonged supplementation.
Afterwards, subjects then embarked on a 3–4 week washout and repeated following the crossover counterbalanced design!
Following is a graph summarizing the exercise testing:
Fig. 1: Exercise protocol[9]
Researchers noted that supplementation with either Zynamite supplement did NOT affect body weight, resting metabolic rate, resting blood pressure, blood lactate concentration or heart rate.[9]
Researchers did observe that the combination of Zynamite + luteolin:
This last point is especially noteworthy as reduced brain oxygenation can increase production of RONS, which can combine with circulating RONS released by contracting muscles during training.[10]
This increase in RONS and decrease in brain oxygen content could impair cognitive function during exercise, thereby reducing performance in complex tasks.[11,12]
Additionally, after 48 hours of supplementation, mean power output was 15% higher in the group receiving the polyphenol supplement than those receiving placebo.
Researchers offered up a trio of reasons why the combination of Zynamite + Luteolin may improve athletic performance following ischemia-reperfusion:
It’s also worth mentioning that the Zynamite + luteolin supplement enhanced mean power output during prolonged sprints carried out after 30 minutes of recovery following the incremental exercise test.
This improvement in prolonged sprint performance was accompanied by enhanced brain oxygenation and larger muscle oxygen extraction during the sprints.[9]
Note: This study was partly financed by Nektium Pharma, who provided the phenolic compounds and participated in the experimental design. Nektium did NOT participate in the data collection, data analysis, and interpretation of results.
The previous two studies found that the combination of Zynamite® + luteolin or quercetin improves exercise performance when ingested at least 48 hours prior to exercise.
The most recent exercise study on Zynamite sought to determine if a single dose of the supplement could improve athletic performance. This would help determine if the effects of Zynamite® are more acute-based (a la citrulline, VASO6, nitrates, etc.) or saturation-based (e.g. creatine, beta alanine, betaine, etc.).
40 healthy, physically active subjects (20 men and 20 women) took part in the double-blind crossover counterbalanced design and received each of three treatments[13]:
For each training session, subjects performed three Wingate tests interspaced by 4 minutes of rest and ended with a final 15-second sprint after ischemia.[13]
Here’s a graph illustrating the exercise protocol:
Figure 1: Exercise protocol[13]
After all subjects completed all treatment regimens, researchers collected the data and documented that treatments A and B (the two Zynamite + Quercetin supplements) improved peak power output (PPO) during the first three sprints by 2.8 (p = 0.04) and 3.8% (p = 0.01), respectively.[13]
Figure 2: Peak Power Output[13]
Additionally, blood lactate concentration was 7.4% lower (on average) in men after the administration of treatment B compared to placebo (p = 0.03).[13]
While previous studies noted that the combination of Zynamite + quercetin improved performance, this study used a quercetin dose that was ~25–50% lower than that noted in previous research, suggesting that the combination of Zynamite + quercetin may have synergistic effects.
This is all the more noteworthy when you consider the fact raised earlier that high-dose antioxidant supplementation can impair training adaptations. Being able to use a lower dose of a powerful polyphenol may allow for the improvement of exercise performance while “toeing the line” and not blunting the beneficial adaptations to intense exercise.
Additionally, researchers noted a greater reduction of muscle tissue oxygenation during the ischemia following administration of Zynamite® combined with quercetin.
This suggests that the combination of Zynamite + quercetin may improve mitochondrial bioenergetics during sprinting and ischemia, which are in line with previous animal studies showing that mangiferin protects mitochondrial function.[14]
Furthermore, this study found that a single dose of Zynamite (and quercetin) is enough to derive benefit, and that prolonged supplementation is not necessarily needed.
Researchers also mentioned that adding sunflower lecithin to the Zynamite®-quercetin mixture (treatment A) had no additional beneficial effects.
Note: This study was was partially financed by Nektium Pharma S.L, (the company that makes Zynamite). Nektium also participated in the experimental design, but was completely excluded from participation in data collection, data analysis and interpretation of results.[13]
The following list of benefits have been noted with mangiferin supplementation, not Zynamite supplementation, specifically.
However, since Zynamite is standardized to mangiferin, and research has noted it has greater effectiveness when combined with the other botanical components naturally-occurring in mango leaves, it’s reasonable to think that some of these benefits may apply to Zynamite supplementation (provided the dose is comparable).
Mangiferin is able to cross the blood–brain barrier and has been found possibly reduce the oxidative stress observed in neurodegenerative disorders.[15]
Additionally, mangiferin has been shown to reduce intracellular Ca2+ concentrations, an activity that may contribute to its protective effects and reduce iron neurotoxicity in cells.
Research suggests that mangiferin may reduce blood glucose levels by inhibiting glucose absorption from the intestine. This is supported by rodent studies noting that mangiferin inhibits the glucosidase enzymes sucrase, isomaltase, and maltase which are involved in the digestion of carbohydrates into simple sugars. This enzymatic inhibition may delay or inhibit carbohydrate breakdown, thereby slowing glucose absorption from the intestine.[16,17]
Additional animal studies find that a 50% ethanolic extract of mangifera indica leaves at a dose of 250 mg/kg produced a significant hypoglycemic effect, both in normal and streptozotocin-induced diabetic animals.
Researchers believe that this was at least in part due to the stimulation of β-cells to release insulin.[1]
As noted above, various studies have also noted that mangiferin administration may offer[1,19]:
This last property may be especially intriguing for supplement brands looking for an alternative to Hordenine, another MAO-inhibiting supplement that currently resides on the FDA’s Advisory (“watchdog”) list.[17]
To date, Zynamite® administration has demonstrated no side effects and no change in heart rate variability or blood pressure.[23]
90-day toxicology studies also find no evidence of mortality or toxic effects male and female rats even when dosing as high as 2000 mg/kg bw/day.[3]
We all love to stack supplements.
As such, it’s no surprise that many of you reading this are wondering what you could stack with Zynamite (provided you can find it in the first place, haha).
Leading the charge is none other than the consummate stimulant...
As we stated above, animal research notes that Zynamite is synergistic with low doses of caffeine.[1]
Researchers also noted that if most caffeine is replaced by Zynamite®, but at least 2% of caffeine is retained, a prominent increase in stimulation can still be achieved.[1]
This is especially noteworthy for individuals looking to lower their caffeine intake (or cycle off of it completely), yet still want to use something to put a little pep in their step.
It should be noted that this synergistic effect has only been shown in animal models, and more human studies are needed to confirm the initial data set.
Still, if the synergism between caffeine + Zynamite is anything like that of caffeine + TeaCrine (theacrine), I’ll be a happy (and energized) camper.
Rhodiola rosea is one of my personal favorite nootropics / adaptogens. I use it damn near every day, especially for late afternoon work sessions when I don’t necessarily need or want more caffeine.
It’s been used by Russians for centuries for its anti-stress and anti-fatigue properties.
Similar to Zynamite, Rhodiola is able to increase feelings of mental energy, boost cognition, and ameliorate mental and physical fatigue in a manner different from caffeine.
Common doses of rhodiola rosea used in studies are between 200-680mg per day.[20]
Tyrosine is an amino acid that provides the “building blocks” necessary to support production of the neurotransmitters/catecholamines dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline).
Intense, prolonged exercise (and other stressful situations) can deplete dopamine levels in the body, which facilitates the onset of fatigue.
Since caffeine and Zynamite both impact dopamine signaling in the brain (and Zynamite acts as a COMT inhibitor), it stands to reason that supplementing with more of the substrate used to synthesize the “mood and motivation molecule” may help to stave off its decline and keep energy, mood, motivation, and focus elevated for longer.
Essentially, you could think of the Tyrosine + Zynamite stack as the dopamine equivalent of a Alpha-GPC or CDP-Choline + Huperzine A stack for enhancing acetylcholine levels in the brain.
It’s no secret that I’m a fan of another caffeine “alternative”, TeaCrine.
It works similar to caffeine, in that it antagonizes adenosine receptors, but binds to the receptors in a different style than caffeine.
Caffeine binds orthosterically, which is akin to “kicking in the front door”, while TeaCrine (and Dynamine) bind allosterically, which is akin to “sneaking in a window.”
Both accomplish the same goal (getting into the house), but the way you “feel” the experience happening (increased alertness, motivation, etc.) is markedly different.
Combining caffeine + TeaCrine has worked very well for me and many others based on anecdotal feedback. And, there’s some research to validate these “n=1” reports.[21,22]
Since caffeine, TeaCrine, and Zynamite all work via slightly different mechanisms, combining the three might be the “ultimate'' rapid-acting, long-lasting energy experience.
The combo caffeine + TeaCrine + Dynamine has been floated as being a possible “trifecta” to fast-acting, prolonged energy, but based on personal experience, and that of others who have used the three ingredients together, the trio leaves individuals feelings somewhat “flat-lined” or “unmotivated.”
This might be due to the fact that all three ingredients are targeting the same receptors in the CNS (adenosine).
By attacking energy enhancement from three different directions, the caffeine + TeaCrine + Zynamite trio may offer a better solution than the Caffeine + TeaCrine + Dynamine combo.
Zynamite is a standardized extract of mangifera indica standardized to >60% mangiferin.
Mangifera indica has been used for centuries in traditional medicine for a wide variety of disorders and ailments due to the diverse array of effects its bioactives offer.
Studies to date show that Zynamite offers fast-acting improvements to both mental and physical endeavors, both on its own and when used in combination with other well-studied compounds, including caffeine and quercetin.
The ingredient is still very new, but the current body of evidence seems very intriguing.
Going forward it would be nice to see future human research compare similar doses of Zynamite to caffeine to placebo as well as to a combo of Zynamite + caffeine on measures of mental and physical performance to see if Zynamite can possibly contend as caffeine “replacement” and to better identify a “sweet spot” dose for the two compounds used together.
They’re one of my favorite supplements to test and formulate.
I love the surge of energy they give as well as the boost in mood and focus they provide.
I also enjoy their vast array of flavors pre workouts come in (except blue razz...the abhorrence I feel for this flavor cannot be fully elucidated by any amount of words, gestures, or expressions).
And yet, for all the reasons I enjoy pre workouts let me tell you one thing I don’t love about today’s pre workouts -- beta alanine.
And the reason I despise seeing beta alanine in pre workouts isn’t what you’re probably thinking. I have no issue with the paresthesia (“the tingles”) brought on by high doses of beta alanine.
Hell, I don’t even get the tingles anymore and haven’t for several years now. And, it’s not that I have anything against the science or theory of beta alanine.
It’s been shown in several studies to enhance athletic performance and endurance across a wide spectrum of sports, including:
So, my gripe with beta alanine isn’t with its tingles or scientific evidence. It works and may help athletes last just a bit longer in the gym or on the field of competition.
The reason that I despise seeing beta alanine in pre workouts is that it really serves no true purpose in there at all for two big reasons:
First, it has no acute ergogenic effects, and thus, confers no immediate benefits.
You see, in my mind (and the attitude I take when consulting on formulations), is that a pre workout should only contain ingredients that have a direct impact and provide an immediate benefit in the forthcoming training session.
Ingredients like caffeine and citrulline have acute effects and are capable of improving your performance in the training session immediately following your hit of pre workout (provided they are dosed correctly).
Saturation-based ingredients, like beta alanine, do not.
Therefore, a pre workout is not the place for saturation-based ingredients that require weeks and weeks of daily supplementation in order to derive benefit. That means ingredients like creatine, PeakO2, and, of course, beta alanine really have no purpose in a pre workout (in my humble opinion).
Furthermore, saturation-based ingredients only work if you take them everyday.
In order to reach the saturation point of beta alanine (179g), you would need to consume 3.2 grams per day everyday for 56 days (7 weeks) before your muscles fully realize the enhanced acidic ion buffering capability.
FYI, you could also take 6.4 grams per day (split across multiple doses) for 28 days to hit this sooner.
Unfortunately, most people don’t use pre workout every day of the week, and still others only use pre workout for certain workouts (i.e. squats and deads).
Therefore, relying on your pre workout to serve as your daily beta alanine supplement simply doesn’t make sense.
But, I’m not done yet with why beta alanine doesn’t need to be in pre workouts…
The majority of people who use pre workouts are those that lift weights to build muscle and improve body composition.
Beta alanine really doesn’t serve much purpose for people who are performing the typical 3x10 workouts with 90-120 seconds of rest between sets because in order to really derive benefit from beta alanine’s endurance-boosting effects, you need to be exercising for greater than 60 seconds.
Since the average resistance-training set lasts 30-45 seconds, beta alanine really isn’t going to do a whole lot of good for those performing a moderate number of repetitions with long recovery periods.
So, this begs the question why are companies putting in pre workouts if you’re not really getting any actual performance benefits from it?
Simple.
The tingles.
Supplement companies toss 2-3 grams of beta alanine into pre workouts to enhance the “sensory” experience of the pre workout.
In other words, they’re doing it to make the consumer think the product is “intense” and “hard hitting” and nothing else.
Don’t be fooled by this cheap trick.
Pre workouts should be geared to enhancing your athletic performance, not to make your face all itchy or give you a “buzz” like crystal meth.
Again, I don’t have anything against beta alanine. It has a time and place, and may benefit certain athletic populations.
But, it serves no purpose in pre workouts for the consumer.
Unless you’re taking multiple doses of pre workout everyday, you will likely never reach saturation, and subsequently never get the benefits of a quality ergogenic.
If you want to supplement with beta alanine go ahead, but there is no need for it to be in pre workout supplements.
And, it’s easy to understand why dieting is so confusion especially when you consider the laundry list of tricksters, charlatans, and “gurus” pushing their own money-making diet as “the secret” to effortless fat loss and better health and wellness.
In recent times, high-fat, low carb diets have been all the rage, thanks in large part to the explosion of keto, Primal, and Carnivore diets.
Yet, for the longest time dietary fat was the most controversial macronutrient, and consuming too much of it was a certified first-class ticket to a coronary.
This constant back and forth has left the average Joe and Jane floundering in a sea of confusion, misdirection, and bad information when all they really need is someone who doesn’t stand to gain from their ignorance to lend a helping hand.
So, for the average individual looking to shed some unwanted body fat and improve their health and wellness, what is the best diet?
As much as you’d like for me to give you a straightforward answer, the truth is, there is no single “best” fat loss diet for every single person all the time.
There are certain immutable truths when it comes to dieting and fat loss (i.e. you need to be in an energy deficit to lose weight), but as far as how that reduced-calorie diet is constructed is highly individualistic.
Most “diets” do work in the beginning, but they fail long-term due to the fact that the diets aren’t sustainable as they leave individuals feeling incessantly hungry and/or the diet is too tedious to maintain day-to-day.
Previous studies have shown that ketogenic or very-low carbohydrate diets (carb <10% daily energy intake) where individuals were allowed to consume protein and fat ad libitum reduced subjective ratings of hunger and desire to eat as well as increased fullness/satiety to a greater extent than higher carbohydrate diets.[2,3,4]
Based on this small body of evidence, keto, carnivore, and Primal lifestyle acolytes champion the low-carb/no-carb diet as the be-all, end-all way to eat to kill hunger, burn fat, and get ripped.
But, a new study disputes these results and finds that a higher carbohydrate, lower fat diet may actually help reduce appetite more.[1]
The study titled, Very Low and Higher Carbohydrate Diets Promote Differential Appetite Responses in Adults with Type 2 Diabetes: A Randomized Trial, sought to compare the effects of a very-low carb diet vs a high-carb diet on self-reported measures of appetite at baseline and after 4 and 16 weeks in overweight or obese type 2 diabetics.[1]
The study included 115 adults (aged 35–68 years old) who were overweight or obese with type 2 diabetes.
Subjects were randomized into one of two energy-restricted (500-1000 calories per day) diets:
Subjects followed this diet recommendation for 2 years.
During the first 3 months (12 weeks) of the study, researchers provided subjects with 30% of the “key foods” representative of each person’s assigned diet to help them hit their macronutrient targets.
After the initial 12 weeks, participants were given with “key food packs” along with a 50-dollar voucher to subsidize the purchase of these “key foods” every other month.
During the study, participants prepared and purchased their own meals according to guidelines outlined by the research staff.
Furthermore, subjects all participated in the same professionally-supervised 3-day workout program which consisted of 60-min exercise classes containing a mix of moderate-intensity cardio and resistance exercise.
After 16 weeks, researchers found that:
"The primary findings of this study showed that prescriptive energy-restricted, isocaloric HC and VLC diets promoted comparable effects on fasting perceptions of appetite in overweight/obese individuals with type 2 diabetes. However, the HC diet resulted in greater “daily overall” fullness and reduced prospective consumption. Despite these observed differences, body weight changes were similar in both groups."[1]
“In summary, a prescribed energy-reduced HC diet promoted greater perceptions of fullness and reduced perceptions of prospective consumption over the day compared to an energy-matched VLC diet in individuals who were overweight or obese with type 2 diabetes.”[1]
The interesting thing (and the thing that Keto zealots always hit on) is that fat is "more filling" and leads to less cravings than high carb diets that are lower in fat.
As the researchers point out, a previously conducted "meta analysis" (which included all of 3 studies, fyi) found that higher fat, lower carb diets more effectively suppressed hunger and cravings than higher carb, lower fat diets.[5]
The present study shows that a high-carb diet can feel more filling and leave dieters with less feelings of hunger than a high fat diet.
Interestingly, while previous studies found that higher fat diets are better for keeping hunger at bay while dieting, when you start to dig further into the aforementioned studies showing low-carb/keto diets suppress hunger to a greater extent than high-carb diets, you’ll find the appetite-suppressing effects of high fat diets don’t last forever.
For example, Martin et al.[4] found that an ad libitum very-low carb diet (<20 g carbohydrates per day) reduced hunger ratings compared to a low-calorie high-carb diet (55% calories from carbohydrate after 12 weeks.[4]
However, after 6 months and 24 months, there were no differences in hunger ratings between the low carb and high carb diets.[4]
In other words, low-carb diets may help to reduce feelings of hunger or fullness more than higher-carb diets in the early days and weeks of a diet, but those effects subside with time.
The present RCT continues to drive home the point that there is no one diet that is "perfect" for everyone...some individuals experience higher satiety following a higher carb, lower fat diet while others experience higher satiety and less hunger going low carb and high fat.
One of the reasons that the higher carb diet may have led to greater satiety (even though both groups had roughly the same amount of calories removed from the diet) is that the individuals consuming more carbs consumed greater total volume of food daily (~1430g for the high-carb diet compared to ∼970g for the low-carb diet).[6]
This makes sense that the higher carb diet would consume a greater volume of food compared to the high-fat, very-low carb dieters since fat is more energy dense than carbohydrates.
FYI, fat contains 9 calories per gram and carbohydrate contains 4 calories per gram.
What this means is that if two people are eating the same amount of calories, but one eats high carb and one eats low carb, the high-carb dieter eats a greater volume of food for the same amount of calories compared to the high-fat dieter.
We also know that higher-volume foods tend to reduce hunger and perceived feelings of appetite, too.[7]
This may explain why the high-carb group experienced greater fullness during the day along with a lower desire to eat -- the got to eat more food.
One thing that would be interesting to see is what would happen if both diets had a higher contribution of protein, to the tune of 1 gram per pound.
We know that protein is the most satiating macronutrient (meaning it helps keep you feeling full), and the most metabolically expensive for the body to digest.
Would these differences be even greater if protein was equated between the groups, or would the differences be eliminated?
Personally, I’m still wondering why so many nutrition trials continue to “underdose” protein intake when one of the metrics they’re gathering is weight loss. But, that’s a topic for another article.
Both higher carb, low-fat diets and low carb, high fat diets can work for weight loss, and this has been shown time and time again in research.[8,9,10,11,12]
So long as calories and protein intake are controlled for, it really doesn’t matter which diet an individual follows.
It’s worth noting that both groups experienced similar reductions in body weight (again driving home the fact that calories are king for weight loss).
Individuals following the very-low carb diet experienced greater reductions in blood glucose-lowering medication and greater improvements in glycemic and blood lipid profile. This makes sense given the fact that the very-low carb group consumed very little carbohydrates, which directly impact insulin secretion (and the need for it).
In closing, both high-carb and low-carb diets can work for weight loss, and the “belief” propagated by low-carb zealots that high-fat diets are more satiating isn’t entirely true.
High-fat diets can be more satiating for some dieters, but others fare better on a higher-carb, lower fat diet.
Lastly, this study was performed in overweight diabetics -- individuals who are known to have impaired hunger and satiety hormone function (ghrelin, leptin, and glucagon-like peptide 1). So if a high-carb, reduced-calorie diet can help those individuals feel fuller and experience weight loss, imagine what it can do for individuals with normal hormone function.
What do you think about the study and which diet is best for killing hunger on a cut?
The reason for this is that plant-based proteins generally contain less leucine compared to animal-based proteins.[1]
This is important because leucine has been identified as the “anabolic” trigger of muscle growth, which means if your meal doesn’t contain enough leucine (or you don’t get enough) throughout the day, you are not maximizing muscle protein synthesis.
In order to achieve a similar leucine content to animal-based proteins, individuals would need to consume higher amounts of individual plant proteins (~50-60g).[4]
Table 2: Representative amount of protein[4]
However, with this higher overall food intake comes increased calorie intake, which may not be advantageous for those looking to maintain their weight or lose it.
There’s also the concern that plant proteins come with various “antinutrients”, such as phytates and tannins, which have been shown to reduce the digestibility and bioavailability of amino acids contained in protein.[2]
The combination of incomplete/deficient amino acid profiles and the presence of antinutrients result in plant proteins typically having lower biological values and PDCAAS rating.[3]
There’s also the consideration that consuming large quantities of food (like the amounts consumed by physically active people looking to increase performance and/or build mass) can become prohibitive at some point, meaning the foods are so voluminous that you get full, feel stuffed, and have trouble hitting your macro needs.
Consuming this many plant foods could also lead to bloating, flatulence, and/or GI distress (not exactly ideal).
For these reasons, individuals (including those that do and do not consume animal proteins) routinely turn to protein powder supplements.
Whey protein is the typical choice when it comes to purchasing a protein powder; however, amidst the rising popularity of plant-based diets, veganism and vegetarianism, as well as those seeking to diversify their protein sources, plant-based protein powders are becoming more mainstream.
As we mentioned, plant proteins are incomplete proteins, meaning they are deficient in one or more of the nine essential amino acids (generally, lysine and/or methionine).[4]
They also tend to have lower leucine contents on a per-gram basis compared to animal proteins.
To circumvent these issues, and create a plant-based protein powder than can go toe-to-toe with whey protein, supplement companies and manufacturers have started creating vegan protein powder blends containing multiple plant protein sources.
The goal (hope) of these plant protein blends is to make some just as effective as whey protein.
And while this sounds promising in theory, will combining multiple plant proteins actually make something as effective as whey protein, which could arguably be considered as one of the most bioavailable protein sources available?
Well, a recently published study sought to answer that very question.
The team of researchers hypothesized that a high-quality plant-based protein blend formulated to achieve a PDCAAS rating of 1.0 and similar leucine content would be bio-equivalent to whey protein isolate as defined by blood essential amino acid.[4]
Therefore, the primary question the team was seeking to answer was:
Can a plant-based protein blend that’s formulated to match the leucine and PDCAAS of whey protein isolate produce similar increases in the blood of essential amino acids?
Researchers had a secondary object to assess the leucine kinetics over a 4-hour period of the plant protein blends in comparison to whey protein isolate.
Researchers conducted a randomized, double-blind, 4 × 4 William square cross-over study to assess the bio-equivalence of the blood essential amino acid response over 4 hours post-ingestion of 3 distinct high-quality (PDCAAS = 1.0) plant-based protein blends versus whey protein isolate in healthy, resistance-trained adult men.
20 men, between the ages of 18–35, with a Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 took part in the study.
Figure 1. Flow of participants through the study.[5]
Participants were instructed to abstain from protein supplements for one day prior to each of their respective visits to the lab.
The four proteins used in the study were:
To create Blend #3 researchers hydrolyzed the pea and pumpkin proteins used in Blend #1 using a food-grade enzyme sold by Novozymes North America, Franklinton, NC, USA.
To try to make the comparison as similar as possible (and give the plant proteins a chance to compete with whey protein), the researchers matched the leucine and total essential amino acid content, so that each protein had a PDCAAS of 1.0.[5]
Subjects reported to the lab on four separate occasions to receive their protein shake. Each visit was separated by a washout period consisting of a minimum of four days but no more than 14 days.
Researchers measured blood levels of all nine essential amino acids for 4 hours following ingestion of the protein shake.
In the day preceding each lab visit, the men consumed a standardized dinner consisting of two frozen meals based on their individual body mass, age, and activity level (total nutritionals for both meals: Hungry-Man® Fajita Chicken, per serving: Calories 960, Carbohydrates 158 g, Protein 60 g, Fat 16 g), followed by an overnight fast that lasted 12 hours.
Subjects were also instructed to drink water ad libitum.
The research staff also collected a 24-hour dietary recall for each subject at the beginning of the trial. Researchers made a photocopy of the recall and gave it to each subject so that they could duplicate their same food intake before each subsequent visit.
This helps to keep blood amino acid levels similar between testing days and helps offset the possibility for any aberrations that may occur as a result of one’s daily diet.
The primary findings from this study were that even when matched for leucine (2.6g), essential amino acid content (12g), and PDCAAS ratings (1.0), the three plant-based protein blends were not bioequivalent to the WPI control, as assessed by tracking blood levels of leucine and essential amino acids over 4 hours post-consumption.[5]
Figure 3. (a) Mean blood leucine over 4 hours per time point of each study product; (b) Mean and 95%CI total sum leucine iAUC (nmol/mL) by study product, obtained using the trapezoidal rule.[5]
2.6 grams of leucine is the amount of leucine naturally occurring in the whey protein isolate used for the study.
This is noteworthy as the “threshold amount” of leucine needed to stimulate muscle protein synthesis (MPS) is between 2-3 grams of leucine per meal.[6,7]
While the researchers were able to administer a significantly smaller amount of plant-based protein to the men while still matching leucine levels (33–34 g instead of 50-60g), the subjects did not experience a similar rise in blood essential amino acid levels (including leucine, one of the nine EAAs) to that of whey protein isolate.
In fact, plant-based proteins yielded 30–40% lower in total essential amino acid area under the curve over 4 hours post-ingestion.[5]
Figure 2. (a) Mean concentration of blood eAA over 4 hours following ingestion of each study product; (b) Mean and 95%CI total sum plasma eAA iAUC (nmol/mL) over 4 hours by study product. The area under the curve above baseline vs. time (minutes) was obtained by using the trapezoidal rule.[5]
However, by the end of the 4-hour measurement plant-based protein blend #1 and blend #3 yielded similar blood leucine levels to that of whey protein isolate.
While previous studies have compared various plant-based proteins to whey protein matching total protein and/or leucine content, this study was able to match the leucine, total essential amino acids, and PDCAAS rating of whey protein with a considerably smaller total serving size of plant-based proteins.
However, despite matching the leucine, total EAAs, and PDCAAS of whey protein, none of the plant-based protein blends were able to match the blood leucine or total EAA kinetic response of whey protein isolate.
Previous studies have shown that hydrolyzing plant-based protein (e.g. wheat protein) leads to a considerable postprandial (after feeding) increase in blood amino acid availability; however, an equal amount of whey protein resulted in a greater postprandial increase in blood eAA concentrations.[8]
In this study, the researchers only “mildly” hydrolyzed the plant proteins used in Blend #3 (~15%). Perhaps if they had more extensively hydrolyzed the pea and pumpkin proteins, they might have been able to match the leucine and EAA kinetic response of whey protein isolate.
However, the issue with greater hydrolysis is that it leads to adverse flavor changes (chemically, bitter taste).[9]
Regarding the differences in postprandial blood amino acid levels, researchers attributed this to a mix of differing amino acid configurations and reduced digestibility compared to whey protein.
Additionally, the team also suggests the postprandial kinetics of dietary amino acids found in plant proteins may have also impacted the results. The reason for this is that previous studies have shown that plant-based proteins are transported into tissues at different rates than dairy proteins.[10]
Despite the differences in immediate postprandial spike in blood amino acid levels between plant-based proteins and whey protein isolate, the researchers concluded that plant-based proteins are:
“...able to be absorbed by the blood stream with a good efficiency, thus proving to be a viable alternative to the consumption of animal proteins.”[5]
Even though researchers cobbled together various plant-based protein sources to mimic the leucine, total EAA content, and PDCAAS of whey protein, all three blends failed to simulate the postprandial amino acid kinetics of good ole whey protein isolate.
One potential improvement that could be explored in future trials is to add additional free from L-Leucine to the plant-based protein powder to increase the leucine spike and see if it could match whey protein's leucine kinetics.
Additionally, further hydrolysis of the plant-based protein may have yielded similar postprandial leucine and total EAA kinetics, but then again, further hydrolysis would have made the taste of plant-based protein powders even worse than they already are.
Plus, hydrolysis adds a further step to the manufacturing process, which increases the overall cost of the product, and for those seeking “more natural” products, hydrolysis is a step in the opposite direction.
Despite whey protein isolate leading to greater initial spikes in amino acids (0-2 hours post ingestion), by the 4-hour mark, the difference between the blends was negligible.
One thing that the researchers did not test for, which would be a very interesting investigation for future trials, is to compare leucine, total EAA, and PDCAAS-matched plant-based protein blends vs whey protein on muscle protein synthesis.
So, as a consumer and connoisseur of protein powder, what does this mean for you?
Well, in my opinion, no matter how many plant proteins you “Frankenstein” together, they likely won’t ever be as good as what whey protein (or dairy proteins) have to offer.
Does this mean you can’t build muscle, promote recovery, and kick ass in life using only plant-based proteins?
Of course, not!
Research from Babault et al. showed that supplementation with pea or whey protein (50 grams per day) led to similar increases in muscle gain (as determined by biceps brachii) measurement.[11]
(It's also worth noting that the study was funded by Roquette, producers of NUTRALYS pea protein. But the funding company had no part in the study design, data collection and analysis or preparation of the manuscript.
However, three of the researchers on the paper were employed by Roquette at the time of publication.)
However, realize that plant proteins by and large are less bioavailable than animal proteins, and plant-based protein powders almost always cost more than dairy-based protein powders.
A 2019 critical review comparing anabolic properties of animal-based vs plant-based proteins concluded[13]:
"Plant-based protein sources that are rich in fiber and micronutrients may be valuable [127], but they have lower anabolic potential than animal-based proteins. Strategies to improve these properties by increasing protein intake or preferentially improving protein quality (i.e., their amino acid composition) include selective breeding, fortifying plant-based proteins with specific essential amino acids, mixing several plant proteins, and mixing plant- with animal-based protein sources."
Essentially, plant-based proteins can have their benefits, but head-to-head compared to animal-based protein powders they are inferior, unless they are mixed or heavily fortified to simulate the characteristics of whey protein and other animal-based proteins.
Plus, plant-based protein powders (typically) taste inferior.
If you’re looking to “optimize” your post-workout leucine and EAA spike, whey continues to be the way to go.
However, if you’re just looking to supplement your daily protein intake, either whey protein or plant-based protein could work.
Subsequently, droves of l-arginine based pump pre workouts and nitric oxide supplements were released, and they were gobbled up by the millions, much to the supplement companies’ delights. And, while consumers thought they were getting savage pumps from their arginine supplements, as it turns out, those arginine-fueled pump pre workouts weren’t doing much of anything.
How come?
Free form L-arginine, like the kind in your pre workout, has terrible bioavailability, often getting degraded in the stomach before it ever can be absorbed by your intestines and transmitted into the bloodstream. So basically, all those dollars you spent on L-arginine based pump pre workouts, were essentially wasted.
In an effort to find a truly effective nitric oxide boosting supplement, researchers stumbled upon L-Citrulline, an amino acid prevalent in watermelon that survived transportation through the stomach, significantly increased plasma arginine levels, and boosted nitric oxide and muscle pumps.
For several years now, L-Citrulline has reigned supreme as the king of nitric oxide boosters, with numerous studies demonstrating its effectiveness at increasing blood flow, exercise performance, and fatigue resistance.[1,2,3]
Recently though, a new ingredient has emerged. One that rivals has the potential to rival citrulline in its ability to boost nitric oxide and generate massive muscle pumps.
That ingredient is VASO6.
Ahead, we’re getting up close and personal with this next generation nitric oxide boosting supplement to learn what it is, what it does, and why you want it in your pump pre workout.
VASO6™ is a proprietary blend of gallate-enhanced oligomers comprised of dimers, trimers, tetramers and pentamers derived from green tea that stimulate nitric oxide production, induce vasodilation and promote vasorelaxation.
That’s quite a lot to chew on, so let’s take a moment and break that down piece by piece.
VASO6 is an oligomer derived from green tea.
An oligomer is a subcategory of polymers consisting of a “few” monomers.
A monomer is a molecule that can be bonded to other similar molecules to form a polymer (“many” monomers).
So, a monomer is a single molecule, a “dimeter” is two monomers bonded together, and a “trimeter” is three monomers bonded together.
Got it?
Good.
Now, how is an oligomer different from a polymer?
Well, an oligomer is made of the same monomer units as a polymer, but it’s size is considerably smaller (MW<10 kDa), and a polymer can technically be infinitely long, as there’s no real limit on its length.
No, not really.
While VASO6 is derived from green tea, it is far from your typical garden variety green tea extract standardized for EGCG. To understand what makes VASO6 so unique, let’s dig deeper into the bioactive compounds present in green tea, or rather grape seed extract, as that’s where things really got started for this novel nitric oxide boosting ingredient.
A researcher from the University of South Florida named David Fitzpatrick was investigating the vasodilating properties of compounds naturally occurring in grape seed and green tea called proanthocyanidins.[4,5,6,7,8]
Proanthocyanidins are oligomeric flavonoids naturally occurring in a variety of plants formed from combinations of catechin and epicatechin molecules along with their gallic acid esters.[9] They are some of the most abundant polyphenols in our diets and are currently being researched for their role in promoting health and protecting against illness and disease.
Through the course of his research, FItzpatrick identified several compounds that promote vasodilation, the widening of blood vessels. The most active compound within grape seed called epicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate, or C1-gallate for short. He would later apply for a patent for C1-gallate for use as a cardiovascular drug.[10]
In the patent, Fitzpatrick details that during the isolation and characterization of grape seed extract he identified and separated the compounds into seven fractions (A–G). Of those seven fractions, he and his team noted that only four of the seven fractions (D–G) stimulated vasorelaxation, relaxation of blood vessels.
Following this first separation, a second separation occurred, this time dividing fractions D, E, F, & G into 25 separate compound peaks using high-performance liquid chromatography (HPLC).
16 compound peaks were identified as exhibiting vasorelaxation activity, and their proanthocyanidin content was noted. The peak that demonstrated the greatest amount of vasorelaxation activity was Peak G6, a trimeric procyanidin gallate.
Thus, VASO6 is short for vasorelaxant peak G6.
Indeed I did.
VASO6™ is derived from green tea, and it contains only the most bioactive oligomeric compounds exhibiting the highest endothelium-dependent relaxation (EDR).
According to Compound Solutions, the developers of VASO6 (as well as Dynamine), they use the methods outlined by David Fitzpatrick to gather the same nitric oxide boosting compounds from green tea as opposed to grape seed extract that FItzpatrick used in his studies.
So, when you compare VASO6 to Green Tea extract you can see that the two are quite different. Traditional green tea extract contains a wide assortment of polyphenols, catechins, and other bioactive goodes, while VASO6 contains only those fractions that induce endothelium-dependent relaxation (EDR) via the release of nitric oxide.
Furthermore, the addition of gallic acid (galloylation) to the oligomer increases its biological activity (and effectiveness), thus highlighting the fact that VASO6™ isn't your “standard” green tea extract.
As we explained above, the compounds present in VASO6 have been shown to exhibit endothelium-dependent relaxation (EDR) activity in vitro. They do this by causing a release of endothelial nitric oxide, which subsequently increases levels of cyclic guanosine monophosphate (GMP) in the vascular smooth muscle cells.
This series of reactions culminates in both vasodilation and vasorelaxation, which means you get an increase in blood flow, nutrient, and oxygen delivery as well as a reduction in blood pressure. In fact, research shows that the compounds present in VASO6™ leads to 50% vasodilation. Compare that to the 5% vasodilation of arginine, and you can see just how powerful VASO6 is.[10,11]
So, not only do the compounds in VASO6 help drive more blood to your working muscles, they also reduce the strain on your cardiovascular system to pump that additional blood throughout your body.
This translates to a better functioning cardiovascular system, exercise performance, and muscle pumps!
VASO6 increases nitric oxide production and promotes vasorelaxation. This reduces the amount of work your cardiovascular system has to do while at the same time increasing the amount of blood flow delivered to your muscles.
Why is this important?
Increasing blood flow to your muscles leads to two things:
The increased energy and stamina is due to the fact that driving more blood to your working muscles supplies them with additional oxygen and nutrients, which allows them to continue performing at a high level for longer.
Additionally, when you train, the repeated muscle contractions generate metabolic waste products. As these accumulate, fatigue begins to set in and ultimately you have to end your set. With increased blood flow to the muscle, these metabolic waste products can be cleared more efficiently allowing you to train for longer before succumbing to fatigue.
Regarding blood flow and pumps, your blood is more than 50% water. As you exercise, blood is shuttled to those muscles cells, which pull in water to deal with the build up of metabolites generated as a result of your muscles contracting. As more and more water is pulled into the muscle cells, they begin to swell, resulting in one seriously savage muscle pump.
In addition to boosting exercise performance and muscle pumps, the compounds present in VASO6™ may promote cardiovascular health, due to its actions on endothelin-1 (ET-1).
Endothelin-1 is a peptide secreted by endothelial cells that induces vasoconstriction, counteracting the effects of nitric oxide. This is the exact opposite of what you want to occur during intense exercise, especially if you’re chasing the pump in your workout.
The compounds in VASO6 inhibit endothelin-1 activity, resulting in greater bioavailability of nitric oxide[14], and therefore better blood flow, arterial flexibility, and cardiovascular function.
Basically, with VASO6 you get the best of everything -- greater blood flow, less stress on your cardiovascular system, better performance, and bigger muscle pumps!
When supplementing with VASO6, you may experience:
Recommended dosing for VASO6 is 300-600mg.
VASO6 is a non-stimulant nitric oxide booster that can be stacked with any of the following:
VASO6 is powerful enough on its own, but if you’re wanting to get those “sleeve-busting” pumps, consider stacking it with L-Citrulline, Agmatine, FitNOx, or any of the numerous amino-bound nitrates.
In the current nutrition climate, carbohydrates are under attack from all fronts. They’re blamed for just about everything horrific that can happen to you from a physiological and physique perspective, and even more recently, they are even some who state that carbs aren’t even all that useful for athletic performance, which is just laughable by the way.
Amidst this damning of all things carbohydrate-related emerges a type of carb considered by even the most diehard carbophobe or keto zealot to be useful. It might even be “healthy”, though don’t say that too loud, or the keto klansmen might hunt you down.
This beneficial carbohydrate we’re referring to is none other than resistant starch.
There’s a pretty good chance you’ve never heard of this type of carbohydrate, but sit back, relax, and enjoy your cup of bulletproof coffee (or Ritual AM) as we delve into all things resistant starch.
Most of you reading this are familiar with the concept of starches. They’re abundantly found in foods like potatoes, sweet potatoes, and pasta.
What starches actually are, are a plant’s form of stored energy.[1] In a sense, starch is to plants what glycogen is to humans -- the stored form of glucose.
Plants produce starch from glucose to create a supply of energy for those times when food is scarce. Tubers (i.e. sweet potatoes), roots, and seeds typically contain higher amounts of starch as they serve as the “fuel reservoir” for the infant plant during its early phases of growth.[2]
Similarly, when we eat food, our liver and muscles store glucose in the form of glycogen to be utilized when needed for activity and intense exercise.
In plants, starch can be found in two forms: amylose and amylopectin. Between these two, glycogen is more similar to amylopectin, since the sugar molecules in glycogen and amylopectin are highly branched, while amylose has a strictly linear structure.
Now, here’s where resistant starch enters the picture...
Resistant starch is defined as a “portion of starch that cannot be digested by amylases in the small intestine and passes to the colon to be fermented by microbiota.”[3]
In other words, resistant starch is a type of fiber.
Our bodies can’t digest it, but our gut bacteria use it for fodder. This is why “resistant starch” is called resistant -- it resists breakdown in the stomach and small intestine. Once it reaches the large intestine, gut bacteria use it for food and ferment it into short-chain fatty acids, or SCFAs for short.[3]
Now, the idea of a resistant starch seems pretty straightforward -- it’s part of a starch molecule that we can’t digest. But as things usually go, it’s not that simple.
There’s not just one type of resistant starch, but four (or five) different types depending on which studies you read.[3,4]
Designation |
Description |
Example |
Type I |
Physically inaccessible starch |
Coarsely ground or whole-kernel grains |
Type II |
Granular starch with the B- or C-polymorph |
High-amylose maize starch, raw potato, raw banana starch |
Type III |
Retrograded starch |
Cooked and cooled starchy foods |
Type IV |
Chemically modified starches (man-made) |
Cross-linked starch and octenyl succinate starch |
Type V |
Amylose-lipid complex |
Stearic acid-complexed high-amylose starch |
TABLE 1: Types of resistant starches[3]
If that’s not enough to muddy up the waters concerning resistant starch, consider this -- different types of resistant starch can be present simultaneously in the same food, and on top of that, how you cook your food also impacts to the amount of resistant starch changes.
For example, if you purchase a green banana at the store on Sunday and allow it to ripen, the resistant starches present when the banana is green turn into regular starches as the banana becomes more and more yellow.
Furthermore, researchers haven’t come to a consensus on how to quantify the amount of resistant starch in each food. Depending on which paper your read, you’re going to find that the same food can have vastly different amounts of resistant starch.
The final “kink” with the various types of resistant starch is that each resistant starch has a different impact on your body’s glycemic response, meaning each will affect blood sugar levels a tad bit differently.[5]
Now, we’re not here to get bogged down in the minutiae of how each resistant starch impacts your blood sugar levels. We’re more concerned with the big picture of what resistant starches do and what, if any, benefits they have to offer.
So….
Resistant starch primarily functions like a soluble, fermentable fiber. Like other soluble fibers (i.e. the kind found in black beans and oats), it passes through your stomach and small intestine undigested. When it reaches your colon, the “good” gut-friendly bacteria feast on it.[6]
As you probably know, the human microbiome has received an inordinate amount of attention lately with new studies emerging weekly it seems. The is due to a variety of reasons including new links that have been found between the gut’s impact on mental health[11], the gut’s impact on physical performance[10], and the simple fact that our gut flora (bacteria in our gut) outnumber the cells in our body 10 to 1.[7]
Another way of looking at it is this. Of all the food we eat, only 10% of our cells are really nourished by it. The other 90% feeds on the resistant starches and fermentable fibers we consume on a daily basis.[8,9]
When you look at it that way, it might be worthwhile to start upping your intake of fiber-rich foods.
Research has shown that resistant starch feeds the “good” gut bacteria, which not only helps increase the number of bacteria, but also increase the diversity as well.[12,13]
As the gut bacteria digest these resistant starches, they form a number of compounds, including an assortment of gases (methane, hydrogen, carbon dioxide) as well as short-chain fatty acids (acetate, propionate, butyrate, and valerate).[14,15] Smaller amounts of organic acids (lactate, succinate, and formate), alcohols (methanol and ethanol) and, branched short-chain fatty acids (isobutyrate and isovalerate) are also generated.
Out of all of these compounds, the one we’re most interested in is butyrate.
Butyrate is the preferred energy source of the cells lining our colon, and it has been shown to impart several other benefits including:
Furthermore, butyrate also promotes a normal phenotype for cells of our colon, which may serve as a measure of protection from certain diseases such as colorectal cancer.[16] And, compared to other soluble fibers, resistant starch is superior for ramping up butyrate production[17], which makes consumption of resistant starch a priority if you’re trying to improve gut health or rebuild your microbiome following a run of antibiotics.
Now, let’s take a look at some of the other benefits that come with resistant starch, and why they’re so popular in the low/no-carb communities.
Numerous studies have been conducted on the effects of resistant starch intake, and from those studies, researchers have found several positive correlations associated with resistant starch intake, including:
Sky-high blood sugar levels and insulin resistance are an increasingly common occurrence these days in both adults and children. These conditions are strongly associated with a host of diseases, including obesity, type 2 diabetes, and metabolic syndrome.
Several studies have note that resistant starch intake may improve insulin sensitivity (independent of gut bacteria)[19], and decrease postprandial (after a meal) blood glucose levels.[20]
One particularly interesting study noted that consuming 15 and 30 grams per day of resistant starch led to better insulin sensitivity in overweight and obese men, equivalent to could be expected with a 10% drop in body weight.[21]
Even more noteworthy, is that resistant starch exerts something called a “second meal effect”. What this means, is that not only does resistant starch lower blood sugar response following the meal it is consumed, but also lowers blood glucose and insulin levels in the next meal as well![22]
As we mentioned above, consuming resistant starch leads to increased levels of butyrate. This short-chain fatty acid serves as a powerful anti-inflammatory agent for the cells lining our colon and fortify the integrity of our gut by decreasing intestinal permeability (a.k.a. “leaky gut”). This helps prevent various toxins and other ne’er-do-wells out of the bloodstream, helping keep us free from illness and disease.[23,24]
Additional research has noted that resistant starch intake is also associated with a reduced risk of colorectal cancer. Researchers believe this is due to a few different mechanisms including[25]:
In the instance, the short-chain fatty acids resulting from fermentation of resistant starch aren’t immediately needed by the cells of the colon, they enter the bloodstream where they can impart their anti-inflammatory effects in other regions of the body.
One of the main reasons resistant starch has gained such immense popularity, especially in the fad diet world, is due to some research indicating it may boost weight loss.
How is that?
For starters, resistant starch has fewer calories per gram than regular starch. Resistant starch contains two calories per gram while regular starch contains four calories per gram. So, the greater amount of resistant starch a food has, the few calories it will contain.
Second, resistant starch serves as a soluble fiber. Various studies show that soluble fiber intake helps reduce appetite and increase satiety.[25,26] Additional research has noted that incorporating resistant starch into meals exerts the same effect, leading people to eat fewer calories.[27,28]
And, since weight loss ultimately boils down to calories in vs calories out, this aids to weight loss.
A few other notable benefits associated with the consumption of resistant starches includes[19]:
For the individual eating a well rounded diet, high in fruits, vegetables, lean proteins, and whole grains, on average their gut bacteria may be exposed to as much as 20 grams of resistant starch per day.[14]
What foods are highest in resistant starch?
Here’s a table to help you figure that out…
Food |
Resistant Starch |
Glycemic Index |
g/100 g |
||
Grain and cereal products |
||
Buckwheat |
1.8 |
51 |
Bread (white) |
1.2 |
69 |
Bread (wholemeal) |
1.0 |
72 |
Millet |
1.7 |
71 |
Rice (brown) |
1.7 |
66 |
Rice (white) |
1.2 |
72 |
Spaghetti (wholemeal) |
1.4 |
42 |
Spaghetti (white) |
1.1 |
50 |
Breakfast cereals |
||
All-Bran (Kellogg's) |
0.7 |
51 |
Cornflakes |
3.2 |
80 |
Muesli |
3.3 |
66 |
Porridge oats |
0.2 |
49 |
Shredded wheat |
1.2 |
67 |
Weetabix |
0.1 |
75 |
Vegetables |
||
Broad beans |
1.2 |
79 |
Potatoes (white) |
1.3 |
80 |
Potatoes (sweet) |
0.7 |
48 |
Sweetcorn |
0.3 |
59 |
Yam |
1.5 |
1.5 |
Legumes |
||
Beans (baked) |
1.2 |
40 |
Beans (kidney) |
2.0 |
29 |
Peas (chick) |
2.6 |
36 |
Lentils |
3.4 |
29 |
Table 2: Comparison of resistant starch content and glycemic index for commonly consumed starchy foods[3]
Now, a word of caution regarding intake of resistant starch. Research notes that resistant starch seems to be well tolerated up to an intake of around 40-45 grams per day. Should you consume more than that, you might be in store for some GI distress, including diarrhea and bloating. This is due to the fact that high amounts of resistant starch can more or less “overwhelm” the fermenting capacity of our gut bacteria.
Also, if you’re coming from a diet that’s typically low in fiber and resistant starch, increase your intake of these type of foods slowly. Going from 0 to 100 with fiber is begging for a lot of gas, bloating, cramping, and trips to the bathroom.
As demonized as carbohydrates are these days, it appears that resistant starch may be the one carb that all of us can get behind. They can aid blood sugar regulation and insulin sensitivity, improve gut health, help keep us full, and may even reduce our risk of various cancers.
If you're struggling with weight loss, high blood sugars, or digestive problems, resistant starch provides an excellent option to get things moving in the right direction. Just remember to start slowly, or things are going to be freely flowing from you!
The world of nootropics is fascinating.
Where else can you readily find compounds that not only make you smarter, improve your ability to remember, and at the same time ward off cognitive decline?
Yes, nootropics are awesome, and the really cool thing, is that we’ve only begun to scratch the surface of the powers of nootropics. Science is still learning about the intricacies of the human brain, and with each new discovery comes with it the potential for new nootropics to preserve and enhance our cognitive abilities throughout our lifetime.
One of the newest nootropics to enter the market in recent years is NeuroFactor.
It’s showing up in several nootropic formulas, and even some pre workouts.
We’ve got everything you want to know about this booming brain-booster ahead as we do a deep dive into all things NeuroFactor.
NeuroFactor™ is an all-natural, patented compound made from the whole fruit (including the bean) of the coffee plant, Coffea arabica. It was developed by nutraceuticals company FutureCeuticals for the purpose of enhancing the production of a powerful protein in the brain called brain-derived neurotrophic factor (BDNF).
We’ll get more into the specific actions of NeuroFactor a bit further down below, but first let’s discuss what led to the creation of NeuroFactor a bit more.
When you go to make your cup of coffee in the morning, chances are you either flip on the Keurig machine and toss in a pod of coffee grounds or dump some pre-ground coffee into your Mr. Coffee and click “Brew”.
But, there are probably a few of you that are more “refined” and consider yourself a coffee connoisseur, and no Mr. Coffee or Keurig will do for you. So, you take the time to grind your beans (using a burr grinder of course) and then brew your coffee in a French Press.
Whatever way you enjoy your coffee, you have in some way, shape, or form used the coffee bean in the brewing process.
But, have you ever given much thought to what it takes to get that bean you so love?
Probably not.
You might think the typical coffee bean grows on trees or bushes…
And you’d be partially correct.
You see, the coffee bean as we know it isn’t really a bean at all. It’s actually a seed that comes from coffee fruit.
The coffee fruit (or berries) are typically harvested by a machine or picked by hand. The outer fruit is then removed in order to extract the beans. Following this, the beans are collected and transported for processing, drying, roasting, packaging and shipping.
What about the fruit?
It’s usually discarded as it was believed there wasn’t much benefit to it, other than to provide the coffee seeds (“beans”) that brew up each day.
However, recently scientific research has shown that coffee fruit contains powerful antioxidants that have the potential to impart tremendous healthful powers.[1,2]
As a result of these findings, scientists developed processes that have allowed them to collect and concentrate this potent blend of antioxidants found in coffee fruit at the height of freshness and potency.
The result of these pioneering efforts led to a concentrated whole coffee fruit extract, rich in antioxidants, called NeuroFactor™.
Through years of careful research (including two HUMAN trials), scientists from FutureCeuticals discovered that consuming small amounts of whole coffee fruit concentrate (NeuroFactor) significantly increases levels of brain-derived neurotrophic factor.[3,4]
In fact, NeuroFactor increased levels of BDNF up to 143% from baseline measurements and kept them elevated for at least two hours. Technically speaking, levels of brain-derived neurotrophic factor can remain elevated longer than two hours, but researchers conducting the trials stopped tracking after two hours had elapsed.
Due to these findings, researchers may begin using NeuroFactor in the treatment of BDNF-dependent health conditions in humans.
You’re probably thinking:
“That’s great and all, but what the heck is brain-derived neurotrophic factor and why is elevating it good?”
Let’s address those questions now.
Brain-derived neurotrophic factor is a neutrophin, a type of protein active in the brain as well as the central and peripheral nervous systems. It serves a critical role in the growth, development and repair of neurons, specialized cells that transmit nerve impulses throughout the body.[4,6]
Additionally, BDNF has been documented to play a role in neuroplasticity, which is a fancy way of saying this powerful neuro protein helps your brain adapt to new situations, changes in the environment, or any potential brain injury.[7,8]
On top of that, BDNF also supports the survival of existing neurons and encourages the growth, regeneration and creation of new neurons and synapses, indicating BDNF is a key player in neurogenesis.[9]
In other words, brain-derived neurotrophic factor is really, really important, and increasing it is a very good thing, particularly if you want to live a longer, healthier, more mentally adept life!
Interestingly enough, brain-derived neurotrophic factor may also help you lose weight, in addition to its brain-building benefits.
Research has shown that the powerful brain protein can suppress food intake via hippocampal signaling.[10] Studies in rats have shown that infusions of BDHF help lower body weight and reduce hunger.
Human studies have documented that people who are overweight, obese, or type 2 diabetics have low levels of BDNF.[10,11,12]
The fat-fighting effects of brain-derived neurotrophic factor may be due to its ability to activate the stress response and induce UCP1 (uncoupling protein 1)– a powerful uncoupling protein that creates brown fat, which your body readily burns for fuel.[13]
One other way in which BDNF may support a healthy weight is due to its ability to improve insulin resistance.[14] Acting directly on the brain, BDNF regulates glucose metabolism, which supports a healthy insulin response, maintains steady blood sugar levels, and helps prevent fat gain.
We’ve already mentioned that two different human trials have shown that NeuroFactor can significantly increase BDNF levels, but is there anything else you can do?
YOU BET!
In addition to supplementing with NeuroFactor, several other things have been shown to impact BDNF levels including:
One of the most effective ways to increase BDNF is by exercising.[15,16] In fact, high-intensity exercise increases not only levels of brain-derived neurotrophic factor, but improves memory as well.
Even better, the increase in BDNF doesn’t only last the day you exercise, but may last up to several weeks after you train.[17]
If you’re walking around stressed all of the time, not only are you increasing cortisol and torpedoing your testosterone levels, you’re also hurting your BDNF levels too.
Research shows that both chronic and acute stress decreases BDNF[18,19], with acute stress having the bigger impact.
We know that sunshine is important for a lot of things -- creating vitamin D, enhancing levels of serotonin, getting a nice tan, etc. It may also impact your body’s production of BDNF as well.
An analysis of 2,851 individuals in the Netherlands documented that BDNF were linked to the number of hours a person was exposed to sunshine. Levels were higher in the spring and summer, and lower in the fall and winter.[21]
As if you didn’t have enough reasons to get outside and enjoy nature, here’s another one!
Animal studies note that chronic sleep deprivation reduces BDNF, and it increases levels of two inflammatory cytokines, interleukin-1 (IL-1b) and tumor necrotic factor (TNF).[20]
These findings back the results of another study which showed that humans battling insomnia has significantly lower levels of the important brain protein.[22]
Fasting, especially intermittent fasting, is all the rage these days, and for a number of reasons. Well, here’s another one you can add to the list -- fasting increase levels of brain-derived neurotrophic factor up to 400%!
Research shows that subjects utilizing alternate-day fasts, where they only consumed 600 calories worth of food on their “fasting” days, noted that production of BDNF increased between 50-400%!with a single meal of about 600 calories on a fast day, can boost the production of BDNF by 50 to 400 percent, depending on the region of the brain being examined.[23,24]
There’s several other means you can use to get your brain-derived neurotrophic factor levels on the rise, but these are the most common and readily achievable.
Of course, we’re here to talk about how NeuroFactor increases BDNF levels, so let’s take a quick look at the two human studies that proved the coffee fruit extract to be beneficial for boosting BDNF.
For the pilot study on NeuroFactor, researchers recruited 25 healthy, non-smokers between the ages of 18-55 years old with a BMI between 18 and 25 kg/m2. Test subjects could not use any type of medication or supplement for 15 days leading up to the study.[3]
The 25 subjects were then randomly divided into groups of five and received one of the following treatments:
Three of the extracts contained various amounts of caffeine:
Subjects fasted for 12 hours prior to baseline measurements, then consumed a single, 100 mg dose of each material. Plasma samples were then collected at 30 minute intervals beginning after ingestion and ending two hours after ingestion.
At the end of the trial, only NeuroFactor led to any significant increase in brain-derived neurotrophic factor (up to 143% above baseline), indicating there’s something else going on in the fruit of coffea arabica outside of the caffeine or chlorogenic acid, which was plentiful in the green coffee bean extract and caffeine powders.[3]
Researchers concluded:
“These results indicate that WCFC (NeuroFactor) could be used for modulation of BDNF-dependent health conditions.”[3]
Shortly after the results of the first study were published, a follow up study was conducted to confirm the findings of the first and provide greater understanding of the novel nootropic.
For this study, researchers used a single dose, placebo-controlled, within-subject study involving 20 healthy subjects ages 25 to 35.[4]
Each subject consumed all three treatments according to the following dosing schedule:
For each case, subjects has to fast for 12 hours prior to blood sample collection. Three blood draws were collected at 0 hours, 1 hour, and two hours following ingestion of the given treatment.
Researchers again noted significant increases in subjects consuming the 100mg dose of NeuroFactor. Though this time the increase weren’t up as high as the first trial.
For this study, subjects on average experienced an increase of plasma BDNF by 91% at 60 minutes and 66% at 120 minutes compared to baseline.[4] While it’s not as high as the first trial, it’s still a significant boost in powerful brain protein.
Again, coffee came up short as it did not have any significant impact on BDNF levels.
To get the BDNF-boosting benefits of NeuroFactor, you would need to consume 100mg per day. This is the dose proven to be effective in research trials to increase brain levels of BDNF.
Unfortunately, no.
You can’t get the same benefits from coffee that you would get from NeuroFactor.
Research even compared the consumption of coffee to that of NeuroFactor and found that only NeuroFactor led to significant increases in brain-derived neurotrophic factor.
But, that doesn’t mean you have to swear off coffee entirely. You can still take your NeuroFactor alongside your morning cup of coffee to enjoy the brain-boosting benefits of both, as numerous studies have espoused the brain-boosting benefits of coffee.
The world of nootropics is an ever-expanding one, and NeuroFactor™ is one of the newest ones to pique the interest of biohackers. It’s backed by two human studies showing it significantly increases levels of the important neuro-protein BDNF.
Brain-derived neurotrophic factor is associated with cognitive health, memory, learning, and helping your brain adapt to new situations or come back from an injury.
NeuroFactor is non-stimulative and fits nicely into any nootropic stack.
Work deadlines, overdue bills, rush hour traffic, and crying newborns.
What do these four things have in common?
They all cause stress.
Stress is nothing new to us; it’s a part of everyday life.
At times, stress can be helpful, and even necessary, in order to get things done. Giving just enough of a mental boost to get going and get sh*t done.
There’s even a phenomenon known as “The Yerkes-Dodson law,” which describes how performance increases with certain amounts of physiological or mental stress. But, like most things in life, more is not always better, especially in the case of stress.
Too much stress leads to a cavalcade of consequences including decreased performance (mentally and physically), reduced productivity[1], and low testosterone levels.[2] It can even promote unwanted weight gain, too!
So, what is it about stress that does this?
Well, as you probably know, your body is hardwired to release the hormone cortisol in response to stress. When cortisol levels rise, your “fight or flight” response kicks into gear, which stimulates the sympathetic nervous system and your adrenal glands to release a cascade of hormones including epinephrine (adrenaline) and noradrenaline (norepinephrine). These hormones increase heart rate and motivate you to get moving ASAP.
In acute bursts, these spikes of hormonal activity can be great for beating a tight deadline, dominating a workout, or speaking a wildebeast for dinner (if we’re back in prehistoric times).
However, if we’re chronically stressed, cortisol levels become chronically elevated for prolonged periods of time, which can negatively affect every physiological system in your body, including your adrenal glands and thyroid.
When faced with chronic stress, individuals quite frequently turn to synthetic pharmaceuticals to artificially dampen their cortisol response. But with those, often come a host of undesirable drawbacks.
Fortunately, mother nature has provided a supreme stress relief supplement in adaptogens.
These powerful agents help soothe stress and control cortisol to help you stay calm, cool, and collected no matter how tumultuous your life my get.
If you’re not familiar with adaptogens, sit back, relax, and get ready to understand just what in the hell an adaptogen is and why it should be a priority on your supplement list.
Adaptogens are healing plants that improve your body’s response to stress. In other words, adaptogens help restore, balance, and protect your body from stress.
The term “adaptogen” was first coined in 1947 by the Russian scientist Dr. Nikolai Lazarev; however, it wasn’t until 1968 that adaptogen was formally defined thanks to the work of Israel Brekhman, PhD and Dr. I. V. Darymovhe. These days you can find adaptogens in all kinds of supplements including pre workouts, nootropic pills, stress-relief aids, weight loss supplements, and even standalone adaptogen supplements.
The two scientists set forth three criteria which a compound must satisfy in order to qualify as an adaptogen:
Now, that all sounds fairly convoluted, so, to put it in more layman’s terms, an adaptogen must:
Now that you’ve got a grasp of what an adaptogen is, and what it does. The next question on your mind is…
“How Does It Work?”
Well, the scientific answer to that as defined by researchers is:
“the beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO).
The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the “stress-sensor” protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.”[3]
Chances are most of you reading that had not the slightest clue what was stated, so let’s see if we can break it down into something that actually makes sense for the everyday health enthusiast.
When we experience a stressor, the body goes through three phases:
Upon encountering the stressor, an “alarm” is sounded in the body, and it releases hormones, such as adrenaline, that improves concentration and performance to help us handle the task we’re about to face.
“Resistance” is literally that -- we’re resisting or “dealing with” the obstacle that made us alarmed. This could be lifting weights, being chased, or facing a deadline.
After we’ve dealt with the stressor, we become fatigued and enter the “exhaustion” phase.
Adaptogen supplements work at a molecular level by maintaining balance in the hypothalamic, pituitary, and adrenal axis (HPA axis, for short), by basically lengthening the “resistance” phases. This allows us to enjoy the “sweet spot” of the stress response where we’re stimulated from the rush of catecholamines and hormones for longer while at the same time holding off exhaustion. So, rather than crash during, or immediately after, a stressful encounter, we maintain homeostasis and keep going about our day.
In a sense, adaptogens allow us to “hack” our stress response.
No doubt adaptogens are pretty intriguing. Anything that could help us deal with the myriad of stressful situations that we encounter on a daily basis sounds like a must-have kind of thing.
But, aside from helping not feel so stressed out all the time, is there really any reason to use adaptogens?
YOU BET THERE IS!
Adaptogens have been extensively studied in both animals and humans, and researchers have found a slew of significant benefits that adaptogens may impart to the body, including[4,5,6,7,8]:
Essentially, adaptogen supplements may improve just about anything related to physical or mental performance.
Racing against the clock to finish that report for your boss? -- Adaptogens can help.
Heading into a set of max rep squats on leg day? -- Yep, adaptogens can help that too.
Trying to keep your cool while dealing with a screaming baby? -- You’re definitely going to want some adaptogen supplements around!
Anyway you look at it, adaptogens can help make a stressful situation much more manageable and help you be more successful in how you deal with it.
So, the next question is…
There are well over a dozen different adaptogens regularly used in various supplements and nootropic pills. Each with its own different mechanisms of actions and benefits. But, far and away, the two that are the most researched and widely used are ashwagandha and rhodiola rosea.
Ashwagandha (Withania Somnifera) is grown in bushes that are native to India and has traditionally been used for anxiety, insomnia, nightmares, mild obsessive compulsive disorder, and nervous exhaustion. More recently, ashwagandha has been extensively studied for its stress-lowering properties as well as its ability to improve physical and mental performance. And, believe it or not, this old world herb even has been used in the treatment male infertility and thyroid dysfunction.
Rhodiola Rosea (a.k.a. golden root) is a perennial flowering plant typically grown in colder regions of the globe (even in the arctic!). Similar to ashwagandha, rhodiola has a long history of use in traditional medicine for treating a wide assortment of disorders, including anxiety and depression. Modern research has noted that supplementing with rhodiola is effective for staving off both physical and mental fatigue, which explains the increased use of rhodiola in pre workout supplements and nootropic pills.
Adaptogens have been around for thousands of years and used to treat all manner of disease and disorder. They improve our ability to encounter and respond to all manner of stress, and they even help us come out of the stressful situation feeling less “beat up.”
As such, adaptogen supplements are on the rise aiming to help you think more clearly, have greater energy, and be more productive. Given the ever-increasing demands placed on us, adaptogen supplements may just be the all natural “silver bullet” we need to fix our escalating levels of stress, anxiety, and fatigue.
Caffeine is purely awesome. Just ask anyone who’s worked the late shift, raised an infant, or spent their days training at 4am.
Caffeine gives us energy and focus; it boosts our mental and physical performance, and it can even make us a bit more pleasant to be around, too.
But, as great as caffeine is, it’s not a perfect chemical. It does come with a few drawbacks, including the dreaded tolerance build up and nasty withdrawal symptoms. There are also a few other negatives that have been associated with caffeine consumption that have been promoted by various experts and gurus over the years.
One of the most common potential negatives regarding caffeine is regarding its purported ability to constrict blood vessels, which in the world of athletic performance and weight lifting equates to decreased performance, stamina, and nutrient delivery as well as massively reduced muscle pumps -- something none of us really want.
But, is this statement actually based on any science?
Or, is it just one of the many myths thrown around by “gurus” and “experts”?
Let’s take a look at the belief that caffeine constricts blood vessels and see what the research has to say.
So...
YES….and….
No.
You see, caffeine (and coffee) does both constrict and dilate blood vessels.
How is this possible?
To answer that question, let’s take a deeper look into exactly how caffeine works in the body and what areas of the body are affected.
Undoubtedly when asked this question, people will quickly say that caffeine gives them energy or “wakes them up”, but how does it actually do this?
Well...
Caffeine is a xanthine molecule found in coffee, tea, and cocoa which acts in the body’s cells via numerous mechanisms of action across a wide range of molecular targets.
First and foremost, caffeine serves as an antagonist of the adenosine receptors. This means that caffeine binds to adenosine receptors, which prevents the actual adenosine molecule from binding to its partner receptor.
Secondly, caffeine inhibits phosphodiesterase (PDE) enzymes. Yes, these are the same family of enzymes that are the target of male enhancement products, such as Viagra.
Thirdly, caffeine acts as a sensitizer of calcium liberation channels, meaning that caffeine increases release of calcium, which we’ll discuss more about it a bit.
Caffeine also antagonizes GABA receptors[2] and impacts the cardiovascular system through a number of interesting means, which brings us to the topic at hand...
Our analysis of how caffeine impacts blood flow begins with a discussion of the endothelium -- a rather extensive tissue in the human body that forms the barrier covering the walls of your blood vessels and arteries.
Blood vessels (and arteries) are composed of several different cell types. The outer layer is made up primarily of connective tissue, which helps the blood vessels stick (adhere) to tissues within the body. The middle layer of cells consists of smooth muscle cells, which govern how wide or narrow (vasodilation or vasoconstriction, respectively) a blood vessel gets, which means that smooth muscle cells can directly impact blood flow. Keep this in mind, as we’ll bring this up again in a moment.
The final and innermost layer of vessels are comprised of single layer of endothelial cells and other “supporting” cells. Endothelial tissue is both structural and functional as it is serves as the outer layer of arterial walls and selectively permits compounds to pass through it, meaning it’s rather picky in what it allows to cross through it and into or out of the artery.
Here’s a diagram of a blood vessel to help clear things up[5]:
What does this have to do with caffeine?
Everything…
Caffeine acts directly on the endothelial cell, stimulating the production of nitric oxide.
How does it stimulate nitric oxide?
That’s where things get complicated…
Caffeine stimulates the release of calcium ions (Ca2)+ from the endoplasmic reticulum, leading to an increase in the concentration of intracellular calcium in the cytoplasm, which is typically abbreviated as iCa2+. This release of calciums leads to the formation of a complex with calmodulin (a calcium-binding messenger in our cells) which favors the activation of endothelial nitric oxide synthase (eNOS), resulting in nitric oxide production.
Now, under normal circumstances, there is a minimal amount of calcium residing in the cytoplasm, but not enough to activate eNOS. However, researchers believe that caffeine lowers the threshold required for the “calcium-induced calcium release” mechanism, meaning that this cellular mechanism can be activated when levels of calcium are at their resting value in the presence of caffeine.[4]
But, that’s not all….
Caffeine doesn’t just impact the endothelial tissue, but actually affects the vascular smooth muscle cells themselves, both directly and indirectly!
The initial action of caffeine on smooth muscle cells results in vasoconstriction!
Immediately, all of those against stimulants, especially caffeine in pre workouts, will immediately say, “SEE! I TOLD YOU CAFFEINE CAUSES SHRINKAGE!”
As famed college football analyst, Lee Corso would say….”Not so fast….”
After this brief constrictive action, caffeine prompts a “significant vasodilator effect”.[1] This happens through a few different mechanisms, which we’ll briefly discuss:
There are various mechanisms that explain these effects.
There’s also some “indirect” mechanisms at play here too. Chief among these is the effects of caffeine on the vascular smooth muscle cells by nitric oxide. If you remember, endothelial cells can allow certain molecules to cross through its protective barrier. Nitric oxide is one such compound, and once eNOS in the endothelial cell synthesizes nitric oxide, it quickly diffuses to the smooth muscle cell, leading to vasodilation.
If all of that sounds rather complicated and complex (because frankly, it kind of is), here’s an illustration that should hopefully clear things up a bit[1]:
And here’s another graph showing the indirect actions at work[1]:
And...here’s a table summarizing all of the effects caffeine exerts on vascular smooth muscle cells[1]:
If you’ve ever had a migraine, you’ve undoubtedly felt the searing pain that shoots through your head the instant you see any bright light. And to alleviate that mind-melting pain, you’ve probably taken some migraine medication.
9 times out of 10, the medicine you used to quash that pesky migraine was Excedrin (or the generic store brand).
What is it about Excedrin that makes it so effective for putting a stop to a migraine’s paralyzing effects?
Caffeine.
You see, when you have a migraine, levels of adenosine in the head and neck can increase up to 68% above normal, non-migraine concentrations.[6] And, in the head and neck, adenosine dilates blood vessels.
When caffeine antagonizes adenosine receptors, and subsequently prevents adenosine from binding to its receptor, it causes a reduction in cerebral blood flow, and with that reduction also comes some much needed relief from your headache and migraine.
But that’s not all caffeine does to relieve pain.
It also[7,8]:
By now, hopefully you realize that caffeine isn’t the terrible, vasoconstricting, pump-killing stimulant you’ve been let to believe it is. Not only is caffeine not vasoconstrictive, it actually promotes vasodilation through the production of nitric oxide and its effects on smooth muscle cells.
Suffice it to say that this myth has been BUSTED.
You can still enjoy your caffeine pre workout and get massive pumps.
Beta alanine enhances endurance and stamina.
And citrulline malate boosts nitric oxide...and delivers some pretty killer muscle pumps, too.
We’re all familiar with these ingredients and know what their “signature” benefits are...but what else can these staples of performance do? (if anything at all…)
Are they only useful for helping athletes to increase power, strength, performance, and physique or do they offer a little lagniappe for those times you’re not exercising?
ABSOLUTELY!
And that brings us to the topic for today’s post -- 25 uncommon benefits of everyday supplements.
The king of bodybuilding supplements may also be one of the most underrated brain-building supplements too.
Research has shown that the brain uses a tremendous amount of ATP (energy) when performing difficult tasks.[1] Since creatine enhances phosphocreatine stores in the brain, it helps the brain generate more ATP. Furthermore, creatine may also improve cognitive function (short-term memory, intelligence, reasoning, etc.) by elevating levels of dopamine and mitochondrial function.[2,3,4]
In addition to its ability to enhance power, strength, and cognition, creatine may also help lower blood sugar levels.[5,6,7] Creatine’s blood glucose lowering properties may be due, in part, to its ability to enhance GLUT4 function.
Research has noted that when individuals consume creatine in addition to training, they have better blood glucose regulation compared to those combined with exercise,
A 12-week study noted that individuals supplementing with creatine in addition to exercise were better at controlling blood sugar levels following a high carb meal compared to those individuals who only exercised.[6]
Rhodiola has long been known for its ability to help improve the body’s response to stress, but recent research has noted it also shows promise for enhancing exercise performance, especially during endurance-based exercise.[7,8,9].
Ashwagandha is an incredibly popular adaptogen, widely used in traditional medicine for managing stress. Additional human research into this stress-combating herb has noted that it can reduce blood sugar levels in both healthy individuals as well as those with diabetes.[10,11,12,13]
Curcumin has gained immense popularity in recent years due to its powerful anti-inflammatory properties, but additional research suggests that the principal curcuminoid of turmeric may also be useful for reducing stress and combatting symptoms of depression.[14]
In addition to its mood-elevating, stress-lowering qualities, curcumin also has been shown to benefit working memory and attention in healthy adults, according to preliminary research.[15]
Grape seed extract has been explored for its pro-cardiovascular function qualities in recent years due to its ability to promote vasorelaxation and vasodilation. However, the benefits of grape seed extract extend beyond the heart and its intricate network of veins, arteries, and capillaries.
Gallic acid is a components of grape seed extract that has been shown to inhibit the formation of fibrils by beta-amyloid peptides in various lab trials.[16,17,18,19]]
Several studies in humans and animals have noted that ashwagandha improves immune system function by decreasing inflammation and upregulating the activity of natural “killer” cells.[17,18,19]
These “killer” cells are the ones that fight infection from viruses, bacteria, and other toxins in order to keep you free from illness and disease.
The liver is tasked with filtering the blood, cleansing it of any impurities, toxins, or other hazardous compounds that could infect the blood. It just so happens that your favorite morning pick me up (i.e. coffee) may help promote liver health and protect against cirrhosis. Research has noted that individuals consuming 4+ cups of coffee per day have an 80% lower risk of developing cirrhosis.[23,24]
Choline is an essential nutrient found in eggs that is best known for its role in the production of acetylcholine, the “learning” neurotransmitter. As it turns out, this brain-boosting compound may also benefit those looking to drop unwanted body fat.
Research has noted that supplementing with choline leads to a reduction in body mass without a loss in static strength.[25]
Betaine (trimethylglycine or TMG) is a staple of pre workout formulations due in large part for its ability to enhance power and strength. Additional research has noted that it may also be effective for combatting symptoms of depression.
Betaine increases levels of S-adenosylmethionine (SAMe), which enhances the productions of feel good hormones such as serotonin and dopamine that can help treat depression. Additional research has shown that supplementing with SAMe and betaine improved symptoms of anxiety and worthlessness in people who previously had responded poorly to antidepressants.[26]
A double-blind, randomized controlled trial noted that supplementing with B12 (cobalamin) increased blood levels of betaine. This increase in betaine was associated with improvements in brain function and memory as well as faster reaction times.[27]
One of the prominent roles betaine serves in the body is as a methyl donor. In case you weren’t aware, methyl groups play a vital role in a number of physiological processes, including DNA methylation, phosphatidylcholine synthesis, and protein synthesis.
Betaine donates a methyl group to homocysteine, transforming it into methionine, one of the three amino acids used by the body to generate creatine.
The B Vitamin family is pretty well known for its role in helping the body produce energy, yet that’s not all these essential nutrients are good for. As it turns out, they also benefit mood and cognition, too.
Studies have shown that when individuals take high doses of B-vitamins, they experience less stress and mental fatigue along with better performance in cognitive tests.[29,30]
Berberine is a compound that is traditionally supplemented for its blood sugar-regulating properties. Yet, this nutrient also supports cardiovascular health, thanks to its ability to reduce blood pressure and dilate blood vessels.
Studies have shown that berberine inhibits angiotensin-converting enzyme (ACE) and releases nitric oxide and cGMP into blood vessels. These two actions, along with berberine’s ability to block alpha-adrenoreceptors lead to greater blood vessel dilation.[31,32]
Derivatives of berberine have been shown to inhibit acetylcholinesterase, the enzyme that degrades the “learning” neurotransmitter acetylcholine. Inhibiting this enzyme, leads to greater levels and action of acetylcholine, which benefits memory, learning, and cognition.[33]
Biotin (Vitamin B7) is essential to proper fat metabolism in the body. When taken in combination with chromium, biotin has been shown to lower risk factors of cardiovascular disease, including lowering LDL (“bad” cholesterol and raising HDL (“good”) cholesterol.[34,35]
Additionally, high doses of biotin (~1500 mcg per day) have been documented to reduce blood triglycerides in those with elevated levels.[34]
Biotin stimulates insulin production, which enhances glucose uptake into skeletal muscle cells. Additionally, biotin also activates glucokinase, a liver enzyme promotes glycogen synthesis.[36,37,38]
Studies have shown that daily supplementation of biotin reduce fasting blood sugar levels by an average of 45% as well as diabetic neuropathy in patients with type 2 diabetes.[39,40]
Commonly supplemented for heart and brain health, fish oil may also benefit muscle recovery following intense training. Research notes that EPA and HDA enhance muscle contractile recovery and reduces muscle oxygen consumption, which supports resistance to muscle fatigue.[41]
Ginger is a spice commonly used in Asian and Indian cooking for the pungent “bite” it adds to culinary fare. It also benefits those with blood sugar issues too. Research has shown that ginger supplementation can reduce fasting blood glucose and HbA1c (an important long-term diabetic marker) in humans.[42]
A comprehensive systematic review and meta-analysis noted that ginger supplementation improved markers of c-reactive protein as well as cholesterol and triglyceride profiles in humans.[42]
Ginger can also help lower blood pressure by stimulating muscarinic receptors and blocking calcium channels.[43]
Bacopa monnieri is an age-old herb commonly used for brain health, longevity, and relaxation. Modern research has found that it may also be an effective anti-inflammatory agent as well. More specifically, bacopa inhibits COX (Cyclooxygenase) and LOX (Lipoxygenase). It also reduces TNF-α (Tumor Necrosis Factor-alpha).[44]
As a result, bacopa is being more extensively explored as a possible treatment for arthritis.[45]
Theobromine is a relative of caffeine found alongside it in chocolate and coffee. While typically known for its smooth, long-lasting energy, theobromine also supports cardiovascular health, exercise performance, and brain function due to its ability to increase blood flow via vasodilation.[46]
Deficiency of magnesium can result in brain artery spasm and the increased release of pain substances in the body. High doses of supplemental magnesium (~600mg) has been shown to significantly reduce headache frequency, severity, and duration.[47]
Capsaicin is the pungent alkaloid that gives chili peppers their distinctive, tongue-numbing “bite”. It’s also commonly included in weight loss supplements and fat burners for its ability to boost metabolism and suppress hunger.
Now, new research has shown that the fiery compound may improve exercise performance too. n ingredient found in chili peppers that contributes to the hot and spicy flavor of the chili pepper. When men were given 12 mg of capsaicin, 45 minutes prior to a session of squats, their total mass lifted increased along with a decrease in rate of perceived exertion (RPE).[48]
I love pre workout.
There’s something irresistible about the increased energy, tunnel vision focus, and heightened mood that pre workout supplements provide. It’s borderline addictive, I swear.
Pre workout supplements exert their glorious effects through a combustible cocktail of stimulants, nootropics, and ergogenics, that culminate in an experience rivaled by few things and, on top of that, they can actually help you to perform better in your workouts too.
In other words, pre workouts are awesome.
And if that’s not enough to entice you, pre workouts also taste pretty damn good, too, or they should in this day and age.
Yet, as commonplace as pre workouts are, few consumers really understand how they increase energy, focus, and performance.
That’s why we’re here.
In today’s article, we’re going to give a “primer” of sorts into the many stimulants you’re likely to encounter the next time you purchase your tub of pre workout.
And with that, let’s begin our dive into the best pre workout stimulants!
Let’s get something clear right off the bat, the reason so many people love pre workout supplements is because of caffeine. It’s the rock-solid foundation upon which 99.9% of all great pre workouts are built (the other 0.1% is for those rare exceptional stimulant free pre workouts).
Caffeine can be found far and wide these days. It’s not only found in coffee, tea, and chocolate, but supplement companies and food manufacturers have now put it in candy bars, peanut butter, and whey protein shakes too!
Most of you know that caffeine is a godsend when you’re struggling to shake off the cobwebs and keep your eyes open. But, how does it give that unmistakable boost in energy and focus
First and foremost, caffeine acts as an adenosine receptor antagonist, meaning that caffeine more or less “blocks” the slot on receptors where adenosine could dock.
Why is this important?
Adenosine is purine nucleoside that binds or “docks” to adenosine receptors in the brain. In doing so, adenosine causes a reduction in nerve cell activity, resulting in feelings of fatigue and tiredness.
Since caffeine has the extremely rare ability to easily cross the blood-brain barrier (BBB), it can “elbow out” adenosine, leading to greater energy and alertness.
Now, the second reason caffeine is awesome has to do with its effects on dopamine levels. You see, a nice “side effect” of adenosine receptor antagonism is that your dopamine system works more efficiently.
In case you weren’t aware, dopamine is the neurotransmitters that has a massive impact on motivation, decision-making, and mood. It also affects movement and memory too!
Research notes that caffeine causes a significant increase in dopamine production, and with greater dopamine levels, you get the enhanced motivation, determination and focus to crush your workout.[1]
In addition to increased energy and motivation, caffeine also exerts some unique effects on exercise performance too. Research has shown it up-regulates fatty acid oxidation (a.k.a. “fat burning”), which may spare glycogen stores for the more intense work in your training. It also helps reduces neuromuscular fatigue, improves stamina, and at certain doses (400-600mg) boosts strength.[2,3]
When you take all of those benefits into account, it’s no wonder why caffeine is the pre workout stimulant.
Effective dose: 3-6mg/kg of bodyweight
When running through the list of the best pre workout stimulants available, you won’t get very far without running into our next stimulant in synephrine.
Naturally occurring in Citrus Aurantium (bitter orange), synephrine (or p-synephrine) is structurally similar to another well-known stimulant in ephedrine. However, ephedrine is a derivative of phenylpropanolamine and does NOT contain a para-substituted hydroxy group, like synephrine does.
Why is this important?
The addition of the parahydroxygroup on the p-synephrine molecule, as well as the lack of the methyl group on the side chain affect the stereochemistry and, as a result, the receptor binding characteristics and the pharmacokinetic actions, including the ability of p-synephrine to cross the blood-brain barrier.
This is all in addition to the fact that synephrine is considerably safer for human consumption, and actually legal to use in pre workout supplements, too! (More on that in a moment)
The differences between synephrine and ephedrine don’t end there either. They also differ in regards to which receptors they bind to in the body.
Ephedrine and m-synephrine (a relative of the p-synephrine) have a greater affinity for alpha, beta-1, and beta-2 receptors, which can lead to increased heart rate and/or blood pressure.
Synephrine (or p-synephrine) exhibits little or no binding to α‐1, α‐2, β‐1, and β‐2 adrenergic receptors, meaning that it does not come with the adverse cardiovascular effects (increase in heart rate and blood pressure) that other phenylethylamine and phenylpropylamine derivatives (i.e. ephedrine) do.[4,7]
As a beta receptor agonist, synephrine triggers lipolysis, which liberates stored fatty acids from adipose tissue, freeing them up to be oxidized (“burned”) for energy. Greater availability of free acids in the bloodstream during training may help preserve glycogen reserves, saving them for the really intense work at the end of your training session when you’re trying to do those hardcore “finishers”.
This may also be the reason that when synephrine is taken prior to exercise it has been shown to enhance performance and reduce the onset of fatigue.[6]
Several other studies have also noted that synephrine leads to greater thermogenesis, glucose and cholesterol metabolism. It may also reduce food intake. Due to these effects, synephrine is quite frequently found in thermogenic supplements and fat burners to help individuals lose weight rapidly.
One final reason to embrace synephrine, is that among the stimulants commonly found in pre workout supplements, synephrine is one of the few that actually had a fair amount of research conducted in humans demonstrating its effectiveness on performance and fat loss.
Effective Dose: 26-100mg
Another popular stimulant found increasingly in pre workout supplements these days is Hordenine. It’s naturally occurring in a variety of plants, namely bitter orange and barely.
Similar to synephrine, hordenine functions as a central nervous system stimulant and beta adrenergic receptor agonist, meaning it leads to an increase in adrenaline and noradrenaline. This has the added effects of triggering lipolysis, which enhances fatty acid availability.
In addition to its pro-fat burning benefits, where hordenine really appeals to supplement manufacturers is actions as an MAO inhibitor.[7]
MAO (Monoamine oxidase) is an enzyme that degrades monoamines, such as dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine).
By inhibiting MAO, hordenine “protects” these powerful brain chemicals from breakdown, which helps their energy and focus boosting effects to last longer during training.
Hordenine also functions as a noradrenaline reuptake inhibitor which prevents noradrenaline (norepinephrine) from being reabsorbed.[8,9] This again increases the amount of time you feel amped up and ready to unleash seven kinds of hell on the iron.
To date, no studies have been performed assessing exercise performance using hordenine in isolation. There have been a handful of studies involving products which include hordenine showing benefit, but whether those benefits are solely attributable to hordenine isn’t certain.[10]
Dosage: There is a distinct lack of human research with hordenine, as such, there is no effective or “ideal” dose noted in the literature. However, based upon anecdotal feedback the target dose to use as well as the dose most commonly found in pre workouts is 50mg.
Simply put, creatine flat out works.
Best of all, creatine is readily available and it’s dirt cheap.
So when you take all of those factors into consideration, you’ve got nothing to lose by supplementing with creatine.
But, what happens when you stop taking creatine?
Will your hard earned gains evaporate and your muscles shrivel to the size of that of a twelve year old girl?
We’re going to answer that very question today, as we explore the topic of what happens when you cycle off creatine.
To begin to answer that question, we first need to understand what creatine is and what it does in the body.
So…
Creatine is a substance naturally occurring in red meat and produced by the human body. It’s created from three amino acids (glycine, arginine, and methionine).[1,2]
Chemically known as α-methyl guanidine-acetic acid, creatine is primarily stored (about 95%) in skeletal muscle tissue in the form of phosphocreatine. The remaining 5% is stored in your liver, kidneys, and brain. How much creatine your body stores at any given time is based on a few factors[1]:
Creatine primarily helps build muscle and strength in two ways:
The main mechanism by which creatine aids muscle growth is by improving energy production in the body.
The simplest unit of cellular energy is a molecule called adenosine triphosphate. You probably know this molecule by its more common name ATP.
The more ATP your muscle cells can store, the more quickly they can regenerate it and continue powering your muscles during training.[3]
In order for a cell to get energy from ATP, it must first break the larger ATP molecule into several smaller ones. During this process, several byproducts are generated which your body can recycle to generate more ATP. The byproduct we’re most interested in with respect to creatine, is adenosine diphosphate (ADP).
Now, here’s where creatine enters the energy producing picture…
When you ingest creatine, it binds to a phosphate molecule and your body then stores it in the form of phosphocreatine. During the ATP regeneration process, creatine donates its phosphate group to ADP, transforming it into the energy behemoth that is ATP.[4] This ultimately increases your muscles’ ability to perform at a high level for longer periods of time before fatiguing.
Unfortunately, the body’s natural creatine stores (i.e. without supplementation) are pretty low[5], and once they become depleted, your ability to rapidly replenish ATP goes downhill pretty quickly. That’s when your muscles start turning to glucose and/or fatty acids for ATP production.
However, when using a creatine supplement, such as Creapure creatine monohydrate, you can significantly increase your creatine stores, up to 20%![6]
With greater creatine reserves in your muscles, you have significantly more efficient energy production and ATP regeneration, which leads to improvements in[7,8,9]:
In other words, supplementing with creatine enables you to move more weight for more reps, which provides a greater training stimulus for your muscles, ultimately giving them a reason to grow! As a result of the increased workload, and provided you're consuming a calorie surplus, you will build muscle and increase strength.
But, there’s another way that creatine improves lean mass gains...
The second mechanism by which creatine enhances muscle growth is that it increases the water content of muscle cells[10], which causes an expansion of the muscle cell. You body interprets this expansion as a “threat” of sorts to the cell’s survival and doubles down by reinforcing the structure of the cell. This leads to increased size and strength.
But there’s more to cellular hydration and muscle growth…
It also positively affects nitrogen balance and the expression of various genes that ultimately impact hypertrophy (a.k.a. muscle growth).[10,11]
Together, these mechanisms enable you to train longer and bang out more reps while staving off fatigue. Ultimately, you’re accomplishing more work during your training sessions, and in the presence of a surplus of calories, you will “make gains” and increase muscle growth.
Now, let’s say you’ve been supplementing with creatine for a while and for whatever reason you decide to stop using creatine. The inevitable question is...
If you choose to stop creatine (which there is no need to do, barring medical issues), you may notice a slight decrease in muscle fullness along with some decline in performance, strength, and stamina. However, you will by no means "lose muscle" or lose your gains unless you eat at a dramatic deficit or take a long hiatus from training.
Remember, the muscle you gained was a result of improvements you made in performance and eating a surplus of calories. Creatine doesn’t actually build muscle or create it. It simply helps you to perform more work during training.
As such, when you stop taking creatine, the muscle you built while supplementing with creatine will remain in place.
However, you may notice less muscle fullness (due to reduced water retention) as well as a slight drop off in performance (due to lower stores of creatine in the muscle).
This leads to another question…
NO.
There is no need to cycle creatine for the fit, healthy individual.
The main reason individuals cycle compounds is to give their body a break as well as restore normal hormone production and ease the burden on vital internal organs, such as the liver. This is especially true when discussing the topic of anabolic steroids, which downregulate natural testosterone production, place unnecessary stress on the liver, and can lead to permanent shut down.
But, don’t make that assumption with creatine. While it does reduce natural creatine production in the body[12], supplementing with creatine is actually a very good thing.
Aside from the slew of performance and cognitive benefits of creatine, supplementing with it also reduces the burden on the body to synthesize creatine, which is quite taxing, and should you stop taking creatine, your body resumes its normal rate of production.[13]
Last but not least, let’s review the dosing for creatine.
Creatine is a saturation-based ergogenic, meaning that you need to take it consistently and continually to see its benefits. It does not offer any acute benefits, as say, caffeine or citrulline does.
As such, simply consume 5 grams per day of creatine and in a couple weeks time you will start seeing the benefits, or, if you want to accelerate things a bit, you can take 20 grams per day for 5 to 7 days to “load” your muscles with creatine. After that first week, you can lower to a “maintenance” dose of 5 grams per day.
One last little creatine biohack…
If you really want to get the most out of creatine, you might want to take it post workout and without any caffeine, as some research indicates consuming creatine with caffeine inhibits absorption.[14]
Creatine is the most studied, proven, and time-tested supplement in the history of sports nutrition. No matter if you’re an elite endurance athlete, competitive powerlifter, aspiring bodybuilder, or casual gym rat, if you’re not supplementing with creatine, you’re seriously missing out.
Countless studies have shown that creatine…
This is all in addition to a slew of other benefits we’ll get into in future articles.
Plus, creatine is incredibly affordable, available, and best of all...SAFE.
Will you lose your gains if you stop taking creatine?
Not by a long shot.
But, why would you want to stop taking creatine when there’s so much to be gained from supplementing with it?!