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Cognitive enhancement

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Cognitive enhancement

Nootropics (/n.əˈtrɒpɨks/ ), also referred to as smart drugs, memory enhancers, neuro enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that purportedly improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration.[1][2] The word nootropic was coined in 1972 by the Romanian Dr. Corneliu E. Giurgea,[3][4] 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.

Nootropics vs. cognitive enhancers

Cognitive enhancers are drugs, supplements, nutraceuticals, and functional foods that enhance attentional control 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.

Giurgea's Nootropic Criteria:

  1. Enhances learning and memory.
  2. Enhances learned behaviors under conditions which are known to disrupt them (e.g. hypoxia (oxygen deficiency)).
  3. Protects the brain from physical or chemical injury.
  4. Enhances the tonic cortical/subcortical control mechanisms
  5. 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 utilizes 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
1. Molecular
2. Physiopathological
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.[7] The most commonly used class of drug is stimulants.[8]

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.[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 not all of the claims from certain nootropics suppliers have 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, and on some campuses use in the past year is as high as 25%.[8][10] The use of prescription stimulants is especially prevalent among students attending academically competitive colleges and students who are members of a fraternity/sorority.[10]

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 a wide therapeutic window.[11] In the United States, unapproved drugs or dietary supplements do not have to have safety or efficacy approval before being sold.[12]

Drugs

Racetams

The word nootropic was coined upon discovery of the effects of piracetam, developed in the 1960s.[13] Although piracetam is the most commonly taken nootropic,[13] 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.[14] Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam shows it at the nanomolar range. Racetams have been called "pharmacologically safe" drugs.[11]

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.[15] 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.[16] In 2008 a systematic review of trials found "little evidence of a beneficial impact" from supplements on cognitive function later in life.[17] 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.[18]
  • Omega-3—linked to the maintenance of brain function. A study done in Norway[19] demonstrated a potential link between Omega-3 consumption during pregnancy and child intelligence test scores.[20] 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.[21]
  • Isoflavones—may be related to cognitive function.[22] A double-blind, placebo-controlled study showed improvement in spatial working memory after administration of an isoflavone combination containing daidzein, genistein & glycitin.[23] 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.[24]
  • 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.[25]
  • 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.[26]

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:

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. 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][36]

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:

GABA blockers

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

  • 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 general GABA inverse agonism.
  • 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

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.[43]

  • Guanfacine is an α2A receptor agonist, FDA approved for and frequently used to treat ADHD symptoms.[44][45] 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.[46] 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.[47]

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:

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

Stress (specifically elevated levels of circulating corticosteroids) has been associated with the cognitive deficits seen in human aging.[59] 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—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.[60]
  • Lemon Balm—displays adaptogen properties; in rats it has been shown to possess GABA transaminase inhibitor activity[61] and in homogenates of human cerebral cortical cell membranes possesses activity at acetylcholine receptors.[62] 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.[63]
  • Passion Flower—possible MAOI and neurotransmitter reuptake activity
  • Rhodiola Rosea—adaptogen; possible MAOI activity[64]
  • 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.[65]
  • 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
  • Phenibut GABA receptor agonist excerting anxiolytic effects
  • Picamilon GABA prodrug which excerts anxiolytic effects by releasing GABA and niacin in the CNS.
  • Valerian—possible anxiolytic effect through agonism at GABA-A receptors
  • Butea frondosa—possible anxiolytic effect[66]
  • Gotu Kola—adaptogen and anxiolytic
  • Foti—adaptogen; possible MAOI activity
  • 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.[67]
  • Many Chinese herbs such as Polygala tenuifolia, Acorus gramineus and Huperzia serrata.[68]
  • Bacopa monnieri[69]
  • Tulsi (Ocimum sanctum, sweet holy basil)[70]

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.[71] 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.[72] 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."[73] 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.[74]
  • Vinpocetine— is reported to have cerebral blood-flow enhancing[75] and neuroprotective effects,[76] and is used as a drug in Eastern Europe for the treatment of cerebrovascular disorders and age-related memory impairment.[77] 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.[78] 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.[79][80]
  • 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.[81]

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.[82]
  • A-349,821—It has nootropic effects in animal studies.[83]
  • ABT-239 – strong H3 receptor inverse agonist that is more active than ciproxifan, but its investigation into human use was dropped after it was discovered to cause QT prolongation in subjects

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.

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. 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.[93]
  • 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..

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.[94] Folk use in Ayurvedic medicine purports "enhancement of curiosity"; Brahmi rasayana has been shown to improve learning and memory in mice[95]
  • 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.
  • Fipexide—drug for Dementia
  • Piperic acid—allegedly a mild serotonergic, nootropic, antistress, anxiolytic, and allegedly has mild to moderate memory enhancing effects.
  • 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[96] and object recognition tests[97]
  • Royal Jelly—Increases brain cell growth and diversity, only demonstrated in-vitro, improbable in-vivo (it has been reported to stimulate the growth of glial cells[98] and neural stem cells in the brain.[99])
  • Curcumin—significant in-vitro activity, but in-vivo activity limited by low bioavailability unless accompanied by ingestion of piperine

Other nootropics

Other substances sometimes classified as nootropics include jujube, mexidol, hydergine,[11] noopept, selank, semax and bifemelane.

See also

References

External links

  • "A Pandora's box full of smart drugs" by Ann Robinson (The Guardian: February 23, 2010)
  • "Brain Gain: The underground world of "neuroenhancing" drugs" by Margaret Talbot (The New Yorker: April 27, 2009)
  • Business Week
  • Closer Look at Nootropic Brands
  • Erowid
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