AMPH Research Articles

Approche historique du trouble déficit de l’attention hyperactivité et de sa prise en charge

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder affecting 5% of children and nearly 3% of adults. This frequent disorder, often associated with comorbidities, is part of a developmental trajectory from childhood to adulthood, and can have repercussions in various areas of individual functioning. We present a non-exhaustive narrative review, focusing on the evolution of the concept of ADHD and its management in children and adolescents. On the 18th century, the first European clinical descriptions, by Melchior A. Wiekard and Cornelius A. Kloekhof and later Alexander Crichton, focus on attention deficit using the term of “attentio volubilis”. A century later, Désiré Magloire Bourneville introduced the concept of “mental instability”; he formalized his models of education and advocated the creation of “special classes” in ordinary schools. By the beginning of the 20th century, Alfred Binet writes “Le portrait de l’instable” (The portrait of the unstable) and already highlights the value of positive reinforcement in the school context. Then, Georges Still, a pediatrician, described the syndrome of “loss of moral control”, in children with no impairment of “general intelligence”, with no identifiable somatic cause; which he associated with “Minimal Brain Damage” referring to minor brain lesions. This theory is taken up in studies on Van Economo-Cruchet encephalitis, which in its hyperkinetic form is similar to ADHD as we know it today. American psychiatrist Charles Bradley publishes his first study on the administration of benzedrine sulfate. Bradley supports a multi-factorial model of behavioural disorders and insists on a global management strategy, combining a psychological and a biological dimension. In 1963, Conners and Eisenberg published the first article on the effect of methylphenidate on children's behaviour and learning. Efficacity of treatements on ADHD symptoms both attested of the neurological underpinnings of this behavioral disorder. Then, two theoretical currents evolved: a neuroanatomical and neurobiological approach on the one hand, and a psychoanalytical current on the other. Polemics about the recognition of the disorder and its causality emerged, contributing to poor identification, delayed access to diagnosis and specific care in France. Wood et al., published a preliminary study on the evolution of “Minimal Brain Dysfunction” in adulthood, representing the beginnings of the developmental perspective of ADHD. Over the last forty years, the contribution of neuroscience (cognition, imaging, electrophysiology, genetics, epigenetics, etc.) has enabled us to develop integrative theoretical models of understanding that describe the complexity of the disorder: a multi-path model was proposed by Sonuga-Barke and Fairchild in 2012. Taken together, these empirical data aim to establish a model for understanding ADHD, and neuroscientists agree that multimodal approaches and “big data” analyses that integrate genetic, imaging and phenotypic data are particularly important for advancing a comprehensive model of understanding, and also for approaching the clinical heterogeneity of this disorder. The international classifications are first clinical categorizations based on predominantly behavioral criteria – initially focusing on inattention (DSM 3), then reintegrating hyperactivity (DSM-3R) introducing the term “attention deficit hyperactivity disorder”, defining ADHD subtypes: inattentive, impulsive/hyperactive, combined (DSM 4). This neuroscientific research has enabled classifications to evolve from a categorical approach to a dimensional and neurodevelopmental approach (DSM-5 and CIM 11), positioning ADHD within a model of etiological understanding. Nowadays, ADHD is the subject of an international consensus statement. The publication of the French 2023–2027 National Strategy for Neurodevelopmental Disorders demonstrates the public authorities’ commitment to this disorder. 2024 is the founding year of the French ADHD Society. Federating scientific investigations based on big data will allow us to improve our understanding of this disorder, improve treatments, understand specific clinical features and their specific trajectories, promote early intervention. ADHD has been identified for centuries, under a variety of names, and has been the subject of theoretical and societal controversy at various times. It is definitely not a contemporary disorder; the future looks promising for the benefit of patients.

Global occurrence, distribution, and ecological risk assessment of psychopharmaceuticals and illicit drugs in surface water environment: A meta-analysis

Psychopharmaceuticals and illicit drugs (PIDs) in aquatic environments can negatively impact ecosystem and human health. However, data on the sources, distribution, drivers, and risks of PIDs in global surface waters are limited. We compiled a dataset of 331 records spanning 23 PIDs in surface waters and sediments across 100 countries by conducting a systematic review and meta-analysis of 108 studies published between 2005 and 2022. Most PIDs were sewage-derived, as wastewater treatment rarely achieved complete removal. The highest total PID levels were in Ethiopia, Australia, and Armenia, with many highly contaminated samples from low- and middle-income countries with minimal prior monitoring. Socioeconomic factors (population, GDP) and environmental variables (water stress) influenced the distribution of PIDs. 3,4-Methylenedioxy amphetamine hydrochloride (MDA), Δ9-tetrahydrocannabinol (THC), and 11- Δ9‑hydroxy-tetrahydrocannabinol (THCOH) posed the greatest ecological risks, especially in Oceania and North America. PIDs in surface waters present risks to aquatic organisms. Our findings elucidate the current status and future directions of PID research in surface waters and provide a scientific foundation for evaluating ecological risks and informing pollution control policies.

Reinforcing systems of the brain and quantification of their work

BACKGROUND: The reinforcing systems of the brain are represented by the ventral forbrain dopaminergic bundle, which innervates the emotiogenic structures of the limbic system. Their study shows the reproduction of unconditioned (self-stimulation, self-administration) and conditioned reflex (preference for place, temperature, color) reactions. The quantitative assessment of the brain’s reinforcing systems remains unclear. For self-stimulation of brain structures, the change of the pedal presses in the Skinner chamber and some calculated coefficients are used, for example, the “mismatch coefficient”, which characterizes the temporal characteristics of the pedal pressings. AIM: To develop, test, and substantiate an additional objective quantitative method for assessing the reinforcing systems of the brain, called the “addiction coefficient”, based on an analysis of the effect of three psychoactive compounds (amphetamine, morphine and ethanol) in different doses on self-stimulation of the lateral hypothalamus in rats. MATERIALS AND METHODS: The main method for studying the reinforcing systems of the brain was the reaction of self-stimulation of the lateral hypothalamus in Wistar rats, which was modulated by the administration of psychoactive substances. The psychomotor stimulant amphetamine (phenamine) hydrochloride (0.5, 1, 2, and 4 mg/kg), narcotic analgesic morphine hydrochloride (1, 2, 4, and 8 mg/kg), and ethanol (0.5, 1, 2, and 4 g/kg) administered intraperitoneally were used as inductors of reinforcing. The control was the administration of of 0.9% NaCl solution (0.1, 0.2, 0.4, and 0.8 ml/rat). RESULTS: The use of different controls, characterized by an increase or decrease in the self-stimulation reaction in response to the introduction of 0.9% NaCl solution, showed that calculated coefficients, including the “mismatch coefficient”, can change in different directions and do not objectively reflect the reinforcing effects of pharmacological substances. The proposed “addiction coefficient”, which reflected the component of psychic dependence, changed unidirectionally toward an increase. The degree of this increase can be tens and hundreds of percent of the control and is significantly independent of the initial values of self-stimulation. As expected, the “addiction coefficient” increased most clearly after amphetamine administration and less significantly after morphine and ethanol injections. CONCLUSIONS: The “addiction coefficient” of a psychoactive substance, calculated as the ratio of the increase in pedal presses to the value of the “mismatch coefficient”, is a clear quantitative indicator when assessing the reinforcing properties of psychoactive substances in the self-stimulation reaction of the lateral hypothalamus. The “addiction coefficient” does not significantly depend on the initial level of self-stimulation and is recommended for a comparative assessment of the reinforcing properties of primarily related psychoactive compounds.

Alternative routine for reporting chiral amphetamine test results in assessment of attention-deficit/hyperactivity disorder medication: experiences from 2013 to 2023.

This study evaluated an alternative routine for reporting urinary chiral amphetamine results in assessment of attention-deficit/hyperactivity disorder (ADHD) treatment with amphetamine medications and for detecting side-use of illicit racemic amphetamine. Currently in Sweden, only enantiopure d-amphetamine-based ADHD medications (lisdexamphetamine dimesylate and dexamphetamine sulfate) are approved. It is therefore unsuitable to express the chiral result as the l/d-ratio, as before, because l-amphetamine should not be present provided treatment compliance. A new routine for LC-MS/MS chiral amphetamine testing was therefore introduced in 2020, whereby the relative proportion (%) of l-amphetamine and the total amphetamine and creatinine concentrations are reported. Evaluation of the new routine on 24,354 results from 2013 to 2023 revealed that it was useful to distinguish ADHD medication adherence from illicit drug use as the source for a positive test. The l-amphetamine proportion also reflected the enantiomeric content of the medications used. Overall, most results confirmed adherence to ADHD medication, as the l-amphetamine percentage was <1% in 76% of samples (2023) which is the recommended cutoff with enantiopure d-amphetamine medications. However, in all years, illicit drug use was indicated (>40% l-amphetamine) in 8.3%-14.5% of cases. In conclusion, this study demonstrated the clinical value and utility of a new routine for reporting urinary chiral amphetamine results to differentiate adherence to ADHD medication from illicit drug use. Unlike the l/d-amphetamine ratio, it considers differences in total amphetamine concentration and urine dilution, factors that can affect the interpretation.

Clinical characteristics of chemsex users attended in a ngo in madrid

IntroductionThe intentional use of drugs before or during sexual intercourse (chemsex) is a phenomenon of special importance in the MSM (men who have sex with men) population due to its impact on mental, physical and sexual health.ObjectivesThe objective of this study was to describe the sociodemographic and medical characteristics, psychoactive substances use of a sample of users with sexualized drug use (chemsex) attended by the non-govenrmental organization Apoyo Positivo in the program “Sex, Drugs and You”.MethodsA cross-sectional descriptive analysis of a sample of users attended by the non-govenrmental organization Apoyo Positivo in the program “Sex, Drugs and You” was performed.Results230 participants were included. Most common drugs used during sexual intercourse were: mephedrone, cocaine, poppers, GHB and methamphetamine. The frequencies of substances consumed during sex were: mephedrone (95%), methamphetamine (80%), GHB (92.2%), ketamine (52%), poppers (alkyl nitrites) (95%), cocaine (89 .7%), speed (amphetamine sulfate) (49.6%) and drugs for erectile dysfunction (86%). 61.3% reported having practiced slamsex intravenous substance use at some time in their life, being a habitual practice at the time of collecting information for 50.7%. The most frequent genitally transmitted infections were: syphilis, chlamydia and gonorrhea. Users reported having been diagnosed with the following genitally transmitted infections: hepatitis B virus (7.4%), hepatitis A virus (18.6%), syphilis (69.6%), human papillomavirus (16 %), herpes (9.4%), chlamydia (43%), gonorrhea (60.5%) and candidiasis (9.7%).ConclusionsSlamsex and STIs are usually reported in our sample. Interventions for chemsex users must include a colaborative model which includes professionals from different areas, including internists and emergency physicians, psychiatrists, psychologists, nurses, social workers and sexologists.Disclosure of InterestNone Declared

Separation of Amphetamine from Captagon Tablets and Analysis by Fourier Transform Infrared Spectroscopy

Effective and rapid detection methods in the field of forensic drug analysis are crucial for reducing overall analysis time and improving reliability. The purpose of this study is to develop a simple and rapid method for the separation of amphetamine from captagon tablets and analysis by means of Fourier transform infrared spectroscopy (FTIR). In this study, the separation of amphetamine using a variety of solvents, including chloroform, Acetonitrile, dichloromethane, methanol and water, were studied. The results obtained show that the separation using a mix of acetonitrile (ACN) with methanol (MeOH) gives a matching percentage close to 97.14% of amphetamine sulfate when compared with the IR spectrum given in the reference (SWGDRUG) library. This method can be used as a confirmatory test for positive results within minutes without false positives.

Driving under the Influence of Amphetamine: Analytical Evaluation of Illegal or Prescription Drug Intake Using Chiral UHPLC-MS-MS.

Differentiation between consumption of illegal and prescription drugs remains an important aspect in forensic toxicology. While illicit amphetamine is most often racemic, the medicinal drugs marketed in Denmark for the treatment of attention-deficit hyperactivity disorder contain the pure (S)-enantiomer or a prodrug thereof. In this study, we present a simple and efficient analytical workflow to provide information about the origin of amphetamine consumed in forensic cases concerning driving under the influence of drugs (DUID). Following quantification of amphetamine and methamphetamine using our conventional multi-target ultra-high performance liquid chromatography-tandem mass spectrometry method, determination of (R)- and (S)-amphetamine was performed by reinjecting the sample extract on a Phenomenex LUX® AMP chiral column using the same analytical instrument and mobile phases. Chiral separation was performed isocratic within a run time of 6 min. The analytical workflow was applied to blood samples from 5,248 suspected DUID cases within a 2-year period. Amphetamine was detected in 18.7% of the samples, of which both enantiomers were detected in 89.5% of the cases, indicating the consumption of illegal racemic amphetamine. In 6.1% of the positive cases, both amphetamine and methamphetamine were detected, indicating either co-consumption of both amphetamines or consumption of methamphetamine. In the remaining 4.4%, only (S)-amphetamine was detected indicating the consumption of prescription drugs containing (S)-amphetamine or a prodrug thereof. Implementation of a simple and rapid chiral method in the conventional analytical workflow for routine forensic casework proved to be an efficient way to elucidate whether a positive amphetamine result originates from illegal or prescription drug consumption, without increasing turnaround time nor costs to any significant extent, as no additional sample preparation was required.

Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD», and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.

Accumulation of amphetamine in hair after contact with street amphetamine

Drugs and drug metabolites can be incorporated into hair in different ways. In addition to passive diffusion from blood and accumulation from sweat, sebum and surrounding tissues, substances can be incorporated into hair through external contamination. Still, little is known about the effects of external contamination of hair with amphetamine. Amphetamine is a commonly used illegal drug and usually applied nasally. Handling and physical contact with powder containing amphetamine can easily lead to direct or indirect contact with hair, which might lead to positive hair results even without consumption. The aim of this study was to elucidate the impact of external contaminations through contact with amphetamine on hair analysis results. 25 subjects simulated the handling of amphetamine in a realistic manner over a short period of time that would be expected in a typical consumption setup. A hair and a urine sample were collected before the start of the study to rule out previous amphetamine abuse or external contamination. One gram of street amphetamine containing approximately 16% amphetamine sulfate was handed out to a total number of 15 participants. Under supervision the subjects prepared several lines of amphetamine for nasal consumption using personal items like credit cards and banknotes. Another group of 10 participants received 10 g of street amphetamine and packaged it into 10 bags, each containing approximately 1 g of powder. After the handling of amphetamine, hands were not be washed for 3 h. The experimental procedure was repeated on five consecutive days. Further hair and urine samples were taken at the fifth day and again after four and eight weeks. The samples taken at the Institute of Forensic Medicine in Freiburg were submitted to amphetamine analysis. The analysis comprised a washing procedure (water, acetone and petroleum ether), overnight methanolic extraction, subsequent solid phase extraction and LC-MS/MS detection of amphetamine enantiomers. Although consumption could be excluded, the handling of street amphetamine led to accumulation of amphetamine in hair. Amphetamine was detected in relatively high concentrations directly after the exposition to amphetamine, but was still detectable four and eight weeks later. As expected washing of the hair samples was not sufficient to remove external amphetamine contamination. Obviously, amphetamine was incorporated and accumulated in the hair matrix via diffusion, preventing rapid wash-out during the decontamination procedure. External contamination of hair with amphetamine cannot be efficiently removed by a hair washing procedures prior to hair analysis. The interpretation of positive amphetamine results in hair must be carried out with caution as “false positive” results might occur. Further studies should look more closely at the quantity of amphetamine enantiomers incorporated into hair by other routes (blood stream, sweat, sebum) to improve the basis of interpretation for hair analysis results.

Enantiomeric profiling of amphetamines in wastewater using chiral derivatisation with gas chromatographic-tandem mass spectrometric detection

Enantiomeric profiling can supplement wastewater-based epidemiology (WBE) by providing additional information on drug origin (licit or illicit), improving consumption estimates, i.e., differentiating between disposal and consumption, and offering an insight into the potency of drugs available on the illicit drug market. We report on the enantiomeric profiling of amphetamines in wastewater using R(-)-α-methoxy-α-(trifluoromethyl) phenylacetyl chloride (R-MTPCl), a chiral derivatising agent and GC–MS/MS. The method performed well when evaluated against the SANTE/12682/2019 guidelines in terms of recovery (81–99%), accuracy (99–111%), repeatability (1–8%RSD) and linearity (LOQ–1000 ng/mL). The LOD and LOQ were 120 ng/L and 400 ng/L, respectively. The method was applied to samples of raw wastewater from two Slovene municipalities with unusual levels of amphetamines: Ljubljana (LJ1) and Velenje (VE1). LJ1 had an anomalously high mass load of MDMA (3,4-methylenedioxymethamphetamine) identified during SCORE 2020, and VE1 is a representative sample of the consistently high mass load of amphetamine. A second Ljubljana sample (LJ2) was chosen as a representative sample. The presence of racemic MDMA (EF = 0.511) in LJ1 indicated the disposal of the unused drug into the sewer, while the enrichment of R-MDMA (EF = 0.666) in the combined extract sample from Ljubljana (LJ2) indicated consumption. In the case of Velenje and Ljubljana, it is impossible to distinguish between the direct disposal and consumption of amphetamine and methamphetamine. Also, since amphetamine/methamphetamine-based prescription medications are unavailable in Slovenia, racemic amphetamine in VE1 (EF = 0.514) and LJ2 (EF = 0.459) indicate racemic and the more potent S-amphetamine are sold on the illicit drug market. Only S-methamphetamine was detected in wastewater (LJ2: EF = 0), indicating the presence of only the more potent S-methamphetamine on the illicit drug market. Overall, enantiomeric profiling provided useful information on amphetamine residues. In addition, chiral derivatisation can be a cost-effective alternative to using chiral chromatographic columns for the enantiomeric profiling of amphetamines in wastewater.

A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of AR19, a Manipulation-Resistant Formulation of Amphetamine Sulfate, in Adults With Attention-Deficit/Hyperactivity Disorder.

Objective: To assess the efficacy and safety of AR19 in the treatment of attention-deficit/hyperactivity disorder (ADHD) diagnosed by DSM-5 criteria in adults from 18 through 55 years of age. AR19 is a pellets-in-capsule, immediate-release amphetamine sulfate investigational formulation with physical and chemical barriers designed to resist manipulation to deter snorting, smoking, and intravenous injection.Methods: This randomized, double-blind, placebo-controlled, fixed-dose, forced titration, multicenter trial investigated the safety and efficacy of AR19 from September 2018 to April 2019. Study participants were randomized and titrated to 20 mg or 40 mg AR19 daily or placebo. Study medication was dosed once in the morning and again 4 to 6 hours later for a period of 5 weeks. The primary efficacy measure was the total score on the Adult ADHD Investigator Symptom Rating Scale (AISRS).Results: Participants (N = 320) were randomized and received at least 1 dose of study medication. Demographics and baseline characteristics were similar across treatment groups. The least squares mean treatment differences versus placebo (97.5% CI) were -7.2 (-11.3 to -3.1) for the AR19 20-mg group and -7.3 (-11.4 to -3.2) for the AR19 40-mg group (each P < .001). The most common treatment-emergent adverse events occurring in participants in the AR19 treatment groups were insomnia, dry mouth, decreased appetite, palpitations, headache, and tachycardia and are consistent with the known safety profile of amphetamine sulfate.Conclusions: AR19 demonstrated efficacy on all endpoints and was generally well tolerated, supporting the efficacy and safety of AR19 20 mg and 40 mg in adults with ADHD.Trial Registration: ClinicalTrials.gov Identifier: NCT03659929.

Med Check: Naloxone and Opioid Overdose; Evekeo ODT and ADHD in Children; Theta Burst Protocol and Depressive Disorder; Brilaroxazine Phase 2 Trials

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Naloxone and Opioid Overdose; Evekeo ODT and ADHD in Children; Theta Burst Protocol and Depressive Disorder; Brilaroxazine Phase 2 TrialsTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:28 May 2021https://doi.org/10.1176/appi.pn.2021.6.14Higher Naloxone Dose Approved for Opioid OverdoseIn April the Food and Drug Administration (FDA) approved Kloxxado, a higher dosage of naloxone nasal spray for the emergency treatment of known or suspected opioid overdose. The newly approved product, developed by Hikma Pharmaceuticals, delivers 8 mg of naloxone into the nasal cavity. The FDA had previously approved 2 mg and 4 mg naloxone nasal spray products.The FDA approved Kloxxado based on previous findings about the safety and effectiveness of Narcan injection (naloxone hydrochloride) for treating opioid overdose. Hikma Pharmaceuticals also submitted its own safety and effectiveness data.“Over the last several years, the FDA has taken a number of steps to improve availability of naloxone products, including encouraging manufacturers to pursue approval of over-the-counter naloxone products; requiring drug manufacturers for all opioid pain relievers and medicines to treat opioid use disorder to add new recommendations about naloxone to the prescribing information; and extending the shelf life of naloxone nasal spray from 24 months to 36 months,” the agency said in a statement.Evekeo ODT Approved for ADHD in Young ChildrenIn April the FDA approved Evekeo ODT (amphetamine sulfate) by Arbor Pharmaceuticals for treating attention-deficit/hyperactivity disorder (ADHD) in patients aged 3 to 5 years. Evekeo ODT, a mixture of dextroamphetamine sulfate and levoamphetamine sulfate, was previously approved for treating ADHD in patients aged 5 to 17 years, with tablets ranging in dose from 5 mg to 20 mg. Evekeo ODT will be available in a new 2.5 mg orally disintegrating tablet for patients 3 to 5 years old. The recommended starting dose for patients in this age group is 2.5 mg daily, and a second dose may be administered after 4 to 6 hours.Evekeo ODT is a Schedule II controlled substance and comes with a boxed warning noting that central nervous systems stimulants have a high potential for abuse and dependence. The boxed warning advises health professionals to assess their patients’ risk of abuse and dependence before prescribing the drug, and to monitor patients for signs of abuse and dependence as therapy continues.Theta Burst Protocol Cleared for Treating Major Depressive DisorderBrainsWay announced in April that its Theta Burst protocol has been approved by the FDA for treating major depressive disorder. Theta Burst is a three-minute protocol that uses the company’s Deep Transcranial Magnetic Stimulation (Deep TMS) system. TMS uses magnetic fields to stimulate parts of the brain and activate neural pathways to improve symptoms of depression.In a study of 146 patients with major depressive disorder, patients treated with the three-minute protocol experienced reductions in depression scores similar to those who received the standard 20-minute sessions, the company said in a statement. The standard treatment protocol consists of 20-minute sessions five times a week for four to six weeks, followed by treatment twice a week for up to 12 weeks as needed for maintenance.Brilaroxazine Promising in Phase 2 TrialsReviva Pharmaceuticals’ investigational drug brilaroxazine appeared to be safe and effective for treating schizophrenia and schizoaffective disorder in a phase 2 clinical trial, the company announced in April.In the trial, 234 adults who had acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either treatment with brilaroxazine or placebo for four weeks. The primary endpoint was reduction in total Positive and Negative Syndrome Scale (PANSS) from baseline to the end of the treatment. At the end of four weeks, the PANSS total score was reduced by 20 points in patients who took brilaroxazine, which the company said in a statement is a “statistically significant treatment difference from the placebo.” ■ ISSUES NewArchived

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A single-dose, comparative bioavailability study comparing amphetamine extended-release oral suspension with extended-release mixed amphetamine salts capsules.

To evaluate the relative bioavailability of a single dose of amphetamine extended-release oral suspension (AMPH EROS) compared with a single dose of extended-release mixed amphetamine salts (ER MAS) in healthy, fasted adult subjects. The study population consisted of healthy adult volunteers. The study drug used in this study was 7.5mL of 2.5mg/mL AMPH EROS equivalent to 18.8mg of amphetamine base administered after an overnight fast of at least 10hours. AMPH EROS comprises a 3.2:1 enantiomeric ratio of d-amphetamine to l-amphetamine. The reference product was one 30mg ER MAS capsule (equivalent to 18.8mg of amphetamine base). Relative bioavailability between the products was determined by a statistical comparison of the area under the curve and maximum concentration (Cmax) for d-amphetamine and l-amphetamine. PK (PK) blood samples were collected prior to dosing (0-hour) and at 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60hours after drug administration, totaling 20 samples in each period. The mean subject age was 35.0 (standard deviation ±8) years, and the overall study population comprised 19 (63.3%) males and 11 (36.7%) females. The contrasts for geometric mean ratios for all assessed PK parameters (for both l- and d-amphetamine) between the test article AMPH EROS and reference product ER MAS fell within the prescribed 80% to 125% limits. The overall PK profile of single-dose AMPH EROS 7.5mL was found to be comparable with a single dose of oral ER MAS 30mg.

A Molecularly Imprinted Polymer-based Dye Displacement Assay for the Rapid Visual Detection of Amphetamine in Urine.

The rapid sensing of drug compounds has traditionally relied on antibodies, enzymes and electrochemical reactions. These technologies can frequently produce false positives/negatives and require specific conditions to operate. Akin to antibodies, molecularly imprinted polymers (MIPs) are a more robust synthetic alternative with the ability to bind a target molecule with an affinity comparable to that of its natural counterparts. With this in mind, the research presented in this article introduces a facile MIP-based dye displacement assay for the detection of (±) amphetamine in urine. The selective nature of MIPs coupled with a displaceable dye enables the resulting low-cost assay to rapidly produce a clear visual confirmation of a target’s presence, offering huge commercial potential. The following manuscript characterizes the proposed assay, drawing attention to various facets of the sensor design and optimization. To this end, synthesis of a MIP tailored towards amphetamine is described, scrutinizing the composition and selectivity (ibuprofen, naproxen, 2-methoxphenidine, quetiapine) of the reported synthetic receptor. Dye selection for the development of the displacement assay follows, proceeded by optimization of the displacement process by investigating the time taken and the amount of MIP powder required for optimum displacement. An optimized dose–response curve is then presented, introducing (±) amphetamine hydrochloride (0.01–1 mg mL−1) to the engineered sensor and determining the limit of detection (LoD). The research culminates in the assay being used for the analysis of spiked urine samples (amphetamine, ibuprofen, naproxen, 2-methoxphenidine, quetiapine, bupropion, pheniramine, bromopheniramine) and evaluating its potential as a low-cost, rapid and selective method of analysis.

Med Check: Unapproved, Misbranded Opioids; Treating Adults With ADHD; Improve Cognition in Patients With Schizophrenia

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Unapproved, Misbranded Opioids; Treating Adults With ADHD; Improve Cognition in Patients With SchizophreniaTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:8 Oct 2020https://doi.org/10.1176/appi.pn.2020.10b1FDA Warns Websites Hawking Unapproved, Misbranded OpioidsIn September the U.S. Food and Drug Administration (FDA) sent warning letters to 17 website operators for illegally selling unapproved and misbranded opioids online. Misbranded opioids include those offered for sale without a prescription and opioids that lack adequate directions for use. Tramadol and oxycodone are among the opioids being offered for sale, and several of the websites offer opioids online without a prescription.“Those who illegally sell opioids online put consumers at risk and undermine the significant strides we have made to combat the opioid crisis,” said Donald D. Ashley, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, in a press release.The agency noted in the release that people who buy prescription drugs, including opioids, from illegal online pharmacies may put their health at risk because the products may be counterfeit, contaminated, expired, or otherwise unsafe. The agency added that illegal online pharmacies can also pose other risks to consumers, including credit card fraud, identity theft, and computer viruses.AR19 Shows Promise for Adults With ADHDIn September Arbor Pharmaceuticals LLC announced positive safety and efficacy results from a phase 3 study in adults of AR19, its investigational immediate-release, amphetamine sulfate capsule for the treatment of attention-deficit/hyperactivity disorder (ADHD). The drug is designed to resist manipulation for non-oral use such as snorting, smoking, or injecting and is currently under review by the FDA.In the study, 320 adults aged 18 to 55 years with ADHD were randomized to receive 20 mg of AR19, 40 mg of AR19, or placebo daily for five weeks. Researchers measured improvement according to the Adult ADHD Investigator Symptom Rating Scale. At the fifth week, patients in either group who took AR19 dropped roughly 7 more points on the scale than the placebo group dropped. The most common side effects, which were reported by more than 5% of patients who took AR19, were insomnia, dry mouth, lowered appetite, palpitations, and tachycardia.FDA Receives NDA for Parkinson’s Drug SPN-830Supernus submitted a New Drug Application (NDA) in September for SPN-830, its apomorphine infusion pump for the continuous treatment of on-off episodes in adults with Parkinson’s disease (PD) whose motor control is unsatisfactory with oral levodopa and at least one other noninvasive PD therapy. During off episodes, motor symptoms like stiffness or tremor return even though the patient is taking medication for PD.The company submitted the NDA based on the results of the phase 3 TOLEDO study (conducted in Europe) and an open-label study (conducted in the United States). Both 12-week studies included adults with average daily off episodes that lasted at least three hours. All patients kept diaries of their motor symptoms.In the TOLEDO study, 106 patients received either SPN-830 or placebo. The mean daily off time decreased a mean of 2.47 hours for those in the SPN-830 group compared with a mean decrease of 0.58 hours in the placebo group. In the U.S. study, all 94 patients took SPN-830 and their mean daily off episodes decreased by three hours. Most of the side effects reported by patients were mild or moderate and included problems at the infusion site, nausea, and dyskinesia.BI 425809 May Improve Cognition in Patients with SchizophreniaBoehringer Ingelheim’s investigational compound BI 425809 improved cognition in stable adult patients with schizophrenia in a phase 2 trial, the company announced in September.In the study, patients with schizophrenia in 11 countries were randomized to receive either 2 mg to 25 mg of BI 425809 or placebo daily for 12 weeks. All patients were medically stable with no hospitalization for worsening of schizophrenia in the three months before randomization. They were also psychiatrically stable with no exacerbations in their symptoms in the three months before randomization.At 12 weeks, cognitive function improved in patients who took BI 425809, as measured by the composite Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. This series of tests assesses patients’ speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. There were no differences in psychiatric adverse events or suicidality between groups. ■ ISSUES NewArchived

Synchrotron far-infrared spectra for the characterisation of molecular crystals of forensic interest: Amphetamine, methamphetamine, MDA, MDMA and substituted methcathinones

This combined laboratory and theoretical investigation focussed on a suite of crystalline phenethylamine-class molecules of forensic interest: amphetamine sulfate, levo- and dextro-methamphetamine hydrochloride, 3,4-methyl​enedioxy-methamphetamine (MDMA) hydrochloride, 3,4-methylenedioxy-​amphetamine (MDA) hydrochloride, and the hydrochloride salts of two substituted (4-fluoro and 4-methyl) methcathinones. Far-infrared (far-IR) spectra across the 30–600 cm−1 wavenumber range were recorded at the Australian Synchrotron light source. Resolved absorption profiles enabled vibrational features to be assigned via comparison to periodic density functional theory (p-DFT) performed at the B3LYP-D3/6-311 G(d) level. The calculations accurately reproduce the experimental spectra (frequencies and peak intensities) for ordered molecular crystal-type samples, such as methamphetamine stereoisomers and two substituted methcathinones. Significant band broadening for amphetamine sulfate was observed, likely due to crystal disorder, while MDMA and MDA showed convolved stretching modes from comparatively impure samples. For all seven molecular crystals investigated, previously unpublished peak assignments and relative band intensities have now been systematically compiled; completing the spectral region that lies between the more thoroughly studied terahertz and mid-IR regions. These results can be incorporated in spectral libraries and databases to enable far-IR statistical analyses to be performed on forensic samples of mixed or impure compounds.

Pharmacokinetics of AR19, an Immediate-Release Amphetamine Sulfate Formulation Designed to Deter Manipulation for Administration Via Nonoral Routes: Bioequivalence to Reference Racemic Amphetamine Sulfate, Dose Proportionality, and Food Effect

Objectives: We evaluated the pharmacokinetics (PK) of an investigational immediate-release amphetamine (AMP) sulfate formulation (AR19) designed to deter nonoral administration versus reference racemic amphetamine sulfate (RA-AMPH). We investigated AMP bioavailability from AR19, the effect of taking AR19 with food or sprinkling the capsules on food, and dose proportionality. Methods: Participants received AR19 (20 mg) or reference RA-AMPH (20 mg) (bioequivalence study) or AR19 5 or 30 mg (dose comparison study). Food effect study participants received AR19 (20 mg) as intact capsule while fasted or after high-fat/-calorie meal, or as pellets sprinkled on applesauce or yogurt (≥6-day washout). Blood samples were analyzed for dextroamphetamine (d-AMP) and levoamphetamine (l-AMP) PK: Cmax, AUClast, AUCinf, λz, T½, and Tmax. Safety was assessed. Results: Bioequivalence, dose comparison, and food effect studies included 36, 24, and 36 participants. The 90% confidence intervals (CIs) of Cmax, AUClast, and AUCinf for AR19 20 mg versus reference RA-AMPH or AR19 with intact capsule and meal or sprinkled AR19 pellets on food versus fasted were between 80% and 125%. Dose-normalized Cmax/D, AUClast/D, and AUCinf/D for AR19 5 versus 30 mg had CIs within 80%-125%. Mean ± standard deviation (SD) Tmax was comparable for AMP (d-AMP; l-AMP) following AR19 20 mg (2.84 ± 1.05; 3.05 ± 1.22) versus reference RA-AMPH (2.52 ± 0.75; 2.75 ± 1.00), and AR19 5 mg (2.48 ± 0.57; 2.65 ± 0.65) versus AR19 30 mg (2.55 ± 0.56; 2.72 ± 0.65). Mean ± SD Tmax for AMP (d-AMP; l-AMP) was higher with intact capsule and meal (5.59 ± 1.57; 5.59 ± 1.59) versus fasted (2.85 ± 0.76; 2.97 ± 0.79). No serious adverse events were reported. Conclusion: AR19 was bioequivalent to reference RA-AMPH. Bioavailability was similar at doses between 5 and 30 mg and was not impacted by meal consumption or sprinkling on food. AR19 at tested doses was well tolerated.

The prediction of far-infrared spectra for molecular crystals of forensic interest – Phenylethylamine, ephedrine & pseudoephedrine

Synchrotron far-infrared (far-IR) spectra were measured for a representative set of pharmaceutical-type molecular crystals: phenylethylamine hydrochloride salt, ephedrine base and its hydrochloride salt, and pseudoephedrine base and its hydrochloride salt. Resolved spectral profiles in the 30–600 cm−1 range allowed for comparison of absorption bands to simulated spectra obtained by periodic density function theory (DFT) code. The B3LYP-D3/6-311G(d) level of theory returned highly accurate predictions of the experimental far-IR spectra for well-ordered crystalline samples, including an agreement between relative peak intensities almost unprecedented for organic crystal systems of this size. Simulated far-IR spectra for the phenylethylamine hydrochloride and ephedrine base samples do not match to the same degree; potentially due to higher disorder within the solid-state. These comparisons to theory generally allowed for confident assignment of prominent absorption bands to low-lying vibrational modes. The experimental spectra (including those for related illicit drug compounds: amphetamine sulphate, methamphetamine hydrochloride, MDA hydrochloride, and MDMA hydrochloride), peak assignments, and relative band intensities are compiled and evaluated for their inclusion in spectral libraries and their application to chemometric analysis for mixed compounds of pharmaceutical and forensic interest.

Locomotor Effects of Substituted Amphetamines and Cathinones in Mice: Structure‐Activity Relationships

Substituted amphetamines represent one of the largest and most pharmacologically‐diverse classes of abused drugs. Modifications to the amphetamine base structure are seemingly limitless, and novel psychoactive substituted amphetamines continuously emerge on the illicit market. Amphetamine analogues containing a ketone at the beta carbon are referred to as cathinones, which are typically the active constituents in abused “bath salts” products. Each “generation” of cathinone analogues introduces new structural motifs, most likely in response to regulatory control of previous compounds. One recently identified “bath salts” constituent is 4‐chloroethcathinone (4‐CEC), consisting of the base amphetamine structure with the addition of an ethyl side chain, a chlorine at the 4‐position, and a ketone group at the beta carbon. In these studies, we compared 12 structurally‐analogous substituted amphetamines and cathinones increasing in structural complexity from amphetamine to 4‐CEC in order to assess structure‐activity relationships for locomotor stimulant and toxic effects in mice. Automated photobeam chambers were used to record various aspects of mouse locomotor activity including jump count, time in stereotypy, vertical time, speed, and distance. Full dose‐effect curves were determined for each compound, starting with a dose that produced saline‐like distance traveled, and increasing in half‐log units until distance decreased from that drug's peak, or until lethal effects were observed. For the substituted amphetamines, increasing the length of the side chain increased maximal effectiveness on locomotor endpoints. As compared to analogous unsubstituted compounds, addition of a chlorine at the 4‐position did not substantially impact distance traveled, but increased time spent in stereotypy. These same trends were also observed with the substituted cathinones. Interestingly, 4‐CEC produced lethality in all subjects at doses on the ascending limb of the dose‐effect curve for distance traveled. Further development of structure‐activity relationships for these drugs may determine which moieties of their chemical structures are involved in producing specific pharmacological effects, and may allow predictions about abuse liability or toxic effects of new pharmacological entities with similar structural motifs.Support or Funding InformationThese studies supported by DA022981, R01‐DA039195, and DEA/FDA HHSF223201610079C.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.