Adrinall

WHAT IS IT?

Adrinall is a very comprehensive nootropic with an extended-release delivery system to keep you sharp and focused all day long.  With a beautiful combination of blends that support energy, neurotransmitter levels, adaptive responses, cellular energy, and absorption - Adrinall stands apart from the rest by being a nootropic that truly does it all.

WHY WOULD I TAKE IT?

Ever feel foggy while you’re at work or school?  Maybe you’re wondering why this coffee or those energy drinks aren’t quite doing the trick anymore?  Adrinall is for those looking to seek an edge whether it’s in the office, at school, or on the field.  If you think your memory could be a little sharper, if you want your mind more clear, or if you want to somehow increase your bandwidth - then you will be awaited by Adrinall.

HOW DOES THIS WORK?

Adrinall works through a complex route of overlapping metabolic pathways that ultimately improve the activity of the primary neurotransmitter of memory, Acetylcholine.  Additionally, Adrinall supports mood, energy levels, and an overall sense of well-being. For a more comprehensive breakdown see: (link to longer writeup) 

HOW MUCH SHOULD I TAKE?

The suggested use on the Adrinall bottle makes reference to three capsules daily.  This is best taken on an empty stomach, usually first-thing in the morning. However, for those of you that find that three capsules at once is a bit too intense, we suggest two capsules in the morning on an empty stomach, and then one more in the afternoon to sustain effects.  Please note, that due to the precise delivery route to the small intestine that up to 90 minutes of gastric transit time may be necessary before the capsule contents actually deploy.

Caffeine is arguably the “Gold-Standard” of nootropics

Caffeine is probably the most widely used psychoactive stimulant on planet earth today.  Initially, we humans fell in love with caffeine through tea and coffee that honestly dates back as far as 15,000 years ago in China and pre-dates any known writing systems.  That’s a lot of caffeine usage! But, even though we know that we like how caffeine makes us feel, what’s it really doing for us? There’s many ways to answer that question and we’ll go through everything from the qualitative to the quantitative.  

For starters, here’s a fun list of things that have been clinically associated with at least moderate caffeine use:1

Now that all sounds pretty good, right?  Not only does caffeine do all the above, but also stimulates fat lipolysis and resting energy expenditure.2 Caffeine, needless to say, might be the hero that fuels humanity to do more, to say more, and generally be better at it. 

But how? Why? ...and for those answers, let’s dive into the mechanism:

Caffeine, itself, it also known as 1,3,7-trimethylxanthine is an alkaloid that antagonizes the body’s adenosine receptors and this results in excitability!  Adenosine’s normal job in the body is to “suppress arousal” and “promote sleep”. This is pretty much why you feel tired in the evenings (along with some help from melatonin, etc.) and is also why you can’t go to sleep if you consume caffeine too late in the day….long story short: caffeine suppresses your body’s natural ability to feel tired.  Now these receptors for Adenosine, when blocked, inhibits another enzyme called phosphodiesterase (you may have heard of these enzymes before in viagra commercials when they reference PDE-5 inhibitors) which causes an increase in cyclic-Adenosine Monophosphate (cAMP: a signaling molecule and ATP precursor) resulting in an amplification of intracellular signaling molecules and energy levels.  But wait! That’s not all! This “adenosine receptor antagonism” also results in the subsequent release of the monoamine class of neurotransmitters (dopamine, serotonin, adrenaline, and norepinephrine) in addition to acetylcholine (which we also get to talk more about later). These monoamine neurotransmitters are simply the basis of what makes you feel good and controls your most basic instincts.  Here’s a lovely chart that describes what they do:  

Now let’s bring this back to Adrinall.  The amount of caffeine that you’ll actually find in a 3-capsule serving size is actually just under 225mgs.  If you made two really big strong cups of coffee, you’d probably land at a similar dosage, but we didn’t want this to be that simple.  So, we added a special form of caffeine. One that has a very convenient effect of actually lasting for a substantial duration of time, Caffeine SRTM.  Now Caffeine SRTM, though similar in effect to typical Caffeine Anhydrous, is different in duration.  Caffeine SRTM is actually a micro-encapsulated form of caffeine that does allow for some “quick burst” energy, but also has a delayed-release effect that can last up to 3 hours or more.  This decreases the likelihood of experiencing a typical “crash” once the caffeine has worn off, but instead creates a sustained period of enhanced energy levels allowing for more productivity throughout your day.  See the table below for a projected time scale of caffeine release from Caffeine SRTM.

Maximizing neurotransmitter production & abundance

The most prominent neurotransmitters that are affected by Adrinall are: dopamine, norepinephrine, and serotonin.  Now, Adrinall does this through several different pathways, first of dopamine and norepinephrine.  These two neurotransmitters are actually in a smaller subset known as the catecholamines, which aslo includes adrenaline.  Not only are the catecholamines similar in their structure, but also share similar precursors in the form of three amino acids: Phenylalanine, Tyrosine, and Dihydroxyphenylalanine (aka L-DOPA).  Now, when forming catecholamines from amino acids, there’s a few simple steps that differentiate them from being candidates for protein synthesis and turn eligible neurotransmitters - one of these steps is the hydroxylation of Phenylalanine at the “para” position to accomplish the transformation into Tyrosine, followed by a second hydroxylation at the “meta” position of Tyrosine to form L-DOPA.  It is from this final amino acid, L-DOPA, that all catecholamine neurotransmitters are formed.  Not only does the Caffeine in Adrinall help support the release of these “feel good” chemicals, but we also chose to add Mucuna pruriens extract because it is the most viable source of L-DOPA in the food supply.  Through the use of Mucuna pruriens, we’re able to provide a sufficient amount of L-DOPA to act as a neurotransmitter precursor to increase levels of Dopamine and Norepinephrine - this increases motivation, goal-oriented behavior, and reward-seeking through accomplishing tasks.  Not only are these amino acid precursors needed for the production of neurotransmitters, but also various b-vitamin coenzymes like Pyridoxal-5’-Phosphate (P5P - the active form of Vitamin B6) that help facilitate the “decarboxylation” process where an amino acid actually becomes a neurotransmitter.  Vitamin B12 also plays a minor role in this process as a methyltransferase coenzyme in the form of Methylcobalamin. Adrinall also supplies both P5P and Methylcobalamin, but also goes one step further to provide Sulbutiamine - a rare, fat-soluble form of Vitamin B1 that is able to cross the blood-brain barrier and has been shown to reduce fatigue.3  Furthermore, this effort to increase neurotransmitter levels is supported by Satiereal® - a specialty extract of Saffron.  Now Saffron is pretty interesting. Not only is it a really delicious & expensive spice to have in your kitchen, but it also has some clinical backing on being able to reduce snacking in mildly overweight healthy women4, but also has some activity on increasing dopamine production5.

In addition to increase neurotransmitter levels, we also focused on the neurotransmitter transporters responsible for their reuptake.  Though this step still includes the catecholamine family, but now expands to include the activity of Serotonin (right) into the monoamine family of neurotransmitters.  Serotonin actually governs a lot of things in the body from how sleepy you might feel, to how well your body generates heat, to how hungry you might feel. The actual domain that Serotonin has to deal with the central unifying factor of: resource availability, scarcity, and abundance6.  Now when you combine the former and the latter concepts just mentioned - it starts to make a lot more sense as to how those two factors combine to regulate mood.  If you’re hungry and there’s no food around - ya might start to get depressed, conversely, if you’re full and there’s an abundance of food - you might be pretty satisfied.  Serotonin is definitely somewhat of a “feel good” neurotransmitter, especially when it is in abundant in the CNS. Most typical antidepressants take advantage of the serotonergic systems and either have some sort of binding affinity to the many serotonin receptors or have some sort of impact on the serotonin transporter proteins.  Usually, the most common mechanism for increasing Serotonin levels is to prevent their uptake via a “Selective Serotonin Reuptake Inhibitor” or SSRI. It’s these compounds that will bind the Serotonin transporters in a competitive fashion to inhibit their reuptake into the presynaptic cell, which leaves an abundance of serotonin in the synaptic cleft where it can actually bind to its receptors.  

So what does Adrinall do to accomplish this same task?  

In the regions of South Africa, as far back as 16627, there has been documented evidence of the consumption of a specific herb that is claimed to cause transient euphoria, mood elevation, reductions in anxiety, and acts as a mild appetite suppressant - Sceletium tortuosum aka Kanna8.  The most well-studied form of Kanna is a specialty extract called Zembrin®.  In fact, during a study that was assessing the safety and tolerability of a few dosages, two notable effects occurred: 1) when it came to adverse event reports (AER’s) there were cases of headache, abdominal pain, and upper respiratory tract complaints - these reports occurred at the highest frequency...IN THE PLACEBO GROUP 2) then there were several cases of unsolicited positive effects on well-being logged in patient diaries of some patients in the Zembrin® groups including better sleep and improved coping with stress9.  Another detail behind the actual mechanisms of Zembrin® was discovered later that same year when not only was the activity on the Serotonin (5-HT) transporter confirmed, but PDE4 (remember those phosphodiesterase enzymes from the Caffeine segment?) inhibition also occurred.  This combination of 5-HT reuptake and PDE4 inhibition was believed to be a synergistic effect in attenuating what’s called “subcortical threat responsivity”10.  In a clinical setting, anxiety is actually measured either through activity in the amygdala - where threats are detected and then subsequent promotion of defensive responses through the subcortical threat circuit which includes the hypothalamus, midbrain, and brainstem11.  Anxiety at its root is based on sensing of threats, fear, and dangerous situations - and through Serotonin reuptake and PDE4 inhibition, we can find some respite from the scary outside world, which is why Zembrin® is such an important factor in Adrinall.  It keeps you focused on the things that matter most.

Cholines, Acetylcholine, and the neurotransmitter of Memory

Choline, itself, is an essential nutrient for proper functioning in the body.  As a precursor to the neurotransmitter, Acetylcholine, Choline plays a vital role in the communication between the central nervous system (CNS) and other various parts of the body including muscle tissue, multiple glands, and other neurons12.  In Adrinall, we provide several different Choline derivatives such as Choline Bitartarate, Alpha-GPC, CDP-choline, and Phosphatidylcholine in the form of our own blend termed “CholinaceTM”.  It is the mission of CholinaceTM to act as Acetylcholine precursors to further support proper functioning of the mind-muscle connection in the peripheral nervous system (PNS) and to support memory formation and retrieval in the CNS.  In a clinical setting, just with Choline Bitartarate alone, pupil size (a cognition-sensitive biomarker) significantly

decreased after choline intake and correlated positively with the hit distance to the targets and

the number of target misses, and negatively with reaction times.  The changes in pupil size suggest that choline uptake alters cholinergic functions in the nervous system13.  Alpha-Glycerylphosphorylcholine (Alpha-GPC) is another Acetylcholine precursor that also crosses the blood-brain barrier and seems to be one of the most efficacious precursors to Acetylcholine synthesis14.  

Cytidine 5’-Diphosphocholine (CDP-Choline) though not quite as efficacious at increasing Acetylcholine as Alpha-GPC, also can cross the blood-brain barrier - but also has its own set of mechanisms seemingly independent of its activity as an Acetylcholine precursor.  CDP-Choline is an essential intermediate in the synthesis of phospholipids and has been experimentally shown to increase norepinephrine and dopamine levels in the CNS16.  Additionally, we also provide Phosphatidylcholine derived from Sunflower Lecithin, thus providing four total sources of acetylcholine precursors.  It is this combination of four cholinergic sources, that we’ve coined as Cholinace™. 

Helping the Brain Adapt with Adaptogens

Adrinall’s Neuro-Adaptogen Matrix covers quite a spectrum of desirable effects that result from the combination of Lion’s Mane Mushroom, Bacopa monnieri, Green Tea Extract, Rhodiola crenulata, Black Pepper, and the Madagascar Periwinkle. 

Lion’s Mane Mushroom, (Hericium erinaceus) is perhaps most known for its two main principal components: Hericinones - responsible for the in vitro stimulation of nerve growth factor (NGF)17 and Erinacines - also responsible for in vitro stimulation of nerve growth factor18 and acts as a kappa opioid receptor agonist19.  It is through these mechanisms that Lion’s Mane Mushroom is considered a neurotrophic due to its ability to increase NGF, but not particularly a neuroprotective agent20.  The activity of Lion’s Mane suggests that it plays more of  a role in regeneration of damaged neurons, even in the peripheral nervous system (PNS) and does so through modulating the activation of cAMP response element-binding (CREB), which also plays a substantial role in what’s known as long-term potentiation in the hippocampus - a very memory-centric mechanism in a very memory-centric portion of the brain21.

Bacopa monneiri (Brahmi) is an ayurvedic plant that originates from India.  The name “Brahmi” itself, comes from the word “Brahma”, the mythical ‘creator’ in the Hindu pantheon.  Because the brain is the centre for creative activity, any compound that improves brain health is called “Brahmi”, which also means ‘bringing knowledge of the supreme reality’22, which is pretty cool.  Where Brahmi/Bacopa goes further is through is through the activity of Bacoside A, a compound that has been suggested to enhance protein kinase activity in the hippocampus which may also contribute to its nootropic action and thus it would aid in the repair of damaged neurons by enhancing kinase activity, neuronal synthesis and restoration of synaptic activity and ultimately nerve impulse transmission23.  Now Bacopa is an interesting adaptogen in the sense that in the acute phase of supplementation, there doesn’t seem to be any perceivable effects.   However, after 12-weeks of supplementation, an interesting phenomenon appeared when subjects noticed a “lack of forgetting” new information acquired during the trial24, 25.  

Green Tea Extract (GTE) gets much of its protective effects from the primary antioxidant compound (-)-epigallocatechin gallate (EGCG)26, which is able to cross the blood-brain barrier27 and protect against ᵝ-amyloid-induced oxidative cell death28.  The ability for EGCG to cross the blood-brain barrier makes GTE a very attractive neuroprotective agent and antioxidant specific to the central nervous system.  Though an attractive mechanism, a clinical study in subjects with mild cognitive impairment showed significant improvements in cognitive functioning at 8-weeks supplementation, but even furthermore improvements in correct word count reading after 16-weeks supplementation - indicating that semi-chronic use of GTE needed to actually obtain significant results29.

The Madagascar Periwinkle (Vinca minor), is host to over 50 different types of alkaloids30, one in particular, Vincamine & its esterified derivative Vinpocetine, are able to cross the blood-brain barrier where it can exhibit its neuroprotective effects31.  Probably the two most notable targets of these Vinca alkaloids are phosphodiesterase 1 (remember these PDEs from earlier?) as well as the blocking of voltage-dependent sodium channels32.  This blocking for the sodium channels combined with activity on PDE results in vasodilation for the CNS, which not only enhances oxygen delivery, but increases cellular metabolism33.

Though Vinca alkaloids can have an improvement on oxygen delivery to CNS tissues, we also help prepare the CNS for less than optimal oxygen conditions through the use of a special form of Rhodiola called Rhodiola crenulata.  Now, Rhodiola crenulata though sharing some of the same active compounds, is distinctly different from the more common Rhodiola rosea.  R. crenulata actually grows at a higher altitude than its rosea cousin, and because of this - is thought to provide some benefits for those either in high-altitude or in low-oxygen conditions.  To investigate this potential application, subjects were placed in a hypobaric chamber to simulate an altitude of 4300m and then tasked to perform an incremental exercise on a cycle ergometer until exhaustion.  Supplementation with Rhodiola crenulata resulted in an approximately 13% increase in time to exhaustion34.  The mechanism behind this increase in endurance was then investigated in vitro to see if the active components of Rhodiola crentulata would have on Hypoxia Inducible Factor (HIF-1ɑ).  It was then shown that only two compounds, salidroside & tyrosol, had a significant effect on increasing HIF-1ɑ expression35.

Adrinall’s Neuro-Adaptogen Matrix is based off checking boxes in 5 distinct areas of cognitive enhancement: increasing NGF and potential neuron growth through use of Lion’s Mane Mushroom; increasing neuronal repair via Bacopa monnieri; improving neuroprotection by providing brain-specific antioxidants through Green Tea Extract, increasing cerebral blood flow and oxygen delivery with Vinca alkaloids, and then finally enabling adaptive responses even when oxygen is in low supply from HIF-1ɑ activation from Rhodiola crenulata.

Energy that is REAL vs. Energy you FEEL

What many people do not understand is that often times, they’ll confuse a rush of neurotransmitter activity that makes them feel good for “energy”.  This isn’t actual energy in the terms of our bodies, but having elevated levels of neurotransmitters might make them feel energetic, but not actually have the cellular energy to back that up.  REAL energy is something that is actually more tangible than this “feeling of energy” that so many people get from stimulants or neurotransmitter boosters.  However, with Adrinall - we actually wanted the best of both worlds.

REAL energy inside the body is found from carbohydrate and fat metabolism and results in the formation of adenosine triphosphate or ATP.  ATP is pretty much the “electricity” that the human body runs on, which is fueled by the body’s ability to obtain Phosphorus, and ultimately at the smallest level the exchange electrons between a whole host of various molecules.  This begins to paint a very “mitochondiro-centric” point-of-view of where energy is actually produced and larger macronutrients are broken down. With Adrinall, we’ve chosen to opt for a two-pronged approach to facilitating oxidative phosphorylation, and proper electron transport, through the use of Creatine (a known phosphagen) and CoEnzyme Q10, an antioxidant and electron carrier in the electron transport chain.

The REAL difference is in the Absorption System

Most common nootropics in the market today, should showcase a lot of the features found in Adrinall, but what most fail to do is get those active ingredients to reach sufficient levels in the blood.  Now typically, you would probably see a formulation like this but be delivered in a standard gelatin capsule, which subjects the previously mentioned active ingredients to substantial damage and degradation in the harsh pH-environment of the stomach.  This means that you aren’t getting 100% absorption, and in fact, you’re probably getting significantly less. With Adrinall, we’ve come up with two separate ways of maximizing the bioavailability of these natural compounds: 1) by utilizing a capsule technology that bypasses digestion in the stomach with targeted delivery to the small intestine and 2) using enzyme inhibitors that minimize potential breakdown in the liver, so absorption is as complete as possible.

Black pepper has been used in foods as far back as 2,000 BCE.  It’s almost in our DNA at this point to add a little black pepper on our mashed potatoes or our scrambled eggs, but the cool thing about black pepper is that it is a well known absorption-enhancer36.  Now, usually black pepper accomplishes this task through one of its primary alkaloids, piperine.  Piperine provides a substantial benefit for anything delivered orally, as it inhibits P-glycoprotein and Cytochrome P450 3A4 (CYP3A4), which are located in the stomach lining and in the liver37.  The role of CYP3A4 and P-glycoprotein is particularly involved in the identification and elimination of foreign substances, but through the inhibition of CYP3A4 - like with piperine - absorption of accompanying compounds can be enhanced.  Secondly, this same alkaloid piperine can actually also cross the blood-brain barrier where it can still enhance absorption, but also inhibits the monoamine destroying enzyme MAO(monoamine oxidase)38.  Inhibition of MAO can result in increases neurotransmitter levels, such as dopamine, norepinephrine, and serotonin. Through piperine’s 2-part mechanism, both on CYP3A4 and MAO we’re not only able to increase absorption of all of our ingredients in Adrinall, but also increase neurotransmitter levels even further through the inhibition of MAO.

Secondly, to avoid any potential damage or deterioration to the ingredients found in Adrinall, we’ve encased the whole formulation in a hypromellose capsule known as DRcaps™.  Being that DRcaps™ are made from hypromellose, this material is very resistant to breakdown in the acidic environment of the stomach - and thus protects its contents.  This can be visualized in the graphic (right) of DRcaps™ traversing the stomach, as evidenced by Gamma Scintigraphy. When these hypromellose capsules arrive at the small intestine, they can actually act as a prebiotic - this is due to the fact that many of the symbiotic bacteria of the gastrointestinal tract can actually metabolize the hypromellose in a more pH-neutral environment.  Once they are able to penetrate the DRcaps™, the payload inside deploys directly into the small intestine. This mechanism is also further evidenced by other preliminary work that assessed the dissolution of DRcaps™ in an in vitro stomach model.  When compared to normal vegetarian (cellulose) capsules, DRcaps™ released their contents over a time-span ranging from as little as 60 minutes and lasting over 420 minutes (7-hours!) as seen in the graphic on the left39.  Now the only catch noted with these capsules and this delivery system was the fact that - better absorption will always be achieved in a fasted state, as co-consumption with food can further complicate the pH-environment, as well as promoting activity of potential symbiotic bacteria of the stomach, itself.  So, when consuming Adrinall, it is always better to take it on an empty stomach.

Needless to say, we’ve put a lot of work into Adrinall.  We’ve made absolutely certain that you’re well energized - all day long.  That you’ve got enough Acetylcholine to make memories for a lifetime, and have awesome neuromuscular control while you’re at it.  We’ve included some adaptogens that protect, promote growth and repair, assist in oxygen utilization, and well - help you adapt to potential stressors as well. Then on top of it all, we’ve put together a combinatory enhanced-absorption system that delivers all these crucial ingredients in an efficacious manner, and then does it - all day long.

References:

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