Nootropic [ noh-uh–trop-ik, ‐-troh-pik ] – 

“(of a drug or other substance) capable of enhancing memory, concentration, or other cognitive functions and of preventing cognitive decline”

In the alternative health scene, there seems to be a growing interest in the concept of “enhancing cognition” or “boosting” brain function. I placed “boost” in quotation marks because that word only generically describes what people want to achieve when they take a nootropic supplement and the idea behind it needs nuance. As the definition above states; “or other cognitive functions”, implies that becoming smarter isn’t the only benefit behind a nootropic supplement. With that being said, I took it upon myself to find a variety nootropic supplements on the market, compare the formulations, and distill the common ingredients found in them. Having a clear idea of what facet of cognitive function each ingredient improves should help someone pick a nootropic supplement depending on their individual aspirations. 

Ingredient	Functions
Alpha GPC (L-α-glycerophosphorylcholine)	Alpha GPC is a form of choline, which is essential for brain development and function for several reasons.  Humans can partially synthesise choline via the liver when phosphatidylethanolamine is methylated by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT) to form phosphatidylcholine but most of our choline intake comes from food. During gestation, high choline concentrations in the brain and spinal cord are important for neural tube closure and brain development. In research conducted on rats, extra choline exposure in utero resulted in enhanced visuospatial and auditory memory by as much as 30% throughout the offspring’s lifespan, as well as timing and temporal memory.  Dietary choline deficiency also decreases s-adenosylmethionine (SAMe) because choline is metabolised into betaine, which can be used to synthesize SAMe and this results in undermethylation of DNADNA undermethylation can have deleterious effects on brain development as this can lead to altered gene expression and changes in stem cell proliferation and development (Zeisel, 2006)  Choline is a precursor to membrane phospholipids that are necessary for nerve cell myelination and brain function, such as phosphatidylcholine and sphingomyelin. This is party why choline has been suggested to have a neuroprotective role against age-related memory decline. Choline is also a precursor to acetylcholine, a neurotransmitter involved in motor neuron transmission (muscle contractions) and cholinergic activity in the brain, influencing cognitive functions (Bekdash, 2016, p. 383-385) In the brain, NMDA (N-methyl-D-aspartate) acts as a glutamate receptor and glutamate is a primary excitatory neurotransmitter which plays an important role in synaptic plasticity and this mechanism is thought to be pivotal in memory formation. Glutamate transmission is thought to be modulated by acetylcholine and given that acetylcholine is released during wakefulness, it helps to coordinate cognitive states throughout the day (Cools & Arnsten, 2021)  Alpha-GPC is a semi-synthetic derivative of lecithin, which is converted to phosphorylcholine upon ingestion, a metabolically active form of choline that reaches cholinergic nerve terminals and increases acetylcholine levels In experimental animals, alpha GPC facilitates memory and learning, improves brain transduction mechanisms (biochemical functions that modify neuronal activity), and even mitigates age-related structural changes in the frontal cortex and hippocampus (Traini et al, 2013)  Additionally, alpha GPC has also shown promise in increasing motivation, which is likely because alpha GPC is able to increase expression of dopamine in the frontal cortex (brain region associated with communication, memory, attention, thinking) and cerebellum Dopaminergic neurons are located in three distinct nuclei of the brain, one of them being the ventral tegmental area (VTA) and dopaminergic neurons in this area project to the nucleus accumbens, a region that plays a crucial role in processes of motivation (Tamura et al, 2021)
Sage (Salvia officinalis)	Over 900 species of the Salvia plant are distributed around the world and have been used traditionally to treat a wide variety of ailments, from respiratory tract infections, to digestive complaints and to enhance “head and brain” functions  Salvia plants are rich in polyphenols, including phenolic acids and flavonoids, as well as essential oils and some of these compounds have been shown to possess neuro-protective and cognition-enhancing effects via several mechanisms In research investigating the effects of amyloid-b peptide (the protein associated with the progression of Alzheimer’s disease) in rats, Salvia attenuated the activity of pro-inflammatory cytokines, such as TNF-a, IL-6, and nitric oxide, indicating anti-inflammatory and anti-oxidant benefits Salvia can also inhibit acetylcholinesterase (the enzyme which breaks down acetylcholine) activity and given acetylcholine’s role in cognitive function, it is likely it’s increase would coincide with improvements in memory (Lopresti, 2016)  Studies using extracts of Salvia in both young adult and elderly participants showed reductions in anxiety and increases in vigilance and happiness, resulting in better mood ratings  Additionally, significant improvements in memory scores, including word presentation, immediate and delayed word recall, simple reaction time, picture presentation, choice reaction time, digit vigilance tasks, spatial and numeric working memory, and delayed word and picture recognition (Ertas et al, 2023)   Out of the broad range of polyphenols found in Sage, certain compounds, such as 1,8-cineole and rosmarinic acid, have been isolated as strong candiates for exhibiting the anti-cholinesterase activity that results in increased acetylcholine and subsequent cognitive benefits  Out of the other cognitive enhancements behind Sage extracts, particularly strong benefits were seen in episodic (relating to learning and retrieving information about experiences that occur during daily life) and declarative memory (recalling past events or experiences) and these benefits can occur even after a single dose (Edwards et al, 2021)
L-theanine	Theanine is a derivative of glutamic acid and is a major constituent of green tea. It tends to be most prized for its ability to improve relaxation and sleep because of its action on GABA (an inhibitory neurotransmitter) and glycine, which also coincides with an increase in dopamine release  Additionally, theanine administration has also shown to increase brain-derived neurotrophic factor (BDNF) and inhibit a range of cellular proteins implicated in neurodegeneration, which indicates theanine’s potential neuroprotective benefit, as BDNF is important for survival and growth of neurons (Lardner, 2013)  Theanine’s NMDA receptor agonist activity is likely the main driver of its stress-reducing (anxiolytic/anti-depressant) and cognitive enhancing effects In a randomised trial comparing L-theanine to placebo, theanine supplementation resulted in significant improvements in stress-related symptom, sleep latency, and “daytime dysfunction” scores in comparison to placebo-controlled  In regards to cognitive function scores, theanine supplementation resulted in significant improvements in executive function (skills that facilitate planning and meeting goals, staying focused, following directions, amongst others) and verbal fluency (a function that facilitates information retrieval from memory) scores (Hidese et al, 2019)  A systematic review of trails using theanine and/or caffeine vs placebo revealed that cognition composite scores (blend of cognition scores from different trials) improved with theanine and inhibition control improved with theanine and caffeine  Theanine combined with caffeine was also associated with a decrease in task-related reactivity in the brain region associated with mind-wandering within the default mode network, resulting in improved concentration and decreased distractability (Sohail et al, 2021)
N-acetyl-tyrosine	N-acetyl-tyrosine is a form of the amino acid, tyrosine, which is converted to L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor to the neurotransmitters dopamine and norepinephrine The enzyme responsible for this conversion, tyrosine hydroxylase, is about 75% saturated with tyrosine and given that other enzymes involved in catecholamine synthesis have lower saturation rates, it is possible to significantly increase brain catecholamine levels by increasing tyrosine intake A commonly reported effect of tyrosine in trials is that it can prevent decrements in cognitive task performance, reduce inhibition reaction time, and improve convergent thinking (reaching a well-defined solution to a problem), whilst under physically or mentally tasking conditions Scores of working memory were high, whilst under physical stress via cold exposure and in situations requiring multi-tasking (Hase et al, 2015) Tyrosine’s cognitive enhancement can be explained by it’s action in the brain, where it only enhances neurotransmitter synthesis in actively firing neurons, therefore inhibiting neurotransmitter depletion during periods of increased brain activity  Another review investigating the effects of tyrosine supplementation found consistent improvements in working memory in both physically and mentally challenging situations, as well as in symptoms of depression (Jongkees et al, 2015)  In aging, there is a progressive decline in brain dopamine receptor and transporter binding, leading to impairments in working memory Given that aging has also been shown to be accompanied by compensatory up-regulation of dopamine synthesis capacity, increasing tyrosine dose in the elderly could have negative effects of cognition A trial investigating the effects of different tyrosine doses on cognition in the elderly and young adults, showed that higher doses (between 150mg/kg of body weight and 200 mg/kg) had unfavourable effects on working memory in the elderly but not in young adults  In the elderly, it is possible that a rapid increase in tyrosine levels could lead to a decrease in tyrosine hydroxylase, resulting in a down-regulation of dopamine synthesis (Rest et al, 2017)
Huperzia A	Huperzia A (Hup A) is an alkaloid compound derived from a plant within the Huperziaceae family, 33 of which are used for medicinal purposes but Hup A is specifically isolated from Huperzia serrata Huperzia A’s cognitive-enhancing effects are primarily rooted it’s potent acetylcholinesterase (AChE) inhibition, therefore it is likely that Hup A has similar biochemical activity to AChE inhibiting compounds found in Sage and unsurprisingly, Hup A seems to efficiently improve age-associated learning and memory decline in both animals and humans (Ferreira et al, 2014) It should be noted that Huperzia serrata or Hup A is not the only Huperziaceae plant or active compound that exhibits cognitive-enhancing effects, as Huperzia saururus has been shown to contain a cocktail of alkaloids, such as sauroine, sauroxine, 6-hydroxylycopodine, N-acetyllycodine, lycopodine, lycodine, N-methyllycodine, and clavolonine, which likely act synergistically to exert AChE inhibiting effects Additionally, Huperzia saururus have a marked effect on hippocampal synaptic plasticity in rats, which manifests as a reduction in threshold to generate long-term potentiation (LTP) of synaptic transmission This improvement in LTP, the process where synaptic connections between neurons become stronger with frequent activation, is likely the driver of Huperzia’s memory-improving effect (Ortega et al, 2006)  Huperzia is commonly studied as an adjunct to Alzheimer’s disease treatments because it’s bioactive compounds can help in several neurological areas that are affected by neurodegenerative disorders In Alzheimer’s disease, cholinergic neurons and neurotransmitter systems are heavily impacted and this results in progressive loss of cognitive functions, such as memory, attention and executive functions As an acetylcholinesterase inhibitor, Hup A has better permeation through the blood-brain barrier, higher oral bioavailability and longer duration of AChE inhibition in comparison to pharmaceutical AchEIs, such as galanthamine, donezepil, tacrine and rivastigimine Aggregation of amyloid-beta peptides and hyperphosphorylated Tau proteins are the primary pathological alterations found in Alzheimer’s disease and A-β peptides impact on neurons and glial cells result in the activation of pro-inflammatory cascades, oxidative stress, tau phosphorylation, damage of synaptic structure and neuronal death  Huperzia extract could mitigate the ramifications of neuro-inflammation as Hup A has been shown to decrease reactive oxygen species and extracts of huperzia selago can reduce nitric oxide (a pro-inflammatory molecule) production and transcription of pro-inflammatory genes (Thu et al, 2020)

Finally, I found three other ingredients that are frequently added to nootropic formulas; lion’s mane mushroom, which is prized for it’s nerve-protective compounds that I briefly wrote about here, and nicotinamide (vitamin B3) and cyano/methylcobalamin (vitamin B12), which I have also written about here. 

References

Bekdash, R.A. (2016). The benefits of natural products for neurodegenerative diseases. Springer. http://dx.doi.org/10.1007/978-3-319-28383-8_24

Cools, R., & Arnsten, A.F.T. (2021). Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine. Neuropsychopharmacology, 47, 309–328. https://doi.org/10.1038/s41386-021-01100-8

Edwards, K.D., Dubberke, A., Meyer, N., Kugel, S., et al. (2021). Assessment of the effects of a Sage (Salvia officinalis) extract on cognitive performance in adolescents and young adults. MedRxiv.https://doi.org/10.1101/2021.05.28.21257776

Ertas, A., Yigitkan, S., & Orhan, I.E. (2023). A focused review on cognitive improvement by the genus salvia L. (Sage)—from ethnopharmacology to clinical evidence. Pharmaceuticals, 16(2), 171. https://doi.org/10.3390/ph16020171

Ferreira, A., Rodrigues, M., Fortuna, A., Falcão, A., et al. (2016). Huperzine A from Huperzia serrata: a review of its sources, chemistry, pharmacology and toxicology. Phytochemistry reviews, 15, 51–85. https://doi.org/10.1007/s11101-014-9384-y

Hase, A., Jung, S.E., & Rot, M.a.h. (2015). Behavioral and cognitive effects of tyrosine intake in healthy human adults. Pharmacology, biochemistry and behaviour, 133, 1-6. https://doi.org/10.1016/j.pbb.2015.03.008

Hidese, S., Ogawa, S., Ota, M., Ishida, I., et al. (2019). Effects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: a randomized controlled trial. Nutrients, 11(10), 2362. https://doi.org/10.3390/nu11102362

Jongkees, B.J., Hommel, B., Kühn, S., & Colzato, L.S. (2015). Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands–A review. Journal of psychiatric research, 70, 50-57. https://doi.org/10.1016/j.jpsychires.2015.08.014

Lardner, A.L. (2013). Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders. Nutritional neuroscience, 17(4), 145-155. https://doi.org/10.1179/1476830513Y.0000000079

Lopresti, A.L. (2016). Salvia (sage): a review of its potential cognitive-enhancing and protective effects. Drugs in R&D, 17, 53-64. https://doi.org/10.1007/s40268-016-0157-5

Ortega, M.G., Vallejo, M.G., Cabrera, J.L., et al. (2006). Huperzia saururus, activity on synaptic transmission in the hippocampus. Journal of ethnopharmacology, 104(3), 374-378. https://doi.org/10.1016/j.jep.2005.11.002

Rest, O.V., Bioemendaal, M., Heus, R.D., & Aarts, E. (2017). Dose-dependent effects of oral tyrosine administration on plasma tyrosine levels and cognition in aging. Nutrients, 9(12), 1279. https://doi.org/10.3390/nu9121279

Sohail, A.A., Ortiz, F., Varghese, T., Fabara, S.P., et al. (2021). The cognitive-enhancing outcomes of caffeine and l-theanine: a systematic review. Cureus, 13(12), e20828. https://doi.org/10.7759%2Fcureus.20828

Tamura, Y., Takata, K., Matsubara, K., & Kataoka, Y. (2021). Alpha-Glycerylphosphorylcholine increases motivation in healthy volunteers: a single-blind, randomized, placebo-controlled human study. Nutrients, 13(6), 2091.https://doi.org/10.3390/nu13062091

Thu, D.K., Vui, D.T., Huyen, N.T.N., Duyen, D.K., et al. (2020). The use of Huperzia species for the treatment of Alzheimer’s disease.  Journal of basic and clinical physiology and pharmacology, 31(3). https://doi.org/10.1515/jbcpp-2019-0159

Traini, E., Bramanti, V., & Amenta, F. (2013). Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent. Current alzheimer research, 10(10), 1070-1079. https://doi.org/10.2174/15672050113106660173

Zeisel, S.H., (2006). The fetal origins of memory: the role of dietary choline in optimal brain development. The journal of pediatrics, 149(5), s131-s136. https://doi.org/10.1016/j.jpeds.2006.06.065