Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.

Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

Amphetamines Improve the Motivation to Invest Effort in Attention-Deficit/Hyperactivity Disorder.

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior.SIGNIFICANCE STATEMENT A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.

Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

OBJECTIVES: Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. METHODS: Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. RESULTS: Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P  = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. CONCLUSION: Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Treatment with psychostimulants and atomoxetine in people with psychotic disorders: reassessing the risk of clinical deterioration in a real-world setting.

BACKGROUND: Although attention-deficit hyperactivity disorder (ADHD) is often comorbid with schizophrenia spectrum and other psychotic disorders (SZSPD), concerns about an increased risk of psychotic events have limited its treatment with either psychostimulants or atomoxetine. AIMS: To examine whether the risk of hospital admission for psychosis in people with SZSPD was increased during the year following the introduction of such medications compared with the year before. METHOD: This was a retrospective cohort study using Quebec (Canada) administrative health registries, including all Quebec residents with a public prescription drug insurance plan and a diagnosis of psychotic disorder, defined by relevant ICD-9 or ICD-10 codes, who initiated either methylphenidate, amphetamines or atomoxetine, between January 2010 and December 2016, in combination with antipsychotic medication. The primary outcome was time to hospital admission for psychosis within 1 year of initiation. State sequence analysis was also used to visualise admission trajectories for psychosis in the year following initiation of these medications, compared with the previous year. RESULTS: Out of 2219 individuals, 1589 (71.6%) initiated methylphenidate, 339 (15.3%) amphetamines and 291 (13.1%) atomoxetine during the study period. After adjustment, the risk of hospital admission for psychosis was decreased during the 12 months following the introduction of these medications when used in combination with antipsychotics (adjusted HR = 0.36, 95% CI 0.24-0.54; P < 0.0001). CONCLUSIONS: These findings suggest that, in a real-world setting, when used concurrently with antipsychotic medication, methylphenidate, amphetamines and atomoxetine may be safer than generally believed in individuals with psychotic disorders.

In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Evaluation of the difference in adsorption of amphetamine-type drugs on deep eutectic solvent-functionalized graphene oxide/ZIF-67 composite: Experiment and theoretical calculations.

Herein, the capture and separation properties of the deep eutectic solvent-functionalized magnetic graphene oxide/ZIF-67 composite (ZMG-DES) towards amphetamine-type drugs (MDMA, MAM and AM) from water were investigated. Kinetic and isotherm models showed that the adsorption behaviors were monolayer chemisorption. Batch experiment results showed that the maximal adsorption of MDMA (933.652 µg⋅g-1) was 2.3 and 2.8 times higher than that of MAM (412.849 µg⋅g-1) and AM (328.652 µg⋅g-1), respectively, and this superiority remained consistent under varied environmental influences (pH, background ion and humic acid). Theoretical calculations and characterization analyses demonstrated the methylenedioxy group of MDMA led to the highly selective adsorption. Electrostatic potential (ESP) distribution indicated that the methylenedioxy added electron-rich areas and provided more adsorption sites. The Independent Gradient Model (IGMH) quantified the adsorption contribution of the functional groups in each system, which the contribution of the methylenedioxy reached 25.23%, significantly exceeding that of -NH- (18.80%) and benzene ring (20.76%), and proved that the H-bonds formed methylenedioxy enhanced adsorption. Furthermore, the Hirshfeld surface analysis proved that the methylenedioxy and -NH- of MDMA acted as H-bond acceptor and donor, respectively, which synergistically promoted the adsorption. The present study will help us to understand the structure-property relationship between amphetamine-type drugs and ZMG-DES.

Screening of Astec® CHIRALDEX™ G-PN and LIPODEX™ D gas chromatography columns for enantioseparation of amphetamine derivatives.

Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms of clinical studies about possibly different effects of the two enantiomers of novel amphetamine derivatives. For this reason, there is a big demand for enantioseparation method development of this new substance class. Regarding gas chromatography, cyclodextrins proved to be effective for enantioseparation of NPS. In our attempt, an Astec® Chiraldex™ G-PN column containing 2,6-di-O-pentyl-3-propionyl-γ-cyclodextrin and a Lipodex™ D column containing heptakis-(2,6-di-O-pentyl-O-acetyl)-ß-cyclodextrin as chiral selector served as stationary phases in a Shimadzu GCMS-QP2010 SE system. Because of the special coating, maximum temperature is limited to 200 °C isothermal or 220 °C in programmed mode. To ensure detection, trifluoroacetic anhydride (TFAA) was used to increase sample volatility.1 As a result, 35 amphetamines were tested as their TFAA-derivatives. A screening method with a temperature gradient from 140 °C to 200 °C at a heating ramp of 1 °C per minute and final time of 5 min, showed baseline separation for seven and partial separations for 16 trifluoro acetylated amphetamines using the Chiraldex™ G-PN column. Six baseline and nine partial separations were observed with the Lipodex™ D column, respectively.

The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) with co-occurring substance use disorder (SUD) is associated with poor treatment outcomes. Two randomized controlled trials, utilizing robust doses of stimulants, demonstrated a significant effect on treatment outcomes in patients with ADHD/SUD. This study aimed to investigate differences in executive functioning and explore the dose-dependent effect of OROS-methylphenidate (MPH) in patients with comorbid ADHD and amphetamine use disorder (ADHD+AMPH) and patients with ADHD only. METHODS: Three groups (ADHD+AMPH, ADHD only, and healthy controls) were assessed repeatedly with a neuropsychological test battery. An exploratory within-subject single-blinded design was employed where the ADHD only group received a maximum dose of 72 mg OROS-MPH, the ADHD+AMPH group a maximum dose of 180 mg, whereas the healthy subjects did not receive any study medication. Both ADHD groups received the same dose titration up to 72 mg OROS-MPH. RESULTS: The ADHD+AMPH group demonstrated a significantly poorer motor inhibition and spatial working memory and reported more severe ADHD symptoms compared to the ADHD only group. 180 mg OROS-MPH was associated with a significant improvement in executive functioning in the dual diagnosis group. However, the exploratory study design and recruitment issues do not allow for any conclusion to be drawn regarding the effect of 180 mg OROS-MPH. CONCLUSION: Patients with ADHD+AMPH present with more severe neurocognitive deficits compared to ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.

The involvement of calcium in the toxic effect of 4-methylethcathinone on SH-SY5Y cells.

Neurotoxicity induced by psychoactive substances is often accompanied by an imbalance of intracellular calcium ions. It is unclear whether calcium ions play a role in the toxicity induced by psychoactive substances. In the present study, we aimed to evaluate the occurrence of calcium dysregulation and its contribution to cytotoxicity in human neurotypic SH-SY5Y cells challenged with a recently developed psychoactive substance 4-methylethcathinone (4-MEC). An increase in the intracellular calcium was detected by inductively coupled plasma atomic emission spectrometry and Fluo-3 AM dye in SH-SY5Y cells after being treated with 4-MEC. The increase of intracellular Ca2+ level mediated G0/G1 cell cycle arrest and ROS/endoplasmic reticulum stress-autophagy signaling pathways to achieve the toxicity of 4-MEC. In particular, N-acetyl-L-cysteine, a classical antioxidant, was found to be a potential treatment for 4-MEC-induced toxicity. Taken together, our results demonstrate that an increase in intracellular calcium content is one of the mechanisms of 4-MEC-induced toxicity. This study provides a molecular basis for the toxicity mechanism and therapeutic intervention of psychoactive substances.

Qualitative Exploration of the Experiences of People Who Use Captagon and Therapists in Jordan.

Background: Captagon (Fenethylline) is an amphetamine type stimulant (ATS) and one of the most popular substances of use in the Middle East. This study aims to describe and analyze the trajectory of captagon use, severity of addiction and withdrawal symptoms and its effect on quality of life from the perspectives of people who use captagon, who receive treatment as well as therapists. Methods: This study took a qualitative approach, using semi-structured, audio-recorded interviews, which were transcribed verbatim, translated to English and coded using Nvivo software for thematic analysis. Results: Data saturation was achieved after interviewing a total of 27 participants (7 therapists and 20 patients using captagon either alone or among other illicit drugs), most of which were male (n = 22). Their ages ranged between 18-48 years (median= 27). Four main themes were identified during the interviews: (1) Definition and sought effects of captagon; (2) the downside of captagon use and withdrawal symptoms associated with captagon use; (3) motivations for captagon use and to treatment; and (4) the impact of Covid-19 on captagon's use and on treatment. Conclusion: This qualitative study has illustrated for the first time the several challenges and complicating factors that people who use captagon and therapists face in Jordan. Findings call attention to implementing effective interventions to raise public's awareness of the negative impact of such use, with focus on high-risk groups, address the needs of different users and encourage the use of international treatment guidelines.

Applicability of a Chemiluminescence Immunoassay to Screen Postmortem Bile Specimens and Its Agreement with Confirmation Analysis.

Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children. Toxicological investigation consists in screening and, subsequently, confirming the result with specific techniques, such as liquid chromatography with tandem mass spectrometry (LC-MS/MS). As there is no screening test on the market to test postmortem bile specimens, the novelty of this study was in investigating the applicability of a chemiluminescence immunoassay, designed for other matrices and available on the market, on bile and validate its use, testing the agreement with LC-MS/MS analysis. Bile specimens were obtained from 25 forensic cases of suspected death from overdose and intoxication. Sample preparation for bile screening consists simply in centrifugation and dilution. Confirmation analysis allows simultaneous identification of 108 drugs and was validated on bile. Kappa analysis assessed a perfect agreement (0.81-1) between the assays for benzodiazepines, methadone, opiates, cocaine, oxycodone, cannabinoids, buprenorphine and pregabalin; a substantial agreement (0.41-0.6) was reported for barbiturates. No agreement was assessed for amphetamines, due to an abundance of putrefactive amines in postmortem specimens. In conclusion, this fast and easy immunoassay could be used for initial screening of bile specimens, identifying presence of drugs, except amphetamines, with reliability.

Toxicokinetics of MDMA and Its Metabolite MDA in Rats.

OBJECTIVES: To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA. METHODS: A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis. RESULTS: In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: T=10.362C-1.183, R2=0.974 6; T=7.397 3C-0.694, R2=0.961 5 (T: injection time; C: concentration ratio of MDMA to MDA in plasma). CONCLUSIONS: The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.

Amphetamine pretreatment blunts dopamine-induced D2/D3-receptor occupancy by an arrestin-mediated mechanism: A PET study in internalization compromised mice.

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised ß-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

High Intensity Interval Training can Ameliorate Hypothalamic Appetite Regulation in Male Rats with Type 2 Diabetes: The Role of Leptin.

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity.

Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.

Impulsive choice in individuals with comorbid amphetamine use disorder and attention deficit-hyperactivity disorder.

BACKGROUND: Amphetamine use disorder (AMPH) and attention deficit-hyperactivity disorder (ADHD) often co-occur and are associated with poor treatment outcomes. Elevated impulsivity is a core feature in both disorders. Little is known however about the specific neurocognitive profile regarding different facets of impulsivity, and specifically impulsive choice, in comorbid populations. METHODS: Three groups (ADHD + AMPH, ADHD only and healthy controls (HC)) were assessed with self-reported impulsivity and cognitive tasks of impulsive choice, operationalized as delay aversion (DA) and reflection impulsivity. RESULTS: Twenty-nine participants with comorbid ADHD + AMPH, 25 participants with ADHD only and 116 HC completed screening, including self-rating scales, and cognitive testing. 20, 16 and 114 participants completed computerized cognitive tasks in the ADHD + AMPH group, ADHD group and HC group, respectively. The ADHD + AMPH group reported significantly higher motor, attentional and non-planning impulsiveness, and showed a significantly higher degree of impulsive choice, compared to both groups. There were no differences in task-related impulsiveness between ADHD only and HC. CONCLUSIONS: The current findings suggest that individuals with ADHD + AMPH have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, that ADHD + AMPH is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings in order to develop effective and targeted treatment for comorbid patients. TRIAL REGISTRATION: EudraCT, 2012-004298-20.

Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits.

OBJECTIVES: This research aimed to systematically review the acute effects of amphetamine (AMP), a dopamine-releasing agent, on working memory (WM) and other cognitive performances. The investigation also aimed to review the impact of personality traits on the subjective and objective effects of AMP and possible links between personality traits and effects of AMP. METHODS: Previous double-blind controlled studies assessing the main effects of AMP on WM and other cognitive performances in healthy volunteers were systematically reviewed. An electronic search was performed in the PUBMED and SCOPUS databases. Narrative reviews of the influence of personality traits on the subjective and objective effects of AMP were included. RESULTS: Nineteen WM studies were included in the current review. Seven studies found effects of AMP on spatial WM, but only one study found the effect of AMP on verbal WM. Thirty-seven independent studies on other aspects of cognitive performance were identified. Twenty-two reported effects of AMP on cognitive functions. Studies also showed that personality traits are associated with the subjective effects of AMP. However, few studies reported the impacts of personality traits on the objective (such as WM) effects of AMP. CONCLUSION: Overall, findings indicate that AMP has mixed-effects on spatial WM and other cognitive functions, but it lacks effects on verbal WM. Although there are insufficient studies on objective measures, studies also indicated that the subjective effects of AMP administration are linked to between-person variations in personality traits.

Information Scanning Impacts Nonmedical Drug Use Among College Students: A Longitudinal Study of Scanning Effects.

Health information that is acquired through information scanning has been shown to play an important role in shaping individual beliefs and health behavior. This study examines the direct and indirect effects of the breadth of scanning from media and interpersonal sources about two risk behaviors (nonmedical use of amphetamines and marijuana) on subsequent drug use behavior through changes to perceived norms. We test effects of scanning using a longitudinal online survey design with data collected at six-month intervals over three time points among 800 Israeli undergraduate students in their freshman year. Of the 800 respondents who participated in the first wave, 62.4% completed the second wave (N = 499), among which 347 (69.5%) completed a follow-up 6 months later. Results of cross-lagged structural equation models find that scanning information about amphetamines from interpersonal sources at 6 months predicted an increased likelihood of nonmedical use of amphetamines at 12-months. In addition, young adults who scanned information about marijuana from media sources at 6 months reported greater nonmedical marijuana use at 12 months. Breadth of scanning about marijuana from media sources mediated the relationship between perceived norms and marijuana use at 12 months. Results also showed indirect effects of scanning at baseline on nonmedical drug use at 12 months through scanning from the same source at 6 months. These findings contribute to our understanding of the role of information scanning and perceived norms in shaping substance use behaviors, and suggest that scanning may serve as a potential early indicator of risk.

Captagon-induced Brugada phenocopy: A report of two cases.

Brugada phenocopies (BrP) represent electrocardiogram changes identical to those of true congenital Brugada syndrome but are induced by reversible clinical conditions. Previous cases have been reported in patients following recreational drug use. This report presents two cases of type 1B BrP associated with Fenethylline abuse, a recreational drug known by its trade name, Captagon.

Genome-wide survey and functional analysis reveal TCF21 promotes chicken preadipocyte differentiation by directly upregulating HTR2A.

BACKGROUND/AIM: Previously, we showed that transcription factor 21 (TCF21) promotes chicken preadipocyte differentiation. However, the genome-wide TCF21 binding sites and its downstream target genes in chicken adipogenesis were unknown. METHODS: ChIP-Seq and RNA-Seq were used to screen candidate targets of TCF21. qPCR and luciferase reporter assay were applied to verify the sequencing results. Western blotting, oil red-O staining and pharmacological treatments were performed to investigate the function of 5-hydroxytryptamine receptor 2A (HTR2A), one of the bonafide direct downstream binding targets of TCF21. RESULTS: A total of 94 candidate target genes of TCF21 were identified. ChIP-qPCR, RT-qPCR, and luciferase reporter assay demonstrated that HTR2A is one of the bonafide direct downstream binding targets of TCF21. HTR2A expression in adipose tissue was upregulated in fat line broilers. Also, the abundance of HTR2A gradually increased during the adipogenesis process. Interestingly, pharmacological enhancement or inhibition of HTR2A promoted or attenuated the differentiation of preadipocytes, respectively. Furthermore, HTR2A inhibition impaired the TCF21 promoted adipogenesis. CONCLUSIONS: We profiled the genome-wide TCF21 binding sites in chicken differentiated preadipocytes revealing HTR2A as the direct downstream target of TCF21 in adipogenesis.