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 Nootropic vs. cognitive enhancer
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The term cognitive enhancer is not to be confused with the word "nootropic". Nootropics are by definition cognitive enhancers, but a cognitive enhancer is not necessarily a nootropic.
A cognitive enhancer is a substance that enhances concentration and memory. The first synthetic cognition enhancers to see widespread use were the amphetamines. The word "nootropic" has been abused by researchers who wish to promote a certain drug as side-effect free. The word was first coined by Corneliu E. Giurgea in 1972. He stated that nootropic drugs should have the following characteristics:
- They should enhance learning and memory.
- They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
- They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
- They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
- They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.
- Note: section 5. of Giurgea's original definition has been gradually dropped by most researchers.
 Availability and prevalenceAt present, there are several drugs on the market that improve memory, concentration, 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 difficulties such as Alzheimer's disease, Parkinson'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 many of the claims attributed to most nootropics have not been formally tested.
In academia, modafinil has been used to increase productivity, although its long-term effects have not been assessed in healthy individuals. Stimulants such as methylphenidate 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 in the past year, and on some campuses the number is as high as 25%.
 HazardsThe 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 effects and wide therapeutic window; however, any substance ingested could produce harmful effects. An unapproved drug or dietary supplement does not have to have safety or efficacy approval before being sold. (This mainly applies to the USA, but may not apply in the EU or elsewhere.)
 ExamplesThe term "drug" here is used as a legal designation. Although some of the effects of these substances may be similar to others, only those substances that have shown cognitive effects are included.
 Dietary sources and supplements
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Omega-3 has been linked to helping retain brain function. A study done in Norway, demonstrated a potential link between Omega-3 consumption during pregnancy and child intelligence test scores.
Caffeine has been 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. Caffeine has also been shown to have more of an effect on improving cognitive performance and sustaining attention in older adults. Chronic pretreatment of caffeine in animals has shown to reduce ischaemic brain damage, in addition to reducing the risk of Parkinson’s disease.
Antioxidants have been found in some studies to protect brain tissue from oxidative damage. A study demonstrated possible connections between consumption of leafy green vegetables containing Vitamin E, Folate and Antioxidants, and mental ability test scores.
Polyphenolics (also known as phenols) in fruits and vegetables may help brain functioning. The darker colored fruits and vegetables tend to be high in phenolics, therefore possessing large antioxidant and anti-inflammatory activity. In rats, a 2% blackberry supplemented diet was shown effective in reversing age related deficits and neural function.
Isoflavones may be related to cognitive function.
Adult brains use amino acids, which are typically found in protein rich food, for the production of enzymes that transport molecules, structural material and neurotransmitters, along with other essential molecules. Based on biological theory, it can be speculated that amino acids have effects on cognitive function: tyrosine and phenylalanine, which help to produce the catecholamines dopamine, norepinephrine, and epinephrine, could aid alertness since catecholamines stimulate alertness. Tryptophan could perhaps stabilize mood and influence learning and memory, with some studies suggesting deficits in memory due tryptophan depletion and other studies show how tryptophan helps to improve decision making (Blaun 1996). Foods high in carbohydrates, which do not contain tryptophan, help to push tryptophan into the brain by triggering the release of insulin. Insulin stimulates muscles to take up competing amino acids. Even calcium, which typically comes in many protein-rich foods, helps regulate nerve impulse transmission (Kiefer, 2007). Important neurotransmitters include acetylcholine and serotonin. Acetylcholine is essential in memory formation and maintenance. It is found in egg yolks and organ meats. Serotonin helps with sleep regulation and anxiety reduction. It is manufactured from tryptophan (Blaun, 1996).
Iron is also important for staying mentally sharp as it is required to transport oxygen to the blood; all humans require it but women are more likely to be iron-deficient.
Some studies found certain supplements to be beneficial only in certain situations. For example, supplemental tyrosine has been found to be beneficial in stressful conditions.
 Nootropics and racetamsThe word nootropic was coined upon discovery of the effects of piracetam, developed in the 1960s. Although piracetam is the most commonly taken nootropic, there are many relatives in the family that have different potencies and side effects. Other common racetams include pramiracetam, oxiracetam, and aniracetam. There is no generally-accepted mechanism for racetams. In general, they show no affinity for the most important receptors, although modulation of most important central neurotransmitters, including acetylcholine and glutamate, have been reported. Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam shows it at the nanomolar range. Racetams have been called "pharmacologically safe" drugs.
Other substances sometimes classified as nootropics include hydergine, vinpocetine, bifemelane, huperzine A (cholinergic activator below), and dimethylaminoethanol (DMAE).
 StimulantsStimulants are often seen as smart drugs, but may be more accurately termed productivity enhancers. Some stimulants can enhance cognition and memory in some people, but cause psychosis in others. They generally have a very substantial side-effect profile and are not considered classical "nootropic" drugs. These typically improve concentration and a few areas of cognitive performance, but only while the drug is still in the blood. Some scientists recommend widespread use of stimulants such as methylphenidate and amphetamines by the general population to increase brain power.
- Eugeroics ("Wakefulness Enhancers") - unproven primary mechanisms but proven efficacy
- Xanthines - reduces fatigue perception
 DopaminergicsDopaminergics are substances that affect the neurotransmitter dopamine or the components of the nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention, alertness, and antioxidant activity. Dopamine is the primary activity of stimulants like methylphenidate (Ritalin) or amphetamine. Dopaminergic nootropics include dopamine synthesis precursors, dopamine reuptake inhibitors, monoamine oxidase inhibitors, and other compounds:
- Metabolic precursors - raise levels
- L-Phenylalanine - purported cognitive improvement
- L-Tyrosine (or N-Acetyl-L-Tyrosine, more bioavailable form) - purported cognitive improvement
- L-DOPA (L-3,4-dihydroxyphenylalanine) - precursor to catecholamines (dopamine); neurotoxic effects documented
- Biopterin - A rare vitamin (coenzyme) that is synthesized in the pineal gland & crucial to the biosynthesis of dopamine
- Pyridoxal-phosphate (or PLP, pyridoxal-5'-phosphate, P5P, active form of Vitamin B6) - plays a role in the conversion of L-DOPA into dopamine (via the enzyme aromatic L-amino acid decarboxylase).
- Reuptake inhibitors - stabilize/improve levels
- MAO-B inhibitors - prevent breakdown
- Dopamine agonists
 Memory enhancementMemory can come from many different processes, but is dependent on the ability to store and recall information.
 CholinergicsCholinergics 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:
- Choline - precursor of acetylcholine and phosphatidylcholine
- DMAE - precursor of acetylcholine
- Meclofenoxate - probable precursor of acetylcholine, approved for Dementia and Alzheimer's
- Alpha-GPC - thought to be the only cholinergic to deliver choline to the brain across the Blood-brain barrier, it is sold under its chemical name.
- Acetylcholinesterase inhibitors
- Reuptake inhibitors and enchancers
- Coluracetam - choline uptake enhancer
 GABA blockersThe GABAA α5 receptor site has recently displayed memory improvements when inverse agonized.
 Glutamate activatorsThe AMPA transmitter and the AMPA receptors are currently being researched, and there are signs that significant memory improvement and possible alertness enhancement may occur when agonized. The drug class for AMPA system modulation is called Ampakines. Although there are many Ampakines currently in-research, those mentioned here are significantly notable, and/or show reasonable signs of coming to market.
Some racetams have shown this activity, such as aniracetam
- CX-717 - Going through FDA approval for memory-impairing illnesses
- IDRA-21 - believed to improve memory by significantly enhancing long-term potentiation but used only in animals - incredibly potent
- LY-503,430 - Being developed for Parkinson's but showing increase in BDNF, specifically in areas of memory and higher cognitive skills
 cAMPCyclic adenosine monophosphate is a secondary messenger that, if increased, has shown memory improvements. One common method is by decreasing the activity of phosphodiesterase-4, an enzyme that breaks down cAMP. Typical effects include wakefulness and memory enhancement.
- Propentofylline - nonselective phosphodiesterase inhibitor with some neuroenhancement
- Rolipram - PDE4 inhibitor, shows alertness enhancement, long term memory improvement and neuroprotection
- Mesembrine - PDE4-inhibitor with possible serotonergic activity
 Otherα2A 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 for and frequently used to treat ADHD symptoms. Studies have shown guanfacine 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.
 SerotonergicsSerotonin 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:
- Reuptake inhibitors
- SSRIs - Class of antidepressants that increase active serotonin levels by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus.
- Sceletium tortuosum - active constituent mesembrine shown to act as a potent SSRI and PDE4 inhibitor
- Hypericum perforatum - inhibits reuptake of serotonin (as well as Norepinephrine, Dopamine, GABA and Glutamate) via activation of TRPC6
- MAO-A inhibitors
- Reuptake enhancers
- Tianeptine - paradoxical antidepressant, improves mood and reduces anxiety
 Anti-depression, adaptogenic (antistress), and mood stabilizationStress, depression, and depressed mood negatively affect cognitive performance. It is reasoned that counteracting and preventing depression and stress may be an effective nootropic strategy. The term adaptogen applies to most herbal anti-stress claims.
The substances below may not have been mentioned earlier on the page:
- Beta blockers - anxiolytic
- Lemon Balm - Displays adaptogen properties. Has also shown to possess GABA transaminase inhibitor properties
- Passion Flower - possible MAOI and neurotransmitter reuptake activity
- Rhodiola Rosea - adaptogen; possible MAOI activity
- St John's Wort - herbal SSRI that has been approved (in Europe) to treat mild depression
- Ginseng (including Siberian ginseng) - adaptogenic effects shown
- Sutherlandia frutescens - possible anti-inflammatory reducing pain from those illnesses
- Kava - anxiolytic herb
- Tea - contains many different adaptogens
- Theanine - GABAergic activity producing relaxation, also increases brain serotonin and dopamine levels
- Grape seed extract - has shown some efficacy in reducing bodily stress
- Adafenoxate - possible anxiolytic effect
- Valerian - possible anxiolytic effect through agonism at GABA-A receptors
- Butea frondosa - possible anxiolytic effect
- Gotu Kola - adaptogen and anxiolytic
- Foti - adaptogen; possible MAOI activity
- Berberine - alkaloid, found in various herbs, with antidepressant properties; acts as a sigma receptor agonist; also shown to act as a mild tyrosine hydroxylase inhibitor
 Blood flow and metabolic functionBrain 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. Vasodilators mentioned are only those which have shown, at minimum, probable mental enhancement.
- Blessed Thistle - increases blood circulation, improving memory.
- Coenzyme q-10 - antioxidant; increases oxygen usage by mitochondria.
- Creatine - protects ATP during transport.
- Lipoic acid - improves oxygen usage and antioxidant recycling, possibly improving memory.
- Pyritinol - Drug. Similar to B vitamin Pyridoxine.
- Picamilon - GABA activity and blood flow improver.
- Ginkgo biloba - vasodilator; it has also been shown to act as a negative allosteric modulator of GABA-A receptors, and as an antagonist at GABAA-rho receptors (formerly known as GABA-C receptors)
- Vinpocetine - increases blood circulation (vasodilator) and metabolism in the brain; 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 exasperate depressive symptoms as an adverse effect.
 Nerve growth stimulation and brain cell protectionNerves are necessary to the foundation of brain communication and their degeneracy, underperformance, or lacking can have disastrous results on brain functions. Antioxidants are frequently used to prevent oxidative stress, but do not improve brain function if that is their only activity.
- Idebenone - antioxidant
- Melatonin - antioxidant
- Glutathione - chief antioxidant
- Acetylcarnitine (Acetyl-L-Carnitine Arginate or Hydrochloride) - neuroprotective
- Citicoline (Cytidine 5-diphosphocholine) - neuroprotective
- Inositol - implicated in memory function, deficit linked to some psychiatric illnesses. It has shown to be particularly efficacious in OCD patients
- Anticonvulsants inhibit seizure related brain malfunction if a person has seizures
- Phosphatidylserine - possible membrane stabilizer
- Lion's Mane Mushroom - Stimulated myelination in an in vitro experiment and stimulated nerve growth factor in an in vitro experiment with human astrocytoma cells. Also improved cognitive ability, in a double-blind, parallel-group, placebo-controlled trial.
- SAM-e (S-Adenosyl methionine) - crucial for cellular regeneration (fuels DNA methylation), also involved with the biosynthesis of dopamine & serotonin.
- Acetylcysteine (L-cysteine) - precursor to antioxidant glutathione
- Apoaequorin (Calcium-binding protein) (CaBP) - (Prevagen®) neuroprotective
- (Dopamine enhancers) - dopamine is an antioxiant and can enhance dendrite extensio
 Direct hormonesThese 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
- Pregnenolone - increases neurogenesis
- Orexin - Significant wakefulness promoter
 Secondary enhancersThese are substances which by themselves may not improve brain function, but may have benefits for those lacking them (in the case of hormones) or may alter the balance of neurotransmitters.
 Unknown enhancementOther agents purported to have nootropic effects but which do not (yet) have attributable mechanisms or clinically significant effects (but may upon refinement of administration) are mentioned here.
Nootropics with proven or purported benefits:
- Bacopa monniera - shown to possess adaptogenic properties; enhances memory and concentration. Folk use in Ayurvedic medicine purports "enhancement of curiosity".
- Brahmi rasayana - improved learning and memory in mice.
- Fipexide - drug for Dementia
- Gerovital H3 - famous anti-aging mixture, most effects disproven, but some mind enhancement shown
- Sulbutiamine - fat soluble vitamin B1 derivative . Some shown memory improvement
- Royal Jelly - Increases brain cell growth and diversity, only proven in-vitro, improbable in-vivo
- Curcumin - Significant in-vitro activity, but in-vivo activity is limited by low bioavailability
 Other nootropicsThese substances have been linked to better cognitive function, but may not be the cause. See correlation does not imply causation
- Moderate use of alcohol - Moderate drinkers tend to have better cognitive function than both abstainers and heavy drinkers.
 See also
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