Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson's disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th version (ICD-9) diagnosis codes 314.0-314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson's disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0-3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8-15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.

The demonstrated role of PKCβ in  mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, ruboxistaurin. Despite the interest in development of ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.

Chemical waste from the clandestine production of amphetamine is of forensic and environmental importance due to its illegal nature which often leads to dumping into the environment. In this study, 27 aqueous amphetamine waste samples from controlled Leuckart reactions performed in Germany, the Netherlands, and Poland were characterised to increase knowledge about the chemical composition and physicochemical characteristics of such waste. Aqueous waste samples from different reaction steps were analysed to determine characteristic patterns which could be used for classification. Conductivity, pH, density, ionic load, and organic compounds were determined using different analytical methods. Conductivity values ranged from 1 to over 200 mS/cm, pH values from 0 to 14, and densities from 1.0 to 1.3 g/cm3 . A capillary electrophoresis method with contactless conductivity detection (CE-C4 D) was developed and validated to quantify chloride, sulphate, formate, ammonium, and sodium ions which were the most abundant ions in the investigated waste samples. A solid-phase extraction sample preparation was used prior to gas chromatography-mass spectrometry analysis to determine the organic compounds. Using the characterisation data of the known samples, it was possible to assign 16 seized clandestine waste samples from an amphetamine production to the corresponding synthesis step. The data also allowed us to draw conclusions about the synthesis procedure and used chemicals. The presented data and methods could support forensic investigations by showing the probative value of synthesis waste when investigating the illegal production of amphetamine. It can also act as starting point to develop new approaches to tackle the problem of clandestine waste dumping.

The orexigenic peptide ghrelin (GHR) interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement and feeding circuits. Pharmacological inactivation of GHR-Rs via administration of the drug JMV 2959 attenuates the rewarding/reinforcing effects of several drugs of abuse including alcohol, morphine, amphetamine and nicotine. One view of these results is that inactivation of GHR-Rs taps into brain reinforcement/feeding circuits acted upon by drugs of abuse. An alternate explanation is that JMV 2959 may induce malaise, which in turn may limit reinforcement as well as food ingestion. This is a variable of interest given that nicotine alone can induce malaise which may be enhanced by JMV 2959. In the present study, we assessed the capacity of JMV 2959 to produce malaise using a conditioned taste aversion (CTA) task. Adult male rats were allowed to consume a 0.1% sodium saccharin solution and then injected IP with either vehicle, 0.4mg/kg nicotine, 3mg/kg JMV 2959, a combination of 0.4mg/kg nicotine and 3mg/kg JMV 2959, or 32mg/kg lithium chloride (a positive control known to support induction of CTA). Lithium chloride produced a robust avoidance of the saccharin solution in subsequent 2 bottle (water and saccharin) tests, whereas JMV 2959 alone did not induce CTA. The combination of JMV 2959 and nicotine induced a moderate degree of CTA that was similar to that produced by nicotine alone. These results suggest that JMV 2959 is unlikely to limit either reinforcement or food ingestion via induction of malaise.

Attention-deficit/hyperactivity disorder (ADHD) is defined as a disorder of impaired attention and/or behavioral control. Studies suggest that the condition can dispose individuals to a higher risk of automobile accidents. ADHD symptoms respond to pharmacotherapy in a majority of uncomplicated cases. Evidence on how pharmacotherapies for ADHD impact driving behavior or outcomes could allow clinicians to support on-road safety rationally. We therefore undertook a review to identify the evidence base to date indicating positive or negative effects of pharmacotherapies on driving behavior in individuals with ADHD. Further, we evaluated the level of evidence for these effects, their specificity to ADHD, and how they may inform clinical care. We identified studies involving pharmacotherapy for ADHD that evaluated driving-related activities or outcomes. We then categorized these studies by the mode of measurement used and by the ADHD specificity of the driving behaviors measured. Finally, we extracted themes of interest to clinical practice in pharmacologic intervention. In total, 14 studies, involving 2-61 subjects diagnosed with ADHD, looked at computer-measured, observer-measured, or self-reported driving behavior correlates of pharmacotherapy during simulation or on-road driving. Of these studies, 13 involved psychostimulant agents and two used atomoxetine. All but three investigations (one of methylphenidate, one of mixed amphetamine salts, and one of atomoxetine) found favorable changes in measures such as steering and braking behaviors or reaction to unexpected events. One study found adverse effects on driving at hour 17 following mixed amphetamine salt administration. Four studies compared two pharmacotherapies, and each found differences in measured driving behavior between the therapies. One study explored impact on ADHD-specific driving impairments, and the same study was the only one to explore correlation of clinical measures (ADHD symptoms and self-reported driving behavior) with medication-associated changes-finding dissociation between changes in ADHD symptoms and changes in measured driving measures. While data to date are limited on the ADHD-specific effects of pharmacotherapies used for ADHD on driving, it is clear from our review that these agents have effects on driving-relevant behaviors. Further research is urgently needed to develop an evidence base for clinically predictable effects of pharmacotherapy on driving safety in individuals with ADHD. If possible, clinicians should evaluate the positive and negative effects of pharmacotherapy on driving in their clients.

Amphetamine selective molecularly imprinted sol-gel polymer tablets, MIP-tablets, for solid-phase microextraction of biofluid samples were prepared. An acetonitrile solution of deuterated amphetamine template and silane precursor, 3-(propylmethacrylate) trimethoxysilane, was soaked into the pores of polyethylene tablet substrates and polymerized by an acid-catalysed sol-gel process. Application of the resultant MIP-tablets to extract amphetamine from human urine samples followed by LC-MS/MS analysis was investigated. The extraction protocol was optimised with respect to pH of sample, addition of sodium chloride, extraction time, desorption solvent and desorption time. The final analysis method determined amphetamine in human urine with a limit of detection (LOD) of 1.0ng/mL and a lower limit of quantification (LLOQ) of 5ng/mL. Validation demonstrated accuracy of the method was 91.0-104.0% and inter-assay precision was 4.8-8.5% (RSD). Extraction recovery was 80%. The MIP-tablets could be re-used and the same tablet could be employed for more than twenty extractions.