Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

SUPRAS extraction approach for matrix-independent determination of amphetamine-type stimulants by LC-MS/MS.

Monitoring of amphetamine-type stimulant (ATS) confronts clinical labs with a high number of samples involving a variety of biological matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), routinely used for confirmation of ATS abuse, requires of laborious and matrix-dependent sample treatment methods, this increasing analysis time and cost. In this work, a universal and single-step sample treatment, based on supramolecular solvents (SUPRAS), was proposed for simplifying ATS confirmation in seven biological matrices. The SUPRAS was synthesized in situ in the sample (900 µL of basified oral fluid, urine, serum, sweat or breast milk or 50 mg of digested hair or fingernails) by the addition of hexanol (200 µL) and tetrahydrofuran (900 µL). The mixture was vortex-shaken and centrifuged and the SUPRAS extract was subsequently analyzed by positive ion mode electrospray LC-MS/MS. The method was fully validated for amphetamine (AMP), methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA) and N-methyl-3,4-methylenedioxyamphetamine (MDMA). Maximum ion suppression or enhancement was 9% and 7%, respectively, and extraction recoveries (87-111%) and within- (0.1-6.7%) and between-day (0.3-9.7%) CVs were all within required values. The lower limits of quantification (LLOQ) for biological fluids (5 ng/mL), and hair and fingernails (100 ng/g) were all well below the cut-offs established by worldwide organizations. Confirmation of MDA was carried out in five urine samples that tested positive for ATS by immunoassay. The SUPRAS-LC-MS/MS methodology succeeded in developing a hitherto unexplored and universal tool for quantifying ATS in a comprehensive pool of biological matrices of interest in forensic and clinical samples.

Schedules of Controlled Substances: Extension of Temporary Placement of 10 Synthetic Cathinones in Schedule I of the Controlled Substances Act. Final order.

The Administrator of the Drug Enforcement Administration is issuing this final order to extend the temporary schedule I status of 10 synthetic cathinones pursuant to the temporary scheduling provisions of the Controlled Substances Act. The 10 substances are: 4-methyl-N-ethylcathinone (4-MEC); 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP); alpha-pyrrolidinopentiophenone ([alpha]-PVP); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone); 2-(methylamino)-1-phenylpentan-1-one (pentedrone); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone); 4-fluoro-N-methylcathinone (4-FMC); 3-fluoro-N-methylcathinone (3-FMC); 1-(naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (naphyrone); and alpha-pyrrolidinobutiophenone ([alpha]-PBP) [hereinafter 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP, respectively], including their optical, positional, and geometric isomers, salts, and salts of isomers. The current final order temporarily placing 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP into schedule I is in effect through March 6, 2016. This final order will extend the temporary scheduling of 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP for one year, or until the permanent scheduling action for these 10 substances is completed, whichever occurs first.

[Austrian expenditures on psychopharmaceutical drugs between 2006 and 2013]. / Analyse der Ausgaben für Psychopharmaka in Österreich von 2006 bis 2013.

OBJECTIVES: Health costs, which are increasing at a yearly rate of 4 %, represent 11% and thus a large share of Austria's gross domestic product (GDP). High expenditures derive frommental health care costs, including medication. In this article we investigate whether the costs and usage of psychopharmaceutic products in Austria are rising. METHOD: We did a descriptive analysis of the sales figures and number for packaging units of pharmaceutical products of ATC-classes N05 and N06 in all Austrian hospitals, pharmacies and medicine chests for the years 2006-2013. All data were provided free of charge by IMSHealth. RESULTS: The sales volume and number of prescribed packaging units of pharmaceuticals of ATC-classes N05 and N06 increased over the time period in question. In 2013, about 25% more packaging units were being sold than in 2006. Among the two ATC-classes, however, the indication subgroups developed differently. Expenditures increased a total of about 31%within the period of consideration. CONCLUSIONS: The increase in psycho-pharmaceutical sales exceeds the expansion rates of other health expenditures (17.8 %). During the 9 years of observation, 25% more psychopharmaceutical products were sold. This may result from increased prevalence of mental disorders, higher usage or an increment in prescriptions.

Multicriteria wavenumber selection in cocaine classification.

Cocaine ATR-FTIR spectra consist of a large number of wavenumbers that typically decreases the performance of exploratory and predictive multivariate techniques. This paper proposes a framework for selecting the most relevant wavenumbers to classify cocaine samples into two categories regarding chemical composition, i.e. salt and base. The proposed framework builds a wavenumber importance index based on the Bhattacharyya distance (BD) followed by a procedure that removes wavenumbers from the spectra according to the order suggested by the BD index. The recommended wavenumber subset is chosen based on multiple criteria assessing classification performance, which are recalculated after each wavenumber is eliminated. The method was applied to ATR-FTIR spectra from 513 samples of cocaine, remarkably reducing the percent of retained wavenumbers and yielding near to perfect classifications in the testing set. In addition, we compared our propositions with other methods tailored to wavenumber selection; we found that the proposed framework, which relies on simple mathematical fundamentals, yielded competitive results.

A New Nomenclature for Psychotropic Drugs.

INTRODUCTION: Current classifications of psychotropic drugs, developed in the 1960s, are based on beliefs about clinical effectiveness. This article evaluates the scientific validity of current drug terms and possible alternative classifications. METHODS: A historical, conceptual, and empirical review of the psychopharmacology literature is provided. Consistency of classification is examined by 3 major categories: chemical structure, pharmacodynamic mechanism, and clinical efficacy. RESULTS: Current drug terms based on clinical effectiveness are not valid scientifically, either claiming efficacy which is disproven or ignoring other areas of clinical efficacy. Hence, clinical efficacy is not a consistent and scientifically valid way of classifying psychotropic drugs. Chemical structures are also heterogeneous for drugs with similar clinical efficacy. The most consistent way to define drug classes is pharmacodynamic mechanism. Specific drug groups identified are: monoamine agonists ("antidepressants" and "stimulants"), dopamine blockers ("antipsychotics"), second messenger modifiers ("mood stabilizers), and gabaergic agonists ("anxiolytics" or "hypnotics"). CONCLUSIONS: Consistent with a recent proposal of psychopharmacology organizations, this article proposes a new nomenclature based mainly on biological pharmacodynamic mechanisms. Specific terms that are scientifically valid and clinically practical are suggested. It is hoped that this new language would allow for more meaningful and accurate communication between clinicians and patients.

[Conservative treatment of patients with intermittent claudication].

The article deals with the analysis of the results of randomized placebo-controlled studies of various therapeutic agents currently available in Russia, as well as the results of meta-analyses and Cochrane reviews of medicamentous treatment of patients with intermittent claudication. The results of these studies gave grounds to recommend the most efficient agents in the new edition of the "National Guidelines on management of patients with lower-limb arterial disease" (2013).

Schedules of controlled substances: temporary placement of 10 synthetic cathinones into Schedule I. Final order.

The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule 10 synthetic cathinones into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act (CSA). The 10 substances are: 4-methyl-N-ethylcathinone (``4-MEC''); 4-methyl-alpha-pyrrolidinopropiophenone (``4-MePPP''); alpha-pyrrolidinopentiophenone (``[alpha]-PVP''); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (``butylone''); 2-(methylamino)-1-phenylpentan-1-one (``pentedrone''); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (``pentylone''); 4-fluoro-N-methylcathinone (``4-FMC''); 3-fluoro-N-methylcathinone (``3-FMC''); 1-(naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (``naphyrone''); and alpha-pyrrolidinobutiophenone (``[alpha]-PBP''). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cathinones and their optical, positional, and geometric isomers, salts and salts of isomers into schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, import, export, engage in research, conduct instructional activities, and possess), or propose to handle these synthetic cathinones.

Establishment of drug codes for 26 substances. Final rule.

On July 9, 2012, the President signed into law the Synthetic Drug Abuse Prevention Act of 2012 (SDAPA). SDAPA amends the Controlled Substances Act by placing 26 substances in Schedule I. DEA is publishing this rule to establish drug codes for these 26 substances, and to make technical and conforming amendments in accordance with SDAPA.

Schedules of controlled substances: temporary placement of three synthetic cathinones in Schedule I. Final Order.

The Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cathinones under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are 4-methyl-N-methylcathinone (mephedrone), 3,4-methylenedioxy-N-methylcathinone (methylone), and 3,4-methylenedioxypyrovalerone (MDPV). This action is based on a finding by the Administrator that the placement of these synthetic cathinones and their salts, isomers, and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and its implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cathinones.

Stimulants and doping in sport.

Stimulants have been frequently detected in doping control samples and represent a structurally diverse class of compounds. Comprehensive sports drug-testing procedures have been developed using gas or liquid chromatography combined with mass spectrometric detection, and they have revealed various adverse analytical findings, as demonstrated with 2 examples, 4-methylhexan-2-amine and methoxyphenamine. Moreover, the necessity of controlling the use or misuse of stimulating agents is outlined by means of pseudoephedrine, a compound that was prohibited in sports until the end of 2003. Since the ban was lifted, monitoring programs proved a significant increase in pseudoephedrine applications as determined from urine samples collected in competition. As a consequence, a reimplementation of this drug in future doping controls was decided.

[Psychopharmacological treatments in childhood and adolescence]. / Psychopharmaka im Kindes- und Jugendalter.

Compared to adults, the use of psychopharmacological substances in childhood and adolescence is significantly more controversial. Often sensation-seeking media reports on the negative effects of psychopharmacological treatments of children and adolescents intensify this controversy on a regular basis. In addition, even pharmacologically trained experts--though frequently without expertise in Child and Adolescent Psychiatry--question the seriousness and thus the demands for treatment of psychiatric disorders in childhood and adolescence. Considering this background evidence based treatment decisions in pediatric psychopharmacology are of utmost importance. Effective psychopharmacotherapy needs to be distinguished from ineffective treatments. The pros and cons of such evidence based treatment approaches ought to be weighted out carefully together with the patients and their families. The aim of this article is to provide a rational and concise foundation for the use of psychopharmacotherapy for clinicians treating children and adolescents as well as to point out the currently best evidence for psychopharmacological treatments of selected disorders in child and adolescent psychiatry.

A data mining approach to in vivo classification of psychopharmacological drugs.

Data mining is a powerful bioinformatics strategy that has been successfully applied in vitro to screen for gene-expression profiles predicting toxicological or carcinogenic response ('class predictors'). In this report we used a data mining algorithm named Pattern Array (PA) in vivo to analyze mouse open-field behavior and characterize the psychopharmacological effects of three drug classes--psychomotor stimulant, opioid, and psychotomimetic. PA represents rodent movement with approximately 100,000 complex patterns, defined as multiple combinations of several ethologically relevant variables, and mines them for those that maximize any effect of interest, such as the difference between drug classes. We show that PA can discover behavioral predictors of all three drug classes, thus developing a reliable drug-classification scheme in small group sizes. The discovered predictors showed orderly dose dependency despite being explicitly mined only for class differences, with the high doses scoring 4-10 standard deviations from the vehicle group. Furthermore, these predictors correctly classified in a dose-dependent manner four 'unknown' drugs (ie that were not used in the training process), and scored a mixture of a psychomotor stimulant and an opioid as being intermediate between these two classes. The isolated behaviors were highly heritable (h(2)>50%) and replicable as determined in 10 inbred strains across three laboratories. PA can in principle be applied for mining behaviors predicting additional properties, such as within-class differences between drugs and within-drug dose-response, all of which can be measured automatically in a single session per animal in an open-field arena, suggesting a high potential as a tool in psychotherapeutic drug discovery.

The art of prescribing pharmacological management of adult ADHD: implications for psychiatric care.

QUESTION: For several years I have seen more adults presenting with attention-deficit/ hyperactivity disorder (ADHD). I realize that historically ADHD has been considered a childhood disorder, but I would like to know more about diagnosing and treating adult ADHD. ANSWER: Your observations about the prevalence and challenges that confront psychiatric nurses concerning the diagnosis and treatment of adult ADHD are correct. ADHD is a relatively common psychiatric disorder with a high occurrence of 2-6% in adults (Kessler et al., 2006). Though generally regarded as a childhood diagnosis, emerging evidence indicates that symptoms of ADHD remain into adulthood, affecting 4.4% of the adult population (Biederman, Monuteaux, et al., 2006). ADHD in adults frequently goes undiagnosed and untreated. This is largely associated with adults minimizing the severity of symptoms and being unaware that they actually have ADHD. Predictably, adult ADHD is associated with increased morbidity. Higher divorce rates, traffic violations, and negative occupational, economic, and psychosocial functions and concomitant psychiatric disorders are common findings in adults with ADHD (Kessler, Adler, Ames, Barkley, et al., 2005). Approximately 70-75% of adults presenting for treatment of ADHD have at least one co-existing psychiatric diagnosis (Kessler et al., 2006; Wilens, Biederman, & Spencer, 2002). Social phobia, bipolar disorder, major depression, and alcohol dependence are the most common co-existing psychiatric disorders in adults with ADHD (Kessler et al., 2006).

Schedules of controlled substances: placement of lisdexamfetamine into schedule II. Final rule.

With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration (DEA) places the substance lisdexamfetamine, including its salts, isomers and salts of isomers into schedule II of the Controlled Substances Act (CSA). As a result of this rule, the regulatory controls and criminal sanctions of schedule II will be applicable to the manufacture, distribution, dispensing, importation and exportation of lisdexamfetamine and products containing lisdexamfetamine.

Pharmacotherapy of attention-deficit hyperactivity disorder in children and adolescents: update on new stimulant preparations, atomoxetine, and novel treatments.

This article reviews data on the safety, tolerability, and efficacy of the extended-delivery stimulant preparations and atomoxetine, including nine methylphenidate formulations, five amphetamine formulations, and one norepinephrine reuptake inhibitor, now indicated for treatment of attention-deficit hyperactivity disorder (ADHD). Six of the nine methylphenidate formulations, three of the five compounds, and the norepinephrine reuptake inhibitor are long-acting, potentially once-daily agents. Data on treatment of common adverse events are described, and data on investigational treatments of ADHD are reviewed.

[Long-acting methylphenidate. An alternative medical therapy for adult patients with attention deficit hyperactivity disorder]. / Retardiertes Methylphenidat. Eine Alternative in der medikamentösen Therapie bei erwachsenen Patienten mit Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung.

We report a 44-year-old female patient with attention deficit hyperactivity disorder (ADHD), combined subtype (DSM-IV: 314.01), who was treated with 0.5 mg of short-acting immediate-release methylphenidate/kg body weight given t.i.d. (total daily MPH IR dosage 45 mg). Under this medication, the patient reported significant reduction of symptoms. However, several times a day she experienced severe rebound phenomena with pronounced concentration disturbances, unrest, and dysphoric mood. After changing the medication to long-acting methylphenidate once daily (total daily OROS MPH dosage 54 mg), the rebound phenomena stopped, with equivalent beneficial clinical effects.