Abstract
A number of experts from diverse disciplines have been calling for an evidence-based approach to the evaluation of the risks and benefits of pharmacological cognitive enhancement. If these drugs can be shown to have positive effects in healthy individuals, then this adds urgency to the question of how to regulate their potential use for enhancement purposes. If no evidence of neuroenhancement effects can be found in the existing literature, then this should be made known to healthy individuals who are ready to accept the risk of consuming psychopharmaceuticals.
This paper summarizes the results of a systematic review of the literature that contributes to this quest by collecting and analyzing the available evidence for the most cited neuroenhancement drugs. Based on meta-analyses, it can be shown that expectations regarding the effectiveness of these drugs exceed their actual effects, as has been demonstrated in single- or double-blind randomized controlled trials. According to these data, it seems that the strongest reason not to use prescription drugs for enhancement purposes at the moment is the lack of evidence both for their effectiveness and their long-term safety in healthy people.
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The primary focus of this paper is not only on cognitive enhancement (Greely et al. 2008), but on neuroenhancement, a more general term that refers to the improvement of cognitive performance as well as of emotional well-being and motivation (Schöne-Seifert and Talbot 2011). Of known interventions, psychopharmacology provides readily available options, particularly, the consumption of psychopharmaceutical prescription drugs by healthy people, which has given rise to heated debate. Furthermore, these drugs are presumed to be already in widespread use for non-medical reasons as cognitive enhancers, which makes the questions regarding their effects and safety of their use by healthy individuals even more urgent.
A number of experts from diverse disciplines have been calling for an evidence-based approach to the evaluation of the risks and benefits of pharmacological cognitive enhancement (Greely et al. 2008). If these drugs can be shown to have positive effects in healthy individuals, then this adds urgency to the question of how to regulate their potential use for enhancement purposes. If no evidence of neuroenhancement effects can be found in the existing literature, then this should be made known to healthy individuals who are ready to accept the risk of consuming psychopharmaceuticals. Such individuals should be more aware that the presumed benefits of psychopharmaceuticals are not empirically supported.
This paper represents a summary of a systematic review of the literature that contributes to this call for evidence by collecting and analyzing the available evidence for the most cited neuroenhancement drugs. This review provides insight into the empirical research (Repantis et al. 2009, 2010a, b).
The drugs that first sparked this debate were the modern antidepressants. In the last decades, extensive research led to the development of new generations of antidepressants. Surveys indicate that antidepressant use has increased rapidly in most developed countries (McManus et al. 2000; Olie et al. 2002; Raymond et al. 2007). The psychiatrist Peter Kramer noted that Prozac® (fluoxetine) and the other selective serotonin reuptake inhibitors (SSRIs) might have a – possibly positive – effect on the mood and personality of individuals in the absence of mood or personality disorder and coined the term “cosmetic psychopharmacology” (Kramer 1993). However, there is next to no research on the evidence that supports or opposes this assumption. It is this consumption of drugs by normally functioning people for non-therapeutic purposes which can be labeled as neuroenhancement.
Furthermore, psychostimulants are apparently popular among healthy people seeking cognitive enhancement (Talbot 2009). This review concerns the possible neuroenhancement properties of two substances, namely, methylphenidate (MPH) and modafinil. Finally, prescription drugs currently available for the treatment of dementia provide a further possibility for neuroenhancement. Of interest are the drugs used for the treatment of dementia due to Alzheimer’s disease, namely, the acetylcholinesterase inhibitors (AChEIs) and memantine. The first category comprises three substances – donepezil, galantamine, rivastigmine – that are recommended for clinical use for the treatment of patients with mild to moderate Alzheimer’s disease (Racchi et al. 2004). Memantine is a NMDA receptor antagonist and is registered for the treatment of moderate to severe Alzheimer’s disease (Sonkusare et al. 2005).
For this review, all published single- or double-blind randomized controlled clinical trials were considered, including cross-over clinical trials, which compare one of these drugs with a placebo. All interventions in all doses and dosing schedules (single dose or repeated doses) for any duration and by any route of administration were considered. Eligible studies were those involving individuals of any age and either sex who show no evidence of psychiatric disorder, cognitive decline or other diseases. The primary outcomes of interest were emotional, cognitive or motivational parameters. These were measured through objective and subjective psychometric scales and neuropsychological tests. For data processing, these tests were grouped into test clusters according to the predominant neuropsychological domain that they were assessing (Spreen and Strauss 1998; Dumont et al. 2005) and these clusters were aggregated for further analyses into the main factors, the outcomes of the study. These were: mood, wakefulness, motivation, attention, memory and executive functions. Secondary outcomes of interest were adverse effects and acceptability of the medication, measured by numbers of participants dropping out during the trials and post-randomization exclusions due to the drugs’ effects.
When numerical data were available, a meta-analysis and a meta-regression for each outcome were performed. For anti-dementia drugs, a statistical analysis was deemed inappropriate and, therefore, not conducted since there were no sufficient data available, and there was large heterogeneity among the studies with respect to outcomes and study interventions.
1 Antidepressants
Regarding the research on antidepressants, an unexpected preliminary result was that the majority of the studies (135 studies) examined the effects of a single dose of an antidepressant. This study design did not allow any effect to be found. It is known from clinical populations that the main effects of antidepressants are seen only after several weeks. The main interest here, as well, was obviously in the effect after a drug intake of several days. But even if the drug was given repeatedly, the studies on these healthy individuals had an adequate duration in only very few cases. For instance, only 17 of the 75 repeated dose trials that were found lasted more than 2 weeks. Nevertheless, from the analysis that was performed, a number of conclusions could be drawn. A positive effect on mood was detected that was increasing from the first to the third assessment (14 studies, average duration 16.9 days, SD = 12). If the trials had been longer and had had more assessment points, one could speculate that this effect would persist or even become stronger or that a ceiling effect would emerge. For the other outcomes, the small number of studies either did not allow for any effect to emerge or for an analysis to be performed. In summary, no consistent evidence for enhancing effects of antidepressants could be found.
Unfortunately many of the studies did not report their results in numbers, and therefore, although they were formally included in the systematic review, their results were not considered in the analyses. This is a well-known weakness in reporting controlled trials (Egger et al. 2001; Higgins and Green 2006), especially those failing to find any significant result. Consequently, the results that were found through our analyses are to be taken with caution. It is likely that, had the non-significant, not reported results been included in the analyses, the effects might have become less significant.
In a number of studies (79 studies), no comment was made on side effects, while in some studies (20 studies), no adverse effects were observed. In 84 studies there were some sort of side effects. These were mild to moderate and only in few cases led to drop-outs. Adverse reactions of antidepressants, usually observed after the initial administration, wore off with continued intake and primarily consisted of gastrointestinal complaints (e.g. nausea, diarrhea, dry mouth, epigastric pain), sleep disturbances, restlessness, tremor, headache, dizziness, fatigue and drowsiness. Furthermore, sedation was a frequently reported adverse effect.
2 Anti-dementia Drugs
Further, studies with anti-dementia drugs were reviewed. However, they were found to be lacking. Only ten trials with donepezil, one with rivastigmine and seven with memantine have been conducted to date. No randomized controlled trials (RCTs) examining the effects of galantamine in healthy individuals were found. Duration of the trials (single dose vs. repeated doses trial) was taken into account in the analysis of available studies. As with antidepressants, anti-dementia drugs show their effect after intake for several weeks. All memantine and the one galantamine trial were, however, single dose trials. Hence, based on these few and insufficient data, no adequate analysis of their potential as neuroenhancement drugs can be performed. Repeated trials have been conducted only with donepezil. These were six small-scale trials, lasting 14–42 days. From these, only two (Beglinger et al. 2005; Fitzgerald et al. 2008) had older persons as participants. The rest of the trials included young healthy participants. This factor complicated the comparison between the results and made it difficult to generalize the results of the latter studies for the main population of interest, namely the growing elderly population.
These few existing studies provide no consistent evidence for a neuroenhancement effect. In one study it was found that donepezil improved the retention of training on complex aviation tasks (Yesavage et al. 2002). In another case, verbal memory for semantically processed words was improved. Donepezil might also improve episodic memory (Gron et al. 2005), but, interestingly, two studies reported transient negative effects on episodic memory (Beglinger et al. 2004, 2005). In a sleep deprivation study, donepezil had no effect when participants were well-rested. Nevertheless, the memory and attention deficits resulting from 24 h of sleep deprivation were attenuated after donepezil intake. This effect however, was seen only in individuals whose performance declined the most after sleep deprivation. Another point that should be made is that in most of the studies a large neuropsychological test battery was applied. However, an effect could be shown in only a few, if not only one, of the tests applied. This could speak either for a selective effect of donepezil or for small effects that in these relatively underpowered studies could be revealed in only one (maybe the most difficult) task. Another possible explanation could be that acetylcholinesterase inhibitors require a pathology of diminished cholinergic transmission to show their effects, and, therefore, it is not possible to optimize performance in healthy individuals who already have an optimal concentration of acetylcholine.
In the majority of the trials, donepezil was well tolerated. In the study of Yesavage et al., no specific adverse effect was reported, but the authors warn that sleep disturbances might become apparent in larger populations (Yesavage et al. 2002). There were some side effects reported in the other five repeated dose trials, but these were benign and only in few cases led to drop-outs. The adverse reactions were mainly gastrointestinal complaints (e.g. nausea), but also headache, dizziness, nightmares and insomnia.
3 Psychostimulants
As for the research on the effects of the two stimulants in question here, 46 studies with methylphenidate (MPH) and 45 with modafinil met the inclusion criteria, and their results are considered here. Among the 46 studies of MPH, four were repeated dose trials (Gilbert et al. 1973; Babkoff et al. 1992; Bishop et al. 1997; Gobbi et al. 2003), two of which were with non-sleep deprived volunteers who received MPH once per day for one (Gobbi et al. 2003) and 6 weeks (Gilbert et al. 1973), respectively. The third was a sleep deprivation study where MPH was given every 6 h for a total of 64 h without sleep (Babkoff et al. 1992), while in the fourth, the drug was given twice after a night of either normal sleep or no sleep (Bishop et al. 1997). Regarding the studies on the effect of MPH in sleep deprived individuals, five studies were found. In addition to the two repeated dose studies mentioned above, the other three single-dose studies consist of one 24-h-sleep-deprivation study (Bray et al. 2004) and two studies on partial sleep deprivation, where the drug was given after 4 h of sleep (Roehrs et al. 1999, 2004). The following studies with modafinil were found: of the 45 studies there were 17 on non-sleep deprived individuals in which 100–400 mg of modafinil were administrated. In only two of those, modafinil was given more than once, in one case twice in the evening and in the morning before the testing (Smith et al. 2004) and, in the other case, in a dose of 400 mg/day for 3 consecutive days (Taneja et al. 2007). There were 28 studies with sleep-deprived individuals and in 17 of them, the drug was given more than once with or without napping between the doses. In general, one of two different protocols was used. In the recovery paradigm, the volunteers were administered a (typically large) dose of 200–400 mg of modafinil after they had become extremely fatigued by sleep deprivation to determine if, and to what extent the drug could restore cognitive performance to baseline levels. In the maintenance studies (preventive paradigm), participants were given smaller (16,7–300 mg), more frequent doses in an attempt to maintain cognitive performance at, or near, baseline levels throughout a period of sleep deprivation (Babkoff and Krueger 1992; Baranski et al. 2004).
The analyses of the results of the trials that gave a single dose of MPH showed a positive effect in one outcome, namely, memory, but no statistically significant effect in the other outcomes: attention, mood and executive functions. In the two repeated drug administration studies, the following results were reported: Gobbi et al. (2003) found that 1 week of MPH significantly increased subjective feelings of energy but did not have any other effects on the other visual analogue scales (VAS) that were used. In another study with a cohort of 27 elderly healthy volunteers, after 6 weeks of daily intake, MPH significantly reduced ratings on a VAS on fatigue but had no effect on five other VAS and no difference on a memory test could be measured (Gilbert et al. 1973). As for the results of the trials giving a single dose of MPH after a night of sleep deprivation, no cognitive enhancing effects were found. In contrast, in one study a negative effect on self-monitoring was observed, with people estimating their performance in a task as better than it actually was (Bray et al. 2004). Repeated intake of MPH during a sustained sleep deprivation period of 64 h (Babkoff et al. 1992) did not effectively reduce sleepiness, while in a study with 36 h of sleep deprivation and in two partial sleep deprivation studies with only 4 h of sleep (Roehrs et al. 1999, 2004), subjective stimulating effects and only a mediocre improvement of attention were found.
As previously mentioned, modafinil was mainly tested in studies with sleep-deprived individuals. However, the fact that trials with non sleep-deprived participants have been performed allowed also for an analysis to be performed. A moderate, positive effect on attention emerged, but no significant effects on mood, memory and motivation could be found. Only two studies with repeated administration of modafinil in well-rested individuals have been performed and, hence, a statistical analysis was not feasible (Smith et al. 2004; Taneja et al. 2007). In the shorter of the two, no effect of an evening and a morning dose of 100 mg on attentional tasks was found (Smith et al. 2004). In the other study, which focused on mood, modafinil was given in a 400 mg dose per day for three consecutive days, and it increased the scores in both the Positive and Negative Affect Scales (Taneja et al. 2007), results which speak for a general mood-elevating effect but with a simultaneous increase of negative affect, namely, anxiety. In sleep-deprived individuals, the effects were more global: a single dose of modafinil after a sleep deprivation of about 36 h (recovery paradigm) had, according to these metaanalyses, a positive effect on wakefulness, executive functions and memory. No evidence of effects on mood and attention was found. Therefore, it can be said that in these paradigms, wakefulness and (to some degree) cognitive functions were maintained. Also, during sustained sleep deprivation over several days and nights (preventive paradigm), repeated intake of modafinil was shown to maintain wakefulness in higher levels than placebo, and this effect lasted for up to 4 days. However, attention and executive functions were not sustained with repeated doses. This fact makes the usability of modafinil as a neuroenhancer in sustained sleep deprivation questionable if one is interested not only in staying awake but also in preserving cognitive performance at high levels at the same time.
Since most of the included papers reported small studies and not large-scale clinical trials, no standardized method of assessing adverse reactions and reporting drop-outs due to adverse effects was used. In a number of studies (26 for MPH and 26 for modafinil), no comment on side effects was made, which leaves us to assume that no severe adverse effects appeared that would deserve a comment in the limited space of a publication. In the majority of the trials, the drugs were well-tolerated. There were some side effects reported, but these were benign and only in few cases lead to drop-outs. For modafinil (Lagarde et al. 1995; Pigeau et al. 1995; Baranski and Pigeau 1997; Caldwell et al. 1999, 2000, 2004; Wesensten et al. 2002; Eddy et al. 2005; Dinges et al. 2006; Gill et al. 2006; Hart et al. 2006; Whitmore et al. 2006), adverse reactions were primarily headache, dizziness, gastrointestinal complaints (e.g. nausea, abdominal pain, dry mouth), increased diuresis, palpitations, nervousness, restlessness, and sleep disturbances and, especially in studies with non-sleep deprived individuals, insomnia. For MPH, a frequently reported side effect (reported in 13 out of 14 trials reporting side effects) (Hink et al. 1978; Wetzel et al. 1981; Strauss et al. 1984; Clark et al. 1986; Peloquin and Klorman 1986; Fitzpatrick et al. 1988; Bray et al. 2004; Brumaghim and Klorman 1998; Rogers et al. 1999; Volkow et al. 1998; Volkow et al. 1999a, b; Mehta et al. 2000) was increased heart rate, while increase in blood pressure was not consistently found. Besides these, typical complaints were headache, anxiety, nervousness, dizziness, drowsiness and insomnia. In total, these drugs seem to be well-tolerated even by this population where the trade-off between side effects and improvement may be less clear. Finally, since the majority of the studies that have been performed were short-term and single-dose studies, no comment can be made on the reinforcing effects, dependence development and drug tolerance of MPH or modafinil in healthy individuals.
4 Conclusion
In conclusion, based on meta-analyses, it was shown that expectations regarding the effectiveness of these drugs as neuroenchancers exceed their actual effects, as demonstrated in single- or double-blind randomized controlled trials. According to these data, it seems that the strongest reason not to use prescription drugs for enhancement purposes at the moment is the lack of evidence both for their effectiveness and their long-term safety in healthy people. The – mostly implicit – interpretations of the inconclusive data at hand have often polarized the academic debate. Nonetheless, no evidence of an effect is not paramount to evidence of no effect. Therefore, the question regarding the implications for research is naturally relevant. If there is a societal demand for pharmacological neuroenhancement, then more studies would be necessary to establish efficacy and safety, the latter factor proving to be particularly important for the long run. Moreover, from a pharmacological point of view, it makes quite a difference whether an intervention is supposed to stabilize a disturbed system or to optimize a normally-functioning system. Therefore, it would probably be more promising and safer to develop neuroenhancement compounds by targeting this particular group of healthy people interested in neuroenhancement. One could argue that if safe and effective neuroenhancement drugs were to become available in the future, there would be no sufficient reason to prohibit their use, just like other non-pharmaceutical interventions are also allowed. Still, whatever means may be employed in the long-run, the normative challenges posed by this development pertain to the individual as well as to society. Unequal access to costly enhancement interventions may give rise to issues of distributive justice. The pressure to use pharmacological neuroenhancement might have (implicit) coercion as a result. On an individual level, concerns regarding the authenticity and “personal identity” of enhanced persons seem to play a major role.
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Repantis, D. (2013). Psychopharmacological Neuroenhancement: Evidence on Safety and Efficacy. In: Hildt, E., Franke, A. (eds) Cognitive Enhancement. Trends in Augmentation of Human Performance, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6253-4_3
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