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Cognitive enhancers are drugs, supplements, nutraceuticals, and functional foods that enhance attentional control and memory. Nootropics are cognitive enhancers that are neuroprotective or extremely nontoxic. Nootropics (such as Modafinil) are by definition cognitive enhancers, but a cognitive enhancer is not necessarily a nootropic.
Protects the brain from physical or chemical injury.
Enhances the tonic cortical/subcortical control mechanisms
Exhibits few side effects and extremely low toxicity, while lacking the pharmacology of typical psychotropic drugs (motor stimulation, sedation, etc.).
Since Giurgea's original criteria were first published, there has been little agreement as to what truly constitutes a nootropic compound. The most well defined criteria to date was established by Skondia in 1979. Skondia uses a metabolic approach, taking into account the pharmacological mode of action.
Skondia's nootropic criteria:
I. No direct vasoactivity
A. No vasodilation
B. No vasoconstriction
II. EEG activity: No change in basic rhythm
A. Quantitative EEG: Increased power spectrum (beta 2 and alpha)
B. Qualitative EEG: Decreased delta waves and cerebral suffering
III. Must pass blood-brain barrier
A. Under normal conditions
B. Under pathological conditions
IV. Must show metabolic activity in:
A. Animal brain metabolism
B. Human brain metabolism (clinical evaluation)
1. A-V differences
a. Increased extraction quotients of O2
b. Increased extraction quotients of glucose
c. Reduced lactate pyruvate ratio
2. Regional cerebral metabolic rates (rCMR)
a. Increased ICMR of O2
b. Increased rCMR of glucose
3. Regional cerebral blood flow: Normalization
V. Minimal side effects
VI. Clinical trials must be conducted with several rating scales designed to objectify metabolic cerebral improvement.
Availability and prevalence
At present, there are several drugs on the market that improve memory, concentration, and planning, and reduce impulsive behavior. Many more are in different stages of development. The most commonly used class of drug is stimulants.
These drugs are used primarily to treat people with cognitive or motor function difficulties attributable to such disorders as Alzheimer's disease, Parkinson's disease, Huntington's disease and ADHD. However, more widespread use is being recommended by some researchers. These drugs have a variety of human enhancement applications as well, and are marketed heavily on the Internet. Nevertheless, intense marketing may not correlate with efficacy; while scientific studies support some of the claimed benefits, it is worth noting that not all of the claims from certain nootropics suppliers have been formally tested.
In academia a Nootropic called modafinil has been used to increase productivity, although its long-term effects have not been assessed in healthy individuals. Stimulants such as methylphenidate, a cognitive enhancer (which is not considered as a Nootropic according to the criteria above), are being used on college campuses, and by an increasingly younger group. One survey found that 7% of students had used stimulants for a cognitive edge, and on some campuses use in the past year is as high as 25%. The use of prescription stimulants is especially prevalent among students attending academically competitive colleges and students who are members of a fraternity/sorority.
Surveys suggest that 3-11% of American students and 0.7-4.5% of German students have used cognitive enhancers in their lifetime.
The main concern with pharmaceutical drugs is adverse effects, and these concerns apply to cognitive-enhancing drugs as well. Cognitive enhancers are often taken for the long-term when little data is available.
Dr. Corneliu E. Giurgea originally coined the word nootropics for brain-enhancing drugs with very few side-effects. Racetams are sometimes cited as an example of a nootropic with few side-effects and a wide therapeutic window. In the United States, unapproved drugs or dietary supplements do not have to have safety or efficacy approval before being sold.
B Vitamins—may influence cognitive function through an effect on methylation and homocysteine levels, as excess homocysteine has been associated with cognitive impairment and the B vitamins work to reduce homocysteine. However, although epidemiological evidence shows an association, two studies did not find B vitamin supplementation improves cognitive function, and another that found an association was criticized. In 2008 a systematic review of trials found "little evidence of a beneficial impact" from supplements on cognitive function later in life. A randomized, placebo-controlled trial in 168 70 year olds with mild cognitive impairment showed that a mix of B vitamins slowed the rate of brain atrophy; the slowing was related to a decrease in homocysteine levels.
Choline— Higher concurrent choline intake was related to better cognitive performance. It improves long-term memory in animal models.
ω-3 fatty acids have been linked to the maintenance of brain function. Omega-3's provide DHA, important in the function and growth of nervous tissue. It is especially important during brain development. A study preformed in Norway demonstrated a potential link between Omega-3 consumption during pregnancy and child intelligence test scores. A cross-sectional population-based study of 1,613 subjects found an association between PUFA intake and decreased risk for impairment of cognitive function & cognitive speed. Another study showed that boys with lower levels of Omega-3 had more behavior issues, including ADHD.
Isoflavones—may be related to cognitive function. A double-blind, placebo-controlled study showed improvement in spatial working memory after administration of an isoflavone combination containing daidzein, genistein & glycitein. In a randomized, double-blind, placebo-controlled study of older, non-demented men & women, soy isoflavone supplementation improved performance on 6 of 11 cognitive tests, including visual-spatial memory and construction, verbal fluency and speeded dexterity; unexpectedly, the placebo group performed better on 2 tests of executive function.
Vitamin D—has positive effects on cardiovascular health and may have positive effects on cognitive function separately; the active form of Vitamin D seems to be involved in brain development and in adult brain function. In particular, metabolic pathways for Vitamin D in the hippocampus and cerebellum have been found. Epidemiological data show that higher Vitamin D levels (>20 ng/mL or 50nmol/L) are associated with better cognitive function, but do not seem to be associated with better memory performance. Vitamin D has also been shown to be necessary in the production of dopamine
A 2007 survey of online databases for herbs used in traditional herbal medicine to treat cognitive decline – without any proof of safety or efficacy – found over 150 plant species, such as Ginkgo biloba and Epimedium which is commonly call 'Goat weed'.
Stimulants are often seen as smart drugs, but may be more accurately termed productivity enhancers. These typically improve concentration and a few areas of cognitive performance, but only while the drug is still in the blood at therapeutic concentrations. Some scientists recommend widespread use of stimulants such as methylphenidate and amphetamines by the general population to increase brain power.
Caffeine—shown to increase alertness, performance, and in some studies, memory. Children and adults who consume low doses of caffeine showed increase alertness, yet a higher dose was needed to improve performance.
The nootropics in this section are purported or shown to enhance concentration or the recollection and formation of memories.
Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the nervous system that use acetylcholine. Acetylcholine is a facilitator of memory formation. Increasing the availability of this neurotransmitter in the brain may improve these functions. Cholinergic nootropics include acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors:
cannabis Due to its AChE-inhibiting properties, Cannabis appears to increase acetylcholine levels and therefore studies suggest it as a treatment for Alzheimer's.Anxiolytic and analgesic found in cannabis. Neuroprotectant, possible Alzheimer's prevention and possible neurogenesis inducer. Possible neurotoxic effects of a notable constituent, THC, have been documented
α5IA—α5 inverse agonist. A number of α5IA analogues exist that, like α5IA, selectively and partially agonize some GABA receptor subtypes while inverse agonizing others, which may provide a nootropic effect without the associated anxiogenic effects of GABA inverse agonism.Template:Medial citation needed
Pantogam has a direct effect on the GABA-B receptor-channel complex.
See also: AMPAkine
Ligands and modulators of the AMPA receptor, an ionotropic glutamate receptor, are being researched for a myriad of conditions, from Alzheimer's to ADHD. Although there are many AMPAkines being researched, those mentioned here show signs of entering the market in the near future. Other notable drugs with AMPA-modulating activity include aniracetam and tianeptine.
CX-717—pending FDA approval for memory-impairing illnesses and ADHD
Rolipram—PDE4 inhibitor, shows alertness enhancement, long term memory improvement and neuroprotection
Mesembrine—PDE4-inhibitor with possible serotonergic activity
α2A receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal cortex.
Guanfacine is an α2A receptor agonist, FDA approved the treatment of ADHD. Guanfacine has been found to strengthen working memory, reduce distractibility, improve response inhibition, increase regional cerebral blood flow, reduce locomotor hyperactivity, and improve attentional control in animal models, as well as enhance memory function in humans. Another study found no effect on healthy male adult's executive functions and working memory, and small decrements on 2 tasks relating to the sedative effect of guanfacine.
Serotonin is a neurotransmitter with various effects on mood and possible effects on neurogenesis. Serotonergics are substances that affect the neurotransmitter serotonin or the components of the nervous system that use serotonin. Serotonergic nootropics include serotonin precursors and cofactors, and serotonin reuptake inhibitors:
2C-x—it has been reported that some these compounds causes nootropic, stimulant, or anti-anxiety effects at low doses. 2C-D, 2C-I, and 2C-C are examples. However, at hallucinogenic doses, these chemical compounds may be unpredictable. Research on these chemicals is sparse; they require further investigation.
Tianeptine—atypical antidepressant with anxiolytic properties; a hypothesized mechanism of action revolves around modulation of NMDA and AMPA receptors, based on tianeptine's effect of promoting stress-associated impaired neuroplasticity; it increases the extracellular concentration of dopamine in the nucleus accumbens and modulates the D2 and D3 dopamine receptors, but this effect is modest and almost certainly indirect.
Modafinil—purported dopaminergic activity that exhibits the criteria of a Nootropic
Citicoline (INN) (aka: cytidine diphosphate-choline (CDP-Choline) & cytidine 5'-diphosphocholine)—studies suggest CDP-choline supplements partially prevent the loss of dopamine D2 receptors in aged mice, and that CDP-choline supplementation ameliorates memory impairment caused by environmental conditions (in rats). Preliminary research has found that citicoline may have potential in the treatment of attention deficit-hyperactivity disorder.
Sleep is known to be important in memory consolidation, mood, anxiety, appetite, and numerous other physiological processes. Drugs that improve sleep may therefore have an indirect nootropic effect.
Anti-depression, adaptogenic (anti-stress), and mood stabilization
Stress (specifically elevated levels of circulating corticosteroids) has been associated with the cognitive deficits seen in human aging. Many studies show that stress and fatigue negatively impact cognitive functioning in young adults. Some level of stress in the learning environment may aid the ability to focus and retain information. However, stress levels, especially high, sustained or traumatic stressors, hinder declarative memory, spatial reasoning, learning, attention and working memory. Fatigue is also a stressor that impedes attention, processing, retrieval, working memory and short term memory. The effects of stress on cognitive performance seem to be controlled by the sympatho-adrenal system and the hypothalamic-hypophysial-adrenal axis.
Depression and depressed mood negatively affect cognitive performance and memory. Depression was found to increase false memory, especially with negative words or subjects.
It is reasoned that counteracting and preventing depression and stress management may be an effective nootropic strategy. Proper nutrition, adequate sleep, and mechanisms for coping with stress, such as meditation, have been shown to improve learning and cognitive functioning both in the short and long term.
The substances below may not have been mentioned earlier on the page:
Beta blockers—evidence from controlled trials spanning 25 years supports the claim that beta-blockers are effective for reducing anxiety, likely through peripheral blockade of beta-receptors; most data comes from studies of generalized anxiety and acute stress.
Lemon Balm—displays adaptogen properties; in rats it has been shown to possess GABA transaminase inhibitor activity and in homogenates of human cerebral cortical cell membranes possesses activity at acetylcholine receptors. In a randomized, double-blind, placebo-controlled study of 18 healthy volunteers, 600 mg of 'Melissa officinalis' extract attenuated volunteers' response to a laboratory-induced stress test 1 hour after administration; 300 mg significantly improved speed of mathematical processing 1 hour after administration.
St John's Wort—herbal supplement approved (in Europe) to treat mild depression. Method of action is unproven but exhibits effects similar to both MAOIs and SSRIs. There is evidence that it may decrease the effectiveness of methylphenidate treatment.
Panax ginseng—Multiple randomized, placebo-controlled studies in healthy volunteers have been performed, results include increases in accuracy of memory, speed in performing attention tasks and improvement in performing difficult mental arithmetic tasks, as well as reduction in fatigue and improvement in mood.
IAP(5-APDI) Lifts mood and promotes a peaceful mindset. Anti-anxiety.
2-methyl-2-butanol Anti-anxiety that lifts mood and increases sociability. Although it doesn't have the side effects or toxic metabolites that ethanol has, frequent use may cause dependence.
Blood flow and metabolic function
Brain function is dependent on many basic processes such as the usage of ATP, removal of waste, and intake of new materials. Improving blood flow or altering these processes can benefit brain function. The list below contains only vasodilators that have shown at least probable mental enhancement.
Mildronate may improve the ability of learning and memory, as the drug changes the expression of hippocampal proteins related to synaptic plasticity
Ginkgo biloba—vasodilator. Acts as an NRI. A double-blind, placebo-controlled trial in young healthy females showed an improvement in short-term memory performance 1 hour after administration of a 600 mg dose. An analysis of 29 placebo-controlled RCTs showed that "there is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material." A double-blind, placebo-controlled study in 20 young healthy volunteers showed a dose-dependent improvement in speed-of-attention following administration of 240 mg and 360 mg of Ginkgo extract, effects were measured 2.5h after administration and persisted at least until 6h; various other time- and dose-specific changes (some positive, some negative) in other areas were observed.
Vinpocetine— is reported to have cerebral blood-flow enhancing and neuroprotective effects, and is used as a drug in Eastern Europe for the treatment of cerebrovascular disorders and age-related memory impairment. Also shown to inhibit voltage-sensitive Na+ channels—however, through a similar mechanism to reserpine, Vinpocetine may temporarily deplete the monoamines serotonin, dopamine and norepinephrine by inhibiting VMAT, thus preventing them from reaching the synapse. Vinpocetine may therefore induce or exacerbate depressive symptoms as an adverse effect. However, this effect tends to be reversible upon cessation of Vinpocetine administration, with full remission typically occurring within 3–4 weeks. Vinpocetine has been identified as a potent anti-inflammatory agent that might have a potential role in the treatment of Parkinson's disease and Alzheimer's disease.
Vincamine—increases blood circulation (vasodilator) and metabolism in the brain; related to vinpocetine; used in sustained release.
Nicergoline—an ergot derivative used to treat senile dementia and other disorders with vascular origins; it has been found to increase mental agility and enhance clarity and perception; it decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells; it has been used for more than three decades for the treatment of cognitive, affective, and behavioral disorders of older people.
Experimental histamine antagonists
The H3-receptor decreases neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin. Thus, H3-receptor-antagonists increases cognition, vigilance, and wakefulness.
Ciproxifan—produces wakefulness and attentiveness in animal studies, and produced cognitive enhancing effects without prominent stimulant effects at relatively low levels of receptor occupancy, and pronounced wakefulness at higher doses.
Nerve growth stimulation and brain cell protection
Nerves are necessary to the foundation of brain communication and their degeneracy, underperformance, or lacking can have disastrous results on brain functions. Antioxidants may prevent oxidative stress and cell death, therefore exerting a neuroprotective effect.
These are hormones that have activity not necessarily attributable to another specific chemical interaction, but have shown effectiveness. Only specific nootropic effects are stated.
Vasopressin—memory hormone that improves both memory encoding and recall. Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) was given to 17 children with attention & learning disorders daily for 10 days in a placebo-controlled, randomized, double-blind study; memory & learning were improved compared with placebo; the same study failed to find similar benefits after administration of a single dose.
Other agents purported to have nootropic effects but do not (yet) have attributable mechanisms or clinically significant effects (but may upon refinement of administration) are listed below.
Nootropics with proven or purported benefits:
Polygala tenuifolia (Yuan Zhi)— A randomized, double-blind, placebo-controlled, parallel-group study of the extract of dried roots of Polygala tenuifolia in healthy adults produced memory-enhancing effects. A similar trial with elderly humans also found significant cognitive improvement.
Bacopa monniera (Brahmi) — Shown to possess adaptogenic properties and enhance memory and concentration. Folk use in Ayurvedic medicine purports "enhancement of curiosity"; Brahmi rasayana has been shown to improve learning and memory in mice
Clitoria ternatea (Shankhpushpi) — In traditional Ayurvedic medicine, it has been used for centuries as a memory enhancer, nootropic, antistress, anxiolytic, antidepressant, anticonvulsant, tranquilizing and sedative agent.
^Gazzaniga, Michael S. (2006). The Ethical Brain: The Science of Our Moral Dilemmas (P.S.). New York, N.Y: Harper Perennial. p. 184. ISBN0-06-088473-8.
^Giurgea C (1972). "[Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology] ("Vers une pharmacologie de l'active integrative du cerveau: Tentative du concept nootrope en psychopharmacologie")". Actual Pharmacol (Paris) (in French) 25: 115–56. PMID4541214.
^Sattler, S.; Sauer, C.; Mehlkop, G.; Graeff, P. (2013). "The Rationale for Consuming Cognitive Enhancement Drugs in University Students and Teachers". PLoS ONE8 (7): e68821. doi:10.1371/journal.pone.0068821.edit
^McDaniel, M.A., Maier, S.F., and Einstein, G.O. (2002). "Brain-Specific Nutrients: A Memory Cure?". Psychological Science in the Public Interest (American Psychological Society) 19 (11): 957–75. doi:10.1016/S0899-9007(03)00024-8. PMID14624946.
^Gualtieri F, Manetti D, Romanelli MN, Ghelardini C (2002). "Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs". Curr. Pharm. Des.8 (2): 125–38. doi:10.2174/1381612023396582. PMID11812254.
^Selhub J, Bagley L, Miller J, Rosenberg I (2000). "B vitamins, homocysteine, and neurocognitive function in the elderly". American Journal of Clinical Nutrition71 (2): 614S–620s. PMID10681269.
^Huskisson E, Maggini S, Ruf M (2007). "The influence of micronutrients on cognitive function and performance". J. Int. Med. Res.35 (1): 1–19. PMID17408051.
^Jia X, McNeill G, Avenell A (August 2008). "Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials". J Hum Nutr Diet21 (4): 317–36. doi:10.1111/j.1365-277X.2008.00887.x. PMID18721399.
^NCBI (Dec 2011). "The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort". The American Journal of Clinical Nutrition94 (6): 1584–91. doi:10.3945/ajcn.110.008938. PMID22071706.
^Adams M, Gmünder F, Hamburger M (September 2007). "Plants traditionally used in age related brain disorders--a survey of ethnobotanical literature". J Ethnopharmacol113 (3): 363–81. doi:10.1016/j.jep.2007.07.016. PMID17720341.
^Ghelardini, C; Galeotti, N; Lelli, C; Bartolini, A (2001 May-Jul). "M1 receptor activation is a requirement for arecoline analgesia.". Farmaco (Societa chimica italiana : 1989)56 (5-7): 383–5. PMID11482763.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Yang, YR; Chang, KC; Chen, CL; Chiu, TH (2000 Mar 31). "Arecoline excites rat locus coeruleus neurons by activating the M2-muscarinic receptor.". The Chinese journal of physiology43 (1): 23–8. PMID10857465.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Xie, DP; Chen, LB; Liu, CY; Zhang, CL; Liu, KJ; Wang, PS (2004 Jun 30). "Arecoline excites the colonic smooth muscle motility via M3 receptor in rabbits.". The Chinese journal of physiology47 (2): 89–94. PMID15481791.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Knobel, M (1974 Apr-1975 Mar). "Approach to a combined pharmacologic therapy of childhood hyperkinesis.". Behavioral neuropsychiatry6 (1-12): 87–90. PMID4619768.Check date values in: |date= (help)
^Woodruff-Pak, DS; Vogel RW, 3rd; Wenk, GL (2001 Feb 13). "Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.". Proceedings of the National Academy of Sciences of the United States of America98 (4): 2089–94. PMID11172080.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Tang, L., Wang, R., Tang, X. (2005). "Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC12 cells". Acta Pharmacologica Sinica26 (6): 673–678. doi:10.1111/j.1745-7254.2005.00130.x. PMID15916732.
^ abSpignoli, G; Pedata, F; Giovannelli, L; Banfi, S; Moroni, F; Pepeu, G (1986). "Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition.". Clinical neuropharmacology. 9 Suppl 3: S39–47. PMID3594455.Cite uses deprecated parameters (help)
^Shih, YH; Pugsley, TA (1985 Jun 3). "The effects of various cognition-enhancing drugs on in vitro rat hippocampal synaptosomal sodium dependent high affinity choline uptake.". Life sciences36 (22): 2145–52. PMID2987637.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Micheau, J; Durkin, TP; Destrade, C; Rolland, Y; Jaffard, R (1985 Aug). "Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation.". Pharmacology, biochemistry, and behavior23 (2): 195–8. PMID4059305.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Müller, U; Clark, L; Lam, ML; Moore, RM; Murphy, CL; Richmond, NK; Sandhu, RS; Wilkins, IA et al. (2005). "Lack of effects of guanfacine on executive and memory functions in healthy male volunteers". Psychopharmacology182 (2): 205–13. doi:10.1007/s00213-005-0078-4. PMID16078088.|displayauthors= suggested (help)
^Hansl, NR; Nikolaus R. Hansl, Beverley T. Mead (1978). "PRL-8-53: Enhanced learning and subsequent retention in humans as a result of low oral doses of new psychotropic agent". Psychopharmacology56 (3): 249–253. doi:10.1007/BF00432846. PMID418433.Cite uses deprecated parameters (help)
^Hansl, N. R. (1974). "A novel spasmolytic and CNS active agent: 3-(2-benzylmethylamino ethyl) benzoic acid methyl ester hydrochloride". Experientia30 (3): 271–272. doi:10.1007/BF01934822. PMID4824605. edit
^Smith, AJ; Stone, TW; Smith, RA (2007 Nov). "Neurotoxicity of tryptophan metabolites.". Biochemical Society transactions35 (Pt 5): 1287–9. PMID17956331.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Calderón-Guzmán, D.; Hernández-Islas, JL.; Espitia-Vázquez, I.; Barragán-Mejía, G.; Hernández-García, E.; Santamaría-del Angel, D.; Juárez-Olguín, H. "Pyridoxine, regardless of serotonin levels, increases production of 5-hydroxytryptophan in rat brain.". Arch Med Res35 (4): 271–4. doi:10.1016/j.arcmed.2004.03.003. PMID15325498.
^Lee, NS.; Muhs, G.; Wagner, GC.; Reynolds, RD.; Fisher, H. (Mar 1988). "Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism.". Pharmacol Biochem Behav29 (3): 559–64. doi:10.1016/0091-3057(88)90020-2. PMID3362950.
^Stafford, GI.; Pedersen, ME.; van Staden, J.; Jäger, AK. (Oct 2008). "Review on plants with CNS-effects used in traditional South African medicine against mental diseases.". J Ethnopharmacol119 (3): 513–37. doi:10.1016/j.jep.2008.08.010. PMID18775771.
^Yáñez, M.; Fraiz, N.; Cano, E.; Orallo, F. (Jun 2006). "Inhibitory effects of cis- and trans-resveratrol on noradrenaline and 5-hydroxytryptamine uptake and on monoamine oxidase activity.". Biochem Biophys Res Commun344 (2): 688–95. doi:10.1016/j.bbrc.2006.03.190. PMID16631124.
^Xu, Y.; Ku, BS.; Yao, HY.; Lin, YH.; Ma, X.; Zhang, YH.; Li, XJ. (Jul 2005). "The effects of curcumin on depressive-like behaviors in mice.". Eur J Pharmacol518 (1): 40–6. doi:10.1016/j.ejphar.2005.06.002. PMID15987635.
^Rahman, T.; Rahmatullah, M. (Jan 2010). "Proposed structural basis of interaction of piperine and related compounds with monoamine oxidases.". Bioorg Med Chem Lett20 (2): 537–40. doi:10.1016/j.bmcl.2009.11.106. PMID19969454.
^Herraiz, T.; González, D.; Ancín-Azpilicueta, C.; Arán, VJ.; Guillén, H. (Mar 2010). "beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO).". Food Chem Toxicol48 (3): 839–45. doi:10.1016/j.fct.2009.12.019. PMID20036304.
^ abvan Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, PA.; Hostettmann, K. (Mar 2009). "Monoamine oxidase inhibition by Rhodiola rosea L. roots.". J Ethnopharmacol122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID19168123.
^Invernizzi R, Pozzi L, Garattini S, Samanin R (March 1992). "Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism". Neuropharmacology31 (3): 221–7. doi:10.1016/0028-3908(92)90171-K. PMID1630590.
^Zhang, CL; Feng, ZJ; Liu, Y; Ji, XH; Peng, JY; Zhang, XH; Zhen, XC; Li, BM (2012). "Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.". PloS one7 (12): e51910. PMID23284812.Cite uses deprecated parameters (help)
^Stahl, SM; Pradko, JF; Haight, BR; Modell, JG; Rockett, CB; Learned-Coughlin, S (2004). "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor.". Primary care companion to the Journal of clinical psychiatry6 (4): 159–166. PMID15361919.Cite uses deprecated parameters (help)
^Slemmer, JE; Martin, BR; Damaj, MI (2000 Oct). "Bupropion is a nicotinic antagonist.". The Journal of pharmacology and experimental therapeutics295 (1): 321–7. PMID10991997.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Romberg, RW; Needleman, SB; Snyder, JJ; Greedan, A (1995 Nov). "Methamphetamine and amphetamine derived from the metabolism of selegiline.". Journal of forensic sciences40 (6): 1100–2. PMID8522918.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Silveri MM, Dikan J, Ross AJ, et al. (November 2008). "Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy". NMR in Biomedicine21 (10): 1066–75. doi:10.1002/nbm.1281. PMID18816480.
^Hardeland, R (2005 Jul). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.". Endocrine27 (2): 119–30. PMID16217125.Check date values in: |date= (help)
^Reiter, RJ; Acuña-Castroviejo, D; Tan, DX; Burkhardt, S (2001 Jun). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.". Annals of the New York Academy of Sciences939: 200–15. PMID11462772.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Mehraein, F; Talebi, R; Jameie, B; Joghataie, MT; Madjd, Z (2011). "Neuroprotective effect of exogenous melatonin on dopaminergic neurons of the substantia nigra in ovariectomized rats.". Iranian biomedical journal15 (1-2): 44–50. PMID21725499.Cite uses deprecated parameters (help)
^Kunz, D; Mahlberg, R; Müller, C; Tilmann, A; Bes, F (2004 Jan). "Melatonin in patients with reduced REM sleep duration: two randomized controlled trials.". The Journal of clinical endocrinology and metabolism89 (1): 128–34. PMID14715839.Cite uses deprecated parameters (help);Check date values in: |date= (help)
^Popoli, M (2009). "Agomelatine: innovative pharmacological approach in depression.". CNS drugs. 23 Suppl 2: 27–34. PMID19708723.
^Lupien S, Lecours AR, Lussier I, Schwartz G, Nair NP, Meaney MJ (May 1994). "Basal cortisol levels and cognitive deficits in human aging.". J Neurosci.14 (5pt1): 2893–903. PMID8182446.
^ abcdPALMER, L. K. (2013). The Relationship between Stress, Fatigue, and Cognitive Functioning. College Student Journal, 47(2), 312-325.
^ abcdSingh, Y, Ratna, A (2012). "Immediate and Long-term Effects of Meditation on Acute Stress Reactivity, Cognitive Functions, and Intelligence." Alternative Therapies in Health & Medicine 18, no. 6: 46-53.
^Awad, R.; Levac, D.; Cybulska, P.; Merali, Z.; Trudeau, V.L.; Arnason, J.T. (September 2007). "Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (GABA) system". Can J Physiol Pharmacol.85 (9): 933–42. doi:10.1139/Y07-083. PMID18066140.
^Wake G, Court J, Pickering A, Lewis R, Wilkins R, Perry E (February 2000). "CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory". J Ethnopharmacol.69 (2): 105–14. doi:10.1016/S0378-8741(99)00113-0. PMID10687867.
^Kennedy DO, Little W, Scholey AB (Jul–Aug 2004). "Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm)". Psychosom Med.66 (4): 607–13. doi:10.1097/01.psy.0000132877.72833.71. PMID15272110.
^Panossian A., Wikman G."Evidence based efficacy of adaptogens in fatigue" Planta Medica 2009; 75:9
^Niederhofer, H. (2007). "St. John's wort may diminish methylphenidate's efficacy in treating patients suffering from attention deficit hyperactivity disorder". Medical Hypotheses68 (5): 1189–2007. doi:10.1016/j.mehy.2005.11.004. PMID17254717. edit
^Soman I, Mengi SA, Kasture SB (September 2004). "Effect of leaves of Butea frondosa on stress, anxiety, and cognition in rats". Pharmacol. Biochem. Behav.79 (1): 11–6. doi:10.1016/j.pbb.2004.05.022. PMID15388278.
^Kennedy DO, Wightman EL (Jan 2011). "Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function.". Adv Nutr.2 (1): 32–50. doi:10.3945/an.110.000117. PMID22211188.
^Jesky, R.; Hailong, C. (August 2011). "Are Herbal Compounds the Next Frontier for Alleviating Learning and Memory Impairments? An Integrative Look at Memory, Dementia and the Promising Therapeutics of Traditional Chinese Medicines". Phytotherapy Research25 (8): 1105–1118. doi:10.1002/ptr.3388. PMID21305632.
^Morgan, A.; Stevens, J. (July 2010). "DoesBacopa monnieriImprove Memory Performance in Older Persons? Results of a Randomized, Placebo-Controlled, Double-Blind Trial". The Journal of Alternative and Complementary Medicine16 (7): 753–759. doi:10.1089/acm.2009.0342. PMID20590480.
^Fehske, CJ.; Leuner, K.; Müller, WE. (Jul 2009). "Ginkgo biloba extract (EGb761) influences monoaminergic neurotransmission via inhibition of NE uptake, but not MAO activity after chronic treatment.". Pharmacological Research60 (1): 68–73. doi:10.1016/j.phrs.2009.02.012. ISSN1043-6618. PMID19427589.
^Hindmarch I (1986). "[Activity of Ginkgo biloba extract on short-term memory].". Presse Med (in French) 15 (31): 1592–94. PMID2947108.
^Kaschel R (2009). "Ginkgo biloba: specificity of neuropsychological improvement--a selective review in search of differential effects.". Hum Psychopharmacol24 (5): 345–70. doi:10.1002/hup.1037. PMID19551805.
^Kennedy DO, Scholey AB, Wesnes KA (2000). "The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers.". Psychopharmacology (Berl)151 (4): 416–23. doi:10.1007/s002130000501. PMID11026748.
^Szilágyi G, Nagy Z, Balkay L, et al. (2005). "Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study". Journal of the Neurological Sciences. 229–230: 275–84. doi:10.1016/j.jns.2004.11.053. PMID15760651.
^Dézsi L, Kis-Varga I, Nagy J, Komlódi Z, Kárpáti E (2002). "[Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic acid derivatives as potential therapeutic tools in ischemic stroke]". Acta Pharmaceutica Hungarica (in Hungarian) 72 (2): 84–91. PMID12498034.
^Trejo, F.; Nekrassov, V.; Sitges, M. (Aug 2001). "Characterization of vinpocetine effects on DA and DOPAC release in striatal isolated nerve endings.". Brain Res909 (1–2): 59–67. doi:10.1016/S0006-8993(01)02621-X. PMID11478921.
^Fioravanti M, Flicker L (2001). "Efficacy of nicergoline in dementia and other age associated forms of cognitive impairment". Cochrane Database Syst Rev (4): CD003159. doi:10.1002/14651858.CD003159. PMID11687175.
^Le S, Gruner JA, Mathiasen JR, Marino MJ, Schaffhauser H (June 2008). "Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists". J. Pharmacol. Exp. Ther.325 (3): 902–9. doi:10.1124/jpet.107.135343. PMID18305012.
^Esbenshade, TA; Fox, GB; Krueger, KM; Baranowski, JL; Miller, TR; Kang, CH; Denny, LI; Witte, DG et al. (2004). "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist". Biochemical pharmacology68 (5): 933–45. doi:10.1016/j.bcp.2004.05.048. PMID15294456.|displayauthors= suggested (help)
^Ohsawa, Toshiko. "Sesamol and sesaminol as antioxidants." New Food Industry (1991), 33(6), 1-5.
^Kolotushkina EV, Moldavan MG, Voronin KY, Skibo GG (2003). "The influence of Hericium erinaceus extract on myelination process in vitro". Fiziol Zh49 (1): 38–45. PMID12675022.
^Mori K, Obara Y, Hirota M, et al. (September 2008). "Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells". Biol. Pharm. Bull.31 (9): 1727–32. doi:10.1248/bpb.31.1727. PMID18758067.
^Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T (March 2009). "Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial". Phytotherapy Research23 (3): 367–72. doi:10.1002/ptr.2634. PMID18844328.
^Micheau J, Durkin TP, Destrade C, Rolland Y, Jaffard R (1985). "Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation". Pharmacol Biochem Behav23 (2): 195–8. doi:10.1016/0091-3057(85)90555-6. PMID4059305.
^Bizot JC, Herpin A, Pothion S, Pirot S, Trovero F, Ollat H (2005). "Chronic treatment with sulbutiamine improves memory in an object recognition task and reduces some amnesic effects of dizocilpine in a spatial delayed-non-match-to-sample task". Prog Neuropsychopharmacol Biol Psychiatry29 (6): 928–35. doi:10.1016/j.pnpbp.2005.04.035. PMID15951087.