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Home , Aniracetam, Eugeroic, Neuroenhancement, Nootropic, Oxiracetam, Phenylpiracetam

European Review for Medical and Pharmacological Sciences 2020; 24: 2129-2139 use in the workplace: psychiatric and ethical aftermath towards the new frontier of bioengineering

S. ZAAMI1, R. RINALDI1, G. BERSANI2, A. DEL RIO1, C. CIALLELLA1, E. MARINELLI1

1Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Departmental Section of Legal Medicine, “Sapienza” University of Rome, Rome, Italy 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Rome, Italy

Abstract. – OBJECTIVE: The authors have Key Words: sought to expound upon and shed a light on the Nootropics, , Productivity, rise of nootropics, which have gradually taken Workplace, Bioengineering, Ethics. on a more and more relevant role in workplaces and academic settings. MATERIALS AND METHODS: Multidisciplinary Introduction databases have been delved into by entering the following keys: “nootropics”, “cognitive enhance- ment”, “workplace”, “productivity”, “ethics”, “bio- The use of therapeutic for non-medical engineering”. In addition, a broad-ranging search reasons as cognitive enhancers has been spreading has been undertaken on institutional websites in and its risks seem to have become at least in part order to identify relevant analysis and recommen- acceptable among students and certain groups of dations issued by international institutions and workers. Considering the ever more competitive agencies. Papers and reports have been inde- pendently pored over by each author. This search nature of modern societies, which reverberates on strategy has led to the identification of 988 sourc- workplaces as well, enhancers are reasonably ex- es but only 64 were considered appropriate for the pected to spread even more over time; nonetheless, purposes of the paper after being selected by at long-term consequences arising from their becom- least 3 of the authors, independently. ing mainstream “supplements”, for the purpose of RESULTS: The notion of an artificially en- boosting performance, are as yet unknown. Cog- hanced work performance – carried out by the ‘superworker’ – is particularly noteworthy and nitive enhancers, used by healthy individuals, are resonates with the conception of contempo- widely known as nootropics: drugs, supplements, rary work on so many different levels: the rising and other substances that may improve cogni- need and demands for higher degrees of flex- tive function, particularly , ibility and productivity on the job, the implica- strengthening , creativity or even moti- tions of a ‘24/7’ society, where more and more vation in healthy individuals who choose to use services are available at any time, the ever great- them in an effort to take their performances “to the er emphasis on entrepreneurial spirit, individu- al self-reliance and self-improvement, and last next level”. The word “” was coined in but not least, the impact of an ageing society on 1972 by a Romanian scientist, Corneliu Giurgea, economic standards and performance. who combined the Greek words for “mind” and CONCLUSIONS: Moreover, it is worth men- “bending”1-3. The pharmaceutical substances and tioning that human enhancement technologies compounds known as ‘cognitive-enhancers’ can will predictably and increasingly go hand in hand allegedly boost mental performance, the ability to with gene editing, bioengineering, cybernetics 4 and nanotechnology. Applications are virtually focus and keep concentration . In broader terms, boundless, and may ultimately affect all human such drugs are often claimed to heighten and foster traits (physical strength, endurance, vision, in- motor capabilities, affective skills, (i.e., one’s abili- telligence and even personality and mood). ty to deal with stemming from performing

Corresponding Authors: Raffaella Rinaldi, MD; e-mail: [email protected] 2129 S. Zaami, R. Rinaldi, G. Bersani, A. Del Rio, C. Ciallella, E. Marinelli certain work tasks or eliciting feelings of trust and levels11. (trade name) is a mixture of am- affiliation) and are available for clinical and thera- phetamine salts. It is reportedly used off-label for peutic reasons5. the purpose of increasing focus (among workers Furthermore, stagnant economic conditions and students, in particular) or to get a “high” (a certainly play a role in incentivizing worker com- strong, pleasing feeling of , typical of petition, within which some may feel compelled to recreational drugs)12. Users have shown a tenden- consider substances to enhance their productivity. cy towards polydrug use and at times, adulter- In fact, the key factor accounting for nootropics ants such as and have been use in the workplace is productivity, as measu- found added to the amphetamines13,14. Polydrug red by the amount of work produced per working use, which involves countless substances that are hour, i.e., one of the main drivers of long-term eco- extremely hard to identify and regulate, is a seri- nomic growth and higher living standards6. As a ous threat that is bound to grow as online illicit matter of fact, since the crippling 2008 economic market avenues become ever more accessible. For crisis, productivity has lagged behind pre-crisis that reason, some have called for more invest- levels, with little or no significant steady growth7. ments in toxicological and forensic analytical data Productivity growth goes hand in hand with eco- facilities and better international coordination in nomic growth and development; hence the recent order to tackle that issue15. As for the enhancing slowdown in aggregate labour productivity in le- capabilities of , a 2014 systematic ading economies has been widely characterized review has found that low doses of as a puzzle, even paradox. Still, viewing pharma- could potentially foster cological enhancers as a relatively easy shortcut and retention of information in healthy youth, as towards greater productivity entails significant well as enhance task saliency ( to per- medical and ethical challenges8. form a task) and execution of tedious tasks requir- ing substantial effort16,17. Cognitive Enhancers Used Off-Label: What About Safety and Effectiveness? A Widely Used Central It is worth noting, however, that no drugs are : licensed by medical authorities to be recommend- Methylphenidate (marketed und er the brand ed and prescribed as ‘cognitive enhancers’ as names Ritalin, Equasym, Concerta, Rubifenis such. Thus, the definition ‘performance-enhanc- and Medikinet) acts as a stimulant of the central ing ’ is usually linked to the off-label use of nervous system (CNS)18; its main application is drugs prescribed for specific medical conditions treating ADHD and . It raises levels of by healthy individuals, for the purposes of per- the neurotransmitters and norepineph- formance enhancement; modafinil9, used for the rine19. At above optimal doses, methylphenidate treatment of narcolepsy, or methylphenidate10, reportedly causes off-target effects negatively af- for Deficit Hyperactivity Disorder fecting learning skills20. Adverse side-effects are (ADHD), fall within that category. Users acquire a cause for concern: the dopaminergic activity of such medicines on the internet, or through some- methylphenidate may lead to euphoria and addic- one who does have a prescription. Such dynamics tion (its mode of dopaminergic action is similar to mark a cultural shift in drug abuse dynamics: they that of ). Methylphenidate can reportedly are in fact free of the stigma usually associated exacerbate existing behavioral problems and cen- with street drugs while also appearing safer, al- tral nervous system disorders such as bipolar dis- though there can be no certainty as to their actual ease and psychosis; its peripheral effects should composition and nature; potential dangers are not not be overlooked: higher concentra- as clearly perceived, since the term “medicine” is tions in plasma may in fact cause or worsen heart associated with treatment and cure. problems. Hence, methylphenidate is contraindi- cated for patients with high pressure, heart A Broad-Ranging (and Growing) Array of defects or a family history of heart problems21. Substances: Amphetamines Several pharmaceutical drugs which are com- Hydrochloride Greater monly associated with cognitive enhancing (Ta- and Focus at What Cost? ble I): ≤ Atomoxetine hydrochloride is licensed for Amphetamines, which are used to the treatment of ADHD in children of six years treat ADHD or narcolepsy, heighten dopamine and older, in children over the age of six and in

2130 Nootropics use in the workplace

Table I. Principal pharmacological active substances used as nootropics and performance enhancers, their , therapeutic indications and side effects.

Chemical Brand Mechanism Therapeutic Drug Class Side effects name name of action indications Agitation, Dopamine reuptake ADHD*, anxiety, bladder Amphetamine Stimulant Adderall inhibitor; dopamine Narcolepsy pain, depression, releaser nervousness Dopamine and Ritalin, Anxiety/ noradrenaline Equasym, nervousness, reuptake inhibitor, ADHD*, Methylphenidate Stimulant Concerta, , appetite dopaminergic and Narcolepsy Rubifenis loss, dry mouth, noradrenergic Medikinet nausea, activity stimulant Nausea, vomiting, insomnia, tiredness, Selective ADHD*, constipation, Atomoxetine agent Strattera noradrenaline Narcolepsy appetite loss, dry reuptake inhibitor mouth, dizziness, drowsiness, Insomnia, nausea. Acetylcholinesterase Alzheimer-related Aricept transmission diarrhea. muscle inhibitor enhancer cramps.tiredness. Nivalin, Stimulator of Cognitive Nausea, vomiting, Razadyne, availability of decline in mild Acetylcholinesterase appetite loss, Galantamine Razadyne to moderate inhibitor diarrhea, dizziness, ER, for synaptic Alzheimer’s drowsiness Reminyl transmission disease Cognitive decline in mild Nausea, vomiting, Cholinergic to moderate Acetylcholinesterase appetite loss, Rivastigmine Exelon transmission Alzheimer’s inhibitor dizziness, drowsiness enhancer disease associated diarrhea, weakness, with Parkinson’s disease

Sleepiness, Cholinergic Acetylcholinesterase Alzheimer’s , dizziness Tacrine Cognex transmission inhibitor disease nausea, vomiting, enhancer diarrhea

Current flow N-methyl-d-aspartate blockade through Moderate-to- Psychosis, headache, (NMDA) receptor Namenda channels of severe Alzheimer’s constipation, antagonist N-methyl-d- disease dizziness, sleepiness, aspartate (NMDA) N-methyl-d- aspartate (NMDA) Alzheimer’s glutamate receptors disease modulator; Sleepiness, (discontinued) constipation, Anti-histaminic Dimebon L-type calcium Huntington’s headache, dizziness, channels blocker; disease cough, depression. neurotoxic beta- (discontinued) amyloid proteins blocker Table continued

2131 S. Zaami, R. Rinaldi, G. Bersani, A. Del Rio, C. Ciallella, E. Marinelli

Table I. (Continued). Principal pharmacological active substances used as nootropics and performance enhancers, their mechanism of action, therapeutic indications and side effects.

Chemical Brand Mechanism Therapeutic Drug Class Side effects name name of action indications Modalert, Sleepiness due Vigil, to narcolepsy, Insomnia, nausea, Provigil, Dopamine reuptake obstructive sleep diarrhea, headache, Modasomil inhibitor apnea, shift work dizziness and Modiodal. Sleepiness due to Pain, muscle obstructive sleep Dopamine reuptake weakness, bruising, Eugeroics Nuvigil apnea, narcolepsy, inhibitor severe tingling, skin shift work sleep mouth sores disorder. Positive of the α-amino-3- Alzheimer’s disease, hydroxy-5-methyl- dementia, memory Insomnia nervousness, 4-isoxazolepropionic dysfunction, Nootropil depression mud Weight acid (AMPA) alcoholism, gain Drowsiness receptor, cholinergic Raynaud’s and phenomenon neurotransmission modulator Modulator of the α-amino-3- Draganon, hydroxy-5-methyl- Sarpul, 4-isoxazolepropionic Senile dementia Psychomotor agitation, Racetams Ampamet, acid (AMPA) following stroke; anxiety, motor Memodrin, receptor, cholinergic Alzheimer’s disease restlessness, insomnia Referan and glutamatergic or drowsiness, neurotransmission headache, modulator Positive modulator of α-amino-3- Increased psychomotor hydroxy-5-methyl- Dementia, organic Racetams Oxiracetam excitability, sleep 4-isoxazolepropionic brain syndrome disorders. acid (AMPA) -sensitive glutamate receptors Memory and attention deficits Acetylcholine release in elderly with Racetams Pramistar Nervousness, headache stimulant neurodegenerative and vascular

Anti-amnesic, Acetylcholine release Phenotropil , Headache, insomnia, Racetams stimulant within Carphedon , irritability hippocampal cell

*ADHD: attention deficit, hyperactivity disorder. young adults. In adults, symptoms of ADHD that mechanism in ADHD is unknown. It is a selec- were pre-existing in childhood should be con- tive noradrenaline reuptake inhibitor, causing in- firmed. Atomoxetine, a selective nor-adrenaline creased levels of noradrenaline in the CNS and reuptake inhibitor, is licensed in the UK for the ensuing higher alertness, attention and focus. It management of ADHD although its precise action is generally considered to present no

2132 Nootropics use in the workplace potential compared with methylphenidate, being in addition to its main target, with high affinity devoid of any dopaminergic effect. Nevertheless, at a low nanomolar range in vitro, acting as an its adrenergic effect may lead to cardiotoxicity. It effective sigma1 receptor . Sigma1 recep- is therefore contraindicated in individuals with tor ligands Pre-084 and 4-IBP, in fact, foster neu- existing cardiac defects or heart problems. Stud- ritogenesis. Other compounds, including NMDA ies have shown unwanted side effects associated receptor antagonist memantine and antihistamine with the use of atomoxetine in adults such as dry latrepirdine (dimebon), which also reportedly mouth (16-55%), decreased appetite (12-50%), in- bind sigma1 receptors at its effective dose of mi- somnia (17-35%), nervousness (35%), constipation cromolar range, have been observed to improve (7-20%), erectile dysfunction (5-11%), nausea (12- neurite outgrowth29. In addition to donepezil, oth- 40%), dizziness (6-15%), decreased libido (7%), er AChE inhibitors have been used as potential sweating (5-20%), fatigue (16-25%), increased nootropcs, including tacrine, galantamine and heart rate (17%), hypertension (10%), hot flashes rivastigmine, all of which can apparently height- (10%), depression (10%), and urinary problems en the level of acetylcholine neurotransmitter via (6-10%)22,23. the inhibition of acetylcholine hydrolysis. N-me- thyl-D-aspartate (NMDA) receptor antagonists AChE Inhibitors and NMDA Receptor including memantine (approved for the treatment Antagonists of moderate to severe AD)30, which are aimed at Donepezil hydrochloride is a second-genera- suppressing excitotoxicity caused by β-amyloid tion acetylcholinesterase (AChE) inhibitor struc- and excitotoxic neuronal damage, preventing glu- turally dissimilar from other established AChE tamate-induced overstimulation, and lowering inhibitors. Experimentally, donepezil inhibits abnormal neurotransmitter-mediated activation AChE activity in human erythrocytes. Donepezil of the receptors31. If transient low-level, nonpath- is licensed for the treatment of mild to moderately ological, glutamate-mediated neuronal damage severe symptoms of Alzheimer-related demen- can occur in the brains of healthy individuals, tia24. Donepezil is a selective reversible cholines- it is possible that the neuroprotective effects of terase inhibitor in the CNS, leading to increased memantine might be able to counter the damag- acetylcholine concentration and stimulation of ing effects and enhance memory potential in such muscarinic receptors. Studies in mice have also individuals. Further research is needed to clarify indicated an increase in hippocampal production those points32. Memantine’s presumed neuropro- of insulin-like growth factor I and a protective tective effect may also raise N-acetyl aspartate effect against neurodegeneration25. Donepezil’s (NAA) brain levels, i.e., a marker of density neu- cholinergic activity may result in side effects such ronal and axonal viability and mitochondrial me- as diarrhea, nausea, vomiting and effects on the tabolism. Although the function of NAA within such as insomnia. Stud- axons in the white matter is still not fully known, ies on the use of donepezil in healthy adults have its function might partly involve the synthesis of shown improvement in perceptual learning and neurotransmitters. Memantine’s alleged neuro- skill acquisition. However, recent findings in old- protective capabilities might be gauged by the va- er healthy individuals showed negative cognitive riations in NAA concentrations in brain tissue via effects, such as a significant decrease in memory. magnetic resonance spectroscopy33. Clinical and The cognitive effects of donepezil are believed pre- has pointed out that meman- to depend on the user’s mental status, with pos- tine, at doses producing a steady-state plasma lev- itive effects being more likely to show up when el of 0.5-1 mM, is well tolerated, and could even the reduced cognitive performance is due to ex- lead to some degree of cognitive enhancement34. ternal aggravating factors, such as sleep depriva- tion26. Studies have shown that donezepil, galan- Eugeroics: Fostering Wakefulness and tamine, rivastigmine and other NMDA receptor Alertness antagonist such as memantine and antihistamine Eugeroics such as Modafinil/Armodafinil, also latrepirdine can foster neurite outgrowth to a sig- a central nervous system stimulant, foster wake- nificant extent in an embryonic primary cortical fulness. Modafinil is known to interact with neu- culture system27. In fact, in a rodent model of ba- rotransmitters such as dopamine and norepineph- socortical deterioration, donepezil has been able rinets, although its exact action on the brain has to induce cholinergic sprouting28. Moreover, do- not been fully figured out yet. It is an FDA-ap- nepezil has been found to bind sigma1 receptors proved which directly raises cortical cat-

2133 S. Zaami, R. Rinaldi, G. Bersani, A. Del Rio, C. Ciallella, E. Marinelli echolamine levels, indirectly upregulates cerebral to simple vs. complex tasks in various youth seg- serotonin, glutamate, orexin, and histamine lev- ments. els, and indirectly lowers cerebral gamma-ami- no-butyric acid levels. Aside from its approved Nootropics on the Job: use for the treatment of , modafinil a Double-Edged Sword is reported to be widely used off-prescription As for enhancers use in the workplace, there for cognitive enhancement. There has been little are specific professional categories more liable to consensus, however, as to the actual effectiveness use or abuse performance-enhancers on the job, and nature of the cognitive benefits of modafinil among those: in healthy, non-sleep-deprived humans, despite Military personnel: modafinil has been made its growing popularity35. available to combat personnel in several coun- tries, under medical supervision and clearly de- Racetams fined circumstances. Racetams are a class of drugs that include noo- Militaries of several countries are known to tropics such as piracetam, aniracetam, oxirace- have expressed interest in modafinil as an al- tam, pramiracetam and phenylpiracetam. All such ternative to amphetamine, traditionally used by chemicals share a pyrrolidone nucleus. Piracetam troops to cope with , such as in particular is a nootropic that has been used since during lengthy missions. The Foreign Legion the 1960s and is still considered to be a pioneer used modafinil during certain covert operations, “smart drug”, popular among college students due as conceded by the French government itself. The to its availability in several dietary supplements. A United Kingdom’s Ministry of Defense commis- derivative of the neurotransmitter γ-aminobutyric sioned research into modafinil from QinetiQ and acid (GABA), piracetam has various physiological spent £300,000 on one investigation40. In 2011, it effects that are thought to arise from the improve- was conceded by the Indian Air Force that modaf- ment of cell membrane fluidity36. From a neuronal inil was part of “contingency plans”41. standpoint, piracetam acts as a modulator of neu- In the United States military, modafinil has rotransmission in several transmitter systems (no- been approved for use on certain Air Force mis- tably cholinergic and glutamatergic); in addition sions, and it is being investigated for other uses42. to that, it may positively affect As of November 2012, modafinil is the only drug thanks to its neuroprotective and anticonvulsant approved by the Air Force for the purpose of tack- properties. From a vascular standpoint, piracetam ling fatigue. use is no longer appears to reduce erythrocyte adhesion to vas- approved43. cular endothelium, hinder vasospasm, and favor ≤ Transportation workers: in order to cope microcirculation. Such wide-ranging physiologi- with long shifts, transport workers have been cal effects have led to its use in a broad array of found to use amphetamines and other stimu- clinical indications. It is reportedly effective in the lants44. treatment of cognitive disorders and cortical myo- clonus, vertigo, dyslexia, dementia, and sickle cell Workers Providing Emergency Services anaemia, although some studies37,38 have reported and Care an adverse outcome in the treatment of a patient In the United States, Shift Work Sleep Disor- with a history of mental illness. der is a diagnostic category, with modafinil rec- A 2014 systematic review39 on youth popula- ognised as a medically approved treatment to tions has highlighted that modafinil appears to promote alertness. Prescription in the EU was improve reaction time (p ≤ 0.04), logical reason- also possible for the condition Shift Work Sleep ing (p ≤ 0.05) and problem-solving. Furthermore, Disorder until the restriction imposed by the Eu- methylphenidate appears to improve performance ropean Medicines Agency (EMA) in 2011. A 2013 in novel tasks and attention-based tasks (p ≤ 0.05), survey45 has shown that about 15% to 20% of sur- while reducing planning latency in more complex geons have used cognitive or mood enhancement tasks (p ≤ 0.05). Amphetamine has a potential drugs at least once during their lifetimes. This to improve consolidation of information (0.02 ≥ may be attributed to high workload and intense p ≤ 0.05), resulting in better memory. Improved work-related and private stress. As found in a attention has been reported for all three types of 2012 randomized controlled trial by the Imperi- prescription stimulants, despite a lack of consen- al College London46, modafinil improved perfor- sus on whether these improvements are limited mance on tests of higher cognitive function: those

2134 Nootropics use in the workplace in the modafinil group worked more efficiently The American Medical Association has taken a when solving (F1.38 = 5.24, p stand on nootropics, particularly pharmaceutical = 0.028) and planning (F1.38 = 4.34, p = 0.04) “enhancers” in light of their widespread off-label problems, were less-impulsive decision makers use. Prescription drugs that are FDA-approved (F1.37 = 6.76, p = 0.01), and were more able to to treat attention-deficit hyperactivity disorder flexibly redirect their attention (F1.38 = 4.64, p or narcolepsy are commonly associated with the = 0.038). By contrast, no improvement has been off-label use by students and others seeking to observed in tests of clinical psychomotor perfor- boost memory, learning or other aspects of cog- mance. The trial’s findings show that stressed-out nition. Such use is associated with a variety of doctors might benefit from pharmacological en- adverse mental health conditions and patterns of hancement in circumstances requiring efficient substance misuse. information processing, flexible thinking, and Provided that prescription stimulants un- decision-making under time constraints. No im- doubtedly entail risks, they do not necessarily provement, however, is likely to be seen in the make people smarter. As a matter of fact, avail- performance of basic procedural tasks. able evidence defines the cognitive effects of ≤ Other groups of workers in high-pressure, prescription stimulants to be dose-dependent, competitive environments, such as financial trad- highly variable among individuals, and like- ers, academics and lawyers, have been linked to ly limited or modest, at best, in healthy users. performance-enhancing drugs use for various Not enough conclusive data and information reasons: to keep up with professional demands, to are available as to the patterns of dietary sup- heighten productivity rates or to get over jetlag47. plements and herbal substances used for cog- nitive enhancement. More than 100 substances Can Performance Enhancing Drugs from aminoacids to botanical preparations are Really Yield a Net Benefit? As Doubts advertised on websites as having the ability to Linger, AMA and EU-OSHA Weigh in enhance cognitive performance; nevertheless, When analyzing the effects of the drugs, it their actual safety and effectiveness have not should be borne in mind that despite possible im- been systematically examined. provements in the execution of some cognitive The new AMA policy acknowledges that avail- tasks, with at least temporarily better productivity, able information is somewhat lacking and under- different work-related aspects might be adversely scores the need for more research into the patterns affected by the use of enhancers. Overconfidence of use, as well as risks and benefits, of dietary sup- in one’s abilities stemming from the use of perfor- plements and herbal remedies being promoted for mance-enhancers could in fact penalize teamwork, cognitive enhancement. The AMA will also urge potentially undermining group cohesion and coop- the Federal Trade Commission to examine ad- eration. Furthermore, overestimating one’s abilities vertisements for dietary supplements and herbal on account of drug use may prove risky in terms of remedies that claim cognitive enhancement to en- decision making under critical conditions48,49; after sure that they are not misleading53. Furthermore, all, even “physical enhancement” practices, i.e., co- a 2018 discussion paper by the European Agency smetic surgical interventions are often ethically and for Safety and Health at Work (EU-OSHA) adds to morally controversial, particularly when aimed at and broadens the scope of the analysis, citing the minors, given the daunting difficulties in objectively significance of the social and economic context defining their best interest. It is extremely hard to and taking into account potential ‘trigger’ factors arrive at a universally acceptable risk-benefit analy- within the workplace and changes in working con- sis, when it comes to enhancement50. As a matter of ditions at large. It is worth making a connection fact, performance-enhancing drugs have a potential with other future challenges and ‘emerging risks’ to affect work performance, as well as relationships that EU-OSHA identified and discussed within with others and the success and quality of teamwork. its earlier Foresight (EU-OSHA, 2014) and other A trade-off between better concentration skills and reports54. As for the broader social and economic a decrease in sociability would only be acceptable context within which performance enhancers are when individuals work alone; it is however undesir- used, the increase in precarious employment for- able within the context of teamwork51. ms more insecure, often not protected under stan- In Forbes et al52 various nutrients and dietary dard labour rights and legislation, with low wages supplements found no convincing evidence of im- and at times subject to constant surveillance and provements in cognitive performance. monitoring.

2135 S. Zaami, R. Rinaldi, G. Bersani, A. Del Rio, C. Ciallella, E. Marinelli

Conclusions: Changing Working generation, most life-changing conditions such as Conditions Constitute a Sea-Change hereditary diseases, paralysis, organ failure will Recent research provides an insight into the become curable and reversible thanks to the syner- changing nature of working conditions, partic- gy and interaction of multidisciplinary engineering ularly those associated with the ‘gig economy’. fields within the realm of bioengineering. Genet- Although no studies have been carried out to ical transformation for the purpose of generating investigate a direct relationship between perfor- new forms of treatment has already been success- mance-enhancers and changing working condi- fully achieved by bioengineers. On the other hand, tions, there is some indication in Moscone et al55. this technological enhancement will profoundly In this large-scale study, when workers move into affect society, because of the “interruption” it will more precarious working conditions, that transi- bring about in the human being. Rather than pro- tion may be linked to poorer mental health and an ducing altered and desired characteristics, bioen- increase in prescriptions of psychotropic drugs. It gineering/biomedical efforts focus on gene ther- would be certainly useful to conduct similar stud- apy: therapeutic applications specifically targeted ies in relation to performance-enhancing drugs. to inherited diseases. Gene-editing and bioengi- Undoubtedly, the use of performance-enhancers neering could therefore open up new avenues with may be perceived by workers as a way to cope almost limitless potential. This hot topic has also with monotony or to keep up with the demands of been discussed from a perspective machine and electronically-paced work; besides, in different countries such as Italy, where the code the lack of social and individual control over work of Medical ethics has been updated and is currently conditions, the growing degree of fragmentation more closely focused on medical enhancement and of working times and spaces, and the difficulty in cosmetic medicine. In its current version, the Code striking a balance between gainful employment states that medical doctors being asked to provide and private life all pose a real threat to the work- or prescribe cognitive enhancers must always act ers’ livelihoods and even mental health. In fact, in adherence to the highest standards of respect although pharmacological enhancers can increase and protection for human dignity, identity, integ- and sharpen cognitive capabilities in healthy in- rity, and the inherent genetic traits, abiding by the dividuals (albeit experimental and clinical stud- principles of proportionality and precaution61. ies have so far proven relatively modest over- all effects, likely due to the degree of response When “Curing” Gets Conflated with variability across as well as within individuals), “Improving”, Daunting Ethical they can produce side effects in body systems Challenges Come to the Fore other than the brain. Rivastigmine, for instance, Along with the foreseeable clinical and ther- in healthy elderly subjects can improve learning apeutic applications, breakthroughs in bioengi- on a motor level and the ability to make associa- neering will likely not only be aimed at “curing” tions between symbols and digits; yet, at the same disease but at altering and enhancing human per- time, its intake has been found to negatively affect formance in otherwise perfectly healthy individ- skills related to verbal and visual episodic mem- uals as well. Gene editing techniques generally ory56. Likewise, bromocriptine, a dopamine ago- involve proteins that cut DNA, such as those em- nist, can enhance spatial working memory while ployed in CRISPR-Cas962, transcription activa- lowering probabilistic reversal learning skills in tor-like effector nucleases (TALENs) and -fin- young individuals57,58. ger nucleases63,64. Recent research has confirmed that the most commonly used Cas enzyme, Cas9, Smart Drugs Soon to be Outdated? comes from Streptococcus pyogenes, which has Pharmacological performance and cognitive en- proven viable in mouse and human cells in 201365. hancers may relatively soon be replaced by human The CRISPR molecule is programmed to search biological enhancement technologies (HBETs): for a specific nucleotide sequence among the 3 the augmentation of human capacities by biologi- billion in the human genome. CRISPR then un- cal manipulation59. Engineering applied to biology winds the coils of DNA coils and “cleaves” the has made giant strides over the past decades, be- sequence out of the strand. When carried out in coming one of the fastest-growing scientific fields an embryonic germ line cell, egg or a sperm cells, of the 21th century and possibly leading to a novel gene “edits” will become part of the genetic code conception of the right to enjoy good health60. It that is passed on to future generations. Nonethe- is in fact reasonable to predict that over the next less, errors arising from “overediting” have been

2136 Nootropics use in the workplace observed with targeting linked to the guide RNA 6) Carlin W, Soskice D. Stagnant productivity and low used to target the deletions66. Thus, non-specif- unemployment: stuck in a Keynesian equilibrium. ic and unintended genetic alterations may occur OREP 2018; 34: 169-194. Andrews D, Criscuolo C, Gal PN through engineered nuclease technologies such 7) . The best versus the rest: the global productivity slowdown, diver- as CRISPR-Cas9. It is the very presence of such gence across firms and the role of public policy. “off-target repeats” that calls for extreme caution Organisation for Economic Co-operation and De- and stresses the need for better regulation before velopment 2016. Productivity Working Papers No. techniques such as CRISPR can have acceptably 5, OECD Publishing, Paris. safe clinical applications67,68. Given how high 8) Tomažič T, Čelofiga AK. 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