Eur Arch Psychiatry Clin Neurosci DOI 10.1007/s00406-014-0537-1
REVIEW
Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects Andreas G. Franke • Christiana Bagusat • Sebastian Rust • Alice Engel • Klaus Lieb
Received: 6 August 2014 / Accepted: 1 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Pharmacological ‘‘cognitive enhancement’’ (CE) is defined as the use of any psychoactive drug with the purpose of enhancing cognition, e.g. regarding attention, concentration or memory by healthy subjects. Substances commonly used as CE drugs can be categorized into three groups of drugs: (1) over-the-counter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba; (2) drugs being approved for the treatment of certain disorders and being misused for CE: drugs to treat attention-deficit/hyperactivity disorder (ADHD) such as the stimulants methylphenidate (MPH, e.g. RitalinÒ) or amphetamines (AMPH, e.g. AttentinÒ or AdderallÒ), to treat sleep disorders such as modafinil or to treat Alzheimer’s disease such as acetylcholinesterase inhibitors; (3) illicit drugs such as illicit AMPH, e.g. ‘‘speed’’, ecstasy, methamphetamine (crystal meth) or others. Evidence from randomized placebo-controlled trials shows that the abovementioned substances have limited pro-cognitive effects as demonstrated, e.g. regarding increased attention, increased cognitive speed or shortening of reaction times, but on the same time poses considerable safety risks on the consumers. Prevalence rates for the use of CE drugs among healthy subjects show a broad range from less than 1 % up to more than 20 %. The range in prevalence rates estimates results from several factors
A. G. Franke (&) Department of Social Work and Education, University of Neubrandenburg, University of Applied Sciences, Brodaer Str. 2, 17033 Neubrandenburg, Germany e-mail: [email protected] A. G. Franke C. Bagusat S. Rust A. Engel K. Lieb Department of Psychiatry and Psychotherapy, University Medical Centre Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany
which are chosen differently in the available survey studies: type of subjects (students, pupils, special professions, etc.), degree of anonymity in the survey (online, face-toface, etc.), definition of CE and substances used/misused for CE, which are assessed (OTC drugs, prescription, illicit drugs) as well as time periods of use (e.g. ever, during the past year/month/week, etc.). A clear and comprehensive picture of the drugs used for CE by healthy subjects and their adverse events and safety risks as well as comprehensive and comparable international data on the prevalence rates of CE among healthy subjects are of paramount importance for informing policy makers and healthcare professionals about CE. Keywords Pharmacological cognitive enhancement Stimulant(s) Prescriptive drug(s) Over-the-counterdrug(s)
Introduction Pharmacological enhancement is a phenomenon which is well known from the world of elite athletes [38, 55]. Apart from the world of sports, meanwhile the public media more increasingly reports about the pursuit of pharmacological ‘‘cognitive enhancement’’ (CE) by the use of divergent substances [44]. This phenomenon is described among others by the terms pharmacological ‘‘Neuroenhancement’’, ‘‘Cosmetic Neurology’’, ‘‘Academic Performance Enhancement’’, ‘‘Academic doping’’, ‘‘cognitive enhancement’’ (CE) or even ‘‘Brain Doping’’ [6, 8, 17, 28, 39, 44]. Pharmacological CE is defined as the use of any psychoactive drug by healthy subjects with the aim of enhancing cognitive abilities such as vigilance, attention,
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concentration or memory. Therefore, CE can be distinguished from enhancement purposes during the therapy of a diseased person although the boarders become blurred between both conditions [32, 33, 58]. There are various substances that belong to the group of CE drugs [17, 18, 35]: 1.
2.
3.
The most widespread used group of drugs are over-thecounter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba. Drugs belonging to this group can be bought in supermarkets ‘‘over the counter’’ without having a physicians’ prescription. Prescription drugs. This group consists of various drugs which are labelled with an indication to treat a certain disorder. These drugs are being misused by healthy subjects for the purpose of CE. The most important drugs of this group are (psycho-) stimulants such as methylphenidate (MPH), e.g. RitalinÒ, which is prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Additionally, prescription amphetamines (AMPH)—having the same indication as MPH—such as AttentinÒ or AdderallÒ are also misused for CE. Beyond that, modafinil (e.g. VigilÒ) prescribed to treat the sleep disorder narcolepsy as well as antidementia drugs (acetylcholinesterase inhibitors, N-methyl-D-aspartate antagonists) indicated for the treatment of Alzheimer’s disease is misused by healthy subjects seeking for better cognitive performance. Illicit drugs, especially (psycho-) stimulant drugs such as illicit AMPH, e.g. ‘‘speed’’, ecstasy, methamphetmaine (crystal meth) and others, are also misused for the purpose of CE.
Substances used for CE Caffeine Caffeine is used in various forms such as coffee, caffeinated beverages, energy drinks or caffeine tablets. Whereas caffeinated beverages, the so-called energy drinks and caffeine tablets, have predominantly been used for CE during the last decades, coffee has an ancient tradition and is integral part of our and other cultures. The existence of the first coffee houses has been detected in the beginning of the sixteenth century in the Ottoman Empire. Furthermore, the legend about the pro-vigilant effects of caffeine narrates that sheepherder watched their goats feeding berries from a coffee bush and being awake the whole night [45]. The pro-vigilant effect of caffeine is the indication for CoffeinumÒ, the only caffeine containing approved drug against short time fatigue in Germany [11]. One of the
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characteristics of CoffeinumÒ is that it is only sold in pharmacies, although there is no need for a physicians’ prescription. CoffeinumÒ contains 200 mg of caffeine per tablet and is approved up to 400 mg per day. This amount of caffeine is comparable to a large Starbuck’sÓ-cup (‘‘grande’’) of coffee [51]. Beyond coffee, there exist several caffeinated beverages. One of them stressing the ‘‘energizing’’ effect of caffeine is the group of the so-called energy drinks. One of the most famous agents of the latter is Red BullÒ. It contains 80 mg of caffeine per can (250 ml) and further substances (1,000 mg of taurine, 5.25 g of glucose, 21.5 g of sucrose, 600 mg of glucuronolactone as well as flavouring substances). Energy drinks are marketed especially to young people for ‘‘energizing their lives’’ [37, 41]. Caffeine may lead to short-term tachycardia, hypertonia (via vasoconstriction) and bronchial dilatation [2, 17, 40]. Randomized controlled trials (RCTs) have shown that vigilance and attentiveness are increased and reaction times are shortened [17, 18]. These effects are considerably stronger in subjects who are sleep deprived. However, although the available RCTs show little and inconsistent effects of caffeine on higher cognitive domains (e.g. memory) in healthy subjects, this effect is significant in sleep-deprived subjects leading to the assumption that the pro-cognitive effect of caffeine on higher cognitive domains is an indirect effect mediated by an increase in vigilance, attention and concentration [17, 18]. Interestingly, some studies have shown that the effects of energy drinks are stronger compared to coffee [17, 18]. The reason for this is still unclear given the fact that energy drinks do not contain high amounts of caffeine. In addition, a recent systematic evaluation of the literature revealed a very weak evidence for glucose and a total lack of evidence for taurine as possible CE ingredients [34]. There are only few RCTs comparing the CE effect of caffeine directly to prescription drugs: studies by Wesensten and colleagues and Killgore and colleagues administering 600 mg of caffeine, 20 mg of Dextro-AMPH and 400 mg of modafinil to healthy and sleep-deprived subjects demonstrate that the pro-cognitive efficacy of caffeine is comparable to those of MPH and modafinil (at least regarding the restoration of simple psychomotor performance and objective alertness) [23, 24, 56]. Ginkgo biloba Ginkgo biloba is one of the best-selling OTC drugs. There is a high volume of sales promotion directed to commercials, especially for older customers who are afraid of cognitive decline. The effects in patients with mild cognitive impairment (MCI) or putative early stages of dementia, however, are highly questionable [3].
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With respect to healthy subjects, large RCTs and metaanalyses have shown that Ginkgo biloba has no cognitively enhancing effects neither in younger nor in older healthy subjects: There are no positive effects on vigilance, attention, reaction time or higher cognitive functioning such as memory, no matter which amount of Ginkgo was used or how frequently [17, 18]. A study by Solomon and colleagues among healthy, cognitively non-impaired subjects being older than 60 years showed that after a 6-week use of Ginkgo biloba, the use of Ginkgo biloba did not enhance cognitive performance in standardized neuropsychological tests on attention, concentration, verbal fluency, learning and memory [50]. On the other hand, Ginkgo biloba has nearly no relevant side effects.
We recently concluded that AMPH has stronger effects as compared to MPH regarding vigilance, attention and reaction times [17, 18]. In addition, the abovementioned review also found AMPH to improve consolidation of information [1]. Higher doses of both drugs may have euphoric effects. In this respect, the point of misuse and addiction of AMPH are controversially discussed for many years [4, 17, 25, 26]. Extended release formulations of MPH and AMPH prevent euphoric effects and are therefore protective against the development of substance dependency (e.g. AdderallÒ XR = AdderallÒ extended release).
Amphetamines (AMPH) and Methylphenidate (MPH)
Modafinil (e.g. VigilÒ) is approved for the treatment of narcolepsy, a rare sleep disorder. In Germany, modafinil recently lost the approval for excessive sleepiness in cases of sleep apnoea syndrome and the so-called chronic shift worker syndrome. Comparable to the aforementioned stimulants, RCTs showed that modafinil increases vigilance and attention and shortens reaction time in healthy subjects [17, 18]. Again, in case of sleep deprivation, effects are pronounced compared to pro-cognitive effects in well-rested subjects [17, 18]. A recent meta-analysis described enhancement effects of modafinil in a few cognitive domains such as working memory, attentional interference, spatial planning and executive functioning (used tests: rapid visual information processing test, backward digit span test, clock drawing test, Stockings of Cambridge task, Stroop test) [22]. An older systematic review showed modafinil to improve attention in well-rested individuals. Furthermore, the maintenance of wakefulness, memory and executive functions was significantly better in sleep-deprived individuals treated with modafinil. However, repeated dosages of modafinil did not prevent deterioration of cognitive performance over a longer period of sleep deprivation [48]. An older study assessed therapeutic doses of modafinil during simulated nightshift and revealed attenuated nightshift-associated cognitive disruptions [21]. An important study using the CANTAB test battery as well as an artificial surgical (laparoscopic) simulation setting revealed that modafinil leads to improved working memory and planning behaviour, reduction of impulsiveness and increased flexibility, whereas no effect was detectable regarding psychomotor performance [52]. As mentioned before, RCTs comparing caffeine directly to stimulants as well as modafinil show that the pro-cognitive efficacy of modafinil—at least with respect to simple tasks—is comparable to that of stimulants and caffeine [23, 24, 56].
Drugs containing MPH (e.g. RitalinÒ, ConcertaÒ) and AMPH (e.g. AttentinÒ, AdderallÒ) are approved for the pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). Whereas MPH is approved for ADHD treatment for decades and AMPH containing drugs are approved in several countries for the treatment of ADHD for years, AMPH has reached its approval in Germany only in 2011 (AttentinÒ) and is the first German AMPH containing drug on the market [12]. For both, prescription drugs containing MPH as well as AMPH, the patient needs a specialized prescription according to the German Narcotics Act (Beta¨ubungsmittelgesetz, BtMG). Several AMPH-like substances are illicit drugs, e.g. ‘‘speed’’, MDMA and methamphetamine. These substances act in the central nervous system by reuptake inhibition and/or direct release of the neurotransmitters dopamine and norepinephrine [17, 42, 46, 57]. Most RCTs have shown that both MPH and AMPH increase vigilance and attention in healthy subjects with shortened reaction times without influences on higher cognitive domains. Similar to caffeine, the pro-vigilant effects are pronounced in sleep-deprived healthy subjects [17, 18]. However, one older systematic review claimed for MPH to lead to an improvement of memory functions, whereas no consistent evidence for other enhancing effects could be shown [48]. The most recent systematic review on CE effects of MPH among nonADHD youths concluded that the heterogeneity of the subjects assessed, and the variation in cognitive tasks as well as the lack of replication of the RCTs available leads to difficulties in the interpretation of MPH effects for CE. However, they nevertheless concluded that MPH improves cognitive performance in novel tasks and attention-based tasks and reduces planning latency in more complex tasks [1].
Modafinil
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Eur Arch Psychiatry Clin Neurosci Table 1 Prevalence rates of the use of drugs for CE Study
Franke et al. [14, 15]
Study population
1,548 German high school and undergraduate university students
Design of questionnaire
Prevalence rates Caffeine for CE
Prescription/illicit drugs for CE
P-a-P
Coffee
Prescription stimulants
Lifetime: 53.2 %
Lifetime: 1.29 %
Past year: 8.5 %
Past year: 0.26 %
Past month: 6.3 %
Past month: 0.06 %
Energy Drinks
Illicit stimulants
Lifetime 39 %
Lifetime: 2.6 %
Past year: 10.7 % Past month: 6.3 %
Past year: 0.97 % Past month: 0.26 %
Caffeine tablets Lifetime: 10.5 % Past year: 3.8 % Past month: 0.8 % Mache et al. [29]
1,053 German university students
Online
Caffeine tablets
Prescription and illicit drugs: 1–13 %
Lifetime: 10 %
Cannabis: 13 % Cocaine: 2.3 % MPH: 2.2 % AMPH: 1.1 % ß-Blockers: 2 % Fluoxetine: 1 % Modafinil: 1 % Piracetam: 0.1 %
Middendorff et al. [36]
Franke et al. [13, 20]
7,899 German university students
1,145 German surgeons
Online
P-a-P, RRT
On the scale from 1 = ‘‘never’’ to 5 = ‘‘regularly’’:
‘‘Brain doping’’(e.g. MPH, modafinil, AMPH, cocaine, ecstasy, ß-blockers, cannabis)
Coffee
Lifetime: 5.3 %
1: 44 %, 2: 11 %, 3: 13 %, 4: 12 %, 5: 20 %.
‘‘Soft enhancement’’ (herbal, homoeopathic substances, vitamins, caffeine)
Energy drinks 1: 84 %, 2: 7 %, 3: 4 %, 4: 3 %, 5: 2 %
Lifetime: 5.2 %
Coffee
Prescription or illicit drugs for CE
Lifetime: 66.8 %
Lifetime: 8.9 %
Past year: 61.9 %
Past year: 3.0
Past month: 56.9 %
Past month: 1.4
Past week: 50.5 %
Past week: 0.8
Caffeinated drinks
RRT
Lifetime: 24.2 %
Lifetime 19.9 %
Past year: 15.4 % Past month 9.9 %
Mood enhancement (by the use of prescription antidepressants)
Past week 6.1 %
Last week: 0.4 %
Caffeine tablets Lifetime: 12.6 %
Last month: 0.5 %
5 past year: 9 %
Lifetime: 2.4 %
Last year: 1.0 %
past month: 4.7 % Past week: 3.8 % Ott & BillerAndorno 2014 [43]
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n.a.
Online
n.a.
RitalinÒ, AdderallÒ and/or Modafinil Lifetime: 6.2 %
Eur Arch Psychiatry Clin Neurosci Table 1 continued Study
Study population
Design of questionnaire
Prevalence rates
n.a.
Caffeine for CE
Prescription/illicit drugs for CE
Maher 2008 [30]
1,400 readers of the journal ‘‘Nature’’ from 60 countries
Online
Sattler & Wiegel 2013 [49]
3,486 German university students
Online
DAK 2009 [9]
3,000 German policyholders
P-a-P
n.a.a
n.a.a
Teter et al. [54]
4,580 US-American college students
Online
n.a.
Prescriptive stimulants
2,569 German university students
P-a-P, RRT
Dietz et al. [10]
prescription stimulants and/or beta blockers Lifetime: 20 %
n.a.
Any prescription medication Lifetime: 5 %
Lifetime: 8.3 % Past year: 5.9 % n.a.
Pharmaceuticals or illicit drugs or/and caffeine tablets Past year: 20 %
DAK Deutsche Angestelltenkrankenkasse (huge German health insurance), Gb Ginkgo biloba, n.a. not applicable, Online online questionnaire, P-a-P paper-and-pencil questionnaire, RRT randomized response technique a
No clear distinction between prescription and OTC drugs
Antidementia drugs This group of substances consists of two drug classes with different mechanisms of action: acetylcholine esterase inhibitors (ACh-I such as donepezil, galantamine and rivastigmine) and partial antagonists at the glutamatergic Nmethyl-D-aspartate (NMDA) receptor. Both are approved for the treatment of Alzheimer’s disease (AD): ACh-I for mild to moderate AD and NMDA antagonists for mild to severe AD. ACh-I increases the concentration of acetylcholine in the synaptic cleft via inhibitory effects at the acetylcholinesterase enzyme [19]. Unfortunately, the CE effects of antidementia drugs can hardly be compared to the aforementioned substances because of the different study designs mostly monitoring other aspects of cognition [47]. The results of RCTs regarding CE are at least inconsistent [17, 18]; taken together, the available RCT studies show that antidementia drugs have no consistent effects on cognition, neither regarding vigilance, attention and reaction time nor on memory among healthy subjects [17, 18]. Prevalence rates of CE Since 2006, several studies have been performed to assess the prevalence of use of the abovementioned substances for CE among healthy subjects. The most important and most recent studies are summarized in Table 1. Caffeine containing beverages and drugs are the substances most often used for the purpose of CE. While there are many studies investigating the use of coffee, caffeinated drinks or caffeine tablets in general, there are only
very few studies assessing the prevalence of the specific use of caffeine to enhance one’s own cognitive performance. In a study of our own group, we surveyed 1,548 high school and undergraduate university students using an anonymous paper-and-pencil questionnaire about their use of divergent substances for CE. In this sample, 53.2 % stated to have used coffee for CE at least once in their lifetime, 8.5 % during the last year and 6.3 % during the last month. Prevalence rates for energy drinks were lifetime 39 %, last year 10.7 % and last month 6.3 %. Lifetime prevalence for caffeine tablets was 10.5 %, past-year prevalence 3.8 and past-month prevalence was 0.8 % [15]. The results for caffeine tablets are quite similar to the prevalence rates detected in a study by Mache and colleagues. Within the surveyed 1,053 German university students, 10 % of the participants stated in the online questionnaire that they have already used caffeine tablets at least once in their lifetime to enhance their performance [29]. Another online survey among 7,899 German students asked for the use of various psychoactive drugs for CE [36]. Within that sample, the percentage of participants using coffee for CE was even higher: 20 % stated to use coffee regularly for the reason to cope with their studies (for more details see Table 1). In contrast, there were more students who had never used energy drinks (see Table 1) [36]. Since there was no specific question addressing the use of caffeine tablets, it is not possible to compare this prevalence to the other studies. The consumption of caffeinated substances for CE is also common among surgeons. In an anonymous paper-and pencil study among 951 German surgeons, we found a lifetime, past-year, pastmonth and past-week prevalence, respectively, for coffee
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use of 66.8, 61.9, 56.9 and 50.5 %; respectively for caffeinated drinks 24.2, 15.4, 9.9 and 6.1 %; and respectively for caffeine tablets 12.6, 5.9, 4.7 and 3.8 % [13]. Regarding the group of OTC drugs, Ginkgo biloba is frequently used for CE purposes, especially among older subjects being afraid of cognitive decline. We assessed the use of Ginkgo biloba among 1,672 German university students over the age of 60 who had to fill out a paper-andpencil questionnaire with questions about preventive strategies and other health-related questions. 15.3 % of the participants reported the use of Ginkgo biloba supplements for CE. Interestingly, most of the surveyed people were convinced of a significantly proven pro-cognitive effect of Ginkgo biloba supplements (six-step Likert scale: 1 = ‘‘very correct’’, 6=’’very false’’, all participants 2.35) [16]. Studies regarding the use of prescription and/or illicit drugs vary a lot with respect to their design, the study populations and the specific questions about the used drugs. Therefore, prevalence rates found in different studies have to be compared with caution. Most of the studies investigated the use of substances among high school and/or university students. AMPHs seem to be the most common used prescription drugs for CE among German and USAmerican students [14, 33, 54, 58]. Within the survey of our own group among German high school and university students, 1.2 % stated to have used prescription stimulants at least once exclusively for CE [14]. A Swiss survey found a higher lifetime prevalence rate for non-medical use of prescription stimulants by students: 6.2 % of the surveyed students stated to have already used RitalinÒ, AdderallÒ and/or modafinil [43]. In an online poll by the journal ‘‘Nature’’, 20 % of the participating adult academics answered that they had already used stimulants (MPH, modafinil) or beta blockers for non-medical reasons at least once [30]. However, the study is not representative as only reader of the journal’s announcement participated. Another study by Sattler and Wiegel as well as the abovementioned study by Middendorff and colleagues showed lifetime prevalence rates of approximately 5 % [36, 49]. Similar results were found within a study by Deutsche Angestelltenkrankenkasse (DAK) being a large German health insurance company: approximately 5 % of the 3,000 surveyed policyholders of the surveying health insurance reported having practiced pharmacological CE by the use of prescription or illicit or similar drugs at least once [9]. Generally, there are higher prevalence rates among students practicing CE in the USA than in Europe. Within a sample of 4,580 college students, a lifetime prevalence of 8.3 % and a last year prevalence of 5.9 % were found for the use of prescription stimulants in a web-based survey
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[54]; other studies in the USA showed similar results [31, 32, 53, 58]. The study by Teter and colleagues specifies the most common reasons for the non-medical use: to help with concentration, help study and increase alertness [54]. Other motives such as getting high or to lose weight were also named as well but do not belong to the category of CE. All mentioned studies had to deal with the problem that they directly asked sensitive questions with the risk to receive socially desirable answers. This may well lead to an underestimation of the percentage of individuals practicing pharmacological CE. There are two studies which tried to cope with this problem by using the so-called randomized response technique (RRT), which guarantees a very high degree of anonymity and privacy recognizable by the participant himself [7, 27]. Using this RRT technique, Dietz and colleagues investigated the use of substances for CE among German university students and found that 20 % of the respondents reported to have used prescription stimulants, cocaine, other illicit drugs or caffeine tablets within the last 12 months [10]. This prevalence rate is four times higher than in our previous study using paper-andpencil questionnaires [14, 15]. Another study of our own group using the RRT based on Dietz and colleagues surveyed 1,145 German surgeons about their use of CE drugs. Within the paper-and-pencil questionnaire, 8.9 % of the surgeons stated to have used prescription or illicit drugs exclusively for CE at least once. The same sample had a 2.5-fold higher prevalence rate (19.9 %) as assessed by RRT [13]. Another creative way to handle the risk of dishonest answers in view of the social sensitive issue was shown by the study of Burgard and colleagues. The researchers analysed the wastewater of a college campus in the USA regarding amphetamine and ritalinic acid. Though there was no clear trend for MPH, the analysis over two semesters indicated a higher level of AMPH during periods of high stress as midterms or final weeks and a lower during low stress weeks: AMPH level during the finals week was nearly a factor of 8 times higher than in the first week of the semester [5]. As a consequence of different study designs, study populations and definitions of CE, it is difficult to directly compare the results of different studies. Therefore, only ranges of prevalence rates can be given as it was done in one older meta-analysis addressing the misuse of prescription stimulants (ADHD medication) in 21 studies: 5–9 % of grade and high school students and 5–35 % of college age students have used stimulants within the last year without prescription [58]. There is a need for an up-todate meta-analysis that compares the different results of studies investigating pharmacological CE—not only the use of prescription stimulants—systematically.
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Conclusion Substances used for CE have only very limited pro-cognitive effects as shown in randomized, placebo-controlled studies. However, it is important to distinguish substances having any effect and substances having no effects on cognition. Stimulants such as MPH and AMPH as well as caffeine have at least pro-cognitive effects regarding simple cognitive domains such as vigilance, attention and concentration, whereas antidementia drugs and Ginkgo biloba have no cognitive effects in healthy subjects. Interestingly, the type of effects and the effect sizes of caffeine, AMPH and modafinil are comparable (if given in comparable dosages). With respect to higher cognitive domains, the effects of stimulants are rather week and most likely secondary effects mediated via improved vigilance, attention and concentration skills. The fact that the effects of stimulants are pronounced in sleep-deprived subjects is in line with that view. Studies assessing the prevalence of use of prescription and/or illicit drugs for CE vary a lot with respect to their design, the study populations and the specific questions about the used drugs. Therefore, prevalence rates found in different studies can only be compared with caution. Examples of study design differences are as follows: definition what CE is and how it relates to other possible motives for drug intake such as recreational use, the sample of healthy subjects (high school students, university students, professionals, etc.), the kind of substances and their grouping (e.g. prescription stimulants, any prescription drugs, illicit drugs or various substances throughout the aforementioned groups) and the survey technique (online survey, paper-and-pencil questionnaire, randomized response technique). Hence, a systematic review and metaanalysis are needed to analyse prevalence rates of pharmacological CE among healthy subjects by taking into account the effects of the study design differences mentioned above. Conflict of interest All authors declare that they have no conflict of interest.
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REVIEW
Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects Andreas G. Franke • Christiana Bagusat • Sebastian Rust • Alice Engel • Klaus Lieb
Received: 6 August 2014 / Accepted: 1 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Pharmacological ‘‘cognitive enhancement’’ (CE) is defined as the use of any psychoactive drug with the purpose of enhancing cognition, e.g. regarding attention, concentration or memory by healthy subjects. Substances commonly used as CE drugs can be categorized into three groups of drugs: (1) over-the-counter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba; (2) drugs being approved for the treatment of certain disorders and being misused for CE: drugs to treat attention-deficit/hyperactivity disorder (ADHD) such as the stimulants methylphenidate (MPH, e.g. RitalinÒ) or amphetamines (AMPH, e.g. AttentinÒ or AdderallÒ), to treat sleep disorders such as modafinil or to treat Alzheimer’s disease such as acetylcholinesterase inhibitors; (3) illicit drugs such as illicit AMPH, e.g. ‘‘speed’’, ecstasy, methamphetamine (crystal meth) or others. Evidence from randomized placebo-controlled trials shows that the abovementioned substances have limited pro-cognitive effects as demonstrated, e.g. regarding increased attention, increased cognitive speed or shortening of reaction times, but on the same time poses considerable safety risks on the consumers. Prevalence rates for the use of CE drugs among healthy subjects show a broad range from less than 1 % up to more than 20 %. The range in prevalence rates estimates results from several factors
A. G. Franke (&) Department of Social Work and Education, University of Neubrandenburg, University of Applied Sciences, Brodaer Str. 2, 17033 Neubrandenburg, Germany e-mail: [email protected] A. G. Franke C. Bagusat S. Rust A. Engel K. Lieb Department of Psychiatry and Psychotherapy, University Medical Centre Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany
which are chosen differently in the available survey studies: type of subjects (students, pupils, special professions, etc.), degree of anonymity in the survey (online, face-toface, etc.), definition of CE and substances used/misused for CE, which are assessed (OTC drugs, prescription, illicit drugs) as well as time periods of use (e.g. ever, during the past year/month/week, etc.). A clear and comprehensive picture of the drugs used for CE by healthy subjects and their adverse events and safety risks as well as comprehensive and comparable international data on the prevalence rates of CE among healthy subjects are of paramount importance for informing policy makers and healthcare professionals about CE. Keywords Pharmacological cognitive enhancement Stimulant(s) Prescriptive drug(s) Over-the-counterdrug(s)
Introduction Pharmacological enhancement is a phenomenon which is well known from the world of elite athletes [38, 55]. Apart from the world of sports, meanwhile the public media more increasingly reports about the pursuit of pharmacological ‘‘cognitive enhancement’’ (CE) by the use of divergent substances [44]. This phenomenon is described among others by the terms pharmacological ‘‘Neuroenhancement’’, ‘‘Cosmetic Neurology’’, ‘‘Academic Performance Enhancement’’, ‘‘Academic doping’’, ‘‘cognitive enhancement’’ (CE) or even ‘‘Brain Doping’’ [6, 8, 17, 28, 39, 44]. Pharmacological CE is defined as the use of any psychoactive drug by healthy subjects with the aim of enhancing cognitive abilities such as vigilance, attention,
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concentration or memory. Therefore, CE can be distinguished from enhancement purposes during the therapy of a diseased person although the boarders become blurred between both conditions [32, 33, 58]. There are various substances that belong to the group of CE drugs [17, 18, 35]: 1.
2.
3.
The most widespread used group of drugs are over-thecounter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba. Drugs belonging to this group can be bought in supermarkets ‘‘over the counter’’ without having a physicians’ prescription. Prescription drugs. This group consists of various drugs which are labelled with an indication to treat a certain disorder. These drugs are being misused by healthy subjects for the purpose of CE. The most important drugs of this group are (psycho-) stimulants such as methylphenidate (MPH), e.g. RitalinÒ, which is prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Additionally, prescription amphetamines (AMPH)—having the same indication as MPH—such as AttentinÒ or AdderallÒ are also misused for CE. Beyond that, modafinil (e.g. VigilÒ) prescribed to treat the sleep disorder narcolepsy as well as antidementia drugs (acetylcholinesterase inhibitors, N-methyl-D-aspartate antagonists) indicated for the treatment of Alzheimer’s disease is misused by healthy subjects seeking for better cognitive performance. Illicit drugs, especially (psycho-) stimulant drugs such as illicit AMPH, e.g. ‘‘speed’’, ecstasy, methamphetmaine (crystal meth) and others, are also misused for the purpose of CE.
Substances used for CE Caffeine Caffeine is used in various forms such as coffee, caffeinated beverages, energy drinks or caffeine tablets. Whereas caffeinated beverages, the so-called energy drinks and caffeine tablets, have predominantly been used for CE during the last decades, coffee has an ancient tradition and is integral part of our and other cultures. The existence of the first coffee houses has been detected in the beginning of the sixteenth century in the Ottoman Empire. Furthermore, the legend about the pro-vigilant effects of caffeine narrates that sheepherder watched their goats feeding berries from a coffee bush and being awake the whole night [45]. The pro-vigilant effect of caffeine is the indication for CoffeinumÒ, the only caffeine containing approved drug against short time fatigue in Germany [11]. One of the
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characteristics of CoffeinumÒ is that it is only sold in pharmacies, although there is no need for a physicians’ prescription. CoffeinumÒ contains 200 mg of caffeine per tablet and is approved up to 400 mg per day. This amount of caffeine is comparable to a large Starbuck’sÓ-cup (‘‘grande’’) of coffee [51]. Beyond coffee, there exist several caffeinated beverages. One of them stressing the ‘‘energizing’’ effect of caffeine is the group of the so-called energy drinks. One of the most famous agents of the latter is Red BullÒ. It contains 80 mg of caffeine per can (250 ml) and further substances (1,000 mg of taurine, 5.25 g of glucose, 21.5 g of sucrose, 600 mg of glucuronolactone as well as flavouring substances). Energy drinks are marketed especially to young people for ‘‘energizing their lives’’ [37, 41]. Caffeine may lead to short-term tachycardia, hypertonia (via vasoconstriction) and bronchial dilatation [2, 17, 40]. Randomized controlled trials (RCTs) have shown that vigilance and attentiveness are increased and reaction times are shortened [17, 18]. These effects are considerably stronger in subjects who are sleep deprived. However, although the available RCTs show little and inconsistent effects of caffeine on higher cognitive domains (e.g. memory) in healthy subjects, this effect is significant in sleep-deprived subjects leading to the assumption that the pro-cognitive effect of caffeine on higher cognitive domains is an indirect effect mediated by an increase in vigilance, attention and concentration [17, 18]. Interestingly, some studies have shown that the effects of energy drinks are stronger compared to coffee [17, 18]. The reason for this is still unclear given the fact that energy drinks do not contain high amounts of caffeine. In addition, a recent systematic evaluation of the literature revealed a very weak evidence for glucose and a total lack of evidence for taurine as possible CE ingredients [34]. There are only few RCTs comparing the CE effect of caffeine directly to prescription drugs: studies by Wesensten and colleagues and Killgore and colleagues administering 600 mg of caffeine, 20 mg of Dextro-AMPH and 400 mg of modafinil to healthy and sleep-deprived subjects demonstrate that the pro-cognitive efficacy of caffeine is comparable to those of MPH and modafinil (at least regarding the restoration of simple psychomotor performance and objective alertness) [23, 24, 56]. Ginkgo biloba Ginkgo biloba is one of the best-selling OTC drugs. There is a high volume of sales promotion directed to commercials, especially for older customers who are afraid of cognitive decline. The effects in patients with mild cognitive impairment (MCI) or putative early stages of dementia, however, are highly questionable [3].
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With respect to healthy subjects, large RCTs and metaanalyses have shown that Ginkgo biloba has no cognitively enhancing effects neither in younger nor in older healthy subjects: There are no positive effects on vigilance, attention, reaction time or higher cognitive functioning such as memory, no matter which amount of Ginkgo was used or how frequently [17, 18]. A study by Solomon and colleagues among healthy, cognitively non-impaired subjects being older than 60 years showed that after a 6-week use of Ginkgo biloba, the use of Ginkgo biloba did not enhance cognitive performance in standardized neuropsychological tests on attention, concentration, verbal fluency, learning and memory [50]. On the other hand, Ginkgo biloba has nearly no relevant side effects.
We recently concluded that AMPH has stronger effects as compared to MPH regarding vigilance, attention and reaction times [17, 18]. In addition, the abovementioned review also found AMPH to improve consolidation of information [1]. Higher doses of both drugs may have euphoric effects. In this respect, the point of misuse and addiction of AMPH are controversially discussed for many years [4, 17, 25, 26]. Extended release formulations of MPH and AMPH prevent euphoric effects and are therefore protective against the development of substance dependency (e.g. AdderallÒ XR = AdderallÒ extended release).
Amphetamines (AMPH) and Methylphenidate (MPH)
Modafinil (e.g. VigilÒ) is approved for the treatment of narcolepsy, a rare sleep disorder. In Germany, modafinil recently lost the approval for excessive sleepiness in cases of sleep apnoea syndrome and the so-called chronic shift worker syndrome. Comparable to the aforementioned stimulants, RCTs showed that modafinil increases vigilance and attention and shortens reaction time in healthy subjects [17, 18]. Again, in case of sleep deprivation, effects are pronounced compared to pro-cognitive effects in well-rested subjects [17, 18]. A recent meta-analysis described enhancement effects of modafinil in a few cognitive domains such as working memory, attentional interference, spatial planning and executive functioning (used tests: rapid visual information processing test, backward digit span test, clock drawing test, Stockings of Cambridge task, Stroop test) [22]. An older systematic review showed modafinil to improve attention in well-rested individuals. Furthermore, the maintenance of wakefulness, memory and executive functions was significantly better in sleep-deprived individuals treated with modafinil. However, repeated dosages of modafinil did not prevent deterioration of cognitive performance over a longer period of sleep deprivation [48]. An older study assessed therapeutic doses of modafinil during simulated nightshift and revealed attenuated nightshift-associated cognitive disruptions [21]. An important study using the CANTAB test battery as well as an artificial surgical (laparoscopic) simulation setting revealed that modafinil leads to improved working memory and planning behaviour, reduction of impulsiveness and increased flexibility, whereas no effect was detectable regarding psychomotor performance [52]. As mentioned before, RCTs comparing caffeine directly to stimulants as well as modafinil show that the pro-cognitive efficacy of modafinil—at least with respect to simple tasks—is comparable to that of stimulants and caffeine [23, 24, 56].
Drugs containing MPH (e.g. RitalinÒ, ConcertaÒ) and AMPH (e.g. AttentinÒ, AdderallÒ) are approved for the pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). Whereas MPH is approved for ADHD treatment for decades and AMPH containing drugs are approved in several countries for the treatment of ADHD for years, AMPH has reached its approval in Germany only in 2011 (AttentinÒ) and is the first German AMPH containing drug on the market [12]. For both, prescription drugs containing MPH as well as AMPH, the patient needs a specialized prescription according to the German Narcotics Act (Beta¨ubungsmittelgesetz, BtMG). Several AMPH-like substances are illicit drugs, e.g. ‘‘speed’’, MDMA and methamphetamine. These substances act in the central nervous system by reuptake inhibition and/or direct release of the neurotransmitters dopamine and norepinephrine [17, 42, 46, 57]. Most RCTs have shown that both MPH and AMPH increase vigilance and attention in healthy subjects with shortened reaction times without influences on higher cognitive domains. Similar to caffeine, the pro-vigilant effects are pronounced in sleep-deprived healthy subjects [17, 18]. However, one older systematic review claimed for MPH to lead to an improvement of memory functions, whereas no consistent evidence for other enhancing effects could be shown [48]. The most recent systematic review on CE effects of MPH among nonADHD youths concluded that the heterogeneity of the subjects assessed, and the variation in cognitive tasks as well as the lack of replication of the RCTs available leads to difficulties in the interpretation of MPH effects for CE. However, they nevertheless concluded that MPH improves cognitive performance in novel tasks and attention-based tasks and reduces planning latency in more complex tasks [1].
Modafinil
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Eur Arch Psychiatry Clin Neurosci Table 1 Prevalence rates of the use of drugs for CE Study
Franke et al. [14, 15]
Study population
1,548 German high school and undergraduate university students
Design of questionnaire
Prevalence rates Caffeine for CE
Prescription/illicit drugs for CE
P-a-P
Coffee
Prescription stimulants
Lifetime: 53.2 %
Lifetime: 1.29 %
Past year: 8.5 %
Past year: 0.26 %
Past month: 6.3 %
Past month: 0.06 %
Energy Drinks
Illicit stimulants
Lifetime 39 %
Lifetime: 2.6 %
Past year: 10.7 % Past month: 6.3 %
Past year: 0.97 % Past month: 0.26 %
Caffeine tablets Lifetime: 10.5 % Past year: 3.8 % Past month: 0.8 % Mache et al. [29]
1,053 German university students
Online
Caffeine tablets
Prescription and illicit drugs: 1–13 %
Lifetime: 10 %
Cannabis: 13 % Cocaine: 2.3 % MPH: 2.2 % AMPH: 1.1 % ß-Blockers: 2 % Fluoxetine: 1 % Modafinil: 1 % Piracetam: 0.1 %
Middendorff et al. [36]
Franke et al. [13, 20]
7,899 German university students
1,145 German surgeons
Online
P-a-P, RRT
On the scale from 1 = ‘‘never’’ to 5 = ‘‘regularly’’:
‘‘Brain doping’’(e.g. MPH, modafinil, AMPH, cocaine, ecstasy, ß-blockers, cannabis)
Coffee
Lifetime: 5.3 %
1: 44 %, 2: 11 %, 3: 13 %, 4: 12 %, 5: 20 %.
‘‘Soft enhancement’’ (herbal, homoeopathic substances, vitamins, caffeine)
Energy drinks 1: 84 %, 2: 7 %, 3: 4 %, 4: 3 %, 5: 2 %
Lifetime: 5.2 %
Coffee
Prescription or illicit drugs for CE
Lifetime: 66.8 %
Lifetime: 8.9 %
Past year: 61.9 %
Past year: 3.0
Past month: 56.9 %
Past month: 1.4
Past week: 50.5 %
Past week: 0.8
Caffeinated drinks
RRT
Lifetime: 24.2 %
Lifetime 19.9 %
Past year: 15.4 % Past month 9.9 %
Mood enhancement (by the use of prescription antidepressants)
Past week 6.1 %
Last week: 0.4 %
Caffeine tablets Lifetime: 12.6 %
Last month: 0.5 %
5 past year: 9 %
Lifetime: 2.4 %
Last year: 1.0 %
past month: 4.7 % Past week: 3.8 % Ott & BillerAndorno 2014 [43]
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n.a.
Online
n.a.
RitalinÒ, AdderallÒ and/or Modafinil Lifetime: 6.2 %
Eur Arch Psychiatry Clin Neurosci Table 1 continued Study
Study population
Design of questionnaire
Prevalence rates
n.a.
Caffeine for CE
Prescription/illicit drugs for CE
Maher 2008 [30]
1,400 readers of the journal ‘‘Nature’’ from 60 countries
Online
Sattler & Wiegel 2013 [49]
3,486 German university students
Online
DAK 2009 [9]
3,000 German policyholders
P-a-P
n.a.a
n.a.a
Teter et al. [54]
4,580 US-American college students
Online
n.a.
Prescriptive stimulants
2,569 German university students
P-a-P, RRT
Dietz et al. [10]
prescription stimulants and/or beta blockers Lifetime: 20 %
n.a.
Any prescription medication Lifetime: 5 %
Lifetime: 8.3 % Past year: 5.9 % n.a.
Pharmaceuticals or illicit drugs or/and caffeine tablets Past year: 20 %
DAK Deutsche Angestelltenkrankenkasse (huge German health insurance), Gb Ginkgo biloba, n.a. not applicable, Online online questionnaire, P-a-P paper-and-pencil questionnaire, RRT randomized response technique a
No clear distinction between prescription and OTC drugs
Antidementia drugs This group of substances consists of two drug classes with different mechanisms of action: acetylcholine esterase inhibitors (ACh-I such as donepezil, galantamine and rivastigmine) and partial antagonists at the glutamatergic Nmethyl-D-aspartate (NMDA) receptor. Both are approved for the treatment of Alzheimer’s disease (AD): ACh-I for mild to moderate AD and NMDA antagonists for mild to severe AD. ACh-I increases the concentration of acetylcholine in the synaptic cleft via inhibitory effects at the acetylcholinesterase enzyme [19]. Unfortunately, the CE effects of antidementia drugs can hardly be compared to the aforementioned substances because of the different study designs mostly monitoring other aspects of cognition [47]. The results of RCTs regarding CE are at least inconsistent [17, 18]; taken together, the available RCT studies show that antidementia drugs have no consistent effects on cognition, neither regarding vigilance, attention and reaction time nor on memory among healthy subjects [17, 18]. Prevalence rates of CE Since 2006, several studies have been performed to assess the prevalence of use of the abovementioned substances for CE among healthy subjects. The most important and most recent studies are summarized in Table 1. Caffeine containing beverages and drugs are the substances most often used for the purpose of CE. While there are many studies investigating the use of coffee, caffeinated drinks or caffeine tablets in general, there are only
very few studies assessing the prevalence of the specific use of caffeine to enhance one’s own cognitive performance. In a study of our own group, we surveyed 1,548 high school and undergraduate university students using an anonymous paper-and-pencil questionnaire about their use of divergent substances for CE. In this sample, 53.2 % stated to have used coffee for CE at least once in their lifetime, 8.5 % during the last year and 6.3 % during the last month. Prevalence rates for energy drinks were lifetime 39 %, last year 10.7 % and last month 6.3 %. Lifetime prevalence for caffeine tablets was 10.5 %, past-year prevalence 3.8 and past-month prevalence was 0.8 % [15]. The results for caffeine tablets are quite similar to the prevalence rates detected in a study by Mache and colleagues. Within the surveyed 1,053 German university students, 10 % of the participants stated in the online questionnaire that they have already used caffeine tablets at least once in their lifetime to enhance their performance [29]. Another online survey among 7,899 German students asked for the use of various psychoactive drugs for CE [36]. Within that sample, the percentage of participants using coffee for CE was even higher: 20 % stated to use coffee regularly for the reason to cope with their studies (for more details see Table 1). In contrast, there were more students who had never used energy drinks (see Table 1) [36]. Since there was no specific question addressing the use of caffeine tablets, it is not possible to compare this prevalence to the other studies. The consumption of caffeinated substances for CE is also common among surgeons. In an anonymous paper-and pencil study among 951 German surgeons, we found a lifetime, past-year, pastmonth and past-week prevalence, respectively, for coffee
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use of 66.8, 61.9, 56.9 and 50.5 %; respectively for caffeinated drinks 24.2, 15.4, 9.9 and 6.1 %; and respectively for caffeine tablets 12.6, 5.9, 4.7 and 3.8 % [13]. Regarding the group of OTC drugs, Ginkgo biloba is frequently used for CE purposes, especially among older subjects being afraid of cognitive decline. We assessed the use of Ginkgo biloba among 1,672 German university students over the age of 60 who had to fill out a paper-andpencil questionnaire with questions about preventive strategies and other health-related questions. 15.3 % of the participants reported the use of Ginkgo biloba supplements for CE. Interestingly, most of the surveyed people were convinced of a significantly proven pro-cognitive effect of Ginkgo biloba supplements (six-step Likert scale: 1 = ‘‘very correct’’, 6=’’very false’’, all participants 2.35) [16]. Studies regarding the use of prescription and/or illicit drugs vary a lot with respect to their design, the study populations and the specific questions about the used drugs. Therefore, prevalence rates found in different studies have to be compared with caution. Most of the studies investigated the use of substances among high school and/or university students. AMPHs seem to be the most common used prescription drugs for CE among German and USAmerican students [14, 33, 54, 58]. Within the survey of our own group among German high school and university students, 1.2 % stated to have used prescription stimulants at least once exclusively for CE [14]. A Swiss survey found a higher lifetime prevalence rate for non-medical use of prescription stimulants by students: 6.2 % of the surveyed students stated to have already used RitalinÒ, AdderallÒ and/or modafinil [43]. In an online poll by the journal ‘‘Nature’’, 20 % of the participating adult academics answered that they had already used stimulants (MPH, modafinil) or beta blockers for non-medical reasons at least once [30]. However, the study is not representative as only reader of the journal’s announcement participated. Another study by Sattler and Wiegel as well as the abovementioned study by Middendorff and colleagues showed lifetime prevalence rates of approximately 5 % [36, 49]. Similar results were found within a study by Deutsche Angestelltenkrankenkasse (DAK) being a large German health insurance company: approximately 5 % of the 3,000 surveyed policyholders of the surveying health insurance reported having practiced pharmacological CE by the use of prescription or illicit or similar drugs at least once [9]. Generally, there are higher prevalence rates among students practicing CE in the USA than in Europe. Within a sample of 4,580 college students, a lifetime prevalence of 8.3 % and a last year prevalence of 5.9 % were found for the use of prescription stimulants in a web-based survey
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[54]; other studies in the USA showed similar results [31, 32, 53, 58]. The study by Teter and colleagues specifies the most common reasons for the non-medical use: to help with concentration, help study and increase alertness [54]. Other motives such as getting high or to lose weight were also named as well but do not belong to the category of CE. All mentioned studies had to deal with the problem that they directly asked sensitive questions with the risk to receive socially desirable answers. This may well lead to an underestimation of the percentage of individuals practicing pharmacological CE. There are two studies which tried to cope with this problem by using the so-called randomized response technique (RRT), which guarantees a very high degree of anonymity and privacy recognizable by the participant himself [7, 27]. Using this RRT technique, Dietz and colleagues investigated the use of substances for CE among German university students and found that 20 % of the respondents reported to have used prescription stimulants, cocaine, other illicit drugs or caffeine tablets within the last 12 months [10]. This prevalence rate is four times higher than in our previous study using paper-andpencil questionnaires [14, 15]. Another study of our own group using the RRT based on Dietz and colleagues surveyed 1,145 German surgeons about their use of CE drugs. Within the paper-and-pencil questionnaire, 8.9 % of the surgeons stated to have used prescription or illicit drugs exclusively for CE at least once. The same sample had a 2.5-fold higher prevalence rate (19.9 %) as assessed by RRT [13]. Another creative way to handle the risk of dishonest answers in view of the social sensitive issue was shown by the study of Burgard and colleagues. The researchers analysed the wastewater of a college campus in the USA regarding amphetamine and ritalinic acid. Though there was no clear trend for MPH, the analysis over two semesters indicated a higher level of AMPH during periods of high stress as midterms or final weeks and a lower during low stress weeks: AMPH level during the finals week was nearly a factor of 8 times higher than in the first week of the semester [5]. As a consequence of different study designs, study populations and definitions of CE, it is difficult to directly compare the results of different studies. Therefore, only ranges of prevalence rates can be given as it was done in one older meta-analysis addressing the misuse of prescription stimulants (ADHD medication) in 21 studies: 5–9 % of grade and high school students and 5–35 % of college age students have used stimulants within the last year without prescription [58]. There is a need for an up-todate meta-analysis that compares the different results of studies investigating pharmacological CE—not only the use of prescription stimulants—systematically.
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Conclusion Substances used for CE have only very limited pro-cognitive effects as shown in randomized, placebo-controlled studies. However, it is important to distinguish substances having any effect and substances having no effects on cognition. Stimulants such as MPH and AMPH as well as caffeine have at least pro-cognitive effects regarding simple cognitive domains such as vigilance, attention and concentration, whereas antidementia drugs and Ginkgo biloba have no cognitive effects in healthy subjects. Interestingly, the type of effects and the effect sizes of caffeine, AMPH and modafinil are comparable (if given in comparable dosages). With respect to higher cognitive domains, the effects of stimulants are rather week and most likely secondary effects mediated via improved vigilance, attention and concentration skills. The fact that the effects of stimulants are pronounced in sleep-deprived subjects is in line with that view. Studies assessing the prevalence of use of prescription and/or illicit drugs for CE vary a lot with respect to their design, the study populations and the specific questions about the used drugs. Therefore, prevalence rates found in different studies can only be compared with caution. Examples of study design differences are as follows: definition what CE is and how it relates to other possible motives for drug intake such as recreational use, the sample of healthy subjects (high school students, university students, professionals, etc.), the kind of substances and their grouping (e.g. prescription stimulants, any prescription drugs, illicit drugs or various substances throughout the aforementioned groups) and the survey technique (online survey, paper-and-pencil questionnaire, randomized response technique). Hence, a systematic review and metaanalysis are needed to analyse prevalence rates of pharmacological CE among healthy subjects by taking into account the effects of the study design differences mentioned above. Conflict of interest All authors declare that they have no conflict of interest.
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