Potent psychoactive and neuroactive chemicals that play key roles in modulating receptor sites, synaptic enzymes, membrane structures, cerebral perfusion, biogenic processes, neuroendocrine regulation and more.

Saffron Extract (Crocus sativus)

SAFFRON COMMON NAME

Saffron | Saffron Crocus

TOP BENEFITS OF SAFFRON

• Supports mood*
• Supports cognitive function*
• Supports vision*
• Supports sports performance*

WHAT IS SAFFRON?

Saffron is a spice derived from the flowers of Crocus sativus. It’s been used and traded as a spice for at least 4000 years and is considered the world's most costly spice by weight. Iran produces the majority of saffron: Greece, Kashmir, Morocco, Spain and Turkey are also fairly large growers. Saffron, as a spice, refers to the deep red-maroon colored stigma and styles (called threads). Not all saffron is of the same quality and strength, with price increasing substantially for the highest grades. In general, content of several of saffron’s active compounds are used to determine strength. A greater content of crocin (responsible for saffron's color), picrocrocin (a bitter compound giving the characteristic taste), and safranal (which gives the fragrance) would be graded as higher strength. In addition to these marker compounds, saffron also contains zeaxanthin, lycopene, and other carotenoids. Crocin also belongs to the carotenoid family. Most carotenoids only dissolve in oil (i.e., are fat-soluble). Crocin is water-soluble, which is part of the reason it is used in rice dishes and other water-based food recipes. There’s been a growing interest in the use of saffron for health purposes, including in areas such as mood, cognition, vision, sports performance, appetite regulation, metabolic function, and women’s health.

NEUROHACKER’S SAFFRON SOURCING

There's a long history of saffron adulteration. Because of this, Neurohacker feels its critical to use a standardized saffron extract purchased from an ingredient supplier that can authenticate quality and strength.

The saffron extract we use has been clinically studied, is DNA authenticated, and has a patented profile for marker compounds including crocin, picrocrocin and safranal.

Saffron extract used in our products is GRAS, non-GMO, gluten-free, vegan, Kosher certified and Halal compliant. 

SAFFRON DOSING PRINCIPLES AND RATIONALE

Most saffron studies have used standardized extracts, with doses typically in the range of 20-30 mg per day. While a few studies have used 60 mg, in general, we consider 30 mg to be at the top end of what’s needed when using saffron extracts for specific clinical reasons. Since studies comparing multiple doses have not been published, there’s no information of whether saffron has a threshold effect (i.e., an amount or range less than the full dose where the majority of the response would occur; see Neurohacker Dosing Principles). However, individual (i.e. N of 1) subjective response to saffron does vary considerably, with some persons reporting noticeable differences when taking as little as 1-3 mg of a standardized saffron extract. Depending on the purpose Neurohacker is using saffron for, and the other ingredients it’s combined with, it might be dosed anywhere ranging from a more micro-dose level up (3 mg) up to a studied dose of 30 mg per day. 

SAFFRON KEY MECHANISMS

Cognitive function and Mood

• Supports mood [1–6]
• Protects against cognitive impairment [7–9]
• Promotes focus and attention [10]

Exercise performance

• Enhances reaction times [11]
• Supports muscle strength [11]
• Helps to protect against muscle soreness [12]

Vision

• Supports visual acuity [13,14]
• Protects retinal cells against light-induced damage [15–18]
• Protects retinal cells against damage and degeneration [14,18–22]
• Supports healthy intraocular pressure [23]
• Enhances retinal function [24]

Brain function

• Upregulates brain dopamine levels [25,26]
• Upregulates brain glutamate levels [25]
• Regulates acetylcholinesterase activity [26]
• Upregulates brain-derived neurotrophic factor (BDNF) levels [27,28]

Neuroprotection

• Protects neurons from neurotoxic agents [19,26,29–31]
• Protects against the accumulation of toxic compounds in the brain [32]

Antioxidant defenses

• Upregulates the levels of antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase [GPx]) [22,26,31]
• Replenishes glutathione (GSH) levels [22,26]
• Downregulates reactive oxygen species (ROS) levels and oxidative stress [21,22,26,31]
• Promotes healthy prooxidant-antioxidant balance [33]

Mitochondrial function

• Supports the activity of mitochondrial enzymes [26]
• Upregulates mitochondrial membrane potential [21]

Metabolic function

• Supports cytokine balance [34]
• Supports appetite regulation [35]
• Supports healthy lipid levels and blood pressure regulation [36,37]

References

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Anhydrous Caffeine

Scientific Name:
1,3,7-trimethylxanthine

Uridine Monophosphate

Scientific Name:
Uridine Monophosphate, (UMP)

Cocoa Seed Extract

Cocoa Extract Common Name

Cocoa | Cocoa Bean | Cacao | Chocolate 

Top Benefits of Cocoa Extract

• Supports healthy aging*
• Supports exercise performance*
• Supports brain function*
• Supports visual acuity*
• Supports mitochondrial structure, function, and biogenesis* 
• Supports muscle structure and function* 
• Supports antioxidant defenses* 
• Supports healthy metabolic pathways* 
• Supports healthy gut microbiota*
• Supports cardiovascular function and circulation* 

What is Cocoa Extract?

Theobroma cacao has been cultivated in central and south America for at least 3,000 years. The name Theobroma cacao can be translated as chocolate, food of the gods. This tree is native to the tropical regions of the Americas. The seeds (sometimes referred to as beans) are enclosed in a pod or husk. They  are the source of the cocoa used to make chocolate. Chocolate, especially dark chocolate, has a blossoming reputation as being heart healthy. This is because of the cocoa content. Cocoa has been reported to support many health-promoting and energy-enhancing actions ranging from improving mitochondrial structure and function to enhancing cognitive performance and vision. Cocoa is one of the biggest dietary sources for polyphenol compounds, a category of plant-derived molecules that are increasingly being shown to support healthy aging. It is an especially great food source of (‐)‐epicatechin, a unique flavanol polyphenol. Cocoa is also a rich source of a bitter compound called theobromine. This compound is a weaker cousin of sorts to caffeine, influencing similar brain processes but not quite as strongly. Cocoa flavanols, especially (‐)‐epicatechin, and theobromine can cross the blood brain barrier, supporting brain performance and vision. The synergy between the cocoa flavanol and theobromine content is responsible for cocoa’s ability to support such a wide range of health processes.*

Neurohacker’s Cocoa Extract Sourcing

In general, cocoa flavanol content varies widely, because many flavanols are degraded when cocoa is processed. The result is that, although in theory cocoa-containing products should be a great source of flavanols, in practice many are not. When selecting a cocoa extract it’s important to choose a source that retains high amounts of the cocoa flavanols.

Neurohacker uses ACTICOA® cocoa created by Barry Callebaut. After years of research, and through controlled sourcing and processing, they found a way to retain high amounts of the naturally occurring flavanols found in cocoa beans.

ACTICOA® cocoa is at least 7.5% cocoa flavanols. It also contains about 2% theobromine.

ACTICOA® is non-GMO, gluten-free, and vegan.

Cocoa Extract Dosing Principles and Rationale

When deciding on a dose of a cocoa extract we think it’s important to consider the amount of cocoa flavanols and theobromine. Flavanols are a sub-group of polyphenols, and are one of the main class of active compounds in cocoa bean extracts and powders. Some polyphenols appear to produce threshold responses, while others produce biphasic responses. In either case, above a certain range, more is not better. In addition to flavanols cocoa contains a bitter alkaloid compound called theobromine. Although theobromine is a weaker cousin of sorts to caffeine, it can cause some of the same issues if consumed in excess. So, similar to caffeine we think of theobromine as having a hormetic range (i.e., a dosing range above which results could be poorer). We have selected to dose cocoa extract at an amount of theobromine that is well below the threshold amount, but sourced a cocoa extract that retains high amounts of the naturally occurring flavanols. With both of these compounds we think it’s important to generally follow hormetic dosing principles (see Neurohacker Dosing Principles). *

Cocoa Extract Key Mechanisms 

Mitochondrial biogenesis

• Upregulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) ^1–6
• Upregulates cAMP-PKA-CREB signaling ⁷
• Upregulates nuclear transcription factors of mitochondrial biogenesis (mitochondrial transcription factor A [TFAM]) ^2,5,6,8–10
• Promotes healthy nitric oxide (NO) pathway function ^1,8,10

Mitochondrial structure

• Promotes inner mitochondrial membrane folding (cristae density) ^1,2,8
• Upregulates mitochondrial membrane protein compounds (porin, mitofilin) ^1,5,6,8,10
• Upregulates mitochondrial size/density/number ^1,11

Mitochondrial function

• Supports electron transport chain and oxidative phosphorylation performance (mitochondrial complex I-V performance) ^{1,2,5,8–10,12–14}
• Supports mitochondrial β-oxidation performance ¹¹
• Supports citric acid cycle function via upregulation of citrate synthase ^{3,5,8–10,13}

Exercise performance (ergogenic effects)

• Supports endurance performance ^{3,8,9,13,15,16}
• Supports post-exercise recovery ^17–19
• Supports muscle structure and function ^8,16,20,21
• Promotes muscle angiogenesis/vascularity/capillarity ^2,8,9,13
• Upregulates muscle carbohydrate metabolism ²²
• Supports antioxidant capacity during exercise ²³

Antioxidant defenses

• Upregulates antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], thioredoxin [TRX]) ^4,5,21
• Replenishes glutathione (GSH) levels ^{3–5,14,21,24}
• Supports a healthy mitochondrial redox status ^3,5

Cardiovascular function

• Supports healthy blood flow (endothelial function and endothelium/NO-dependent vasodilation)^25–29
• Supports healthy blood pressure ^{25–27,30–33}
• Supports healthy cholesterol levels ^25,26,34,35
• Supports healthy insulin sensitivity ^{25–27,30–32,36}

Brain function

• Supports cognitive performance ^7,31,37–45
• Supports exercise-induced executive function improvements ⁴⁶
• Promotes motor activity ⁴³
• Promotes cerebral blood flow,^41,47,48 cerebral oxygenation,⁴⁹ and angiogenesis in the hippocampus ⁴⁵
• Cerebral antioxidant ³⁷
• Central nervous system stimulant (theobromine) ⁵⁰
• Adenosine receptor antagonist (theobromine);⁵⁰  regulates neurotransmitters modulated by adenosine – noradrenaline, dopamine, serotonin, acetylcholine, glutamate, and GABA ⁴³
• Phosphodiesterase (PDE) inhibitor (theobromine) — upregulates intracellular cAMP ⁷(long-term potentiation support)
• Upregulates BDNF signaling ^7,51 (neurogenesis support) 

Gut microbiota

• Regulates the composition of the gut microbiota ^52–55
• Regulates gut microbial metabolism ^54,56 

Healthy aging and longevity  

• Increases lifespan (rats, diabetic mice, Drosophila melanogaster, Caenorhabditis elegans) ^41,42,57
• Upregulates the NAD+ Pool ⁵⁸
• Upregulates insulin-like growth factor-1 (IGF-1) signaling ^21,57
• Upregulates SIRT1 ^1,4–6,58
• Upregulates SIRT3 ^4–6
• Promotes resistance to oxidative stress ⁵⁷
• Supports mild mitochondrial uncoupling (UCP1 increase) ^6,11
• Upregulates signaling pathways: AMP-Activated Protein Kinase (AMPK),^3,21 liver kinase B1 (LKB1, also known as serine/threonine kinase 11 [STK11]),³ p38 mitogen-activated protein kinases (p38 MAPK) ²

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Phosphatidylserine

Scientific Name:
Phosphatidylserine, (PS)

Coffeeberry® (caffeine)

Scientific Name:
1,3,7-trimethylpurine-2,6-dione

COFFEEBERRY® COMMON NAME

Coffee Fruit | Coffee Cherry | Coffee Berry

TOP BENEFITS OF COFFEEBERRY®

• Supports cognitive performance*
• Supports exercise performance*
• Supports mood*

WHAT IS COFFEEBERRY®?

Coffeeberry® is made from organic coffee fruits, which are often called coffee cherries. Like cherries, coffee plants produce soft red fruits surrounding a pit or hard seed. The seed (or coffee “bean”) is roasted to make coffee. But it’s the fruit that is being used to make Coffeeberry®. Similar to many fruits, coffee cherries are high in polyphenols. And like coffee beans, they also contain caffeine. There are more than 120 Coffea species. The most popular species is Coffea arabica (commonly known simply as "Arabica"). Coffeeberry® is from Arabica coffee plants grown on sustainable farms. The fruits are handpicked when they are ripe. The caffeine we get in a morning coffee, a cup of tea, or an energy drink can help us perform better physically and mentally.* It does this by promoting arousal (wakefulness), which is a necessary ingredient for being able to pay attention and react quickly. Not surprisingly, this has led to caffeine being one of the most widely used and studied substances for both sports performance and brain function. While caffeine gets most of the attention, coffee polyphenols support healthy function. Most nootropics use pure caffeine; a better approach is using a coffee extract that gives caffeine and the naturally occurring coffee fruit polyphenols. 

NEUROHACKER’S COFFEEBERRY® SOURCING

Coffeeberry® organic whole coffee fruit extract is produced by Futureceuticals, a leader in fruit and vegetable extracts. 

Futureceuticals calls this ingredient CoffeeBerry® Energy, because it contains a minimum of 70% caffeine, along with polyphenols from coffee cherries. 

Made from carefully selected, hand-picked, premium Arabica coffee cherries. 

Sustainably sourced from farms certified Fairtrade International & Rainforest Alliance.

Coffeeberry® is GRAS, Non-GMO Project Verified, gluten-free, vegan, Kosher, organic, and eco-friendly. 

COFFEEBERRY® DOSING PRINCIPLES AND RATIONALE

Because of its content of caffeine, we consider Coffeeberry® Energy to follow hormetic dosing principles (see Neurohacker Dosing Principles) and to have a hormetic range (i.e., a dosing range below and above which results would be poorer). Caffeine is one of the most used, and best studied nootropic and ergogenic compounds. When used as a nootropic (i.e., to promote alertness, focus, reaction time, etc.) caffeine is typically dosed from 50 to 200 mg. When used as an ergogenic (i.e., for sports performance) just prior to exercise the upper end of the dose range can be as high as 600 mg.[1] In both of these cases, responses to caffeine tend to follow an adaptational (i.e., hormetic) curve, with low-to-moderate doses of caffeine supporting better cognitive and sports performance, but doses above the higher end of the range hindering performance. We have selected to dose Coffeeberry® at an amount that delivers the amount of caffeine (~90 mg) found in a small cup of coffee. This is in the middle of the range for nootropic purposes and on the lower end of what’s used for ergogenic purposes.

COFFEEBERRY® KEY MECHANISMS

Brain function

• Adenosine receptor antagonist [2]
• Adenosine decreases the levels of the neurotransmitters acetylcholine, glutamate, serotonin, dopamine and norepinephrine; blocking adenosine receptors, caffeine counters those effects [3,4]
• Upregulates acetylcholine signaling [4–7]
• Upregulates dopamine signaling [4,8–13]
• Upregulates serotonin signaling [4,7,14–17]
• Upregulates glutamate signaling [4,8,9]
• Upregulates GABA signaling [4,7]
• Upregulates noradrenaline signaling [4,16]
• Upregulates cortical activation in the brain [2,4]
• Upregulates cerebral metabolism [2,4]
• Promotes wakefulness [18]

Cognitive function

• Supports cognitive performance [1,4,19–22]
• Supports executive function [23–25]
• Supports information processing rate [2,26,27]
• Supports simple and sustained attention [1,23,27,28]
• Supports vigilance [1,28]
• Supports task switching [27]
• Supports reaction time [1,21,22,27]
• Supports reasoning [20]
• Supports creative thinking [24]
• Protects from mental fatigue [26,28]

Neuroprotection

• Protects against neurotoxic agents [29]
• Protects from neurodegenerative processes [30]

Mood

• Improves mood [4,21,22,25,31]

Physical performance

• Protects from physical fatigue [19,22,23,32]
• Decreases perceived exhaustion [1]
• Supports muscle endurance and strength exercise activities [1]
• Enhances speed, power, and agility during intense exercise [1] 

Other effects

• Upregulates the metabolic rate [33–35]
• Non-selective phosphodiesterase inhibitor [36]

Synergies

• Theobromine as a CNS stimulant, with faster onset and shorter duration than Theobromine [37]
• L-Theanine in cognitive performance [26,38–40]
• Choline donors (e.g., citicoline, alpha-GPC) to support attention, concentration, and working memory [41]
• L-ornithine to support enhanced mood and cognitive performance [42]

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[42]A. Misaizu, T. Kokubo, K. Tazumi, M. Kanayama, Y. Miura, Prev Nutr Food Sci 19 (2014) 367–372.

Phenylethylamine HCL

Scientific Name:
Phenylethylamine, (PEA)

NooLVL™

NooLVL^TM COMMON NAME

Inositol-enhanced Bonded Arginine Silicate

TOP BENEFITS OF nooLVL^TM

• Enhances processing speed and accuracy*
• Supports executive function*
• Boosts energy*
• Promotes muscle performance*

WHAT IS nooLVL^TM?

nooLVL^TM is comprised of two components: Bonded (inositol-stabilized) arginine silicate (Nitrosigine®) plus additional inositol. L-arginine has relatively low bioavailability (~20%) following an oral dose, so high doses are needed to significantly boost blood arginine levels.[1] Nitrosigine® and nooLVL^TM have overcome this limitation by bonding the L-arginine to a silicate–inositol complex, which significantly enhances the bioavailability of L-arginine.[2–5] L-arginine is involved in promoting healthy circulation because it can be used for nitric oxide production. Blood flow to metabolically active tissues, like the brain and muscles, plays a big role in allowing these tissues to perform their functions at a high level. Bonded arginine silicate supports exercise performance and post-exercise recovery by promoting muscle blood flow.[6] It also supports brain performance, enhancing mental accuracy, focus, processing speed, and executive function.[5,7,8]

NEUROHACKER’S nooLVL^TM SOURCING

nooLVL^TM has been clinically studied in humans: It has boosted cognitive performance and energy in eSports athletes.

nooLVL^TM is an upgraded version of Nitrosigine®, an ingredient that supports blood arginine levels and nitric oxide production, enhanced energy, promoted focus and mental acuity, and supported better muscle response following exercise. 

nooLVL^TM is a patented nutritional ingredient from Nutrition 21: It contains Nitrosigine® (l-arginine bonded to silica and inositol with affirmed GRAS) plus added inositol. 

nooLVL^TM is gluten-free, vegan, and non-GMO.

nooLVL^TM is a trademark of Nutrition 21, LLC.

nooLVL^TM DOSING PRINCIPLES AND RATIONALE

Studied dose of nooLVL^TM has been 1600 mg/day: Nitrosigine® has been 1500 mg/day. Since these are the highest doses that have been given in human research, we consider them to be the upper limit we’d be comfortable with for daily dosing. Since it’s possible that the product this is included in might be used more than once a day (i.e., a person could opt to take two servings), we included a half dose per serving (i.e., 800 mg of nooLVL^TM). In Neurohacker’s subjective and objective internal N of 1 testing, the half dose of nooLVL^TM had additive effects when combined with other nootropic ingredients.*

nooLVL^TM KEY MECHANISMS

Vascular function

• L-arginine is the substrate for vascular nitric oxide (NO) production by NO synthase (NOS) [9]
• Upregulates endothelial NOS (eNOS) [silicate] [10]
• Upregulates the blood levels of arginine, silicon, and NO [4]
• Supports healthy vascular function [2]
• Supports healthy blood pressure [arginine] [11] [inositol] [12,13]

Brain function

• Upregulates dopamine release [14–16].
• Regulates dopamine transporter (DAT) activity [17–20]. 
• Supports neurotransmitter signaling [inositol] [21]

Cognitive function

• Supports performance in complex cognitive tests requiring mental flexibility, processing speed and executive functioning [7]

Exercise performance (ergogenic effects)

• Supports exercise performance [arginine] [22]
• Delays time to exhaustion [arginine] [22]
• Delays muscle fatigue [arginine] [23]
• Supports muscle blood flow after exercise [6]
• Protects from muscle damage after exercise and during recovery [6]

REFERENCES

[1]O. Tangphao, M. Grossmann, S. Chalon, B.B. Hoffman, T.F. Blaschke, Br. J. Clin. Pharmacol. 47 (1999) 261–266.
[2]S.D. Proctor, S.E. Kelly, J.C. Russell, Diabetologia 48 (2005) 1925–1932.
[3]S.D. Proctor, S.E. Kelly, D.F. Vine, J.C. Russell, Metabolism 56 (2007) 1318–1325.
[4]D.S. Kalman, S. Feldman, A. Samson, D.R. Krieger, Clin. Pharmacol. 7 (2015) 103–109.
[5]J. Komorowski, S.P. Ojalvo, The FASEB Journal 30 (2016) 690.17–690.17.
[6]S. Rood-Ojalvo, D. Sandler, E. Veledar, J. Komorowski, J. Int. Soc. Sports Nutr. 12 (2015) P14.
[7]D. Kalman, P.D. Harvey, S. Perez Ojalvo, J. Komorowski, Nutrients 8 (2016).
[8]S. Sylla, S.P. Ojalvo, J. Komorowski, The FASEB Journal 32 (2018) 724.12–724.12.
[9]N.W. Rajapakse, D.L. Mattson, Clin. Exp. Pharmacol. Physiol. 36 (2009) 249–255.
[10]B. Buffoli, E. Foglio, E. Borsani, C. Exley, R. Rezzani, L.F. Rodella, Acta Histochem. 115 (2013) 418–424.
[11]J.-Y. Dong, L.-Q. Qin, Z. Zhang, Y. Zhao, J. Wang, F. Arigoni, W. Zhang, Am. Heart J. 162 (2011) 959–965.
[12]A. Santamaria, D. Giordano, F. Corrado, B. Pintaudi, M.L. Interdonato, G.D. Vieste, A.D. Benedetto, R. D’Anna, Climacteric 15 (2012) 490–495.
[13]D. Giordano, F. Corrado, A. Santamaria, S. Quattrone, B. Pintaudi, A. Di Benedetto, R. D’Anna, Menopause 18 (2011) 102–104.
[14]L.P. Liang, S. Kaufman, Brain Res. 800 (1998) 181–186.
[15]M.T. Silva, S. Rose, J.G. Hindmarsh, P. Jenner, C.D. Marsden, Neuroreport 9 (1998) 149–152.
[16]A. Strasser, R.M. McCarron, H. Ishii, D. Stanimirovic, M. Spatz, Neuroreport 5 (1994) 2298–2300.
[17]T.J. Volz, J.O. Schenk, Synapse 54 (2004) 173–182.
[18]J.P. Kiss, G. Zsilla, E.S. Vizi, Neurochem. Int. 45 (2004) 485–489.
[19]J.P. Kiss, E.C. Hennings, G. Zsilla, E.S. Vizi, Neurochem. Int. 34 (1999) 345–350.
[20]V. Chaparro-Huerta, C. Beas-Zárate, M.U. Guerrero, A. Feria-Velasco, Neurochem. Int. 31 (1997) 607–616.
[21]S.K. Fisher, J.E. Novak, B.W. Agranoff, J. Neurochem. 82 (2002) 736–754.
[22]H.U. Yavuz, H. Turnagol, A.H. Demirel, Biol. Sport 31 (2014) 187–191.
[23]A. Schaefer, F. Piquard, B. Geny, S. Doutreleau, E. Lampert, B. Mettauer, J. Lonsdorfer, Int. J. Sports Med. 23 (2002) 403–407.

Celastrus Paniculatus Seed Extract

Scientific Name:
Celastrus paniculatus Willd

Huperzine A

Scientific Name:
Huperzine A extracted  from Huperzia serrata

Pterostilbene as pTeroPure

Scientific Name:
3′,5′-Dimethoxy-4-stilbenol

Theobromine

Scientific Name:
3,7-dimethylxanthine extracted from Theobroma Cacao

Pure Energy (Pterostilbene bound to Caffeine)

Scientific Name:
1,3,7-trimethylxanthine