title: Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review.
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 placebo-controlled 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 meta-analyses 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.
authors.affiliation: Université Paris EST-Créteil, AP-HP, Pôle de Psychiatrie ET d'addictologie des Hopitaux Universitaires Henri Mondor, INSERM U955, Eq 15 Psychiatrie Génétique, DHU PE-psy, Fondation Fondamental Fondation de Coopération Scientifique en Santé Mentale, F-94000 France. Electronic address: guillaume.fond@gmail.com.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Fond
authors.affiliation: Pôle Psychiatrie Universitaire, CHU Sainte-marguerite, F-13274 Marseille Cedex 09, France.
authors.forename: Jean-Arthur
authors.initials: JA
authors.lastname: Micoulaud-Franchi
authors.affiliation: Université Paris EST-Créteil, AP-HP, Pôle de Psychiatrie ET d'addictologie des Hopitaux Universitaires Henri Mondor, INSERM U955, Eq 15 Psychiatrie Génétique, DHU PE-psy, Fondation Fondamental Fondation de Coopération Scientifique en Santé Mentale, F-94000 France.
authors.forename: Lore
authors.initials: L
authors.lastname: Brunel
authors.affiliation: Université Montpellier 1, INSERM 1061, Service Universitaire de Psychiatrie, CHU Montpellier F-34000, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Macgregor
authors.affiliation: INSERM U952, CNRS UMR 7224, UMPC Univ Paris 06, F-75000 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Miot
authors.affiliation: Université Montpellier 1, INSERM 1061, Centre de Référence National Narcolepsie Hypersomnie Idiopathique, Unité des Troubles du Sommeil, CHU Montpellier F-34000, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Pôle Psychiatrie Universitaire, CHU Sainte-marguerite, F-13274 Marseille Cedex 09, France; Faculté de Médecine, EA 3279, Laboratoire de Santé Publique, F-13385 Marseille Cedex 05, France.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Richieri
authors.affiliation: CHU Carémeau, Université de Nîmes, Nîmes F-31000, France.
authors.forename: Mocrane
authors.initials: M
authors.lastname: Abbar
authors.affiliation: Pôle Psychiatrie Universitaire, CHU Sainte-marguerite, F-13274 Marseille Cedex 09, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lancon
authors.affiliation: Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin franklin, Eschenallee 3, 14050 Berlin, Germany.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Repantis
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D003071:Cognition; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D061212:Memory, Episodic; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use; D000077408:Modafinil; D009538:Nicotine / Q000009:adverse effects / Q000627:therapeutic use; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D018697:Nootropic Agents; D008774:Methylphenidate; D007980:Levodopa; D009538:Nicotine; D000077408:Modafinil
keywords: Attention; Cognitive enhancement; Healthy adult; Memory; Performance