While several explanations exist as to PS’s specific mechanism of action, one of the earliest proposals was a powerful and acute blunting effect on cortisol production via ACTH (adrenocorticotropic hormone) reduction. In a double-blind study involving 9 healthy adult males, ranging in age from 18-29, the participants were administered phosphatidylserine for 10 days prior to an acute exercise challenge. Post-exercise measurements found that phosphatidylserine reduced not only ACTH, but also plasma cortisol levels in a statistically significant fashion.
Subsequent studies administering the compound in both acute and chronic fashion suggest that PS, whether through cortisol-mediated mechanisms or otherwise, has a measurable effect on exercise physiology and exercise capacity. In a double-blind, placebo-controlled, randomized trial involving 16 trained athletes, phosphatidylserine was administered for 10 days prior to an acute exercise challenge. Biomarkers of stress and muscle damage (cortisol, creatine kinase, among them), along with exercise markers such as exercise time to exhaustion, sprint performance, and ratings of perceived exertion, were measured post-exercise. While PS administration did not attenuate markers of physiological stress in this study, the authors found that exercise time to exhaustion was significantly altered. Related studies using similar serving sizes have found that chronic PS administration increased shot accuracy in golfers, increased exercise time to exhaustion by 28% in cyclists, and reduced subjective feelings of stress and soreness in others.
Overall, and whether by cortisol or non-cortisol mediated mechanisms, phosphatidylserine appears to play a valuable role in the reduction of both physiological and psychological stress in response to exercise. In combination with its demonstrated effects on exercise capacity improvement, PS may play a critical role in the continued exercise success of bodybuilders in a, "cutting” or recomposition stage.
KSM-66® Full-spectrum Ashwagandha root extract (5% Withanolides)
Withania somnifera Dunal, colloquially known as Winter Cherry or Indian Ginseng, is an herb that features prominently in the traditional Indian medicinal system of Ayurveda. Known as Ashwagandha in Ayurveda, Withania somnifera is a critical ingredient in various Ayurvedic tonics and tinctures prepared as a traditional remedy for the treatment of various ailments.
Recently identified as a potent adaptogenic and target for therapeutic applications, Ashwaghanda has been the subject of numerous animal, pre-clinical, and clinical trials designed to examine its potential effects as an antioxidant, anti-carcinogenic, anxiolytic, antibacterial, antifungal, and immonumodulating compound. Ashwaghanda’s broad therapeutic potential is hypothesized to be the result of its robust phytochemical profile, including a wide swath of alkaloids, sitoindosides, and the highly biologically active withanolide group. As the principally biologically active compounds within Ashwaghanda, withanolides such as withanone, withaferine A, withanolides A, D, and G have been identified, isolated, and extensively studied in the various applications noted above.
In recognition of the potential physiological benefits of withanolides, Core Nutritionals selected KSM-66® to include in its HARD formula. KSM-66® is a full-spectrum Ashwaghanda extract, standardized for 5% withanolides – meaning that KSM-66® not only includes the full range of biologically active compounds within Ashwaghanda, but also that it contains the highest currently available concentration of the principally active withanolides (5%).
The high concentrations of withanolides within KSM-66® has resulted in encouraging results in a number of human, clinical trials – particularly considering many of these trials were conducted using the methodological gold standard of randomization, double-blind delivery, and placebo control. Amongst the most impressive results contained in these trials:
A 27.9% reduction in serum cortisol levels, measured over 60 days in a trial featuring 64 chronically stressed adults.
Statistically significant increases to endurance and stamina, as measured by VO2 max, in a clinical trial featuring 50 healthy, exercise-trained adults.
Increased measures of well-being as reported by self-assessment scales, included in both the clinical trials mentioned above.
Statistically significant increases in serum testosterone levels in a clinical trial featuring 68 infertile men.
Though each of these results is impressive, perhaps the most significant is the 27.9% reduction in cortisol seen in the 60 day trial. As detailed above, cortisol possesses a multitude of potentially degradative physiological effects, including: inhibiting glucose uptake, causing a constriction of the vasculature (vasoconstriction), the breakdown of glycogen, and inarguably the result most would desire to avoid, proteolysis (the breakdown of muscle tissue).
To put it the simplest way possible, cortisol’s chief functions involve either turning on, or shutting off, the very things we as fitness enthusiasts want to avoid or turn on, respectively!
N-Coumaroyldopamine is a natural analogue to the phytochemical N-Caffeoyldopamine, itself found prominently in various plants, including cocoa (Theobroma cacao L.). N-Coumaroyldopamine, its parent compounds, and other analogs that derive from its parent compound, have recently been the subject of phytochemical analyses due to their chemical similarity to sympathomimetic amines known to couple to the beta-2-adrenergic receptor.
Phytochemical analyses were subsequently designed to assess the potency of N-Coumaroyldopamine and N-Caffeoyldopamine as beta-2-adrenergic receptor agonists – or, in simpler terms, their ability to "turn on” the fabled beta-2-adrenergic receptor. In these trials, the phytochemicals were shown to be as potent as several well-known beta-2-adrenergic receptor agonists (salbutamol, procaterol, and fenoterol). You read that correctly: N-Coumaroyldopamine and N-Caffeoyldopamine were found to bind as tightly to the beta-2-adrenergic receptor as well known synthetic compounds!
The desirability of activating the beta-2-adrenergic receptor arises due to the critical role that beta-2-adrenertic receptors play in both skeletal muscle and fat metabolic function. In particular, beta-2-adrenergic receptors have been shown to induce dilation in the vasculature (vasodilation – the process involved in a "pump”), increase oxygen uptake and nutrient transport to skeletal muscle, regulate thermogenesis (the production of body heat), inhibit the pro-adipogenic (fat constructing) effects of other adrenergic receptor types, as well as directly increase lipolysis and the oxidation of fatty acids – the literal burning of fat tissue.
Beta-2-adrenergic receptors achieve these effects via one of the body’s key chemical messengers, known as cAMP (cyclic adenosine monophosphate). cAMP works as a sort of cell-type translator and foreman: it receives an input from, say, a receptor such as the beta-2-adrenergic receptor, and then communicates and directs the types of cells that the beta-2-adrenergic receptor would like to target.
Just within the context of beta-2-adrenergic agonism, this amounts to cAMP increasing resting metabolic rate and caloric expenditure (the amount of calories you burn), improving peripheral sensitivity to glucose and glucose utilization, reduction of gluconeogenesis, induction of AMPk (adenosine monophosphate kinase) release, triggering of lipolysis (the literal burning of fat tissue we spoke about earlier), the inhibition of lipogenesis (the creation of fat tissue), and vasodilation.
Or, in other words, cAMP is involved in nearly every beneficial physiological process that a lifter, runner, hiker, jumper, runner, tumbler, and fumbler would want. cAMP is involved in:
Increasing bloodflow ("pump”).
Reducing muscle protein usage (catabolism).
Increasing muscle protein synthesis.
Increasing adipose utilization.
To say that cAMP is a desirable compound to increase the release of – which activating the beta-2-adrenergic receptor does – would qualify as the understatement of the year!
What we typically refer to as "Estrogen,” is in fact a group of three biologically distinct hormones – estradiol (E2), estrone (E1), and estriol (E3), each possessing different activities in different cell, tissue, and receptor types. When experts refer to either the benefits or downfalls of "estrogen," they really mean to (but probably cannot) identify a specific estrogen.
These specific estrogens, in turn, metabolize into even more specific estrogen sub-compounds, such as the 2-hydroxyestrogens (2-OHE’s), 2-methoxyestrogens, 16a-hydroxyestrone (16-OHE1), and 4-hydroxyestrogens (4-OHE’s). As their parent estrogens, these estrogen metabolites exert different effects depending upon the tissue and cell one is examining. In fact, two estrogen metabolites in particular, 16-OHE1 and 2-OHE, have such contrasting cellular activities that 2-OHE is an estrogen antagonist. Yes, that is correct: there is an anti-estrogen, estrogen.
In recent years, so-called "phytonutrients” have become the focus of clinical research, as these natural compounds have shown the ability to increase the ratio of good, estrogen decreasing estrogens (such as 2-OHE), to bad, estrogen increasing estrogens (such as 16-OHE1). One of these phytonutrients, a dietary indole known as indole-3-carbinol (I3C), is the bioactive phytochemical and a presumed modulator of reduced cancer risk in areas with high cruciferous vegetable consumption. Unfortunately, despite its potent antiestrogenic activity, I3C is highly molecularly unstable, and therefore unsuitable for use as a therapeutic agent or dietary supplement.
Luckily, however, I3C readily metabolizes into the secondary indole 3,3’ diindolylmethane, or DIM for short. When used in a supplemental fashion in clinical trials, DIM appears to possess all the positive effects of its parent compound with respect to antiestrogenic action – promoting the metabolism of beneficial estrogens that themselves reduce estrogenic activity.
Aside from its healthy-estrogen promoting abilities, DIM also exerts its own direct physiological effects, including:
Promoting pathways of internal estrogen metabolism that favour the production of anti-estrogen estrogens.
Adjusting the activity of certain cytochrome enzymes, reducing the activity at the estrogen receptor site.
Limit the cell division and growth of certain estrogens.
Despite the bodybuilding community’s single-minded crusade to eliminate estrogen wherever it lie in wait, compounds such as DIM show us that estrogen is a very diverse set of compounds – and that we should actively pursue increasing certain estrogens that have beneficial, and ironically, anti-estrogenic effects.
Though the literature surrounding L-theanine is still emerging, the amino acid is slowly building a reputation as one of the most interesting and exciting compounds being targeted for therapeutic use. L-theanine is an amino acid found almost exclusively in tea, constituting approximately 1-2% of the dry weight of tea – resulting in a 25–60 mg theanine load per 200 ml serving of liquid tea.
First identified in green tea and in the mushroom Xerocomus badius, L-theanine readily crosses the blood-brain barrier in a dose-dependent manner, and it is thought to in?uence the central nervous system (CNS) through a variety of mechanisms, including:
Increasing the release and concentration of dopamine.
Inhibiting glutamate reuptake and blockade of glutamate receptors in the hippocampus.
Increasing gamma-aminobutyric acid (GABA – a neurotransmitter associated with the regulation of responses) concentrations.
Increasing levels of serotonin.
In addition to these more well-demonstrated effects, emerging electroencephalography trials on theanine suggest that the amino acid may exert a positive effect on alpha waves – a type of brain wave implicated in restful relaxation. Alpha activity has also been associated with increased creativity, increased performance under stress, and improved learning and concentration, as well as decreased anxiety.
Serving Size: 3 Capsules
Servings Per Container: 28 (days)
Amount Per 3 Caps
Phosphatidyl Serine 50% 500mg †
Ashwagandha root extract (5% Withanolides) 600mg †
N-Coumaroyldopamine 40mg †
3,3'-Diindolylmethane (DIM) 200mg †
L-Theanine 300mg †
† Daily value not established.
* Percent values are based on 2,000 calorie diet.
Other Ingredients: Gelatin, Magnesium Stearate, Silicon Dioxide, FD&C Blue, Titanium Dioxide.
Directions: Take 1 capsule 2-3 times per day. For optimal results, take 1 capsule upon waking, 1 capsule midday, and 1 capsule before bed. Do not exceed 4 capsules in a 24 hour period. For best results, use for 4 to 8 weeks. Do not use for longer than 8 continuous weeks without taking a 4 week break.