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.

EnXtra® Alpinia Galanga

ALPINIA GALANGA COMMON NAME

Greater Galangal | Thai Ginger | Siamese Ginger

TOP BENEFITS OF ALPINIA GALANGA

• Sharpens alertness and focus*
• Amplifies caffeine’s nootropic benefits*
• Supports brain and cognitive function*

WHAT IS ALPINIA GALANGA?

Alpinia galanga is native to Southeast Asia, where it’s used as a food and herb. ^[1] It is part of the ginger family, and, similar to ginger, the rhizome, or creeping rootstalk is what’s used. The rhizome has a pungent smell reminiscent of black pepper and pine. The similarity in appearance to the ginger rhizome has led to one of its common names, Thai ginger. In some traditional medical systems, it is regarded as being superior to ginger. EnXtra® is a clinically studied and standardized Alpinia galanga rhizome extract. In human studies, EnXtra® has been complementary to caffeine. In a clinical study, supplementation with EnXtra® supported alertness and focus It’s clinically proven to improve alertness and focus for up to 5 hours with and without caffeine. EnXtra® can be used as a replacement for caffeine or used with caffeine to prevent crash and prolong caffeine’s nootropic benefits. ^[2]

NEUROHACKER’S ALPINIA GALANGA SOURCING

EnXtra® has been used in human clinical studies, where it has enhanced alertness and focus, and amplified the nootropic response to caffeine.

EnXtra® is created by Enovate Biolife, and is standardized for total polyphenols (not less than [NLT] 3%), flavanoids (NLT 4%), polysaccharides (NLT 20%) and pyrocatecollic type tannins (NLT 1%). 

EnXtra® is responsibly sourced. It is cultivated without pesticides in hilly terrain and hand picked to ensure optimum potency. It is DNA authenticated to ensure botanical identification.

EnXtra® is GRAS affirmed, non-GMO, gluten-free, vegan, Kosher certified and Halal compliant.

Grown in India.

EnXtra® is a registered trademark of Enovate Bioscience. 

ALPINIA GALANGA DOSING PRINCIPLES AND RATIONALE

We consider Alpinia galanga to be in the adaptogenic herb category; following hormetic dosing principles (see Neurohacker Dosing Principles) with a high likelihood of having a hormetic range (i.e., a dosing range below and above which results could be poorer). We have selected to dose this at an amount that is consistent with the studied amount in the human clinical studies.*

ALPINIA GALANGA KEY MECHANISMS

Cognitive function

• Supports mental alertness ^[2]
• Supports attention ^[3]
• Supports memory ^[4,5]

Brain function

• Neuroprotective effects ^[4–6]
• CNS stimulant activity ^[7]
• Supports locomotor activity and motor coordination ^[7]
• Downregulates acetylcholinesterase (AChE) levels/activity in the brain ^[4,5]
• Downregulates monoamine oxidase (MAO) A and B levels/activity in the brain ^[5]

Antioxidant defenses

• Upregulates antioxidant enzymes in the brain (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx]) ^[4–6,8]
• Replenishes glutathione (GSH) levels ^[8]
• Downregulates lipid peroxidation ^[6,8]

Other effects

• Supports healthy cardiometabolic parameters ^[8,9]
• Immunostimulant activity ^[10]

Complementary ingredients

• Caffeine — supports sustained attention ^[2]

REFERENCES 

[1] D. Kaushik, J. Yadav, P. Kaushik, D. Sacher, R. Rani, Zhong Xi Yi Jie He Xue Bao 9 (2011) 1061–1065.
[2] S. Srivastava, M. Mennemeier, S. Pimple, J. Am. Coll. Nutr. 36 (2017) 631–639.
[3] S. Shalini Srivastava, BAOJN 3 (2017) 1–10.
[4] J.C. Hanish Singh, V. Alagarsamy, P.V. Diwan, S. Sathesh Kumar, J.C. Nisha, Y. Narsimha Reddy, J. Ethnopharmacol. 138 (2011) 85–91.
[5] J.C. Hanish Singh, V. Alagarsamy, S. Sathesh Kumar, Y. Narsimha Reddy, Phytother. Res. 25 (2011) 1061–1067.
[6] R. Mundugaru, S. Sivanesan, P. Udaykumar, V. Dj, S.N. Prabhu, B. Ravishankar, IJPER 52 (2018) s77–s85.
[7] S. Saha, S. Banerjee, Indian J. Exp. Biol. 51 (2013) 828–832.
[8] P. Kaushik, D. Kaushik, J. Yadav, P. Pahwa, Pak. J. Biol. Sci. 16 (2013) 804–811.
[9] R.K. Verma, G. Mishra, P. Singh, K.K. Jha, R.L. Khosa, Ayu 36 (2015) 91–95.
[10] D. Bendjeddou, K. Lalaoui, D. Satta, J. Ethnopharmacol. 88 (2003) 155–160.

Celastrus Paniculatus Seed Extract

Scientific Name:
Celastrus paniculatus Willd

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 Rainforest Alliance Certified™, Non-GMO Project Verified, gluten-free, vegan, Kosher, organic, GRAS 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]

Complementary ingredients

• 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]

REFERENCES

[1] T.M. McLellan, J.A. Caldwell, H.R. Lieberman, Neurosci. Biobehav. Rev. 71 (2016) 294–312.
[2] G. Burnstock, Advances in Experimental Medicine and Biology 986 (2013) 1–12.
[3] B.B. Fredholm, Pharmacol. Toxicol. 76 (1995) 93–101.
[4] B.B. Fredholm, K. Bättig, J. Holmén, A. Nehlig, E.E. Zvartau, Pharmacol. Rev. 51 (1999) 83–133.
[5] E. Acquas, G. Tanda, G. Di Chiara, Neuropsychopharmacology 27 (2002) 182–193.
[6] A.J. Carter, W.T. O’Connor, M.J. Carter, U. Ungerstedt, J. Pharmacol. Exp. Ther. 273 (1995) 637–642.
[7] D. Shi, O. Nikodijević, K.A. Jacobson, J.W. Daly, Cell. Mol. Neurobiol. 13 (1993) 247–261.
[8] G. Racchetti, A. Lorusso, C. Schulte, D. Gavello, V. Carabelli, R. D’Alessandro, J. Meldolesi, J. Cell Sci. 123 (2010) 165–170.
[9] D. Quarta, J. Borycz, M. Solinas, K. Patkar, J. Hockemeyer, F. Ciruela, C. Lluis, R. Franco, A.S. Woods, S.R. Goldberg, S. Ferré, J. Neurochem. 91 (2004) 873–880.
[10] B.E. Garrett, S.G. Holtzman, Eur. J. Pharmacol. 262 (1994) 65–75.
[11] K.R. Powell, P.M. Iuvone, S.G. Holtzman, Pharmacol. Biochem. Behav. 69 (2001) 59–70.
[12] M. Solinas, S. Ferré, Z.-B. You, M. Karcz-Kubicha, P. Popoli, S.R. Goldberg, J. Neurosci. 22 (2002) 6321–6324.
[13] X. Zheng, S. Takatsu, H. Wang, H. Hasegawa, Pharmacol. Biochem. Behav. 122 (2014) 136–143.
[14] D.J. Haleem, A. Yasmeen, M.A. Haleem, A. Zafar, Life Sci. 57 (1995) PL285–92.
[15] S. Khaliq, S. Haider, F. Naqvi, T. Perveen, S. Saleem, D.J. Haleem, Pak. J. Pharm. Sci. 25 (2012) 21–25.
[16] M.D. Chen, W.H. Lin, Y.M. Song, P.Y. Lin, L.T. Ho, Zhonghua Yi Xue Za Zhi 53 (1994) 257–261.
[17] M. Okada, Y. Kawata, K. Kiryu, K. Mizuno, K. Wada, H. Tasaki, S. Kaneko, J. Neurochem. 69 (2002) 2581–2588.
[18] T. Porkka-Heiskanen, Handb. Exp. Pharmacol. (2011) 331–348.
[19] V. Maridakis, P.J. O’Connor, P.D. Tomporowski, Int. J. Neurosci. 119 (2009) 1239–1258.
[20] M.J. Jarvis, Psychopharmacology 110 (1993) 45–52.
[21] A. Nehlig, J. Alzheimers. Dis. 20 Suppl 1 (2010) S85–94.
[22] C.H.S. Ruxton, Nutr. Bull. 33 (2008) 15–25.
[23] J. Lanini, J.C.F. Galduróz, S. Pompéia, Hum. Psychopharmacol. 31 (2016) 29–43.
[24] K. Soar, E. Chapman, N. Lavan, A.S. Jansari, J.J.D. Turner, Appetite 105 (2016) 156–163.
[25] F.L. Dodd, D.O. Kennedy, L.M. Riby, C.F. Haskell-Ramsay, Psychopharmacology 232 (2015) 2563–2576.
[26] C.F. Haskell, D.O. Kennedy, A.L. Milne, K.A. Wesnes, A.B. Scholey, Biol. Psychol. 77 (2008) 113–122.
[27] S.J.L. Einöther, T. Giesbrecht, Psychopharmacology 225 (2013) 251–274.
[28] A. Smith, Food Chem. Toxicol. 40 (2002) 1243–1255.
[29] M.A. Schwarzschild, K. Xu, E. Oztas, J.P. Petzer, K. Castagnoli, N. Castagnoli Jr, J.-F. Chen, Neurology 61 (2003) S55–61.
[30] M. Kolahdouzan, M.J. Hamadeh, CNS Neurosci. Ther. 23 (2017) 272–290.
[31] S.H. Backhouse, S.J.H. Biddle, N.C. Bishop, C. Williams, Appetite 57 (2011) 247–252.
[32] J.M. Davis, Z. Zhao, H.S. Stock, K.A. Mehl, J. Buggy, G.A. Hand, Am. J. Physiol. Regul. Integr. Comp. Physiol. 284 (2003) R399–404.
[33] K.J. Acheson, B. Zahorska-Markiewicz, P. Pittet, K. Anantharaman, E. Jéquier, Am. J. Clin. Nutr. 33 (1980) 989–997.
[34] A. Astrup, S. Toubro, S. Cannon, P. Hein, L. Breum, J. Madsen, Am. J. Clin. Nutr. 51 (1990) 759–767.
[35] J. LeBlanc, M. Jobin, J. Côté, P. Samson, A. Labrie, J. Appl. Physiol. 59 (1985) 832–837.
[36] O.H. Choi, M.T. Shamim, W.L. Padgett, J.W. Daly, Life Sci. 43 (1988) 387–398.
[37] R. Franco, A. Oñatibia-Astibia, E. Martínez-Pinilla, Nutrients 5 (2013) 4159–4173.
[38] S.J.L. Einöther, V.E.G. Martens, J.A. Rycroft, E.A. De Bruin, Appetite 54 (2010) 406–409.
[39] T. Giesbrecht, J.A. Rycroft, M.J. Rowson, E.A. De Bruin, Nutr. Neurosci. 13 (2010) 283–290.
[40] G.N. Owen, H. Parnell, E.A. De Bruin, J.A. Rycroft, Nutr. Neurosci. 11 (2008) 193–198.
[41] S.E. Bruce, K.B. Werner, B.F. Preston, L.M. Baker, Int. J. Food Sci. Nutr. 65 (2014) 1003–1007.
[42] A. Misaizu, T. Kokubo, K. Tazumi, M. Kanayama, Y. Miura, Prev Nutr Food Sci 19 (2014) 367–372.

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.

Alpha GPC

Scientific Name:
Alpha-glycerophosphocholine

Uridine Monophosphate

Scientific Name:
Uridine Monophosphate, (UMP)

Cognizin Citicoline

Scientific Name:
Cytidine diphosphocholine

Phenylethylamine HCL

Scientific Name:
Phenylethylamine, (PEA)

Saffron Extract (Crocus sativus)

SAFFRON COMMON NAME

Saffron | Saffron Crocus

TOP BENEFITS OF SAFFRON

• Supports mood*
• Supports cognitive function*
• Supports vision* 

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. Saffron has had a wide range and long list of traditional uses. In Traditional Iranian Medicine saffron was thought to be useful for supporting sleep and mood, and to be a heart tonic. And in India it was used as a nerve and heart tonic, and for relaxation and sleep support. 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, sleep, and women’s health.

NEUROHACKER’S SAFFRON SOURCING

There's a long history of saffron adulteration. Because of this, Neurohacker feels it is 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 or different standardizations 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

Mood

• Supports a positive mental-emotional bias [1–9]
• Supports a calm mood [3,4,7–9]

Brain function

• Supports focus and attention [10]
• Supports healthy brain aging [11–13]
• Supports sleep [14–16]
• Supports dopamine signaling [17,18]
• Supports GABA-glutamate signaling [17]
• Supports acetylcholinesterase activity [18]
• Supports brain-derived neurotrophic factor (BDNF) levels [19,20]
• Supports neuroprotective functions [18,21–25]
• Supports long-term potentiation [15]

Vision

• Supports retinal function [26–28]
• Protects macular health [27–29]
• Supports visual acuity [27,29]
• Protects retinal cells against light-induced damage [30–33]
• Protects retinal cells against damage and degeneration [22,27,29,33–36]
• Supports healthy intraocular pressure [37]

Exercise performance

• Enhances reaction times [38]
• Supports muscle strength [38]
• Supports muscle recovery functions [39]

Antioxidant defenses

• Supports antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase [GPx]) [18,21,36]
• Replenishes glutathione (GSH) levels [18,36]
• Supports free-radical scavenging [18,21,35,36]
• Promotes healthy prooxidant-antioxidant balance [40]

Mitochondrial function

• Supports the activity of mitochondrial enzymes [18]
• Supports mitochondrial membrane potential [35]

Metabolic function

• Supports cytokine balance [41]
• Supports appetite regulation [42]
• Supports healthy lipid levels and blood pressure regulation [43,44] 

References

[1]H.A. Hausenblas, D. Saha, P.J. Dubyak, S.D. Anton, J. Integr. Med. 11 (2013) 377–383.

[2]A.L. Lopresti, P.D. Drummond, Hum. Psychopharmacol. 29 (2014) 517–527.

[3]G. Kell, A. Rao, G. Beccaria, P. Clayton, A.M. Inarejos-García, M. Prodanov, Complement. Ther. Med. 33 (2017) 58–64.

[4]A.L. Lopresti, P.D. Drummond, A.M. Inarejos-García, M. Prodanov, J. Affect. Disord. 232 (2018) 349–357.

[5]S. Akhondzadeh, N. Tahmacebi-Pour, A.-A. Noorbala, H. Amini, H. Fallah-Pour, A.-H. Jamshidi, M. Khani, Phytother. Res. 19 (2005) 148–151.

[6]E. Moshiri, A.A. Basti, A.-A. Noorbala, A.-H. Jamshidi, S. Hesameddin Abbasi, S. Akhondzadeh, Phytomedicine 13 (2006) 607–611.

[7]A. Ghajar, S.M. Neishabouri, N. Velayati, L. Jahangard, N. Matinnia, M. Haghighi, A. Ghaleiha, M. Afarideh, S. Salimi, A. Meysamie, S. Akhondzadeh, Pharmacopsychiatry 50 (2017) 152–160.

[8]M. Mazidi, M. Shemshian, S.H. Mousavi, A. Norouzy, T. Kermani, T. Moghiman, A. Sadeghi, N. Mokhber, M. Ghayour-Mobarhan, G.A.A. Ferns, J. Complement. Integr. Med. 13 (2016) 195–199.

[9]A. Milajerdi, S. Jazayeri, E. Shirzadi, N. Hashemzadeh, A. Azizgol, A. Djazayery, A. Esmaillzadeh, S. Akhondzadeh, Complement. Ther. Med. 41 (2018) 196–202.

[10]S. Baziar, A. Aqamolaei, E. Khadem, S.H. Mortazavi, S. Naderi, E. Sahebolzamani, A. Mortezaei, S. Jalilevand, M.-R. Mohammadi, M. Shahmirzadi, S. Akhondzadeh, J. Child Adolesc. Psychopharmacol. 29 (2019) 205–212.

[11]M. Farokhnia, M. Shafiee Sabet, N. Iranpour, A. Gougol, H. Yekehtaz, R. Alimardani, F. Farsad, M. Kamalipour, S. Akhondzadeh, Hum. Psychopharmacol. 29 (2014) 351–359.

[12]S. Akhondzadeh, M.S. Sabet, M.H. Harirchian, M. Togha, H. Cheraghmakani, S. Razeghi, S.S. Hejazi, M.H. Yousefi, R. Alimardani, A. Jamshidi, F. Zare, A. Moradi, J. Clin. Pharm. Ther. 35 (2010) 581–588.

[13]S. Akhondzadeh, M. Shafiee Sabet, M.H. Harirchian, M. Togha, H. Cheraghmakani, S. Razeghi, S.S. Hejazi, M.H. Yousefi, R. Alimardani, A. Jamshidi, S.-A. Rezazadeh, A. Yousefi, F. Zare, A. Moradi, A. Vossoughi, Psychopharmacology 207 (2010) 637–643.

[14]M. Masaki, K. Aritake, H. Tanaka, Y. Shoyama, Z.-L. Huang, Y. Urade, Mol. Nutr. Food Res. 56 (2012) 304–308.

[15]S. Soeda, K. Aritake, Y. Urade, H. Sato, Y. Shoyama, Adv Neurobiol 12 (2016) 275–292.

[16]Z. Liu, X.-H. Xu, T.-Y. Liu, Z.-Y. Hong, Y. Urade, Z.-L. Huang, W.-M. Qu, CNS Neurosci. Ther. 18 (2012) 623–630.

[17]H. Ettehadi, S.N. Mojabi, M. Ranjbaran, J. Shams, H. Sahraei, M. Hedayati, F. Asefi, JBBS 03 (2013) 315–319.

[18]S.V. Rao, Muralidhara, S.C. Yenisetti, P.S. Rajini, Neurotoxicology 52 (2016) 230–242.

[19]T. Ghasemi, K. Abnous, F. Vahdati, S. Mehri, B.M. Razavi, H. Hosseinzadeh, Drug Res. 65 (2015) 337–343.

[20]F. Vahdati Hassani, V. Naseri, B.M. Razavi, S. Mehri, K. Abnous, H. Hosseinzadeh, Daru 22 (2014) 16.

[21]B. Naghizadeh, M.T. Mansouri, B. Ghorbanzadeh, Y. Farbood, A. Sarkaki, Phytomedicine 20 (2013) 537–542.

[22]S. Purushothuman, C. Nandasena, C.L. Peoples, N. El Massri, D.M. Johnstone, J. Mitrofanis, J. Stone, J. Parkinsons. Dis. 3 (2013) 77–83.

[23]Y.S. Batarseh, S.S. Bharate, V. Kumar, A. Kumar, R.A. Vishwakarma, S.B. Bharate, A. Kaddoumi, ACS Chem. Neurosci. 8 (2017) 1756–1766.

[24]L. Tamegart, A. Abbaoui, R. Makbal, M. Zroudi, B. Bouizgarne, M.M. Bouyatas, H. Gamrani, Acta Histochem. 121 (2019) 171–181.

[25]P. Haeri, A. Mohammadipour, Z. Heidari, A. Ebrahimzadeh-Bideskan, Anat. Sci. Int. 94 (2019) 119–127.

[26]A. Lashay, G. Sadough, E. Ashrafi, M. Lashay, M. Movassat, S. Akhondzadeh, Med Hypothesis Discov Innov Ophthalmol 5 (2016) 32–38.

[27]M. Piccardi, D. Marangoni, A.M. Minnella, M.C. Savastano, P. Valentini, L. Ambrosio, E. Capoluongo, R. Maccarone, S. Bisti, B. Falsini, Evid. Based. Complement. Alternat. Med. 2012 (2012) 429124.

[28]B. Falsini, M. Piccardi, A. Minnella, C. Savastano, E. Capoluongo, A. Fadda, E. Balestrazzi, R. Maccarone, S. Bisti, Invest. Ophthalmol. Vis. Sci. 51 (2010) 6118–6124.

[29]G.K. Broadhead, J.R. Grigg, P. McCluskey, T. Hong, T.E. Schlub, A.A. Chang, Graefes Arch. Clin. Exp. Ophthalmol. 257 (2019) 31–40.

[30]R. Maccarone, S. Di Marco, S. Bisti, Invest. Ophthalmol. Vis. Sci. 49 (2008) 1254–1261.

[31]F.D. Marco, S. Romeo, C. Nandasena, S. Purushothuman, C. Adams, S. Bisti, J. Stone, Am. J. Neurodegener. Dis. 2 (2013) 208–220.

[32]A. Laabich, G.P. Vissvesvaran, K.L. Lieu, K. Murata, T.E. McGinn, C.C. Manmoto, J.R. Sinclair, I. Karliga, D.W. Leung, A. Fawzi, R. Kubota, Invest. Ophthalmol. Vis. Sci. 47 (2006) 3156–3163.

[33]M. Yamauchi, K. Tsuruma, S. Imai, T. Nakanishi, N. Umigai, M. Shimazawa, H. Hara, Eur. J. Pharmacol. 650 (2011) 110–119.

[34]R. Natoli, Y. Zhu, K. Valter, S. Bisti, J. Eells, J. Stone, Mol. Vis. 16 (2010) 1801–1822.

[35]B. Lv, T. Chen, Z. Xu, F. Huo, Y. Wei, X. Yang, Int. J. Mol. Med. 37 (2016) 225–232.

[36]L. Chen, Y. Qi, X. Yang, Ophthalmic Res. 54 (2015) 157–168.

[37]M.H. Jabbarpoor Bonyadi, S. Yazdani, S. Saadat, BMC Complement. Altern. Med. 14 (2014) 399.

[38]A. Meamarbashi, A. Rajabi, J. Diet. Suppl. 13 (2016) 522–529.

[39]A. Meamarbashi, A. Rajabi, Clin. J. Sport Med. 25 (2015) 105–112.

[40]T. Kermani, S.H. Mousavi, M. Shemshian, A. Norouzy, M. Mazidi, A. Moezzi, T. Moghiman, M. Ghayour-Mobarhan, G. A Ferns, Avicenna J Phytomed 5 (2015) 427–433.

[41]T. Kermani, M. Zebarjadi, H. Mehrad-Majd, S.-R. Mirhafez, M. Shemshian, F. Ghasemi, E. Mohammadzadeh, S.H. Mousavi, A. Norouzy, T. Moghiman, A. Sadeghi, G. Ferns, A. Avan, E. Mahdipour, M. Ghayour-Mobarhan, Curr. Clin. Pharmacol. 12 (2017) 122–126.

[42]N. Abedimanesh, S.Z. Bathaie, S. Abedimanesh, B. Motlagh, A. Separham, A. Ostadrahimi, J Cardiovasc Thorac Res 9 (2017) 200–208.

[43]F. Ebrahimi, N. Aryaeian, N. Pahlavani, D. Abbasi, A.F. Hosseini, S. Fallah, N. Moradi, I. Heydari, Avicenna J Phytomed 9 (2019) 322–333.

[44]A. Moravej Aleali, R. Amani, H. Shahbazian, F. Namjooyan, S.M. Latifi, B. Cheraghian, Phytother. Res. 33 (2019) 1648–1657.

Gotu Kola ( Centella asiatica ) Whole Herb Extract

GOTU KOLA COMMON NAME

Gotukola | Indian Pennywort | Asiatic Pennywort

TOP BENEFITS OF GOTU KOLA

Supports a calm mood and feelings of contentment*
Supports mental alertness and attention*
Supports a healthy stress response*
Supports circulation*

WHAT IS GOTU KOLA?

In Ayurvedic medicine, gotu kola (Centella asiatica; synonym is Hydrocotyle asiatica) is considered to be a mental rejuvenator (medhya Rasayana), where it was traditionally used as a tonic herb to counter mental fatigue and improve thinking. It was thought to be particularly useful during times of increased mental demands. Other traditional uses included support of blood/circulation, skin regeneration, and general longevity. Modern science has upheld some of this reputation—gotu kola is a nootropic and supports brain repair and rejuvenation processes. It also supports healthy veins and circulation. Gotu kola, unlike many other nootropics that are best taken only at the beginning of the day, is a great fit at the end of a busy day because it is calming and supports repair and rejuvenation processes. Gotu kola contains several characteristic bioactive compounds, including asiaticoside, asiatic acid, madecassic acid, madecassoside, and centelloside. Gotu kola also contains other compounds with biological activity found in other plants such as ursolic acid, rosmarinic acid, and the flavonoids apigenin and rutin^[1].

NEUROHACKER’S GOTU KOLA SOURCING

Gotu kola is a whole herb extract. It is standardized to contain not less than 10% asiaticosides, since this group of active compounds are thought to be the main bioactives.

Gotu kola is Non-GMO and Vegan.

GOTU KOLA DOSING PRINCIPLES AND RATIONALE

Because gotu kola is an Ayurvedic Rasayana herb, we consider dosing to follow hormetic principles similar to herbal adaptogens (see Neurohacker Dosing Principles). Herbal adaptogens tend to have a hormetic zone (or range) where there’s a favorable biological response. It’s important to be in this zone; it’s just as important not to be above it. Based on human studies, where extracts standardized for one or more of gotu kola’s asiaticosides have been used, we consider the target range of asiaticosides to be between about 12.5mg to 50mg for nootropic and mood purposes. The mg amount of gotu kola used will depend on its standardization and will be chosen to deliver an amount of asiaticosides within this range. Our goal with gotu kola, as with all ingredient choices, is to select the appropriate dose keeping in mind both the ingredient and the other ingredients being used in a formulation. In other words, if we are also supplying other adaptogens and nootropic extracts, we are likely to use less gotu kola than if the only herbal adaptogen/nootropic we were using was gotu kola.

GOTU KOLA KEY MECHANISMS

Mood and stress response
Supports a calm mood^[2–8]
Supports healthy behavioral and physiological responses to stress^[8]

Brain function
Supports working memory^[4]
Supports learning and memory^[9–15]
Supports executive function^[10,11]
Supports glutamate decarboxylase (GAD) activity^[16]
Supports GABAergic neurotransmission^[17]
Supports GABA receptor agonist actions [asiatic acid]^[18–20]
Supports glutamatergic AMPA receptors ^[9]
Down-regulates acetylcholinesterase (AChE)^[14,18]
Supports hippocampal synaptic density^[11]
Supports the expression of synaptic markers in the hippocampus and frontal cortex^[21]
Supports brain mitochondrial function^{[10,11,14,21,22]}
Supports brain-derived neurotrophic factor (BDNF)^{[12,13,23,24]}
Supports NMDA receptors^[24]
Supports hippocampal long-term potentiation^[24]
Supports Nrf2 signaling in the brain^{[10,11,21,22]}
Supports antioxidant defenses^{[7,10,11,14,21,22,25]}
Supports neuroprotective functions^[26]

Immune system
Supports innate immunity^[27]
Supports adaptive immunity^[28,29]

REFERENCES

[1] K.J. Gohil, J.A. Patel, A.K. Gajjar, Indian J. Pharm. Sci. 72 (2010) 546–556.
[2] U. Jana, T.K. Sur, L.N. Maity, P.K. Debnath, D. Bhattacharyya, Nepal Med. Coll. J. 12 (2010) 8–11.
[3] P. Puttarak, P. Dilokthornsakul, S. Saokaew, T. Dhippayom, C. Kongkaew, R. Sruamsiri, A. Chuthaputti, N. Chaiyakunapruk, Sci. Rep. 7 (2017) 10646.
[4] J. Wattanathorn, L. Mator, S. Muchimapura, T. Tongun, O. Pasuriwong, N. Piyawatkul, K. Yimtae, B. Sripanidkulchai, J. Singkhoraard, J. Ethnopharmacol. 116 (2008) 325–332.
[5] J. Bradwejn, Y. Zhou, D. Koszycki, J. Shlik, J. Clin. Psychopharmacol. 20 (2000) 680–684.
[6] K.V. Mitha, S. Yadav, B. Ganaraja, Indian J. Physiol. Pharmacol. 60 (2016) 167–173.
[7] P. Chanana, A. Kumar, Phytother. Res. 30 (2016) 671–680.
[8] A. Wanasuntronwong, M.H. Tantisira, B. Tantisira, H. Watanabe, J. Ethnopharmacol. 143 (2012) 579–585.
[9] N.A. Binti Mohd Yusuf Yeo, S. Muthuraju, J.H. Wong, F.R. Mohammed, M.H. Senik, J. Zhang, S.R. Yusof, H. Jaafar, M.L. Adenan, H. Mohamad, T.S. Tengku Muhammad, J.M. Abdullah, Brain Behav. 8 (2018) e01093.
[10] N.E. Gray, J.A. Zweig, M. Caruso, J.Y. Zhu, K.M. Wright, J.F. Quinn, A. Soumyanath, Mol. Cell. Neurosci. 93 (2018) 1–9.
[11] N.E. Gray, J.A. Zweig, M. Caruso, M.D. Martin, J.Y. Zhu, J.F. Quinn, A. Soumyanath, Brain Behav. 8 (2018) e01024.
[12] D.C.R. Sari, N. Arfian, U. Tranggono, W.A.W. Setyaningsih, M.M. Romi, N. Emoto, Iran. J. Basic Med. Sci. 22 (2019) 1218–1224.
[13] G. Sbrini, P. Brivio, M. Fumagalli, F. Giavarini, D. Caruso, G. Racagni, M. Dell’Agli, E. Sangiovanni, F. Calabrese, Nutrients 12 (2020).
[14] A. Kumar, A. Prakash, S. Dogra, Int. J. Alzheimers. Dis. 2011 (2011) 347569.
[15] M.N. Nasir, M. Habsah, I. Zamzuri, G. Rammes, J. Hasnan, J. Abdullah, J. Ethnopharmacol. 134 (2011) 203–209.
[16] R. Awad, D. Levac, P. Cybulska, Z. Merali, V.L. Trudeau, J.T. Arnason, Canadian Journal of Physiology and Pharmacology 85 (2007) 933–942.
[17] T.K. Chatterjee, A. Chakraborty, M. Pathak, G.C. Sengupta, Indian J. Exp. Biol. 30 (1992) 889–891.
[18] M.N. Nasir, J. Abdullah, M. Habsah, R.I. Ghani, G. Rammes, Phytomedicine 19 (2012) 311–316.
[19] T.E. Ceremuga, D. Valdivieso, C. Kenner, A. Lucia, K. Lathrop, O. Stailey, H. Bailey, J. Criss, J. Linton, J. Fried, A. Taylor, G. Padron, A.D. Johnson, AANA J. 83 (2015) 91–98.
[20] K. Hamid, I. Ng, V.J. Tallapragada, L. Váradi, D.E. Hibbs, J. Hanrahan, P.W. Groundwater, Chem. Biol. Drug Des. 88 (2016) 386–397.
[21] N.E. Gray, C.J. Harris, J.F. Quinn, A. Soumyanath, J. Ethnopharmacol. 180 (2016) 78–86.
[22] N.E. Gray, J.A. Zweig, D.G. Matthews, M. Caruso, J.F. Quinn, A. Soumyanath, Oxid. Med. Cell. Longev. 2017 (2017) 7023091.
[23] M. Ar Rochmah, I.M. Harini, D.E. Septyaningtrias, D.C.R. Sari, R. Susilowati, Biomed Res. Int. 2019 (2019) 2649281.
[24] Y. Boondam, P. Songvut, M.H. Tantisira, S. Tapechum, K. Tilokskulchai, N. Pakaprot, Sci. Rep. 9 (2019) 8404.
[25] N. Haleagrahara, K. Ponnusamy, J. Toxicol. Sci. 35 (2010) 41–47.
[26] S. Chen, Z.-J. Yin, C. Jiang, Z.-Q. Ma, Q. Fu, R. Qu, S.-P. Ma, Pharmacol. Biochem. Behav. 122 (2014) 7–15.
[27] M.G. Jayathirtha, S.H. Mishra, Phytomedicine 11 (2004) 361–365.
[28] D. Arora, M. Kumar, S.D. Dubey, U. Sings, Anc. Sci. Life 22 (2002) 42–48.
[29] K. Punturee, C.P. Wild, W. Kasinrerk, U. Vinitketkumnuen, Asian Pac. J. Cancer Prev. 6 (2005) 396–400.

Polygala tenuifolia Root Extract

POLYGALA TENUIFOLIA COMMON NAME

Polygalae Radix | Yuan zhi | Onji

TOP BENEFITS OF POLYGALA TENUIFOLIA

Supports cognitive function*
Supports a healthy stress response*
Supports sleep*
Supports mood*

WHAT IS POLYGALA TENUIFOLIA?

In Traditional Chinese Medicine, Polygala tenuifolia root is one of the most used herbs to support the brain and central nervous system. Traditionally it was often used to reduce forgetfulness and support brain performance during aging (i.e., it’s what we’d consider a nootropic today). It was also commonly used in formulas to support sleep and promote a calmer, more balanced mood. Preclinical research suggests it supports brain protection and repair processes and molecules (such as BDNF and NGF), counters chronic stress, supports sleep, and influences both adenosine signaling—a molecule involved in the sleep homeostatic drive—and GABA signaling—a neurotransmitter involved with relaxation at night and sleep. The roots have several bioactive compounds thought to be relatively unique to this plant including tenuigenin, tenuifolin, yuanzhi-1, tenuifolisides, and tenuifolioses.

NEUROHACKER’S POLYGALA TENUIFOLIA SOURCING

Polygala tenuifolia root extract is a 10:1 extract, which means that 10 parts of the root are used to create 1 part of the extract. This concentrates the active compounds, so less of the herb is needed.

Polygala tenuifolia root extract is Non-GMO and Vegan.

POLYGALA TENUIFOLIA DOSING PRINCIPLES AND RATIONALE

Because preclinical research suggests the potential for adaptogenic properties of Polygala tenuifolia, we consider dosing to follow hormetic principles similar to herbal adaptogens (see Neurohacker Dosing Principles). Herbal adaptogens tend to have a hormetic zone (or range) where there’s a favorable biological response. It’s important to be in this zone; it’s just as important not to be above it. Based on human studies and traditional uses, we’d consider the dose range for concentrated extracts to be about 100-300 mg daily (about 1-3 grams of crude root powder). Our goal with P. tenuifolia, as with all ingredient choices, is to select the appropriate dose keeping in mind both the ingredient and the other ingredients being used in a formulation. In other words, if we are also supplying other adaptogens and nootropic extracts, we are likely to dose P. tenuifolia towards the lower end of the range. 

POLYGALA TENUIFOLIA KEY MECHANISMS

Brain function

Supports learning and memory ^[1–4]

Supports sleep ^[5–7]

Supports glutamate decarboxylase (GAD) activity ^[8]

Supports GABA-Glutamate signaling ^[6,8–10]

Supports adenosine signaling ^[11]

Supports adrenergic signaling ^[3,5,6]

Supports dopamine signaling ^[3,12]

Downregulates acetylcholinesterase (AChE) activity ^[3,4,13]

Downregulates monoamine oxidase (MAO) ^[4]

Supports brain-derived neurotrophic factor (BDNF) ^[14,15]

Supports synaptic transmission in the hippocampus ^[15]

Supports long-term potentiation (LTP)/synaptic plasticity ^[13,15]

Supports the proliferation and differentiation of neural stem cells ^[16,17]

Supports neuroprotective functions

Protects against neurotoxic agents ^[18–20]

Protects from cognitive impairments ^[15,18–23]

Supports antioxidant defenses ^[4,13,20,24]

Stress

Supports healthy behavioral and physiological responses to stress ^[7,10,14]

Gut microbiota

Supports the composition of the gut microbiota ^[25]

Immune System

Supports adaptive immunity ^[26]

Supports macrophage functions ^[27]

Healthy aging and longevity

Supports mitochondrial function ^[22]

REFERENCES 

[1] J.-Y. Lee, K.Y. Kim, K.Y. Shin, B.Y. Won, H.Y. Jung, Y.-H. Suh, Neurosci. Lett. 454 (2009) 111–114.

[2] K.Y. Shin, J.-Y. Lee, B.Y. Won, H.Y. Jung, K.-A. Chang, S. Koppula, Y.-H. Suh, Neurosci. Lett. 465 (2009) 157–159.

[3] H. Zhang, T. Han, L. Zhang, C.-H. Yu, D.-G. Wan, K. Rahman, L.-P. Qin, C. Peng, Phytomedicine 15 (2008) 587–594.

[4] Z. Li, Y. Liu, L. Wang, X. Liu, Q. Chang, Z. Guo, Y. Liao, R. Pan, T.-P. Fan, Evid. Based. Complement. Alternat. Med. 2014 (2014) 392324.

[5] K. Kawashima, D. Miyako, Y. Ishino, T. Makino, K.-I. Saito, Y. Kano, Biol. Pharm. Bull. 27 (2004) 1317–1319.

[6] Q. Cao, Y. Jiang, S.-Y. Cui, P.-F. Tu, Y.-M. Chen, X.-L. Ma, X.-Y. Cui, Y.-L. Huang, H. Ding, J.-Z. Song, B. Yu, Z.-F. Sheng, Z.-J. Wang, Y.-P. Xu, G. Yang, H. Ye, X. Hu, Y.-H. Zhang, Phytomedicine 23 (2016) 1797–1805.

[7] Y. Yao, M. Jia, J.-G. Wu, H. Zhang, L.-N. Sun, W.-S. Chen, K. Rahman, Pharm. Biol. 48 (2010) 801–807.

[8] C.-I. Lee, J.-Y. Han, J.T. Hong, K.-W. Oh, Arch. Pharm. Res. 36 (2013) 1244–1251.

[9] C.-Y. Chen, X.-D. Wei, C.-R. Chen, J. Pharmacol. Sci. 131 (2016) 1–5.

[10] I.-J. Shin, S.U. Son, H. Park, Y. Kim, S.H. Park, K. Swanberg, J.-Y. Shin, S.-K. Ha, Y. Cho, S.-Y. Bang, J.-H. Lew, S.-H. Cho, S. Maeng, PLoS One 9 (2014) e88617.

[11] E.-J. Shin, K.-W. Oh, K.-W. Kim, Y.S. Kwon, J.H. Jhoo, W.-K. Jhoo, J.-Y. Cha, Y.K. Lim, I.S. Kim, H.-C. Kim, Life Sci. 75 (2004) 2751–2764.

[12] H.-L. Yuan, B. Li, J. Xu, Y. Wang, Y. He, Y. Zheng, X.-M. Wang, CNS Neurosci. Ther. 18 (2012) 584–590.

[13] J.-N. Huang, C.-Y. Wang, X.-L. Wang, B.-Z. Wu, X.-Y. Gu, W.-X. Liu, L.-W. Gong, P. Xiao, C.-H. Li, Behav. Brain Res. 246 (2013) 111–115.

[14] Y. Hu, P. Liu, D.-H. Guo, K. Rahman, D.-X. Wang, T.-T. Xie, Pharm. Biol. 48 (2010) 794–800.

[15] W. Xue, J.-F. Hu, Y.-H. Yuan, J.-D. Sun, B.-Y. Li, D.-M. Zhang, C.-J. Li, N.-H. Chen, Acta Pharmacol. Sin. 30 (2009) 1211–1219.

[16] H.-J. Park, K. Lee, H. Heo, M. Lee, J.W. Kim, W.W. Whang, Y.K. Kwon, H. Kwon, Phytother. Res. 22 (2008) 1324–1329.

[17] Y. Chen, X. Huang, W. Chen, N. Wang, L. Li, Neurochem. Res. 37 (2012) 771–777.

[18] Y. Ikeya, S. Takeda, M. Tunakawa, H. Karakida, K. Toda, T. Yamaguchi, M. Aburada, Biol. Pharm. Bull. 27 (2004) 1081–1085.

[19] X.-L. Sun, H. Ito, T. Masuoka, C. Kamei, T. Hatano, Biol. Pharm. Bull. 30 (2007) 1727–1731.

[20] X. Li, Y. Sun, Y. Wei, L. Zhou, L. Liu, P. Yin, Y. Liu, S. Wu, J. Li, C. Lu, Curr. Neurovasc. Res. 15 (2018) 94–102.

[21] T. Kuboyama, K. Hirotsu, T. Arai, H. Yamasaki, C. Tohda, Front. Pharmacol. 8 (2017) 805.

[22] L. Wang, G.F. Jin, H.H. Yu, X.H. Lu, Z.H. Zou, J.Q. Liang, H. Yang, Food Funct. 10 (2019) 7453–7460.

[23] J.-H. Park, J.S. Kim, D.S. Jang, S.-M. Lee, Am. J. Chin. Med. 34 (2006) 115–123.

[24] P. Liu, Y. Hu, D.-H. Guo, B.-R. Lu, K. Rahman, L.-H. Mu, D.-X. Wang, Pharm. Biol. 48 (2010) 828–833.

[25] C.-C. Wang, J.-H. Yen, Y.-C. Cheng, C.-Y. Lin, C.-T. Hsieh, R.-J. Gau, S.-J. Chiou, H.-Y. Chang, Food Nutr. Res. 61 (2017) 1379861.

[26] T. Nagai, Y. Suzuki, H. Kiyohara, E. Susa, T. Kato, T. Nagamine, Y. Hagiwara, S. Tamura, T. Yabe, C. Aizawa, H. Yamada, Vaccine 19 (2001) 4824–4834.

[27] K.-S. Kim, D.-S. Lee, G.-S. Bae, S.-J. Park, D.-G. Kang, H.-S. Lee, H. Oh, Y.-C. Kim, Eur. J. Pharmacol. 721 (2013) 267–276.

Caffeine

Ginkgo Biloba Leaf Extract (24% glycosides)

Scientific Name:
Ginkgo biloba

Bacopa monnieri Leaf Extract

Scientific Name:
Bacopa monnieri

Mucuna pruriens Seed

Scientific Name:
Mucuna pruriens, L-3,4-dihydroxyphenylalanine

Huperzia serrata Leaf extract (1% 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

COMMON NAME

Theobromine

TOP BENEFITS OF THEOBROMINE

• Supports brain function and cognitive performance *
• Supports neuroprotection *

WHAT IS THEOBROMINE?

Theobromine is a bitter compound found in high amounts in cocoa beans (and hence chocolate) and in much lower amounts in tea, yerba mate, guarana and guayusa. Its name comes from the botanical name for the cocoa bean, Theobroma cacao. The amount of theobromine in cocoa powders can vary about 5-fold, from between 2 to 10%. Darker chocolate generally has more theobromine than milk chocolate. Theobromine belongs to a class of alkaloid molecules called methylxanthines, which also includes caffeine. Like caffeine, it supports alertness processes in the brain by influencing the adenosine neurotransmitter system. Theobromine has somewhat similar effects to caffeine in supporting the sensation of being alert or having energy, but with slower onset and longer duration of activity [1–4]. It can be thought of as being a weaker cousin to caffeine, influencing similar brain processes but not quite as strongly. 

NEUROHACKER’S THEOBROMINE SOURCING

Theobromine is non-GMO and vegan.

THEOBROMINE DOSING PRINCIPLES AND RATIONALE

A 2 ounce serving of milk chocolate contains approximately 120 mg of theobromine, while the same amount of dark chocolate contains about 400 mg. Similar to caffeine, theobromine is not a “more is better” ingredient when it comes to being a nootropic. As an example, in a study that compared theobromine doses of 250, 500, and 1000 mg, the lowest dose produced the best subjective experience [5]. This indicates that there’s a high likelihood theobromine may follow hormetic dosing principles (see Neurohacker Dosing Principles), i.e., have a dosing range below and above which results could be poorer. Furthermore, because Neurohacker Collective believes theobromine may have additive effects with other ingredients, especially caffeine, we have selected to dose theobromine at an amount that occurs with dietary intake of chocolate. 

THEOBROMINE KEY MECHANISMS

Brain and cognitive function

• Supports memory and learning [6–8]
• Supports cognitive health [7]
• Influences adenosine receptor activity [2,3,9]
• Supports dopamine levels [10]
• Supports noradrenaline levels [10]
• Supports brain-derived neurotrophic factor (BDNF) [6,8]
• Supports antioxidant defenses [10]

Cellular function

• Influences phosphodiesterase (PDE) activity and intracellular cAMP levels [6,9]
• Influences mTOR signaling [11] 

Complementary ingredients

• Caffeine in supporting energetic arousal, reaction time and information processing [12]

REFERENCES 

[1]B. Gottwalt, P. Tadi, in: StatPearls, StatPearls Publishing, Treasure Island (FL), 2020.

[2]H.J. Smit, Handb. Exp. Pharmacol. (2011) 201–234.

[3]R. Franco, A. Oñatibia-Astibia, E. Martínez-Pinilla, Nutrients 5 (2013) 4159–4173.

[4]E. Martínez-Pinilla, A. Oñatibia-Astibia, R. Franco, Front. Pharmacol. 6 (2015) 30.

[5]M.J. Baggott, E. Childs, A.B. Hart, E. de Bruin, A.A. Palmer, J.E. Wilkinson, H. de Wit, Psychopharmacology 228 (2013) 109–118.

[6]M. Yoneda, N. Sugimoto, M. Katakura, K. Matsuzaki, H. Tanigami, A. Yachie, T. Ohno-Shosaku, O. Shido, J. Nutr. Biochem. 39 (2017) 110–116.

[7]J. Mendiola-Precoma, K. Padilla, A. Rodríguez-Cruz, L.C. Berumen, R. Miledi, G. García-Alcocer, J. Alzheimers. Dis. 55 (2017) 1273–1283.

[8]R. Islam, K. Matsuzaki, E. Sumiyoshi, M.E. Hossain, M. Hashimoto, M. Katakura, N. Sugimoto, O. Shido, Nutrients 11 (2019).

[9]I. Cova, V. Leta, C. Mariani, L. Pantoni, S. Pomati, Psychopharmacology 236 (2019) 561–572.

[10]L. Fernández-Fernández, G. Esteban, M. Giralt, T. Valente, I. Bolea, M. Solé, P. Sun, S. Benítez, J.R. Morelló, J. Reguant, B. Ramírez, J. Hidalgo, M. Unzeta, Food Funct. 6 (2015) 1251–1260.

[11]N. Sugimoto, M. Katakura, K. Matsuzaki, E. Sumiyoshi, A. Yachie, O. Shido, Basic Clin. Pharmacol. Toxicol. 124 (2019) 575–581.

[12]H.J. Smit, E.A. Gaffan, P.J. Rogers, Psychopharmacology 176 (2004) 412–419.

Pure Energy (Pterostilbene bound to Caffeine)

Scientific Name:
1,3,7-trimethylxanthine