Neuroenhancement

3D structure of modafinil

PubMed search results for "Modafinil" in title or abstract[71]

Modafinil is a wakefulness-promoting drug that decreases fatigue, increases vigilance, reduces daytime sleepiness, and improves mood.[4][5][10] Modafinil is currently licensed for treating patients with disorders such as narcolepsy, sleep apnea, and shift work sleep disorder.[2][5] This drug also seems promising in the treatment of depression and bipolar disorder.[5] Modafinil is currently being used by United States Air Force personnel for missions of great duration in an attempt to decrease fatigue amongst aircrew. It has become more popular amongst the general public. In an online poll conducted by Nature magazine, 8.8% of 1400 corresponding readers admitted use of modafinil for non-medical reasons. Their reasoning behind its use was for increasing concentration and focus on a specific task or to counteract sleep deficit and jetlag.[2] A comparison between the sales of modafinil to the number of patients revealed a disproportionate ratio, indicating high abuse.[2]

Modafinil has been reported to improve executive function in healthy non-sleep-deprived individuals, as well as potentially improving attention and learning and memory.[1] Effects on sleep-deprived individuals are even more striking: a single dose resulted in enhanced wakefulness, executive functions, and memory.[10] In the case of sustained sleep deprivation, repeated intake of modafinil helped individuals maintain higher levels of wakefulness than the placebo, but did not help attention and executive function.[2][10] Since the majority of these trials were conducted on military personnel, further research needs to be conducted on the effects of modafinil on the general population. Modafinil may impair one's self-monitoring ability. A common trend found in research studies indicated that participants rated their performances on cognitive tests higher than it was, suggesting an "overconfidence" effect.[2]

Modafinil is becoming increasingly popular among the general population.[8] Apart from a consumer's want to increase his neurological performance, there are financial incentives for manufacturers as well. Modafinil has a market share of more than $700 million a year, indicating a high degree of off-label use.[4] Modafinil is also one of the more easily available neuroenhancement drugs in the market today. Modafinil can be bought from many websites – mostly from Asian countries – as well as from darknet markets.[4][72][73] Modafinil first came into public attention when world champion runner Kelli White was tested positive for illegally consuming modafinil in the Athletics World Championship in 2003, resulting in the loss of her two gold medals.[4]

For research comparing modafinil with similar compounds, investigating combinations and showing trade-off type issues, see #Research topics below.

3D structure of methylphenidate

Methylphenidate (MPH), also known as Ritalin, is a stimulant that is used to treat attention-deficit hyperactivity disorder (ADHD). MPH is known to be highly abused by the general population, especially college students.[2][4] In an online poll conducted by Nature magazine, 12.4% of 1400 corresponding readers admitted use of MPH for non-medical reasons. Their reasoning behind its use was for increasing concentration, sleep deficit, and jetlag.[2]

A comparison between the sales of MPH to the number of patients revealed a disproportionate ratio, indicating high abuse.[2] MPH is believed to have a positive effect on memory consolidation, but studies have not been able to conclusively verify this claim.[2][10] Popular opinion that MPH enhances attention could not be verified.[2][10] Studies of MPH have reported improved problem-solving skills. However, when these studies were repeated to replicate the results, the placebo group scored higher, indicating that MPH may even impair performance.[4]

These inconclusive, and generally negative, results for memory improvement are insufficient to explain the use of MPH for non-medical reasons. Users may have motives other than genuine neuroenhancement that propels its unprescribed use, such as subjective and recreational effects.[2] The lack of any result, positive or negative, indicated that the 10–20 mg dosage may be too low for the drug.[2] Further studies need to be conducted, looking at different doses of MPH.[2][10]

Memantine is an NMDA receptor antagonist and is used to treat patients with moderate to severe Alzheimer's disease, but is also used as a neuroenhancement drug.[3] Studies conducted on memantine were unable to conclusively verify neuroenhancement capability of the drug. Since most of these studies were single-dose tests of memantine, it is possible that these drugs would only show some effect, positive or negative, after continuous intake. Until then, single-dose studies of memantine are not enough to reveal the drug's actual potential.[3]

Donepezil is an acetylcholinesterase inhibitor (AChEI) that is used to treat patients with mild to moderate Alzheimer's disease. While many AChEIs could be potential neuroenhancement substances, donepezil is the most commonly used AChEIs by the general population due to its widespread use for treating Alzheimer's disease.[3]

Most studies on donepezil are unable to conclusively verify the neuroenhancement capability of the drug.[3] In such studies, it was seen participants who took donepezil scored higher than those that took the placebo. Donepezil helps individuals retain training tasks, verbal memory, and episodic memory.[3] In sleep deprivation studies, while donepezil had no effect on well-rested patients, it had a positive effect on patients with 24 hours of sleep deprivation. Such patients benefited from increased memory performance and attention that would otherwise be a deficit in such sleep-deprived conditions.[3] However, this effect was only seen in individuals whose performance declined significantly due to sleep deprivation.[3]

Studies about neuroenhancement: PubMed search results for a query (for titles and abstracts)[74]

Research also explores derivatives of already existing cognitive enhancers that have or could have higher bioavailability, such as N-acetylcysteine amide for NAC[75] and other bioavailability-enhancing strategies.[76] Another approach to enhance efficacy, potency or selectivity that is relevant to medications in general is improving drug delivery,[77][78] including enabling additional routes of administration such as via nanoemulsions for "nose-to-brain" drug delivery[79] or hypothetically via brain implants.[80]

Differential half-lives may also be a topic of research and development. Modafinil substantially increases alertness but, having a long half-life of approximately 13 hours,[81] can delay or impair sleep-onset,[82][21] with there being no marketed shorter-acting version. According to two 2009 studies, armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil.[83][81]

Research may also investigate:

• general safety and efficacy in healthy people in particular[43][84][85][7][41] as well as for long-term use[58][85][35] and also using neuroimaging[85] (and associated brain mapping[86] and neuroimaging intelligence testing)
  • Studies may also measure impacts of regular consumption of chemicals like modafinil on mortality and lifespan in animal models, such as short-lived mice.
• different protocols (e.g. dosages,[61][7] timing and scheduling)
• combinations[77] (e.g. concurrent, cyclic or sequential and precursors, depletions[87][88] and cofactors)
  • One common combination under research is the concurrent combination of l-theanine with caffeine.[89][90][91]
  • One study investigated high-dosage modafinil combined with low-dosage caffeine – 200 mg of each.[92]
  • There are also studies combing different types of cognitive enhancers such as biochemical and behavioral enhancers such as modafinil combined with meditation.[93][94]
  • The multinutrient intervention of uridine combined with choline (CDP-choline or e.g. in eggs) and omega 3 (e.g. in fish) has synergy, improving some measures of cognition and mood better.[95][96][97]
• factors of effects outcomes (including situational, task-difficulty,[98] personal (e.g. genetic[7] or baseline-skill-levels),[61][98][62][41] protocol-related, etc)[33][7]
• interactions (e.g. polypharmacy and combinations)[26][77]
• trade-off-type issues[33][99][98][41]
  • Modafinil can, depending on various factors, at or around the time of consumption:
    • impair sleep due to its long half-life[81][82][21] (See also #Sleep-related, #Modafinil analogs and Orexin antagonist)
    • (slightly) increase the resting heart rate and blood pressure[12][100]
    • impair some types of creativity[1][33] but possibly be beneficial[1] in some creativity domains or creative tasks (like e.g. literary fiction writing)
    • both decrease or increase anxiety[101][102][103][1]
    • have a possible effect of overconfidence[2][98]
    • have risks for side effects like headache[1][100] and have low abuse/addiction potential[1][100]
  • Some pharmacological agents may have issues due to which some may consider them as not viable for enhancement or not consider them to be neuroenhancers – for example "nicotine and amphetamines (such as Adderall)" may result "in substantial loss of cholinergic and dopaminergic receptor responsivity and may ultimately lead to their epigenetic downregulation" (see e.g. Dopamine receptor#Dopamine regulation).[44] Various recreational drugs are partly used due to cognitive enhancement effects[26][37][104][58] on e.g. sociability, mood and/or creativity – in the exemplary case of alcohol this can have substantial effects on health, including long-term negative consequences on cognitive functions.[37] They can also induce tolerance for the effects and addiction could develop from long-term drug instrumentalization.[104]
  • Some domains of cognition that may appear unequivocally desirable to modulate such as mood may be beneficial – albeit not preconditions – for other cognitive functions: for example, phases of depressed mood or depression was often associated with enhanced creativity.[105]
  • Enhancing memory for example may come at the cost of other cognitive domains and if it is for example enhanced during the wrong times, resultant memories may be more "noisy".[86] Forgetting and/or low memorization may be beneficial with current constraints and enhancing either could be beneficial in many situations or nonpathological issues.[41][60] There also is the concept of "enhancement through diminishment" that via addition-by-subtraction interferes with the function of brain regions that are. less essential or counter-productive to task performance. This concept is not to be confused with the "cognitive diminishment" described in #Cognitive diminishment and the "neurodiminishing" described below.[60]
  • There is a possibility that in the future the use of neuroenhancement tools is exploited by adverserial forces or malicious entities to negatively influence performance, called "neurodiminishing"[60] – potentially a form of neurological warfare (also called "neurowarfare"; overlapping or synonymous with "cognitive warfare")[106][107][108][109][110][111] beyond the enhancement of troops' capacities,[112][113][114] for example via electronic warfare,[60] hacking,[115] directed energy sources,[116][60][106][117] manipulation,[118] or other methods.
• differential effects (e.g. comparisons between substances/strategies[33] and per task, cognitive domain[33] or purpose)
  • For example, it was found that methylphenidate (Ritalin) increases alertness more on simple tasks than on difficult ones, while modafinil increases concentration or attention,[21][2] reportedly may significantly outperform methylphenidate "for cognitive enhancement in healthy individuals, 'especially on people undergoing sleep deprivation'",[119] and is thought to also have an impact on decision-making, planning, moral reasoning[120][121] and motivation.[42][38][39][122] Modafinil has replaced dextroamphetamine in certain types of military operations due to its superior side effects profile.[92]
• development of more adequate tests, evaluations or measures about positive effects
  • A study notes that there is a problem of "how to define cognition and whether or not it can be understood in simple computational terms", calling for "studies testing whether putative enhancers improve the performance of sophisticated (highly experienced) subjects dealing with novel circumstances of great complexity and without the benefit of external supervision", which could "bring experiments closer to the human condition and thereby help explain why animal studies on cognition and memory have such a poor record in predicting human outcomes".[86]
  • Neuroimaging could also be used, including for analysis of long-term impacts.[85]
• use of and/or more advanced and/or more accessible technologies for "nutrition assessment (eg, metabolomics and innovative methods of dietary intake assessment) and recently identified biomarkers of nutrition and neurobiological outcomes" for prevention of cognitive impairment as in screening[123]
• general underlying neurobiology such as mechanics and variations underlying types of creativity or attention and focus (attentional processing) – e.g. neurotransmitter systems, neuropeptides, gene expression, neurotrophins, brain metabolites, neuroimaging/network-mapping/neuroanatomy, etc[44][105][124][125][86] (See also Metascience#Factors of success and progress, Albert Einstein's brain and Differential psychology)

Advanced cognitive enhancement that is not viable for use by humans in the near future could build upon research in which receptors to activate or inhibit neurons with proteins were designed, e.g. using "Designer Receptors Exclusively Activated by Designer Drugs" (DREADD).[126] Genetically modified neurons may enable connecting external components to nerves.[127] Researcher reported in 2020 that they bioengineered C. elegans worms to synthesize, fabricate, and assemble bioelectronic materials in its brain cells. They enabled modulation of membrane properties in specific neuron populations and manipulation of behavior in the living animals.[128][129][130]

If organic neuromorphic devices reach a certain point and become biocompatible, novel brain implants could be possible.[131] There also is research of potentially implantable[132] physical artificial neurons.[133] Bioimplants of genetically engineered or stem-cell grown neural tissue may become possible as well.[134] Another approach are wetware computers.

Various compounds contained in foods (sometimes called brain foods) or consumed in isolated forms or herbs such as cinnamon,[135] cocoa powder,[136][45][137][138][91] anthocyanins (e.g. in bilberry and black elderberry),[139] dietary nitrate (in beet root),[91] honeys,[140] polyphenols (in many fruits and vegetables),[91][141][142][143] epicatechin,[144][145] levodopa[43] l-phenylalanine[146][147] and l-tyrosine,[148][87] phenethylamine (PEA),[149] carotenoids like lycopene (in tomato sauce),[149] l-theanine,[150][89][90] apigenin (and chamomile),[151][152] ginger,[153][138][147] herbal infusions (notably lemon balm, rosemary, peppermint and caffeinated drinks),[154][155][156][157][26][147] rhodiola rosea,[77][85][147][158][159] creatine,[160][161][162] omega 3 (e.g. sustainably algae-derived),[167] as well as correction of prevalent micronutrient deficiencies[168][169][170][171][147][172] are investigated for potential minor but significant or additive impacts on cognition (e.g. mild stimulation and/or mood modulation) in healthy non-old individuals. (see also #Diet below)

The dietary component glucose (and its glycogen form) is the main energy source for the brain, with some researchers considering it a "[b]iochemical enhancer" despite of the health impacts of direct consumption. A constant supply of it is needed and simple sugars can spike blood glucose and their glucose supply does not last long. Slowly absorbed carbohydrate-containing food or low-GI food would lead to a slower release of glucose than a quickly absorbed or high-GI food.[173][91][33][147] There is very little research on links between brain glucose metabolism and cognition, despite it also being relevant to neurodegenerative disorders.[174] Lactate (released especially during specific types of exercise) may also be relevant to cognitive enhancement.[175][176][177]

Notable potentially viable pharmacological agents – as final products or as prototypes for similar ones – under early-stage research with potential for substantial effect sizes for specific purposes in specific situations (such as learning periods) also in healthy non-old humans but, in at least most cases, largely unknown effects in humans and safety profiles (and consequently not widely used or not used at all): orexin-A,[119] FGL, PTEN-PDZ, and PI3K-activator PTD4-PI3KAc,[178] dihexa,[179][180][181] d-cycloserine,[182][183][184][41][185] DAT blockers CE-123 and CE-158,[186] ampakines like IDRA-21 and CX717,[187][188][41][147][189] rapastinel,[190][191][192] ISRIB,[193][194] citicoline,[195] selective receptor modulators such as MRK-016 which targets subtypes of GABA_A receptors,[196] modafinil-analogs CRL-40,940 and modafiendz,[100] modafinil-inspired/hybrid TRIs JZ-IV-10 and JZAD-IV-22,[197][198][199] TAK-925 (orexin agonist that promotes wakefulness in ways similar to modafinil),[200][201] wakefulness-inducing or procognitive narcolepsy medication candidates like samelisant,[202][203] pterostilbene,[204][205] CRM acyl-ghrelin mimetics and agonists like ibutamoren,[206][207] and H₃ receptor antagonist pitolisant.[208][202][209]

Some medications like widely used sociability-related GABA receptor agonist phenibut can have durable major side-effects and addiction potential for some at least at some dosages, albeit not necessarily.[210][211][48][212] Other notable repurposed chemicals already widely in use for other purposes and with potential viability for neuroenhancement but in most cases no or few/small trials with healthy non-old humans, limited research on side-effects and/or unvalidated effect-sizes include: CBD,[213][214] neuropeptide cerebrolysin,[22][215] nicergoline,[216][85] huperzine-A,[217] DMAE and meclofenoxate,[85][217][35] vinpocetine,[85][217] palmitoylethanolamide (PEA),[218] and pyritinol.[219][85]

Neurostimulation methods are being researched and developed. Results indicate details of the stimulation procedures are crucial, with some applications impairing rather than enhancing cognition and questions being raised about whether this approach can deliver any meaningful results for cognitive domains. Stimulation methods include electrical stimulation, magnetic stimulation, optical stimulation with lasers, several forms of acoustic stimulation, and physical methods like forms of neurofeedback.[33][126] There are ideas to integrate such headgear into helmets.[119][126]

While neuroenhancement drugs are a potential method for cognitive performance enhancement, transcranial direct current stimulation (tDCS) over the motor cortex (MC) is being seen as another potential method.[220] Although it was originally intended to help patients with brain injuries such as stroke, there has been a lot of interest in the last few years on tDCS's capabilities for healthy individuals as well. Recent studies have already shown improved neuroplasticity from tDCS to facilitate motor learning in young humans, and it may be possible to apply this method to the older segment of the workforce as well.[220]

Stimulating higher cognitive functions of the brain, such as the language function, with tDCS in one study resulted in improved word retrieval. tDCS works by enhancing the connectivity in a given stimulated network, providing neural efficiency in highly specific brain areas critical for task performance.[221] During this time, fMRI images also showed reduced activity in the semantic retrieval processes, suggesting more efficient processing in task-critical areas of the brain.[221] Reduced activity in circumscribed task-related areas has been attributed to consolidation of motor learning and superior memory performance. New research in tDCS is trying to localize the stimulation to affect the desired subset of highly specific task-relevant neurons.[221] In 2022, scientists demonstrated that transcranial alternating current stimulation (tACS) can, depending on the frequency, for one month improve (either) short-term memory or long-term memory in 65–88-years-old people.[222]

Illustration showing an electrode placed deep-seated in the brain

Deep brain stimulation (DBS) is another form of neuroenhancement. Unlike tDCS, though, DBS involves the implantation of a medical device, and is restricted for use for only a few, severe diseases such as Parkinson's disease and dystonia.[223] In one study, DBS improved movement by 39%, reduced disability by 38%, and improved quality of life by 30% for patients with dystonia over a course of 3 months.[223] The patients had a reduction in dystonia symptoms by 50%.[223] Improvement was noticeable within hours to days after DBS application. The benefits of DBS as of now are far more than those of high-dosage trihexyphenidyl, a powerful drug used in the treatment for dystonia.

A study showed that a "visual flicker paradigm to entrain individuals at their own brain rhythm (i.e. peak alpha frequency)" resulted in substantially faster perceptual visual learning, maintained the day following training. In particular, the entrainment substantially accelerated learning (this group "improved at least three times faster than control groups") in a discrimination task to detect targets embedded in background clutter or to identify radial vs. concentric Glass patterns embedded in noise compared to entrainment that does not match an individual's alpha frequency.[229]

Enhancement can also be based on conventional methods; this may be considered neuroenhancement[230] if they are targeted, especially when they are applied to an advanced level or if they are considered from a collective public health intervention[230] perspective. From this perspective, "failing to encourage the pursuit of healthy behaviours" has "adverse effects on population cognitive health".[230]

Conventional methods include those that delay or mitigate brain aging (which is one major preoccupation of neuro-enhancement),[231] including adequate sleep, optimized diet, and physical activity (which has many neuroeffects).[230][232][56][24][22][38][23]

However, they may also be considered as "co-strategies" in parallel to "neuroenhancement", rather than as techniques of cognitive enhancement.[233] Conventional cognitive enhancement methods and "more direct neuromodulatory methods" could be used together[57][134] (e.g. environmental enrichment and nootropics)[125] for desired effects. (see also #Integrated learning enhancement strategies)

Cognitively stimulating and social activities can also have positive effects on the brain.[23]

Environmental protection measures can also protect or enhance cognitive abilities – for example studies have well-validated extensive harmful effects of ubiquitous air pollution (outdoor[234][235][236][237] and e.g. PM_2.5 and CO₂ concentrations indoor[238]) and shown that half of the US population has been exposed to substantially detrimental lead levels in early childhood (mainly from car exhaust whose lead pollution peaked in the 1970s and caused widespread loss in cognitive ability).[239]

Development of education may also be part of neuroenhancement. Results in neuroscience and software – e.g. AI and adaptive online learning environments – can be relevant to this development.[240][241][242][243] Lifelong learning may be considered a way of cognitive enhancement.[42] For the scope of neuroenhancement relating to education and work, see #Scope for cognitive enhancement.

Lifetime-use between 15 and 64[244]

How people spend their time or activities may have major effects on cognition[23][245][28] (and vice versa) and be modulatable in various non-pharmacological ways such as decision-making, prioritization, routines, reflective practices, reasoning-related technologies, gamification,[42] incentives (e.g. economics, economic policy, media policy, curricula, social feedback, norms, etc), and so on. One review suggests that including motivation enhancement measures "such as motivational interviewing and the use of rewards or incentives" makes interventions substantially more successful in achieving improvements in health behaviours.[246] Exemplary activities include sleep, wage labour work, school, social media, TV, volunteering, boredom, exercise, social activities and hobbies.

There is time-use research and research on various types of media uses on cognition. Impacts of screen time as well as play behavior on cognition may depend heavily on the activities, contexts, substituted activities and contents.[245][247] (see also Reality#Media and below)

Motivations to make use of pharmacological cognitive enhancers include "time optimization" and "increase in time awake".[21] Time requirements for neuroenhancers may be an important factor in their selection or adoption.

Integration of digital tool use may increase cognitive capacity and flexibility, lower cognitive load and foster digital fluency.[248][243] Skills in critical thinking, technology-supported inquiry learning,[249][250][243] scientific reasoning abilities (e.g. compare with religious education and the "cognitive style of religious thinking"[251][252]) and problem-solving may be related to the cognitive domain or represent "metacognitive skills".[253][254][243][255] Improvements to education could be considered cognitive enhancements and "educators" may commonly commit to a fallacy whereby it is assumed that if "individual distinct cognitive processes can be enhanced [...] [this] must enhance cognition overall" when they deploy "'teaching to the test'" and prioritize "memorization over generalizable skills such as critical thinking and problem solving".[256]

Another facet of education from a neurological perspective is integration of neuroenhancement options (behavioral, pharmacological, or devices) in learning processes in specific or in various types of training or education (e.g. by students, retrainees or military personnel). This could be considered as part of evidence-based learning and is concerned with ensuring applied methods are safe, effective and are used in the right way – potentially including personalization – for the right purpose(s) at the right time(s) during the learning process(es). In contrast, a DIY-approach (see #Neurohacking and DIY), rather than guided ones, requires at least extensive research by the person seeking to enhance aspects of cognition.

Educational software may also fall into the scope of neuroenhancement (which may depend on the kinds or types of use or features of such).[22][42] Applications of augmented reality technologies (see below) are investigated for general memory enhancement, extending perception and learning-assistance.[257][258][126]

The Internet is sometimes considered as a "powerful cognitive enhancement technology"[241] or as enabling "Internet-extended cognition" or "Web-extended minds" or "human-extended machine cognition".[259][260][261] However, it is not "a simple, uniform technology, [n]either in its composition, [n]or in its use" and as "an informational resource currently fails to enhance cognition", partly due to issues that include information overload, misinformation and persuasive design. Substantial neuroenhancement potential therefore may lie in measures such as individual empowerment (possibly via existing education systems), software development and better collaborative systems for sorting and categorizing information.[241]

One trial investigated a smartphone motivation enhancement application "promoting lifestyle improvement for brain health".[262]

What could be described as "human-computer symbiosis" already permeates daily life, including for example humans' use of Web search software for research or machine translation.[263][264] A "gradual transition from document-centric to more data-centric modes of information representation", as envisioned by Semantic Web developments, could "provide new opportunities for cognitive augmentation and enhancement". This would enable targeted retrieval of specific pieces of task-relevant information and highly flexible modes of information display, in a way that is more advanced or integrated than conventional desktop computer Web search querying,[265] which is further complicated by that enhancement of the reasoning- and inquiry-skills[243] of Web research, media literacy and sophisticated use of literature- and Web-search engines and tools are typically not part of curricula.

Downsides of "merger[s]" with Information and communications technologies (ICTs), often called or misidentified as "AI" in the literature and media, may currently include "loss of privacy, political polarization, psychological manipulation, addictive use, social anxiety and distraction, misinformation, and mass narcissism"[266] and cause – societally detrimental forms of – harm to mental health and well-being.[267] ICTs and AI tools have enhanced many human skills and practices in ways not feasible without such. For example, AI can enhance artists' creative process or creativity.[267] It has been speculated that AI could monitor and advise via factors that are relevant to or affect moral decision-making as one form of moral enhancement.[268] Externalizing or "offloading" information into an external artefact, especially digital ones, allows people to materialize their thoughts, thereby overcoming the limitations of brains.[269] Whether or not technologies are currently "enhancing the way we think and reason, and thus [are] making us smarter" or not (cognitive diminishment) is a topic of debate and research (or more precisely determinants, factors and impacts),[270][269] and may depend on changeable factors such as:

• whether their design is public[270]
• ethical frameworks for design[270]
• policy
• systematic incentives and mechanisms of the contemporary socio-economy which facilitate or determine their use/adoption, patterns of use, success/production, creation/feasibility, and quality
• incentives and mechanisms that are built into the technologies or inherent to them (these may be interdependent with surrounding infrastructures, transparency/product information, standards, design- and policy-decisions that are based on the prior socioeconomic incentives, assessments-/ratings-mechanisms, life-cycle analyses, and metadata)

Nutrition also plays an important role during early brain development.[166][169][271]

A 2021 study showed that the Abecedarian Early Intervention Project resulted in significant changes in midlife brain structure in males. MRI scans showed that several brain regions' and total brain volumes were substantially larger in participants of the childcare program than in the control group.[272][273]

Protection from pollutions (such as direct and indirect vehicular pollution) appears to be of special importance during and before early childhood,[278] with age being the largest factors that affect neurotoxic outcomes for a given pollution.[235]

Concerning aforementioned screen-use, children's exposure to computers as part of school curricula is important to the development of computer literacy.[279]

Play behavior may also extend to the choice of toys, as social-emotional and cognitive skills are developed and enhanced as children play. A study recommends toys that encourage the child to be mentally and physically active.[280] For example, several construction toys like Meccano could facilitate children to learn skills that are embedded in the act of designing and creative thinking.[281][282] Stimulation of creativity during childhood "enhances cognition and even can alter the brain both anatomically and physiologically".[105]

Correction of mild dehydration[91] (which may be especially relevant when chemicals like modafinil have been consumed), listening to various types of music and other audio[283][284][12] (e.g. ambient music, binaural beats or soundscapes for focus and other types for mood, motivation or alertness) or noise-reduction,[12] and intake of – at least specific – fruits (and possibly nuts)[285][286][287][91][288][77] can have immediate (acute) significant effects depending on various factors.

Targeted microbiome alterations such as via various psychobiotics,[294] meditation,[33][28][295] and physical relaxation techniques like cyclic breathing exercises,[296] could have longer-term effects, albeit the research on these interventions is at an early stage with few human trials[291] – which may be needed to, for example, identify beneficial bacterial species and strains to include in a probiotic – despite a study reportedly first showing that the gut microbiota can be a therapeutic target for cognitive enhancement in the year 2011.[297]

Research also investigates differences between adults' learning and children's learning which may enable interventions to selectively enhance learning in adults and children.

The role of sleep in learning can be leveraged by interventions such as "targeting specific neurotransmitter systems pharmacologically", "stimulating sleep-specific brain oscillations" and "cueing memory reactivation during sleep", including via "[o]lfactory and auditory cues".[184]

Desynchronized circadian rhythms have detrimental effects on cognition.[298] In learning and skill development, the sleep episode following initial skill practice is important for consolidation.[299] Sleep evasion which may be useful for increasing time available and wakefulness can be studied in a variety of ways.[189] Sleep is investigated for potential ways to leverage it for acutely (e.g. via complex analogical problem solving or sleep onset periods as creative sweet spots)[300][301] or chonically[301][302] improving types of creativity.

There is research into interventions to enhance sleep as in improving sleep quality, efficiency (sleep latency), and duration (e.g. 7–8 hours for most adults in specific but depending on factors that include genetics, possibly (preceding) exhausting physical activity[303] and possibly factors of "perceived sleep needs"[303]).

Candidate tools or targets for modulation (technological,[304] legal, pharmacological, or otherwise) include glycine, melatonin (which can have side effects), diet and exercise, post-waking cognitive effort such as via alarm clocks that are deactivated by solving simple puzzles,[305][306][307] neuromodulation sleeping caps,[308] lemon balm,[309] tryptophan, valerian, ashwagandha,[310][311] caffeine-[312][303] and meal-timing, circadian rhythm adherence, lightning, screen-use and blue light reduction before sleep, and various optimal sleep environment characteristics[313][314] (which may include indoor air quality, thermal properties of bedding,[299] temperature,[299][303] noise,[303] and outdoor light at night).

Applications of augmented reality technologies are investigated for:[257][258][126]

• general memory enhancement
• providing "just in time" information[315]
• parallel quadcopter operation
• enhancement to detect, classify, and successfully manage (e.g. engage) threats[316]
• spatial awareness[316]
• enhancing visual and multisensory perception[316]
• learning-assistance

Challenges for adoption include "short- and long-term risks of distraction, mental workload, visual occlusion, and technology-induced complacency and skill degradation".[316]

A potential future biochemical strategy for cognitive enhancement is human genetic enhancement which has only been preliminarily, but successfully, tested in animal models and is currently not an available enhancement option to researchers.[33][28][317]

Traits, IQ& language skills

A neurogenetics genome-wide association study (GWAS) meta-analysis investigated genetic correlations of language-related skills, reporting genetic factors of, the so far uniquely human, language-related capabilities, in particular factors of differences in skill-levels of five tested traits. It also used neuroanatomy/neuroimaging data.[320] However, correlations are not to be equated with causal factors and causal factors are neither independent from surrounding factors of society nor necessarily exclusively beneficial.

PubMed search results for clinical trials with nootropic(s), smart drug(s) or cognitive enhancer in the title or abstract[321]

Parents and healthcare providers are concerned about the safety and well-being of those that consume various neuroenhancements.[322]

In a 2011 article by Jayne Lucke, the concept of neuroenhancement is compared to sildenafil. The author states that "recreational users of [sildenafil] had lower confidence in their ability to achieve an erection than non-users, even though they had a significantly better erectile function. They become psychologically dependent on these drugs." The author believes a similar issue can be seen in neuroenhancement users.[322] Moreover, expectations or overestimations regarding the effectiveness of interventions can exceed their actual effects and they can induce overconfidence.[2][24]

If more and more people begin enhancing their minds, people may "eventually feel subtly coerced into enhancing themselves in order to remain competitive in school or the workplace" or in the military, or experience types of peer-pressure.[119][323][47]

Dubljević stated that "making sure that users are well informed, tracking any adverse effects and generating funds (e.g., via taxation or fees) to address related social problems is crucial", suggesting governments could also play a more active role in the addressing of neuroenhancement challenges.[324]

In health systems where production does not sufficiently adjust as in increasing production and reducing production-costs, neuroenhancement may lead to "prescription drug diversion".[35] One review hypothesizes that the limited number of recent randomized controlled trials with healthy people in particular could partly be explained by (the research being influenced by) the media and bioethics literature surrounding pharmaceutical cognitive enhancement in healthy subjects.[7]

Two photos of cognitive enhancer products, often acquired via the Internet from abroad: modafinil tablets and cerebrolysin; one photo of a mail order pharmacy dispenser

There appears to be a lack of various requirements, quality standards, validation and authentication, sampling and lab testing for cognitive enhancers including dietary supplements, (other) chemicals and (other) therapeutic goods,[325][326][327][328][329][330] which may be the result of public safety-governance failure.

This means that if a user is perfectly aware of the current state of science on the risks and benefits of a chemical and personal factors, there can still be risks that the product consumed differs from its label[331] or has a lower quality which in some cases can be dangerous,[332] especially if such are not available through large established shops which have more to lose,[333] assuming such threats to safety are always unintentional and limited to producers and/or retailers (like online pharmacies).

One study raises the question of creating "a knowledge base as part of nutrition and health education in schools and adult education to enable people to counteract marketing and advertising related food supplements, as well as to distinguish meaningful from non-efficacious ingredients or at least to scrutinize products for their potential health risks".[334]

The ethical benefits of neuroenhancement include potentials to:

• improve well-being[43][335][134]
• reduce unhealthy substance use[52][53][55]
• further educational aims[134]
• increase societal productivity[99][336][337][134] in constructive sectors (which is also relevant to aforementioned well-being)[336][134]
• support socioeconomic shifts by "enabling more complex, productive, and inherently fulfilling forms of cooperation"[134] (which may also be relevant to aforementioned well-being)
• enable self-amelioration of widespread mild cognitive deficiencies in cognitively normal individuals[336]
• increase incentives for and the effort behind the development of medical therapies that can benefit people affected by various brain diseases, and in some cases other diseases, such as Alzheimer's disease, and by brain aging. Various cognitive enhancement options – e.g. dietary and/or pharmacological ones – could also be protective against such pathologies (as in preventive healthcare).[338]

Neuroenhancement is often seen analogous to the issue of doping in sports, due to which it is sometimes called brain doping.[322][23][210][25][58] A common concern raised is an unfair advantage of people who consume enhancing drugs over people who don't. Many athletes, however, feel that the only way for them to win against athletes that take performance-enhancing drugs (PED) is for them to take PEDs as well; a similar thought process has developed within the general population in regard to people that consume neuroenhancement drugs.[322] In a research study of 18- to 34-year-olds, 50% of them had little or no objection to the concept of doping.[322] Students, in particular, often feel that cognitive neuroenhancers are acceptable.[322]

Generally, the moral acceptability (including fairness perceptions) of such substances for the purpose of neuroenhancement are an important factor in the decision to use or not use such drugs. Studies found that moral objections against such substances strongly decrease the willingness to use them.[339][340][341]

Many argue that the only option for regulation of neuroenhancements is to allow it to everyone, thus minimizing cheating. Banning the drugs, on the other hand, may have detrimental consequences to society.[8] Not only would it create a black market, amplifying issues caused by illicit use, it would also increase the cost to society from enforcing the law.[322] Neuroenhancement drugs need to be assessed further for their merits and adverse effects, making it easier for policy-makers to make a call on the regulation of such drugs.[10]

In general, cognitive diversity – or some "optimum range of diversity" – was found highly valuable. Novel capabilities due to progress in science and technology may raise related ethical issues.[342] There have also been speculations that cognitive enhancement technologies (CETs) may increase population-level cognitive diversity, e.g. as different people will choose to enhance different aspects of their cognition.[343] Moreover, cognitive enhancements might decrease inequality, e.g. by "leveling the playing field"[344] as well as narrowing the inequality of the "genetic lottery".[7]

Another issue is that of distributive justice, concerned with "who will have access to new cognitive enhancement techniques, and who can experience the cognitive benefits".[323][99][134][35]

A main factor in the costs of cognitive enhancers is their patentability.[33] Online pharmacies and online shops can substantially reduce costs, raise affordability or enable consumers to purchase certain products at all.[329][345][346] Naturally occurring agents (contained in small amounts in foods) may offer "more options to patients who may be of poor socioeconomic backgrounds, or are residents of poorer nations".[77]

Allen Buchanan in a book suggested that "we should embrace the opportunities provided by this emerging pharmacological technology and devote our resources to ensuring that such drugs that are developed and tested properly [e.g. see confounding, reproducibility, #Research topics and cognitive test] and that access to them is equal and open to avoid injustices and the development of black markets".[347]

A new human right to cognitive liberty has been proposed by researchers earlier[354][355] and in a 2023 book by Nita A. Farahany as "an update to other existing human rights to privacy, freedom of thought and self-determination", partly because some neuroenhancement technologies could possibly also be used for ways like "involuntary neural surveillance" (including for business purposes), be vulnerable to hacking or used for manipulation.[356][357][358] Others have suggested "the right to cognitive liberty, the right to mental privacy, the right to mental integrity, and the right to psychological continuity".[354] In 2021 Chile became the first country to approve neurolaw that establishes rights to personal identity, free will and mental privacy.[359]

Neuroenhancement drugs play a key role in some novels and movies, such as Limitless (2011), which may to some degree probe and explore opportunities and threats of using neuro-enhancers in an imaginative way.[360]

Past and projected age of the human world population through time as of 2021[362]

Proponents of cognitive enhancement have argued that there are vast potential benefits for the workforce, especially for the older segment.[220][77] Mainly due to advances in medical technology over the last century, the average human life expectancy has increased significantly. Demographics for developed countries indicate rapid growth of the older segment of the workforce. Advancing age generally shows a pattern in the reduction of the ability to acquire new skills, but integration in the industry today requires employees to be able to acquire and retain new skills more than ever before.[220] With an increase in the ageing population comes an increase in the economic, social, and health burden of age-related disorders and diseases.[77] Enhancing cognitive functions has recently gained substantial increases in attention "because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain function".[361]

A review noted that "even healthy [non-old] individuals who normally function well, are not always performing normally due to sleep deprivation, jet lag, or other stressors, and some might need cognitive enhancers to perform at their best possible level on some occasions".[99] Neuroenhancement thus is concerned with improving capacities in various cognitive domains to approximate their best possible level at more and specific times as well as raising that level, and improving neuropsychological weaknesses or mild deficits that are not diseases.

Concerning public policy and neuroenhancement-related institutionalized structures like education systems, it is not known whether the scope of neuroenhancement also includes the purposes and content that cognition is enhanced for – the ends of cognitive enhancement such as curricula learned in educational institutions or ultimate purposes of tasks at workplaces or, by extension, the methods and frameworks by which such are e.g. selected. It also has not been clarified whether cognitive enhancement also encompasses behavioral interventions or methods (such as mnemonic techniques[33][28] like the method of loci[257]) and differential teaching modes and methods, albeit some studies indicate behavioral interventions fall into the scope of neuroenhancement.

The Reddit forum (subreddit) on nootropics has many readers[368][369][370] and, along with many other related subreddits, enables communication including about topics or questions not yet studied directly or not easily findable in health information on the Internet, experience-based exchange, nootropic-based discussion, and other content for users of cognitive enhancers, which may include marketing. It is an unstructured accessible source of information from past and present users.[369] Researchers have analyzed reports on these websites, such as conducting content analysis of the subreddit r/microdosing.[40] One study used such an approach to highlight some of the gaps in the scientific literature, suggesting "main uses [of memantine] identified on reddit.com were not reported in the medical literature" and provided some data on the usage patterns reported there (see also Clinical trial#Locating trials and Cost of drug development).[371]

The opinion of the general public on the issue of neuroenhancement is scattered.[322][372] In general, the younger population under the age of 25 feel that neuroenhancements are acceptable or that the decision lies in the hand of that individual. Healthcare officials and parents feel concerned due to safety factors, lack of complete information on these drugs, and possible irreversible adverse effects.[322] Such concerns have been shown to reduce the willingness to take such drugs.[373][374][340]

A 2016 German study among 6.454 employees found a rather low life-time prevalence of cognitive enhancement drug use (namely 2.96%), while the willingness to take such drugs was found in every tenth respondent (10.45%).[375] Studies have estimated that between 7–9% of the college population in the United States consumes neuroenhancement drugs. Some studies estimate this figure to be as high as 12% or even 20%.[372] A large-scale survey using a random sample of more than 5.000 German university students found a relatively low 30-days prevalence of 1.2%, 2.3% indicated the use of such drugs within the last 6 months, 3.2% within the last 12 months and during 4.6% during their lifetime, respectively.[373] Of those students, who used such substances during the last 6 months, 39.4% reported their use once in this period, 24.2% twice, 12.1% three times and 24.2% more than three times. It has been shown that consumers of neuroenhancement drugs are much more willing to also use them in the future, e.g. due to positive experiences or a tendency towards addiction.[341][376] Students primarily attribute consumption of these drugs for increased concentration, improved alertness, or to "get high".[322][372] Neuroenhancement drug users rated the positive potential of neuroenhancement drugs higher than non-users, and rated the adverse effects of these drugs lower than non-users, showing more confidence in the result of these drugs. In a survey of 1324 German students, 32% of participants that do not consume neuroenhancement drugs felt they had positive cognitive effects while 12% felt they had a relaxation effect.[372] In contrast, 54% of participants that do consume neuroenhancement drugs felt they had a positive cognitive effect while 25% felt they had a relaxation effect.

A table for the results of a survey conducted on physicians[6]

The need to remain "alert" and "focused" can also be seen in the trend of caffeine consumption. The caffeine consumption for both students and the general population of the US is around 90%.[372][377] Students who consume neuroenhancements also had a higher frequency of consuming psychoactive lifestyle drugs such as cannabis.[372]

A study among German university teachers (including professors) found a very low prevalence of neuroenhancement drug use.[341] Only 0.9% of the respondents reported the use of such drugs. However, 10% of the respondents are willing to take such drugs in the future, which might indicate a potential increase of the prevalence. One reason to use such drugs was work-related stress.

Physicians play an important role in determining the potential abuse of neuroenhancing drugs. While some neuroenhancing drugs do not require a prescription and are easily available, others that require a prescription are up to the discretion of the physician. In a survey conducted among Swiss psychiatrists and general practitioners, the majority of surveyed physicians agreed that their criteria to determine whether or not a dysfunction should be considered a disease is if the patient indicates subjective suffering and/or negative consequences for the everyday ability to work.[6] The surveyed physicians, however, were in majority agreement that they do not prescribe medication without a clear indication of such a dysfunction.[6]