Author’s Accepted Manuscript Innovative mechanisms pharmaceutical cognitive systematic review

of action enhancement:

for A

Guillaume Fond, jean-Arthur Micoulaud-Franchi, lore Brunel, Alexandra Macgregor, Stéphanie Miot, Régis Lopez, Raphaëlle Richieri, Mocrane Abbar, Christophe Lancon, Dimitris Repantis

PII: DOI: Reference:

www.elsevier.com/locate/psychres

S0165-1781(15)00451-5 http://dx.doi.org/10.1016/j.psychres.2015.07.006 PSY9058

To appear in: Psychiatry Research Received date: 9 November 2014 Revised date: 31 May 2015 Accepted date: 5 July 2015 Cite this article as: Guillaume Fond, jean-Arthur Micoulaud-Franchi, lore Brunel, Alexandra Macgregor, Stéphanie Miot, Régis Lopez, Raphaëlle Richieri, Mocrane Abbar, Christophe Lancon and Dimitris Repantis, Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2015.07.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Innovative mechanisms of action for pharmaceutical cognitive enhancement: a systematic review. Running title: pharmaceutical cognitive enhancement in healthy adults. Guillaume FOND* a, Jean-Arthur MICOULAUD-FRANCHIc, Lore BRUNELa, Alexandra MACGREGORb, Stéphanie MIOTf, Régis LOPEZb Raphaëlle RICHIERIc,d, , Mocrane ABBARg, Christophe LANCONc, Dimitris REPANTISh, a Université Paris Est-Créteil, AP-HP, Pôle de psychiatrie et d’addictologie des hôpitaux universitaires Henri Mondor, Inserm U955, Eq 15 Psychiatrie Génétique, DHU Pe-psy, Fondation FondaMental Fondation de coopération scientifique en santé mentale, F-94000 France, Réseau National des centres experts schizophrénie. b Université Montpellier 1, Inserm 1061, Service universitaire de Psychiatrie, CHU Montpellier F-34000, France c Pôle psychiatrie universitaire, CHU Sainte-Marguerite, F-13274 Marseille cedex 09, France d Faculté de médecine, EA 3279, laboratoire de santé publique, F-13385 Marseille cedex 05, France e Université Montpellier 1, INSERM 1061, Centre de référence national narcolepsie hypersomnie idiopathique, Unité des troubles du sommeil, CHU Montpellier F-34000, France f Inserm U952, CNRS UMR 7224, UMPC univ Paris 06, F-75000 Paris, France. g CHU Carémeau, Université de Nîmes, Nîmes, F-31000, France. h Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany.

word count 8067

* Corresponding author: Dr Guillaume Fond , Pole de Psychiatrie, Hôpital A. Chenevier, 40 rue de Mesly, Créteil F-94010, Tel : (+33)01 49 81 32 90

Fax: 01 49 81 30 99,

[email protected]

1

Abstract Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant’s action, whose potential effectiveness was assessed in randomized placebocontrolled trials (RCTs). A systematic review was carried out, using the words “attention”, “memory”, “learning”, “executive functions”, and “vigilance/wakefulness” combined to “cognitive enhancer” or “smart drug”. Methylphenidate, amphetamines, modafinil, nicotine, acetylcholine esterase inhibitors and antidepressants were extensively studied in previous metaanalyses and were not included in the present work. Drugs were classified according to their primary mode of action, namely catecholaminergic drugs (tolcapone, pramipexole, guanfacine), cholinergic drugs (anticholinergics), glutamatergic drugs (ampakines), histaminergic drugs, and non-specified (glucocorticoids). Overall, 50 RCTs were included in the present review. In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However the number of RCTs was limited, and most of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). One explanation for the limited number of recent RCTs with new psychostimulants seems to be the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

Keywords: Cognitive enhancement, performance, memory, attention, healthy adult

2

1. Introduction. The term “pharmaceutical cognitive enhancement” refers to the consumption of drugs by healthy individuals to improve their cognitive functions. It has been suggested that the recent rapid developments in the field of psychopharmacology have increased the possibilities for enhancement of mental functioning, e.g. improving memory, attention or even intelligence. Cognitive enhancement is a popular topic, attracting attention both from the general public and the scientific community (Eickenhorst et al., 2012; Heinz et al., 2012). Prescription stimulants such as methylphenidate and amphetamines are the most frequently consumed smart drugs, especially in college campuses (Franke et al., 2014; Franke et al., 2011; McCabe et al., 2014; Teter et al., 2010; Wilens et al., 2008). Few data exists on students’ perceived effects of cognitive enhancers on cognitive and academic performance (Micoulaud-Franchi et al., 2014; MicoulaudFranchi et al., 2012). Although one of the reasons for taking prescription stimulants seems to be to improve academic performance, no long-term academic benefits from their use have been reported to date. The most commonly reported effect is short-term improvement in alertness and energy levels (Maier et al., 2013; Micoulaud-Franchi et al., 2014; Micoulaud-Franchi et al., 2012). Psychostimulant consumption is not limited to students. Methylphenidate is also used in professions involving high cognitive performance and wakefulness such as surgeons (Franke et al., 2013). Estimation of societal benefits and harms might require more information on effectiveness and prevalence (Forlini et al., 2013). Concerns about coercion are also warranted. Regardless of their position in the normal distribution, healthy individuals might feel compelled to take cognitive enhancers because of real or perceived competitive pressure. As the demand for enhanced cognitive performance is growing, pharmaceutical cognitive enhancement could become a major public health concern (Farah et al., 2004).

Some recent meta-analyses underlined the objective cognitive enhancement properties of these molecules in non-sleep-deprived healthy subjects: methylphenidate and nicotine were found to increase memory, while nicotine and modafinil increased attention (Heishman et al., 2010; Repantis et al., 2010b). However, no clear cognitive enhancement properties of antidepressants or choline esterase inhibitors were reported in healthy subjects (Repantis, 2009; Repantis et al., 2010a). These psychostimulants preferably target dopamine and acetylcholine increase in the

3

brain. However, further potential cognitive enhancers were developed and tested in healthy subjects in the recent decades, with innovative mechanisms of action. The objective of the present work was to carry on a systematic review of the molecules exhibiting potential cognitive enhancement properties assessed in non-sleep-deprived healthy subjects. The primary outcomes of interest were memory, attention, learning, executive functions and vigilance/wakefulness.

2. Methods. 2.1 Search strategy and selection criteria. Types of interventions. All placebo-controlled randomized controlled trials (RCTs) with cognitive enhancers (which were not predefined) were included. Population. Individuals of 18 years or more in a normal state of wakefulness who showed no evidence of psychiatric disorder, cognitive decline or other disease. Search strategy. A specific search strategy was developed for the interface PubMed (MEDLINE database) based on a combination of MeSH terms: “neuroenhancement” OR “cognitive/cognition enhancement” OR “smart drug” as well as indexed terms related to cognitive functions: "memory", "attention", "learning", "executive function", "vigilance", "wakefulness" and the words "controlled trial", "placebo" and "healthy". We searched Medline (1966–2014), Medline In-Process and other non-indexed citations (from 1966 to 2014), Embase (1980–2014), the Cumulative Index to Nursing and Allied Health Literature (1982–2014), PsycINFO (1806–2014), the Cochrane Library database (inception–2014), Biosis Previews (1926–2014), TOXNET database (inception–2014); Web of Science (1975-2014). All relevant references were checked for additional and unpublished citations. We contacted pharmaceutical companies that market the molecules identified as potential cognitive enhancers and authors of trials with incomplete data. All studies were assessed to meet inclusion criteria (GF). A second researcher reviewed the one’s used for analysis (DR). Trials assessing methylphenidate, amphetamines, modafinil, acetylcholine esterase inhibitors, antidepressants, caffeine and nicotine were not included. Last search was conducted May 5, 2014.

4

3. Results Overall, 50 RCTs were included in this qualitative analysis. The presented substances were classified according to their primary type of action. As mentioned above, acetylcholine, dopamine, glutamate, histamine and serotonin receptors have been reported to play a fundamental role in cognition (Gualtieri et al., 2002). Both receptor-operated and potential-operated ionic channels are critically involved. Adenosine, cannabinoid, GABA, opioid and sigma receptors – may also be involved, but no RCT was found for these molecules. Here are presented the effectiveness results of RCTs assessing further catecholaminergic drugs and cholinergic drugs that were not explored in previous meta-analyses, glutamatergic, histaminergic, and melatoninergic drugs. Some substances exhibit mixed mechanisms of action. Glucocorticoids were presented separately.

3.1 CATECHOLAMINERGIC DRUGS

Catecholamines derive from the amino acid tyrosine. Until the 50’s, dopamine was only known to be part of the synthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain, at the same levels as norepinephrine, that its biological role per se was considered. Midbrain dopamine neurons are essential for controlling key functions of the brain, such as working memory. The largest populations of midbrain dopamine neurons are localized in two neighbouring nuclei: substantia nigra and ventral tegmental area (Roeper, 2013). Dopaminergic drugs are defined as substances affecting dopamine’s neurotransmitter or its components –in the nervous system. Dopamine reuptake inhibitors (like amphetamines) have shown to be effective in the regulation of appetite and food intake in obese individuals. However, most of them have been withdrawn due to adverse side effects, such as increase in blood pressure and high abuse potential (Kintscher, 2012).

5

3.1.1 CATECHOLAMINE-O-METHYL TRANSFERASE INHIBITOR: TOLCAPONE Tolcapone (Tasmar®) is a CNS specific catecholamine-O-methyltransferase (COMT) inhibitor. Indicated for the treatment of Parkinson Disease (FDA, 2013), it was introduced into the European Market in 1997 and, subsequently, into the United States Market in 1998. Tolcapone (200 mg single dose) is known to significantly improve executive function and verbal episodic memory performance in healthy adults (Apud et al., 2007; Roussos et al., 2009). Tolcapone 100mg three time a day for 1 day and 200 mg three times a day for 6 days showed no performance variation during a non conventional attentional control task (Magalona et al., 2013).

3.1.2 LEVODOPA (L-DOPA) L-DOPA

(L-3,4-dihydroxyphenylalanine)

(Sinemet®,

Parcopa®,

Atamet®,

Stalevo®,

Madopar®, Prolopa®) is a product of biosynthesis deriving from the amino acid L-tyrosine, in some animals and humans. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine and epinephrine. As a drug, it is used in the treatment of Parkinson's disease and dopamine-responsive dystonia. The results found in seven studies on L-DOPA effects in memory and attention, are summarized in table 1. L-DOPA seems to improve encoding but showed no effect on long-term memory and selective attention (Andreou et al., 2013; Floel et al., 2005; Floel et al., 2008a; Floel et al., 2008b; Knecht et al., 2004; Oranje et al., 2006; Schnider et al., 2010).

3.1.3 DOPAMINE PARTIAL AGONIST: PRAMIPEXOLE Pramipexole (Mirapex®, Mirapexin®, Sifrol®) is a partial/full receptor agonist for dopamine receptors D2, D3 and D4, and has been viewed as the prototype for preferential D3 agonist. Contrary to pharmacological expectations, a 0.5 mg single dose pramipexole has been found to induce sleepiness in healthy subjects (Micallef et al., 2009) and to impair reinforcement learning (Pizzagalli et al., 2008).

6

3.1.4

ALPHA2

ADRENERGICS

RECEPTORS

AGONISTS:

GUANFACINE

AND

CLONIDINE Guanfacine (Tenex®, Intuniv®) and clonidine (Kapvay®, Nexiclon®, Catapressan®, Dixarit®) are α2A receptor agonists, indicated for the treatment of hypertension and AD/HD (FDA, 2013). α2A receptors are mostly concentrated in the prefrontal cortex and the locus coeruleus, and may be involved in attention networks. Guanfacine and clonidine both increased visual learning (Jakala et al., 1999). In another trial, clonidine administration (150-300 µg) was associated with subjective sedation and impaired performance (especially in attention) in 15 young adults (Tiplady et al., 2005). Clonidine impaired working memory while inducing feelings of drunkenness, but did not alter long-term formation of memories. Another study found no effect of guanfacine on executive functions and working memory in a population of healthy male adults (Muller et al., 2005). Guanfacine has also been found to influence emotional memory via modulation of the prefrontal cortex (Schulz et al., 2013).

3.2 CHOLINERGIC DRUGS

Cholinergic drugs are substances that affect acetylcholine’s neurotransmitter or it’s components in the nervous system. Cholinergic cognitive enhancers include acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors. There are three major cholinergic subsystems in the brain, two of which are projection systems with broad, diffuse and rather sparse innervation to wide areas of the brain (Woolf, 1991). In these two projection systems, cholinergic neurons originate either from (i) basal forebrain nuclei from where they innervate mainly the cortex (e.g. neocortex, cingulate cortex) and the hippocampus, or (ii) from brainstem from where they provide widespread innervation to the thalamus and midbrain dopaminergic areas (Everitt and Robbins, 1997). The third cholinergic subsystem arises from a collection of cholinergic interneurons in the striatum, which provides a dense local innervation. These interneurons contribute about 1–3% of the striatal neurons and interact with the rich dopaminergic innervation of the striatum (Graef et al., 2011). The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the

7

nervous system via two types of receptors. The metabotropic G protein-coupled muscarinic ACh receptors (mAChRs), belonging to the multigene family of serotonin, norepinephrine and dopamine receptors, play an important role for memory functions (Graef et al., 2011). The ionotropic cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs), part of the supergen family that includes glycine, GABA and 5HT-3 receptors, appear to be more relevant for attentional functions (particularly sustained attention). On the contrary, there are strong evidence of muscarinic receptors’ involvement with α4β2 subtype (Levin et al., 2006). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed (Biton et al., 2007; Son and Winzer-Serhan, 2008) (for a review see (Yakel, 2013)). After the publication of the cholinergic hypothesis of Alzheimer disease by Bartus et al. in 1982 (Bartus et al., 1982), tremendous efforts were undertaken to find selective acetylcholine receptor agonists (and acetylcholinesterase inhibitors) to counteract cholinergic dysfunction. The search started with M1 mAChR agonists, then selective presynaptic M2 receptor antagonists, and shifted later to nicotinic acetylcholine (partial) agonists. Since 2002, it came back to allosteric M1 mAChR agonists (Froestl et al., 2012). For a review of cholinergic drugs in development, see (Froestl et al., 2012).

ANTICHOLINERGIC DRUGS Biperiden (Akineton®), trihexyphenidyl (Artane® Parkinane®) tropatepine (Lepticur®), are specific muscarinic M1 anticholinergic drugs approved as anti-parkinsonian drugs (FDA, 2013) . Biperiden has been found to enhance episodic memory performance in healthy elderly subjects in one RCT (Wezenberg et al., 2005). Another trial found that 1-2mg trihexyphenidyl improved verbal memory in 24 healthy elderly (Pomara et al., 2010). However, in a third trial, biperiden (4mg) and trihexyphenidyl (5mg) were both found to decrease memory performance (Guthrie et al., 2000).

8

3.3 GLUTAMATERGIC DRUGS Glutamate is one of the main excitatory neurotransmitters and has a strong impact on synaptic plasticity, learning and memory. The overlap and convergence of both dopaminergic and glutamatergic projections in the brain provides a framework for complex neuronal interactions between these receptor systems (Wang et al., 2012). Furthermore, recent evidence identified the endogenous cholinergic signalling via nicotinic acetylcholine receptors (nAChRs) as key players in determining the morphological and functional maturation of the glutamatergic system (Molas and Dierssen, 2014). Glutamatergic AMPA receptors are thought to contribute to information transmission between neurons, whereas NMDA receptors are mainly considered to be coincidence detectors that activate after multiple previous depolarizations. The NMDA receptor activation subsequently leads to a long-lasting increase in synaptic AMPA receptor availability and synaptic potentiation (Artola and Singer, 1987).

AMPAKINES The ampakines take their name from the glutamatergic AMPA receptor, with which they strongly interact. The AMPA receptor gets its name from AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid), which selectively binds to it and mimics the effect of glutamate. Ampakines are a class of compounds known to enhance attention span and alertness, and facilitate learning and memory in animals (Baudry et al., 2012). Their action is theorized as facilitating transmission at cortical synapses, which use glutamate as a neurotransmitter. In turn, it may promote synapse’s plasticity and translate into better cognitive performance. Some members of the ampakine family may also increase levels of trophic factors such as BrainDerived Neurotrophic Factor (BDNF). Recently developed ampakine compounds are more potent and selective for the AMPA receptor. However, none of the newer selective ampakine compounds has reached the market yet (Froestl et al., 2012). Ampakines have been investigated by the Defense Advanced Research Projects Agency (DARPA), the United States Department of Defense Agency, responsible for the development of new technologies by military. Preliminary results were disappointing. Farampator (500mg single dose) improved short-term memory, but appeared also to impair episodic memory in 16 healthy elderly volunteers (Wezenberg et al., 2007). Another AMPA agonist, CX-516 (1-(quinoxalin-6 9

ylcarbonyl)piperidine) (300 to 900 mg, single dose) was found to improve short-term delayed memory in three RCTs (respectively 24 and 50 healthy young individuals and 18 elderly individuals (Ingvar et al., 1997; Lynch et al., 1997; Lynch et al., 1996).

3.5 HISTAMINERGIC DRUGS

H1 ANTAGONIST FEXOFENADINE Contrary to previous anti-H1 drugs, Fexofenadine (Allegra®, Fexidine®, Telfast®, Fastofen®, Tilfur®, Vifas®, Telfexo®, Allerfexo®) does not cross the blood-brain barrier. Its psychostimulant effect has been suggested in the literature. Five RCTs reported no effect of Fexofenadine (180-360 mg, single dose) on attention and vigilance in healthy subjects (Bower et al., 2003; Mansfield et al., 2003; Theunissen et al., 2009; Theunissen et al., 2006; Vacchiano et al., 2008).

3.6 MELATONININERGIC DRUGS. Melatonin (N-acetyl-5-methoxytryptamine) is a natural compound found in animals, plants, and microbes. Circulating levels of this hormone in animals vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Melatonin is produced by the pineal gland in humans. Melatonin receptors appear to be important in mechanisms of learning and memory in mice (Larson et al., 2006). It can initiate offline plastic changes, underlying memory consolidation. This effect is similar to sleep (Gorfine et al., 2007). Products containing melatonin have been available over-the-counter in the United States since the mid90’s. In many other countries, the purchase of melatonin requires a prescription. Agomelatine (Valdoxan®, Melitor®, Thymanax®) is a melatoninergic antidepressant. A single dose of 3mg melatonin specifically enhanced recognition memory accuracy of objects encoded under stress in 27 young volunteers versus 23 placebo controls (Rimmele et al., 2009).

10

3.7 GLUCOCORTICOIDS Tadeusz Reichstein together with Edward Calvin Kendall and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex, which culminated in the isolation of cortisone. Cortisol, better known as hydrocortisone, is a steroid hormone, the glucocorticoid (GC), produced by the zona fasciculata of the adrenal cortex. It is released in response to stress and low level of blood. Its primary functions are to increase blood sugar through gluconeogenesis, suppress the immune system, aid in fat, protein and carbohydrate metabolism, and modify memory. GC are lipophilic hormones and can therefore pass the blood–brain barrier, where they influence numerous regions of the brain. GC receptors have been found in multiple areas of the brain, which are relevant to cognition, namely the hippocampus, the amygdala and the prefrontal cortex. The hippocampus is especially important for declarative or spatial memory, while the amygdala is critical for emotional memory as well as emotional modulation of other types of memory. The prefrontal cortex is crucial for working memory (Wolf, 2003). Cortisol may work with epinephrine to create memories of short-term emotional events. This is the hypothesized mechanism for flash bulb memories storage and may originate as a means to remember what to avoid in the future. Neuroactive steroids may also play a role in the modulation of memory by sigma receptors and modulate GABAA receptor function and various NMDA-evoked responses (Maurice et al., 1999). Human studies investigating the effects of acute GC treatment on memory have reported conflicting (enhancing as well as impairing) results. A meta-analysis of 16 studies (N=563 healthy volunteers, mean age 24.23 years (SD+/-2.15)), which experimentally investigated the acute impact of cortisol treatment (hydrocortisone) on human memory, revealed that the timing of GC application in the course of a study is a relevant variable, which explains a substantial amount of the significant heterogeneity within the effect sizes (Het et al., 2005). The used doses of hydrocortisone ranged from 5 to 100 mg (median=25 mg; DM+/-7.5). Retention interval ranged from 0 (immediate recall) up to 168 h (delayed recall). Four studies, which administered cortisol before retrieval, reported a significant decrease (average effect size of d=-0.49) in memory performance. Twelve studies, which administered cortisol before learning, found on average no effect (d=0.08), but there was heterogeneity within these effect sizes. Further analysis on these experiments indicated that studies administering cortisol in the morning found a 11

significant memory impairment (d=-0.40), while studies conducted in the afternoon observed a small but significant memory enhancement (d=0.22) (Het et al., 2005). A recent RCT showed that 10mg single-dose hydrocortisone administration 45 min prior to the testing was associated with an enhancing effect on inhibitory performance in 54 healthy volunteers (Schlosser et al., 2013), a working memory impairment in another sample of 56 healthy volunteers (Terfehr et al., 2011), and to fewer specific memories on the autobiographical memory testing (Schlosser et al., 2010). Some positive effects of 10 mg hydrocortisone on selective attention were also reported (Henckens et al., 2012)

3.8 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: ACETYL SALICYLIC ACID (ASPIRIN) Several studies reported that non steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing Alzheimer disease, and that patients with rheumatoid arthritis, who often use NSAIDs, have a lower incidence of Alzheimer disease (McGeer et al., 1990; McGeer et al., 1996). Aspirin pre-treatment (600 mg, single dose) was found to improve working memory in healthy adults (Watson et al., 2009).

4. Discussion Important innovative pathways for cognition enhancement were discovered in the last decades, beyond the classical monoamine pathways. However, as showed in our review, few randomized controlled trials were conducted in humans to date. This may be explained by the ethical concerns raised by this issue. Most of the substances reviewed here are not being used at the time for enhancement purposes. Reviewing their presumably enhancing effects can induce a selffulfilling prophecy, particularly if secondary literature overestimates reported positive effects. For example, a recently published analysis of the coverage of one of the first studies of donepezil on healthy individuals (Yesavage et al., 2002) supports our concern (Wade et al., 2014). The media and bioethics literature made strong claims about donepezil being a cognitive enhancing drug. Enhancement language was used while reporting the results of the primary study and

12

magnifying the perceived connection between these results and the cognitive enhancers debate that was alluded to in the primary study. On the contrary, our review highlighted both findings of interest as well as some technical limits of the presented trials. As we included only randomized controlled trials, these studies have the highest quality design. However many of the studies reported here included less than 20 participants, which is often not sufficient to detect a small effect. Some negative results may be due to power lack. It is often discussed whether cognitive tasks carried out in a neuropsychology laboratory are representative of real life (Smith and Farah, 2011). The identification of cognitive enhancement effects should ideally include an optimization in terms of dose, individual genetic characteristics, baseline levels and the nature of the specific task. Individual baseline characteristics seem to make a considerable difference to the outcomes of cognitive enhancement: positive effects seem in fact to be more prominent if the baseline performance of the individual is at the lower end of the normal distribution. This means that cognitive enhancers could potentially enable people with certain deficits to achieve a mean level of performance (Mattay et al., 2000). Some even postulate that this could be one (further) way to narrow the inequality of the “genetic lottery” (Harris, 2011). An inverted U-shape effect was described for dopamine agonists (de Jongh et al., 2008). Low doses may improve and high doses may impair performance. Second, a drug’s effect can be ‘baseline dependent’, indicating that low performing individuals find themselves on the up slope of the inverted U (describing the relationship between receptor occupation and performance), and therefore benefit from administration of an agonist. In contrast, high performing subjects are located at or near the peak of the inverted U. As a result, their performance deteriorates if neurotransmitter levels are further increased. These discrepancies in dose response may be impacted by genetic polymorphisms (de Frias et al., 2005; Farrell et al., 2012; Han et al., 2008; Mattay et al., 2003) as well as by mood and motivation. We found that motivation was hardly evaluated in studies, although this dimension may be a particularly important modulator. Since the majority of the studies that were performed until now were short-term and single-dose trials, no evidence-based statement can be made on long term effects and especially on reinforcing effects, dependence development, drug tolerance and long-term toxicity of these substances when used for cognitive enhancement purposes by healthy individuals. For a meaningful use-risk analysis, long-term effects on the individuals and possibly on the societies

13

should be considered. A further useful debate about concerns on memory enhancement specifically can be read in (Glannon, 2006). In summary, different memory neural networks may intertwine with a physiological optimal adjustment and modify some parameters, which may disrupt the whole system.

5. Perspectives Some potential cognitive enhancers with innovative mechanisms of action have not been tested in healthy subjects to date. GABAα5 blockers may provide a nootropic effect without the associated anxiogenic effects of general GABA inverse agonism (Koh et al., 2013; Milic et al., 2013). Sigma agonists receptors increase acetylcholine release in both the hippocampus and the frontal cortex in rodent models (Matsuno et al., 1995) and may potentiate several NMDA-evoked responses in selected regions of the hippocampus (Hong and Werling, 2000). Piracetam and piracetam-like molecules are thought to be neuroprotective agents with potential enhancement properties, possibly due to their common 2- oxopyrrolidine structure (Gualtieri et al., 2002). Ampakine activity has been established as one of the modes of action of the racetams. However, these drugs have multiple modes of action and produce only weak AMPA receptor activation and it is unclear how significant their ampakine actions are in producing their positive effects. Animal studies suggest memory and wakefulness enhancement properties of several racetams (Barad et al., 1998; Grossman et al., 2011; Lelkes et al., 1998; Mondadori et al., 1986; Samartgis et al., 2012; Scheuer et al., 1999; Trofimov et al., 2005; Tushmalova et al., 1995). It is noteworthy that animal experiments focused on restoring age-impaired cognitive functions (Gualtieri et al., 2002). In the end, the cyclic AMP/phosphokinase A/CREB pathway represents one of the main target for drug development to treat memory dysfunction (Tully et al., 2003). Dopamine D1/D5 receptors are coupled to activation of the cAMP/ PKA/CREB pathway. Thus, D1/D5 receptor agonists may represent an effective pharmacological strategy to activate cAMP signaling to improve synaptic plasticity and memory (Otmakhova and Lisman, 1998). Cyclic nucleotide phosphodiesterases (PDEs) are enzymes, which play an important role in the abovementioned intra-cellular signal transduction pathways. There are 11 families of PDEs (PDE1–PDE11) and most of these families have more than one gene product (e.g., PDE4A, PDE4B, PDE4C, PDE4D). In addition, each gene product may have multiple splice variants (e.g., PDE4D1– PDE4D9). In total, there are more than 100 specific human PDEs. Rolipram, which belongs to

14

the above-mentioned racetams family, is a specific PDE4 inhibitor that has been shown to enhance both hippocampal long-term potentiation, memory transient wakefulness and neuroprotection in mice (Barad et al., 1998; Block et al., 2001) and long-term potentiation in humans (Rutten et al., 2006; Rutten et al., 2007).

6. Conclusion In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However, the number of RCTs was limited and most part of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). Limited number of recent RCTs with new psychostimulants seems to be explained by the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

Conflicts of interest : All authors disclose no conflicts with the present work. Funding source. No funding source. Acknowledgments : We acknowledge the help of Dr Fulvio (Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, I-50121 Firenze, Italy) with a previous version of the manuscript. We express all our thanks to the healthy subjects that participated in the studies discussed in the present paper and the authors that answered our requests for missing data. This work was funded by AP-HP (Assistance Publique des Hôpitaux de Paris), Fondation Fondamental (RTRS Santé Mentale), by the Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02 and ANR-10-COHO-10-01, and by INSERM (Institut National de la Santé et de la Recherche Médicale).

15

REFERENCES

Andreou, C., Moritz, S., Veith, K., Veckenstedt, R., Naber, D., 2013. Dopaminergic Modulation of Probabilistic Reasoning and Overconfidence in Errors: A Double-Blind Study. Schizophrenia Bulletin. 40(3):558-65 Apud, J.A., Mattay, V., Chen, J., Kolachana, B.S., Callicott, J.H., Rasetti, R., Alce, G., Iudicello, J.E., Akbar, N., Egan, M.F., Goldberg, T.E., Weinberger, D.R., 2007. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 32, 1011-1020. Artola, A., Singer, W., 1987. Long-term potentiation and NMDA receptors in rat visual cortex. Nature 330, 649-652. Barad, M., Bourtchouladze, R., Winder, D.G., Golan, H., Kandel, E., 1998. Rolipram, a type IVspecific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proceedings of the National Academy of Sciences U S A 95, 15020-15025. Bartus, R.T., Dean, R.L., 3rd, Beer, B., Lippa, A.S., 1982. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408-414. Baudry, M., Kramar, E., Xu, X., Zadran, H., Moreno, S., Lynch, G., Gall, C., Bi, X., 2012. Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. Neurobiology Disease 47, 210-215. Biton, B., Bergis, O.E., Galli, F., Nedelec, A., Lochead, A.W., Jegham, S., Godet, D., Lanneau, C., Santamaria, R., Chesney, F., Leonardon, J., Granger, P., Debono, M.W., Bohme, G.A., Sgard, F., Besnard, F., Graham, D., Coste, A., Oblin, A., Curet, O., Vige, X., Voltz, C., Rouquier, L., Souilhac, J., Santucci, V., Gueudet, C., Francon, D., Steinberg, R., Griebel, G., Oury-Donat, F., George, P., Avenet, P., Scatton, B., 2007. SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology 32, 1-16. Block, F., Schmidt, W., Nolden-Koch, M., Schwarz, M., 2001. Rolipram reduces excitotoxic neuronal damage. Neuroreport 12, 1507-1511. Bower, E.A., Moore, J.L., Moss, M., Selby, K.A., Austin, M., Meeves, S., 2003. The effects of single-dose fexofenadine, diphenhydramine, and placebo on cognitive performance in flight personnel. Aviaton Space and Environnemental Medicine 74, 145-152. de Frias, C.M., Annerbrink, K., Westberg, L., Eriksson, E., Adolfsson, R., Nilsson, L.G., 2005. Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults. Journal of Cognitive Neuroscience 17, 1018-1025. de Jongh, R., Bolt, I., Schermer, M., Olivier, B., 2008. Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories. Neuroscience and Biobehaviral Reviews 32, 760-776. Eickenhorst, P., Vitzthum, K., Klapp, B.F., Groneberg, D., Mache, S., 2012. Neuroenhancement among German university students: motives, expectations, and relationship with psychoactive lifestyle drugs. Journal of Psychoactive Drugs 44, 418-427. Everitt, B.J., Robbins, T.W., 1997. Central cholinergic systems and cognition. Annual Review of Psychology 48, 649-684.

16

Farah, M.J., Illes, J., Cook-Deegan, R., Gardner, H., Kandel, E., King, P., Parens, E., Sahakian, B., Wolpe, P.R., 2004. Neurocognitive enhancement: what can we do and what should we do? Nature Review Neuroscience 5, 421-425. Farrell, S.M., Tunbridge, E.M., Braeutigam, S., Harrison, P.J., 2012. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-Omethyltransferase inhibition. Biological Psychiatry 71, 538-544. FDA, 2013. http://www.fda.org. Floel, A., Breitenstein, C., Hummel, F., Celnik, P., Gingert, C., Sawaki, L., Knecht, S., Cohen, L.G., 2005. Dopaminergic influences on formation of a motor memory. Ann Neurol 58, 121-130. Floel, A., Garraux, G., Xu, B., Breitenstein, C., Knecht, S., Herscovitch, P., Cohen, L.G., 2008a. Levodopa increases memory encoding and dopamine release in the striatum in the elderly. Neurobiology and Aging 29, 267-279. Floel, A., Vomhof, P., Lorenzen, A., Roesser, N., Breitenstein, C., Knecht, S., 2008b. Levodopa improves skilled hand functions in the elderly. European Journal of Neuroscience 27, 13011307. Forlini, C., Hall, W., Maxwell, B., Outram, S.M., Reiner, P.B., Repantis, D., Schermer, M., Racine, E., 2013. Navigating the enhancement landscape. Ethical issues in research on cognitive enhancers for healthy individuals. European Molecular Biology Organization. Rep 14, 123128. Franke, A.G., Bagusat, C., Dietz, P., Hoffmann, I., Simon, P., Ulrich, R., Lieb, K., 2013. Use of illicit and prescription drugs for cognitive or mood enhancement among surgeons. BMC Medicine 11, 102. Franke, A.G., Bagusat, C., Rust, S., Engel, A., Lieb, K., 2014. Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects. European Archives of Psychiatry and Clinical Neuroscience 264 Suppl 1, S83-90. Franke, A.G., Christmann, M., Bonertz, C., Fellgiebel, A., Huss, M., Lieb, K., 2011. Use of coffee, caffeinated drinks and caffeine tablets for cognitive enhancement in pupils and students in Germany. Pharmacopsychiatry 44, 331-338. Froestl, W., Muhs, A., Pfeifer, A., 2012. Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. Journal of Alzheimers Disease 32, 793-887. Glannon, W., 2006. Psychopharmacology and memory. J Med Ethics 32, 74-78. Gorfine, T., Yeshurun, Y., Zisapel, N., 2007. Nap and melatonin-induced changes in hippocampal activation and their role in verbal memory consolidation. Journal of Pineal Research 43, 336-342. Graef, S., Schonknecht, P., Sabri, O., Hegerl, U., 2011. Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings. Psychopharmacology (Berlin) 215, 205-229. Grossman, L., Stewart, A., Gaikwad, S., Utterback, E., Wu, N., Dileo, J., Frank, K., Hart, P., Howard, H., Kalueff, A.V., 2011. Effects of piracetam on behavior and memory in adult zebrafish. Brain Research Bulletin 85, 58-63. Gualtieri, F., Manetti, D., Romanelli, M.N., Ghelardini, C., 2002. Design and study of piracetam-like nootropics, controversial members of the problematic class of cognitionenhancing drugs. Current Pharmeutical Design 8, 125-138. Guthrie, S.K., Manzey, L., Scott, D., Giordani, B., Tandon, R., 2000. Comparison of central and peripheral pharmacologic effects of biperiden and trihexyphenidyl in human volunteers. Journal of Clinical Psychopharmacoly 20, 77-83. 17

Han, D.H., Yoon, S.J., Sung, Y.H., Lee, Y.S., Kee, B.S., Lyoo, I.K., Renshaw, P.F., Cho, S.C., 2008. A preliminary study: novelty seeking, frontal executive function, and dopamine receptor (D2) TaqI A gene polymorphism in patients with methamphetamine dependence. Comprehensive psychiatry 49, 387-392. Harris, J., 2011. Moral enhancement and freedom. Bioethics 25, 102-111. Heinz, A., Kipke, R., Heimann, H., Wiesing, U., 2012. Cognitive neuroenhancement: false assumptions in the ethical debate. Journal of Medical Ethics 38, 372-375. Heishman, S.J., Kleykamp, B.A., Singleton, E.G., 2010. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology (Berl) 210, 453-469. Henckens, M.J., van Wingen, G.A., Joels, M., Fernandez, G., 2012. Time-dependent effects of cortisol on selective attention and emotional interference: a functional MRI study. Frontiers in Integrative Neuroscience 6, 66. Het, S., Ramlow, G., Wolf, O.T., 2005. A meta-analytic review of the effects of acute cortisol administration on human memory. Psychoneuroendocrinology 30, 771-784. Hong, W., Werling, L.L., 2000. Evidence that the sigma(1) receptor is not directly coupled to G proteins. European Journal of Pharmacology 408, 117-125. Ingvar, M., Ambros-Ingerson, J., Davis, M., Granger, R., Kessler, M., Rogers, G.A., Schehr, R.S., Lynch, G., 1997. Enhancement by an ampakine of memory encoding in humans. Experimental Neurology 146, 553-559. Jakala, P., Sirvio, J., Riekkinen, M., Koivisto, E., Kejonen, K., Vanhanen, M., Riekkinen, P., Jr., 1999. Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 20, 119-130. Kintscher, U., 2012. Reuptake inhibitors of dopamine, noradrenaline, and serotonin. Handb Experimental Pharmacology, 339-347. Knecht, S., Breitenstein, C., Bushuven, S., Wailke, S., Kamping, S., Floel, A., Zwitserlood, P., Ringelstein, E.B., 2004. Levodopa: faster and better word learning in normal humans. Annals of Neurology 56, 20-26. Koh, M.T., Rosenzweig-Lipson, S., Gallagher, M., 2013. Selective GABA(A) alpha5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology 64, 145-152. Larson, J., Jessen, R.E., Uz, T., Arslan, A.D., Kurtuncu, M., Imbesi, M., Manev, H., 2006. Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice. Neuroscience Letter 393, 23-26. Lelkes, Z., Alfoldi, P., Erdos, A., Benedek, G., 1998. Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats. Pharmacology and Biochemical Behavior 60, 835-839. Levin, E.D., McClernon, F.J., Rezvani, A.H., 2006. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berlin) 184, 523-539. Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C.M., Kessler, M., Schehr, R., 1997. Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Experimental Neurology 145, 89-92. Lynch, G., Kessler, M., Rogers, G., Ambros-Ingerson, J., Granger, R., Schehr, R.S., 1996. Psychological effects of a drug that facilitates brain AMPA receptors. International Clinical Psychopharmacoly 11, 13-19.

18

Magalona, S.C., Rasetti, R., Chen, J., Chen, Q., Gold, I., Decot, H., Callicott, J.H., Berman, K.F., Apud, J.A., Weinberger, D.R., Mattay, V.S., 2013. Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers. CNS Drugs 27, 663-673. Maier, L.J., Liechti, M.E., Herzig, F., Schaub, M.P., 2013. To dope or not to dope: neuroenhancement with prescription drugs and drugs of abuse among Swiss university students. PLoS One 8, e77967. Mansfield, L., Mendoza, C., Flores, J., Meeves, S.G., 2003. Effects of fexofenadine, diphenhydramine, and placebo on performance of the test of variables of attention (TOVA). Annals of Allergy Asthma and Immunoly 90, 554-559. Matsuno, K., Senda, T., Kobayashi, T., Mita, S., 1995. Involvement of sigma 1 receptor in (+)N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats. Brain Research 690, 200-206. Mattay, V.S., Callicott, J.H., Bertolino, A., Heaton, I., Frank, J.A., Coppola, R., Berman, K.F., Goldberg, T.E., Weinberger, D.R., 2000. Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12, 268-275. Mattay, V.S., Goldberg, T.E., Fera, F., Hariri, A.R., Tessitore, A., Egan, M.F., Kolachana, B., Callicott, J.H., Weinberger, D.R., 2003. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proceedings of the National Academy of Sciences U S A 100, 6186-6191. Maurice, T., Phan, V.L., Urani, A., Kamei, H., Noda, Y., Nabeshima, T., 1999. Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities. Japanese Journal of pharmacology 81, 125-155. McCabe, S.E., West, B.T., Teter, C.J., Boyd, C.J., 2014. Trends in medical use, diversion, and nonmedical use of prescription medications among college students from 2003 to 2013: Connecting the dots. Addictive Behavior 39, 1176-1182. McGeer, P.L., McGeer, E., Rogers, J., Sibley, J., 1990. Anti-inflammatory drugs and Alzheimer disease. Lancet 335, 1037. McGeer, P.L., Schulzer, M., McGeer, E.G., 1996. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47, 425-432. Micallef, J., Rey, M., Eusebio, A., Audebert, C., Rouby, F., Jouve, E., Tardieu, S., Blin, O., 2009. Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of Ldopa, bromocriptine and pramipexole in healthy subjects. British Journal of Clinical Pharmacology 67, 333-340. Micoulaud-Franchi, J.A., MacGregor, A., Fond, G., 2014. A preliminary study on cognitive enhancer consumption behaviors and motives of French Medicine and Pharmacology students. European review for medical and pharmacological sciences 18, 1875-1878. Micoulaud-Franchi, J.A., Vion-Dury, J., Lancon, C., 2012. [Neuroenhancement in healthy subject? A French case study]. Therapie 67, 213-221. Milic, M., Timic, T., Joksimovic, S., Biawat, P., Rallapalli, S., Divljakovic, J., Radulovic, T., Cook, J.M., Savic, M.M., 2013. PWZ-029, an inverse agonist selective for alpha(5) GABAA receptors, improves object recognition, but not water-maze memory in normal and scopolaminetreated rats. Behavior and Brain Research 241, 206-213.

19

Molas, S., Dierssen, M., 2014. The role of nicotinic receptors in shaping and functioning of the glutamatergic system: a window into cognitive pathology. Neuroscience and Biobehavioral Reviews. 2:315-25. Mondadori, C., Classen, W., Borkowski, J., Ducret, T., Buerki, H., Schade, A., 1986. Effects of oxiracetam on learning and memory in animals: comparison with piracetam. Clinical Neuropharmacoly 9 Suppl 3, S27-38. Muller, U., Clark, L., Lam, M.L., Moore, R.M., Murphy, C.L., Richmond, N.K., Sandhu, R.S., Wilkins, I.A., Menon, D.K., Sahakian, B.J., Robbins, T.W., 2005. Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology (Berlin) 182, 205-213. Oranje, B., Gispen-de Wied, C.C., Westenberg, H.G., Kemner, C., Verbaten, M.N., Kahn, R.S., 2006. No effects of l-dopa and bromocriptine on psychophysiological parameters of human selective attention. Journal of Psychopharmacoly 20, 789-798. Otmakhova, N.A., Lisman, J.E., 1998. D1/D5 dopamine receptors inhibit depotentiation at CA1 synapses via cAMP-dependent mechanism. Journal Neuroscience 18, 1270-1279. Pizzagalli, D.A., Evins, A.E., Schetter, E.C., Frank, M.J., Pajtas, P.E., Santesso, D.L., Culhane, M., 2008. Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacology (Berlin) 196, 221-232. Pomara, N., Yi, L., Belzer, K., Facelle, T.M., Willoughby, L.M., Sidtis, J.J., 2010. Retrograde facilitation of verbal memory by trihexyphenidyl in healthy elderly with and without the APOE epsilon4 allele. European Neuropsychopharmacoly 20, 467-472. Repantis, D., 2009. Antidepressants for neuroenhancement in healthy individuals: a systematic review. Poiesis & Praxis 6:139–174. Repantis, D., Laisney, O., Heuser, I., 2010a. Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. Pharmacological Research 61, 473-481. Repantis, D., Schlattmann, P., Laisney, O., Heuser, I., 2010b. Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review. Pharmacological Research 62, 187-206. Rimmele, U., Spillmann, M., Bartschi, C., Wolf, O.T., Weber, C.S., Ehlert, U., Wirtz, P.H., 2009. Melatonin improves memory acquisition under stress independent of stress hormone release. Psychopharmacology (Berlin) 202, 663-672. Roeper, J., 2013. Dissecting the diversity of midbrain dopamine neurons. Trends Neuroscience 36, 336-342. Roussos, P., Giakoumaki, S.G., Bitsios, P., 2009. Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism. Biological Psychiatry 66, 997-1004. Rutten, K., Prickaerts, J., Blokland, A., 2006. Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiology Learning Memory 85, 132-138. Rutten, K., Prickaerts, J., Hendrix, M., van der Staay, F.J., Sik, A., Blokland, A., 2007. Timedependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. European Journal Pharmacology 558, 107-112.

20

Samartgis, J.R., Schachte, L., Hazi, A., Crowe, S.F., 2012. Piracetam, an AMPAkine drug, facilitates memory consolidation in the day-old chick. Pharmacological Biochemical Behavior 103, 353-358. Scheuer, K., Rostock, A., Bartsch, R., Muller, W.E., 1999. Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain. Pharmacopsychiatry 32 Suppl 1, 10-16. Schlosser, N., Wolf, O.T., Fernando, S.C., Riedesel, K., Otte, C., Muhtz, C., Beblo, T., Driessen, M., Lowe, B., Wingenfeld, K., 2010. Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls. Psychoneuroendocrinology 35, 316-320. Schlosser, N., Wolf, O.T., Fernando, S.C., Terfehr, K., Otte, C., Spitzer, C., Beblo, T., Driessen, M., Lowe, B., Wingenfeld, K., 2013. Effects of acute cortisol administration on response inhibition in patients with major depression and healthy controls. Psychiatry Research. Schnider, A., Guggisberg, A., Nahum, L., Gabriel, D., Morand, S., 2010. Dopaminergic modulation of rapid reality adaptation in thinking. Neuroscience 167, 583-587. Schulz, K.P., Clerkin, S.M., Fan, J., Halperin, J.M., Newcorn, J.H., 2013. Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control. Psychopharmacology (Berlin) 226, 261-271. Smith, M.E., Farah, M.J., 2011. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychology Bulletin 137, 717-741. Son, J.H., Winzer-Serhan, U.H., 2008. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs in rat hippocampal GABAergic interneurons. Journal of Computational Neurology 511, 286-299. Terfehr, K., Wolf, O.T., Schlosser, N., Fernando, S.C., Otte, C., Muhtz, C., Beblo, T., Driessen, M., Spitzer, C., Lowe, B., Wingenfeld, K., 2011. Hydrocortisone impairs working memory in healthy humans, but not in patients with major depressive disorder. Psychopharmacology (Berlin) 215, 71-79. Teter, C.J., Falone, A.E., Cranford, J.A., Boyd, C.J., McCabe, S.E., 2010. Nonmedical use of prescription stimulants and depressed mood among college students: frequency and routes of administration. Journal of substance abuse treatment 38, 292-298. Theunissen, E.L., Elvira Jde, L., van den Bergh, D., Ramaekers, J.G., 2009. Comparing the stimulant effects of the H1-antagonist fexofenadine with 2 psychostimulants, modafinil and methylphenidate. Journal of Clinical Psychopharmacoly 29, 439-443. Theunissen, E.L., Jonkman, L.M., Kuypers, K.P., Ramaekers, J.G., 2006. A combined neurophysiological and behavioural study into the stimulating effects of fexofenadine on performance. Journal Psychopharmacoly 20, 496-505. Tiplady, B., Bowness, E., Stien, L., Drummond, G., 2005. Selective effects of clonidine and temazepam on attention and memory. Journal Psychopharmacoly 19, 259-265. Trofimov, S.S., Voronina, T.A., Guzevatykh, L.S., 2005. Early postnatal effects of noopept and piracetam on declarative and procedural memory of adult male and female rats. Bulletin Experimental Biology Medicine 139, 683-687. Tully, T., Bourtchouladze, R., Scott, R., Tallman, J., 2003. Targeting the CREB pathway for memory enhancers. Nature Review Drug Discovery 2, 267-277.

21

Tushmalova, N.A., Pragina, L.L., Inozemtsev, A.N., Gumargalieva, K.Z., Solov'ev, A.G., Burlakova, E.B., 1995. [Effect of low doses of piracetam on conditional reflex memory in rats]. Biulleten' eksperimental'noĭ biologii i meditsiny 120, 60-61. Vacchiano, C., Moore, J., Rice, G.M., Crawley, G., 2008. Fexofenadine effects on cognitive performance in aviators at ground level and simulated altitude. Aviation Space Environemental Medicine 79, 754-760. Wade, L., Forlini, C., Racine, E., 2014. Generating genius: how an Alzheimer's drug became considered a 'cognitive enhancer' for healthy individuals. BMC medical ethics 15, 37. Wang, M., Wong, A.H., Liu, F., 2012. Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Research 1476, 154-163. Watson, S., Horton, K., Bulmer, S., Carlile, J., Corcoran, C., Gallagher, P., Ferrier, I.N., 2009. Effect of aspirin on hypothalamic-pituitary-adrenal function and on neuropsychological performance in healthy adults: a pilot study. Psychopharmacology (Berlin) 205, 151-155. Wezenberg, E., Verkes, R.J., Ruigt, G.S., Hulstijn, W., Sabbe, B.G., 2007. Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers. Neuropsychopharmacology 32, 1272-1283. Wezenberg, E., Verkes, R.J., Sabbe, B.G., Ruigt, G.S., Hulstijn, W., 2005. Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects. Psychopharmacology (Berlin) 181, 582-594. Wilens, T.E., Adler, L.A., Adams, J., Sgambati, S., Rotrosen, J., Sawtelle, R., Utzinger, L., Fusillo, S., 2008. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. Journal of American Academic Child Adolescent Psychiatry 47, 21-31. Wolf, O.T., 2003. HPA axis and memory. Best Pract Res Clin Endocrinol Metab 17, 287-299. Woolf, N.J., 1991. Cholinergic systems in mammalian brain and spinal cord. Progress Neurobiology 37, 475-524. Yakel, J.L., 2013. Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease. Pflugers Archiv. 465(4):441-50. Yesavage, J.A., Mumenthaler, M.S., Taylor, J.L., Friedman, L., O'Hara, R., Sheikh, J., Tinklenberg, J., Whitehouse, P.J., 2002. Donepezil and flight simulator performance: effects on retention of complex skills. Neurology 59, 123-125.

22

N

Major findings

3.1 CATECHOLAMINERGIC DRUGS 3.1.1 COMT inhibitor: tolcapone

3

Enhancement of verbal episodic memory.

3.1.2 Levo-dopa

7

3.1.3 Dopamine partial agonist : pramipexole

2

Some positive effects in encoding but no effect on memory and selective attention. No enhancement effects.

3.1.4 Alpha2 adrenergics receptors agonists:

5

No enhancement effects.

3

Conflicting results (verbal and episodic memory enhancement in 2 RCTs, memory impairment in 1 RCT).

4

No enhancement effects.

5

No attention or vigilance enhancement effect.

Melatonine

1

Enhancement of recognition memory accuracy.

3.6 GLUCOCORTICOIDS Hydrocortisone

19

guanfacine and clonidine 3.2 CHOLINERGIC DRUGS Anticholinergic drugs

3.3 GLUTAMATERGIC DRUGS Ampakines (farampator and cx-516) 3.4 HISTAMINERGIC DRUGS H1 antagonist fexofenadine 3.5 MELATONININERGIC DRUGS.

Enhancing or impairing effects depending on the time of administration. 3.7 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS Acetyl salicylic acid (aspirin) 1 Working memory improvement. Table 1. Results of randomised controlled trials (RCTs) assessing enhancement properties of new psychostimulants in healthy non-sleep-deprived subjects. N number of RCTs. COMT Catecholamine O-Methyl-Transferase.

23

Highlights • •

• • • • •

Pharmaceutical cognitive enhancement refers to improvement in cognitive function in healthy subjects by the use of drugs. In previous meta-analyses and systematic reviews, methylphenidate was found to enhance memory and modafinil attention. Nicotine was found to increase episodic and working memory as well as attention. Other dopamine agonists, namely tolcapone and levo-dopa, exhibited enhancement properties in respectively verbal episodic memory and encoding. Negative results were found for pramipexole, guanfacine, clonidine ampakines and fexofenadine. Conflicting results were found with hydrocortisone and anticholinergic drugs, depending on the dose and time of administration. Melatonin and aspirin exhibited potential cognitive enhancement properties. There was no RCT assessing effectiveness of piracetam, piracetam-like molecules and phosphodiesterase inhibitors in healthy adults.

24

6. Figure(s)

Identification

PRISMA 2009 Flow Diagram Additional records identified through other sources (n = 57)

Records identified through database searching (memory n =1087) (attention n=837) (learning n=1078) (executive functions n=115)

Included

Eligibility

Screening

Records after duplicates removed (n = 1706)

Records screened (n =1706)

Full-text articles assessed for eligibility (n = 50)

Records excluded with reasons (n = 1495) - animal studies - absence of randomization or no control group - Trials assessing methylphenidate, modafinil, nicotine, caffeine and choline -esterase inhibitors effectiveness - Subjects with p sychiatric , substance use, neurodegenerative or genetic disorders - Subjects aged