Nootropic

Nootropics ( /noʊ.ɵˈtrɒpɨks/ no-eh-tro-pik), also referred to as smart drugs, brain steroids, memory enhancers, and cognitive enhancers as well as intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration.^[1][2] The word nootropic was coined in 1972^[3][4] by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words νους nous, or "mind," and τρέπειν trepein meaning "to bend/turn". Nootropics are thought to work by altering the availability of the brain's supply of neurochemicals (neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by stimulating nerve growth. However the efficacy of nootropic substances, in most cases, has not been conclusively determined. This is complicated by the difficulty of defining and quantifying cognition and intelligence.

Nootropics vs. cognitive enhancers

Cognitive enhancers are drugs, supplements, nutraceuticals, and functional foods that enhance concentration and memory.^[5][6] Nootropics are cognitive enhancers that are neuroprotective or extremely nontoxic. Nootropics are by definition cognitive enhancers, but a cognitive enhancer is not necessarily a nootropic.

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.^[7] The most commonly used class of drug is stimulants.^[8]

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.^[9] 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.^[7] Stimulants such as methylphenidate are being used on college campuses, and by an increasingly younger group.^[7] 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%.^[8]

Recreational drugs

Many recreational substances that are currently illegal or heavily controlled have effects on the brain or long-term functions that are typically considered secondary to their effects on perception. Note that this list is not intended to be exhaustive. This list includes substances that are illegal, or not completely illegal, but are not controlled or exempt under a Drug schedule.

See also: Opium Law, Controlled substances act, and Misuse of Drugs Act 1971

• Tetrahydrocannabinol - Anxiolytic and analgesic found in cannabis. Neuroprotectant, possible Alzheimer's prevention and possible neurogenesis inducer.^[10]
• Amphetamine-type stimulants are described above^{[citation needed]}
• 4-methylaminorex - similar to modafinil but significantly more abuse potential^{[citation needed]}
• Most entheogens, including hallucinogens - drugs or substances that have shown value in psychotherapy, like psilocybin mushrooms, mescaline, MDMA, and LSD.^{[citation needed]}
• MDPV - designer drug, 4x as potent as methylphenidate, greater abuse potential^{[citation needed]}
• Tobacco - Contains nicotine and also has significant MAOI activity^{[citation needed]}

Traditional herbs

A 2007 survey online databases for herbs used in traditional herbal medicine to treat cognitive decline found over 150 plant species, such as Ginkgo biloba.^[11]

Hazards

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.^[7]

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 wide therapeutic window;^[12] 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.^[13] (This mainly applies to the USA, but may not apply in the EU or elsewhere.)

Vitamins and Supplements

• 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.^[14] 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.^[15] A systematic review of trials found "little evidence of a beneficial impact" from supplements on cognitive function later in life.^[16]

• Omega-3—linked to the maintenance brain function. A study done in Norway,^[17] demonstrated a potential link between Omega-3 consumption during pregnancy and child intelligence test scores.^[18]

• Isoflavones—may be related to cognitive function^[19]

Racetams

The word nootropic was coined upon discovery of the effects of piracetam, developed in the 1960s.^[20] Although piracetam is the most commonly taken nootropic,^[20] there are many relatives in the family that have different potencies and side-effects. Studies of the racetams have revealed that these structurally similar compounds often act via different mechanisms. These other common racetams include pramiracetam, oxiracetam, and aniracetam. Their mechanisms of action are not fully understood, however, piracetam and aniracetam are known to act as positive allosteric modulators of AMPA receptors. They also appear to modulate acetylcholinergic systems.^[21] Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam shows it at the nanomolar range. Racetams have been called "pharmacologically safe" drugs.^[12]

Other substances sometimes classified as nootropics include hydergine, vinpocetine, bifemelane, huperzine A (cholinergic activator below), and dimethylaminoethanol (DMAE).^[12]

Stimulants

Stimulants 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.^{[citation needed]} 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.^[8][22]

• Amphetamines
  • Amphetamine (Adderall, Dexedrine)—adrenergic, dopaminergic
  • Lisdexamfetamine (Vyvanse)—dextroamphetamine prodrug
  • Methamphetamine (Desoxyn)—adrenergic, dopaminergic
• Adrenergics
  • Atomoxetine—norepinephrine reuptake inhibitor; approved for ADHD
  • Reboxetine—Norepinephrine reuptake inhibitor; approved in Europe for clinical depression but may also be used off-label to treat ADHD
  • Synephrine (found in Bitter orange)—agonist at α₁ adrenergic receptors
• Cholinergics
  • Arecoline
  • Nicotine
• Eugeroics ("Wakefulness Enhancers")—unproven primary mechanisms but proven efficacy
  • Adrafinil
  • Armodafinil
  • Modafinil
• Xanthines—reduces fatigue perception
  • Caffeine—shown to increase alertness, performance and in some studies memory.^[23] Children and adults who consume low doses of caffeine showed increase alertness, yet a higher dose was needed to improve performance.^[24] Caffeine has also been shown to have more of an effect on improving cognitive performance and sustaining attention in older adults.^{[citation needed]} Chronic pretreatment of caffeine in animals has shown to reduce ischaemic brain damage, in addition to reducing the risk of Parkinson’s disease.^{[citation needed]}
  • Paraxanthine
  • Theobromine
  • Theophylline

Dopaminergics

Dopaminergics 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^[25][26][27]
  • Biopterin—a rare vitamin (coenzyme) that is synthesized in the pineal gland^[28] & 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
  • Amineptine—mild stimulant
  • Methylphenidate—stimulant approved for ADHD; strong DAT inhibition
  • Bupropion—atypical antidepressant; moderate DAT inhibition
• MAO-B inhibitors—prevent breakdown
  • Selegiline—Mild stimulant; irreversible
  • Rasagiline—Mild stimulant; irreversible
  • Rhodiola rosea—Adaptogenic herb; reversible^[29]
• Dopamine agonists
  • Ropinirole—agonist at D2, D3, and D4 receptors
  • Pramipexole—agonist at D2, D3 and D4 receptors
• Others
  • Mucuna pruriens (Velvet Bean)—natural source of L-DOPA
  • Modafinil—purported dopaminergic activity
  • Citicoline (INN) (aka: cytidine diphosphate-choline (CDP-Choline) & cytidine 5'-diphosphocholine)—studies suggest CDP-choline supplements increase dopamine receptor densities,^[30] and suggest that CDP-choline supplementation can ameliorate memory impairment caused by environmental conditions.^[31] Preliminary research has found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder.^[32][33]

Concentration and memory enhancement

The nootropics in this section are purported or shown to enhance concentration or the recollection and formation of memories.

Cholinergics

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:

• Precursors
  • 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 that delivers choline to the brain across the Blood-brain barrier; sold under its chemical name
• Cofactors
  • Acetylcarnitine—amino acid that functions in acetylcholine production by donating the acetyl portion to the acetylcholine molecule
  • Vitamin B₅—cofactor in the conversion of choline into acetylcholine
• Acetylcholinesterase inhibitors
  • Galantamine
  • Lycoris radiata (Red Spider Lily)—natural source for galantamine
  • Huperzine A—also shown to act as an NMDA antagonist and appears to increase nerve growth factor levels in rats^[34]
  • Donepezil
  • Rosemary
  • Sage
  • Marijuana Due to marijuana's AChE-inhibiting properties, studies suggest it as a treatment for Alzheimer's.^[35]
• Reuptake inhibitors and enchancers
  • Coluracetam—choline uptake enhancer
• Agonists
  • Ispronicline
  • Nicotine
  • Arecoline

GABA blockers

The GABA_A α5 receptor site has recently displayed memory improvements when inverse agonized.

• α₅IA—α5 inverse agonist
• Suritozole—α5 partial inverse agonist

Glutamate activators

The 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—pending 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—under development for Parkinson's but showing increase in BDNF, specifically in areas of memory and higher cognitive skills

cAMP

Cyclic 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

Other

α_2A receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α_2A receptors in the prefrontal cortex.^[36]

• Guanfacine is an α_2A receptor agonist, FDA approved for and frequently used to treat ADHD symptoms.[1][2] 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.^[37]

Serotonergics

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:

• Precursors
  • 5-HTP—precursor (intermediate between tryptophan and serotonin)
  • Tryptophan—essential amino acid precursor
• Cofactors
  • Pyridoxal-phosphate (or PLP, pyridoxal-5'-phosphate, P5P, active form of Vitamin B6)—plays role in conversion of 5-HTP into serotonin (via the enzyme aromatic L-amino acid decarboxylase).^[38][39]
• Reuptake inhibitors
  • SSRIs—class of antidepressants that increase active serotonin levels by inhibiting reuptake, also shown to promote Neurogenesis in the hippocampus
  • Sceletium tortuosum—active constituent mesembrine shown to act as an SSRI^[40] and PDE4 inhibitor. (Half-life unknown)
  • Hypericum perforatum—inhibits reuptake of serotonin (as well as Norepinephrine, Dopamine, GABA and Glutamate) via activation of TRPC6
• MAO-A inhibitors
  • Resveratrol^[41]
  • Curcumin^[42]
  • Piperine^[43]
  • Harmal^[44]
  • Rhodiola rosea^[29]
• Reuptake enhancers
  • Tianeptine—paradoxical antidepressant, improves mood and reduces anxiety; action on the NMDA and AMPA receptor, a hypothesized mechanism of action, based on tianeptine's effect of promoting stress-associated impaired neuroplasticity.^[45][46]

Anti-depression, adaptogenic (antistress), and mood stabilization

Stress, depression, and depressed mood negatively affect cognitive performance.^{[citation needed]} It is reasoned that counteracting and preventing depression and stress may be an effective nootropic strategy.^{[citation needed]} The term adaptogen applies to most herbal anti-stress claims.^{[citation needed]}

The substances below may not have been mentioned earlier on the page:

• Beta blockers—reduce somatic symptoms of anxiety^{[citation needed]}
• Lemon Balm—displays adaptogen properties; also shown to possess GABA transaminase inhibitor properties^{[citation needed]}
• Passion Flower—possible MAOI and neurotransmitter reuptake activity^{[citation needed]}
• Rhodiola Rosea—adaptogen; possible MAOI activity ^[47]
• 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.^{[citation needed]}
• Ginseng (including Siberian ginseng)—adaptogenic effects shown^{[citation needed]}
• Sutherlandia frutescens—possible anti-inflammatory, reducing pain from those illnesses^{[citation needed]}
• Kava—anxiolytic herb^{[citation needed]}
• Tea—contains many different adaptogens^{[citation needed]}
• Theanine—GABAergic activity producing relaxation, also increases brain serotonin and dopamine levels^{[citation needed]}
• Grape seed extract—has shown some efficacy in reducing bodily stress^{[citation needed]}
• Adafenoxate—possible anxiolytic effect^{[citation needed]}
• Valerian—possible anxiolytic effect through agonism at GABA-A receptors^{[citation needed]}
• Butea frondosa—possible anxiolytic effect^[48]
• Gotu Kola—adaptogen and anxiolytic^{[citation needed]}
• Foti—adaptogen; possible MAOI activity^{[citation needed]}
• Many Chinese herbs such as Panax ginseng, Polygala tenuifolia, Acorus gramineus and Huperzia serrata.^[49]
• Bacopa monnieri^[50]

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.

• 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. Acts as an NRI.^[51]
• 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.^[52] Vinpocetine may therefore induce or exasperate depressive symptoms as an adverse effect.
• Vincamine—presumably increases blood circulation (vasodilator) and metabolism in the brain; related to vinpocetine; used in sustained release (example of a brand is Oxybral SR (note that this example is not meant to insinuate superiority over other preparations, nor advertise it; it is given due to it's popularity in some regions, inspite of sometimes being more expensive (possibly due to the mechanism which implements it's sustained release form) than other available drugs with the same active ingredient))

Experimental histamine antagonists

The H₃-receptor decreases neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin. Thus, H₃-receptor-antagonists increases cognition 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.^[53]
• A-349,821—It has nootropic effects in animal studies.^[54]

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.

• Idebenone—antioxidant^{[citation needed]}
• Melatonin—antioxidant^{[citation needed]}
• Glutathione—chief antioxidant^{[citation needed]}
• Acetylcarnitine (Acetyl-L-Carnitine Arginate or Hydrochloride) neuroprotective^{[citation needed]}
• Inositol—implicated in memory function, deficit linked to some psychiatric illnesses—has been shown particularly efficacious in OCD patients
• Anticonvulsants—inhibit seizure related brain malfunction if a person has seizures^{[citation needed]}
• Phosphatidylserine—possible membrane stabilizer^{[citation needed]}
• Lion's Mane Mushroom—Stimulated myelination in an in vitro experiment^[55] and stimulated nerve growth factor in an in vitro experiment with human astrocytoma cells.^[56] Also improved cognitive ability, in a double-blind, parallel-group, placebo-controlled trial.^[57]
• SAM-e (S-Adenosyl methionine)—crucial for cellular regeneration (fuels DNA methylation^[58]), also involved with the biosynthesis of dopamine & serotonin^[59]
• Acetylcysteine (L-cysteine)—precursor to antioxidant glutathione^[60]
• Apoaequorin (Calcium-binding protein) (CaBP)—(Prevagen®) neuroprotective^[61][62] (note that orally ingested proteins are not generally bioavailable and are thus unlikely have any effect)
• Uncaria tomentosa (Cat's Claw)—in an in vitro experiment with rats, Cat's Claw (PTI-00703™), inhibited formation of brain beta amyloid deposits^[63][64]
• (Dopamine enhancers)—dopamine is an antioxidant that can enhance dendrite extension^{[citation needed]}

Direct hormones

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
• Pregnenolone—increases neurogenesis
• Orexin—Significant wakefulness promoter

Secondary enhancers

These are substances that by themselves may not improve brain function, but may have benefits for those who lack them (in the case of hormones) or may alter the balance of neurotransmitters.

• DHEA—precursor to estrogen and testosterone

Unknown enhancement

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:

• Bacopa monniera (Brahmi)—shown to possess adaptogenic properties and enhance memory and concentration.^[65] Folk use in Ayurvedic medicine purports "enhancement of curiosity"; Brahmi rasayana has been shown to improve learning and memory in mice^[66]
• Fipexide—drug for Dementia
• Gerovital H3—famous alleged anti-aging mixture, most effects disproven but some mind enhancement shown
• Sulbutiamine—fat soluble vitamin B₁ derivative—caused mice to perform better on operant conditioning tests^[67] and object recognition tests^[68]
• Royal Jelly—Increases brain cell growth and diversity, only demonstrated in-vitro, improbable in-vivo
• Curcumin—significant in-vitro activity, but in-vivo activity limited by low bioavailability

Other nootropics

These substances have been linked to better cognitive function, but may not be the cause. See correlation does not imply causation.

• Alcohol—moderate drinkers tend to have better cognitive function than abstainers or heavy drinkers^{[69][70][71][72][73][74]}

See also

• Cognitive science
• Eidetic memory
• Human enhancement
• Long-term potentiation
• Memory and aging

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External links

• "A Pandora's box full of smart drugs" by Ann Robinson (The Guardian: February 23, 2010)
• Greely H, Sahakian B, Harris J, et al. (December 2008). "Towards responsible use of cognitive-enhancing drugs by the healthy". Nature 456 (7223): 702–5. doi:10.1038/456702a. PMID 19060880. http://www.nature.com/nature/journal/vaop/ncurrent/full/456702a.html. 
• "Brain Gain: The underground world of “neuroenhancing” drugs" by Margaret Talbot (The New Yorker: April 27, 2009)
• Business Week Online - "I Can't Remember" September 1, 2003 at Business Week
• List of Nootropic drugs at Erowid
• The Nootropics Database
• Nootropics