AMPH Research Articles

Chromatographic separation of R-(-)/S-(+)-enantiomers of amphetamine and methamphetamine: differentiation between single methamphetamine consumption and co-consumption with amphetamine using enantioselective quantitative LC-MS/MS analysis.

The differentiation between single methamphetamine consumption and co-consumption with amphetamine is difficult, however possible by enantioselective analysis due to different preferred synthesis pathways of both substances. We quantified (R)-(-) and (S)-(+)-enantiomers of methamphetamine and amphetamine by a fast liquid chromatographic tandem-mass spectrometric method using a Lux® 3-μm AMP 150 × 3.0mm analytical column after simple protein precipitation with methanol. Method validation for quantitative detection showed limits of quantification < 5ng/mL, linearity in a range between 5 and 300ng/mL and bias and imprecision data < 15%. Overall, 134 plasma samples of police cases from the German regions of Franconia and Northrhine-Westphalia were analyzed for the enantiomers of methamphetamine and amphetamine. In 28 cases, the intake of racemic illicit amphetamine could be demonstrated; (R)-(-) / (S)-(+)-amphetamine concentration ratios in these cases were between 1.38 and 4.50 with most of the ratios being < 2.0. These ratios were compared to a subgroup of 25 consumers with a co-consumption of (S)-(+)-methamphetamine and racemic amphetamine detected by the qualitative proof of (R)-(-)-amphetamine but also by (R)-(-) / (S)-(+)-amphetamine concentration ratios (< 1 in 11 of 25 cases). Within our collective of 106 plasma samples after methamphetamine use, 25 samples showed co-consumption with amphetamine which shows that co-consumption of both stimulants is not a rare scenario. Furthermore, we could show that if non-stereoselective methods are used and the concentration ratio of total methamphetamine/total amphetamine is determined, a reliable estimation of co-consumption is not possible.

Reactivity Differences for the Oxidation of FeIIFeII to FeIII(µ‐O)FeIII Complexes Caused by Pyridyl versus 6‐Methyl‐Pyridyl Ligands

The dinucleating bis(tetradentate) ligand susan [= 4,7‐dimethyl‐1,1,10,10‐tetra(2‐pyridylmethyl)‐1,4,7,10‐tetraazadecane] reacts with [Fe(OH2)6](BF4)2 to the complex [(susan){FeIIIF(µ‐O)FeIIIF}](BF4)2. In contrast, the reaction of the ligand derivative susan6‐Me with 6‐methylpyridyl instead of pyridyl donors with [Fe(OH2)6](BF4)2 results in the complexes [(susanMe){FeII(µ‐F)2FeII}](BF4)2 and [(susanMe){FeIIF(µ‐F)FeIIIF}](BF4)2. The synthesis of the µ‐oxo diferric complex [(susan6‐Me){FeIIIF(µ‐O)FeIIIF}]2+ requires the addition of H2O2 as oxidant. The best synthesis is the H2O2 oxidation of the new diferrous precursor [(susan6‐Me){FeII(µ‐F)2FeII}](ClO4)2. The introduction of the 6‐methylpyridine donors results in an elongation of the Fe–Npy bonds. The resulting lower electron donation is not compensated by the µ‐oxo bond but slightly by the Fe–Namine bonds. These structural changes are correlated with the νas(FeOFe) stretching mode, a smaller Mössbauer quadrupole splitting, a smaller ligand field splitting, a weaker antiferromagnetic exchange, and an anodic shift of the redox potentials. This destabilization of the ferric state correlates with the different reactivity of the diferrous precursors to the µ‐oxo diferric complexes: air for susan and H2O2 for for susan6‐Me. Structural analysis indicates a steric repulsion of the 6‐methyl group with the fluorido ligand in cis‐position as origin for the longer Fe–Npy bonds, which seems to be a general phenomenon.

Enantiomeric profiling of amphetamine and methamphetamine in wastewater: A 7-year study in regional and urban Queensland, Australia

Enantiomeric profiling was used in this study to investigate the consumption of amphetamine and methamphetamine in regional and urban Southeast Queensland, Australia over a period of seven years. S(+) methamphetamine was predominantly consumed in both urban and regional areas, showing a two and three fold increase in urban and regional catchments respectively between 2011 and 2017. The ratio of amphetamine to methamphetamine (AMP/METH) in wastewater reflected the expected excretion profile of methamphetamine consumption indicating the presence of amphetamine in this study was primarily the result of methamphetamine metabolism. However, the occasional occurrence of R(−) amphetamine in samples containing higher AMP/METH ratios, suggested the consumption of racemic amphetamine. The R(−) methamphetamine enantiomer was also identified in several samples, possibly indicative that the phenyl-2-propanone (P2P) synthesis process rather than the more typical reduction of ephedrines was also being used to manufacture methamphetamine. Furthermore, we identified two samples with a significantly different enantiomer ratio for the METH and AMP as well as a much lower AMP/METH concentration ratio suggesting contribution from direct disposal of methamphetamine into the sewer. This study demonstrated that enantiomeric profiling in wastewater-based epidemiology can provide valuable information for evaluating the origin of amphetamine in wastewater as either a metabolite of methamphetamine consumption or amphetamine itself.

FREE AND ZEOLITE-IMMOBILIZED PROBIOTIC MIXTURE VERSUS SODIUM VALPROATE IN PREVENTION OF OXIDATIVE STRESS AND MODULATION OF THE L-ARGININE INTRACELLULAR METABOLIC PATHWAYS IN THE RAT BRAIN AND BLOOD FOLLOWING DEXAMPHETAMINE-INDUCED BIPOLAR D

Experimental bipolar disorder (BD) was induced by repeated daily injection of the increasing doses of d -amphetamine sulfate (AMPH) (2-4 mg kg -1 , 18 injections) in male young adult Wistar rats characterized by temporal arousal mimicked mania, and reduced exploratory and locomotor activities associated with behavioural depression under the condition of withdrawal of AMPH. At the end of the injection course, a stimulation of the lipid peroxidation processes and alterations in the mitochondrial and cytoplasmic activities of both arginase and nitric oxide synthase (NOS) were observed in the regions of brain corticolimbic system (prefrontal cortex, striatum, hippocampus and hypothalamus) and blood leukocytes. We have shown for the first time that a reversal treatment with the mixture of the specific probiotics with psycho- and antifungal activities in free (PMF) and zeolite-immobilized (PMZ) forms, and/or with a mood stabilizer, sodium valproate (VPA) inhibited oxidative stress and modulated differentially the L-arginine metabolic pathways in the brain and blood following AMPH-induced BD. Both PMF and PMZ efficiently normalized the activities of arginase isoforms and upregulated the suppressed intracellular NOS along with the gut microbiota restoration and prevention of the histopathological changes in the brain regions accompanied by normalization of rat behaviour.

125 Short Duration Monoballismus

AbstractStudy ObjectiveWhile monoballismus has been reported to be associated with hemorrhagic lesions in the subthalamic nucleus (Ohnishi, 2009) and multiple sclerosis (MS) (Rosa, 2011), the duration has been reported to be at least six days (Soysal, 2012). A patient with epochs of monoballismus lasting for 45 minutes is presented.MethodsCase Study: A 57 year old right handed female with attention deficit hereditary disorder predominantly inattentive on amphetamine sulphate, presented with two years of memory loss. For instance, after ordering food in restaurants, by the time the food arrives, she could not recall what she ordered. At the onset of this symptom, she noted three epochs of her left arm jerking for 45 minutes. The jerking would begin with low amplitude and low frequency and rapidly progress to the forearm and arm of greater magnitude and low frequency. With her right hand she would try to hold down her left arm without success. There was no associated paresis, sensory phenomena, headaches, dizziness, presyncope, loss of consciousness, or strong emotions. She admitted to frequent jamais vu.ResultsAbnormalities: Neurological Examination: Mental Status Examination: Memory: Immediate Recall: 5 digits forward and 2 digits backwards. Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test 8 (hyposmia). CN XII: tongue tremor on protrusion. Motor Examination: Drift Test: positive right pronator drift. Gait Examination: Tandem Gait: unstable. Reflexes: 0-1 throughout. Neuropsychiatric Examination: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 15 (normal). Clock Drawing Test: 3 (abnormal). Center for Neurologic Study Lability Scale: 16 (pseudobulbar affect). Other: MRI with and without infusion: normal.ConclusionTransient tonic-clonic movements of one limb have been described with focal epilepsy associated with diabetic non-ketotic hyperglycemia (Grant, 1985). A metabolic abnormality such as transient hypoglycemia or hyperkalemia can cause a focal dystonia (Soysal, 2012), which theoretically could manifest with monoballismus. This could be a somatic manifestation of underlying conflict, conversion disorder, or as a result of a physical manifestation of panic attack with hyperventilation and tetany (Mihai, 2008). This may be the first manifestation of a generalized cerebral disorder associated with chorea or ballismus such as Wilson’s disease, or Huntington’s Chorea (Mihai, 2008). It is possible that this is a variant of Alien Hand Syndrome with parietal lobe involvement (Shrestha, 2015). But this is unlikely given the absence of hemineglect or hemiagnosia. It is possible that amphetamines may have induced a monochorea. Chronic amphetamine use has been demonstrated to cause chorea (Klawans, 1974) and it theoretically could have caused ballismus movements in this case. In patients who present with short duration monoballismus, evaluation for subthalamic nuclei function, seizure disorders and other origins of ballismus are warranted.Funding AcknowledgementsSmell &amp; Taste Treatment and Research Foundation

A Single-Dose, Two-Way Crossover, Open-Label Bioequivalence Study of an Amphetamine Extended-Release Oral Suspension in Healthy Adults

Objective: The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. Method: In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d - and l -amphetamine concentrations, and pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUCinf were calculated to determine bioequivalence. Safety was monitored throughout the study. Results: The 90% confidence intervals (CIs) for the log-transformed Cmax, AUC0-5, AUC5-last, and AUCinf fell within the accepted 80% to 125% range for establishing bioequivalence for d - and l -amphetamine. The most common adverse events were nausea and decreased appetite. Conclusion: AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.

Chiral analysis of amphetamines in hair by liquid chromatography-tandem mass spectrometry: compliance-monitoring of attention deficit hyperactivity disorder (ADHD) patients under Elvanse® therapy and identification after controlled low-dose application.

Amphetamine (AMP) is used as an illicit drug and also for the treatment of attention deficit hyperactivity disorder (ADHD). Respective drugs most often contain the enantiomer (S)-AMP as active compound or (S)-AMP is formed from the prodrug lisdexamfetamine (Elvanse®) whereas the illicit drug is usually traded as racemate ((R/S)-AMP). A differentiation between the use of the medically prescribed drug and the abuse of illicit street amphetamine is of great importance, for example in retrospective consumption monitoring by hair analysis. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the chiral separation and quantitation of (S)- and (R)-AMP in hair was developed. For this purpose, 20mg hair was extracted and derivatized with N-(2,4-dinitro-5-fluorophenyl)-L(S)-valinamide L(S)-(DNPV) to yield amphetamine diastereomers. Baseline separation of the resulting diastereomers was achieved on a high-pressure liquid-chromatography system (HPLC) coupled to a Sciex QTRAP® 5500 linear ion trap quadrupole mass spectrometer. The method was successfully validated. Analysis of hair samples from nine Elvanse® patients revealed only (S)-AMP in eight cases; one subject showed both enantiomers indicating a (side-) consumption of street amphetamine. The analysis of the 16 amphetamine users' samples showed only racemic amphetamine. Furthermore, it could be shown in a controlled study that (S)-AMP can be detected after administration of even very low doses of lisdexamfetamine and dexamphetamine, which can be of interest in forensic toxicology and especially in drug-facilitated crime (DFC). The method now enables the retrospective compliance-monitoring of ADHD patients and the differentiation between medically prescribed intake of (S)-amphetamine and abuse of illicit street amphetamine.

‘Not … Like a Rum-Ration’: Amphetamine Sulphate, the Royal Navy, and the Evolution of Policy and Medical Research during the Second World War

This article explores the evolution of the Royal Navy’s policy relating to the use of amphetamines during the Second World War. This discussion, which demonstrates the groundbreaking yet restrictive nature of naval drug policy, is placed in the wider context of medical research in the Royal Navy during the conflict, in which the organisation was the last of the Services to develop its own personnel research committee. In turn, the article examines the motivation for utilising the drug, which included considerations relating to both wakefulness, in combat situations, and well-being, in survival at sea situations.

Drug Seeking Behavior of Amphetamine Addicted Sprague-Dawley Rats Is Eliminated after Nutritional Supplementation

Aim: The effectiveness of nutritional supplementation on drug-seeking behavior of amphetamine-addicted rats during withdrawal was investigated using a biased conditioned place preference (CPP) paradigm. Method: Twenty-four male Sprague-Dawley rats exhibiting baseline preference for the black chamber during a 20-minute pre-conditioning exploration of the CPP box completed the study. On alternate days of an 8-day schedule, twelve rats (Group AMP) were randomly selected, given either amphetamine sulfate (5 mg/ml, i.p.) and confined to the white chamber; or vehicle (1 ml saline, i.p.) and confined to the black chamber. A significant increased percentage time spent and number of entries made by Group AMP to the drug-paired, white chamber on the test day confirmed amphetamine addiction. Group AMP subsequently received increasing doses of amphetamine over 6 days. Following acute drug withdrawal, their CPP performance was compared with that of vehicle treated rats (Group SAL). Groups AMP and SAL were equally divided and randomly assigned to animals fed chow reconstituted with the nutritional supplement (AMP-S and SAL-S) over 8 weeks or standard rat chow (AMP-N and SAL-N). CPP performances for all rats were determined blindly from video recordings following this period. Results: Nutritionally supplemented, amphetamine withdrawn rats (AMP-S) exhibited significantly decreased percentage entries and time spent in the white chamber (p < 0.05), indicating preference for the black chamber and diminished drug-seeking behavior. ANOVA revealed that after 8 weeks of dietary supplementation, AMP-S rats behaved like drug-na?ve, control animals. Conclusion: Drug-seeking behavior by amphetamine-addicted animals was eliminated after treatment with a nutritionally supplemented diet.

Accelerated quantification of amphetamine enantiomers in human urine using chiral liquid chromatography and on-line column-switching coupled with tandem mass spectrometry.

Amphetamine (AM) is a powerful psychostimulant existing in two enantiomeric forms. Stereoselective analysis of AM in biosamples can assist clinicians and forensic experts in differentiating between abuse of illicitly synthesized racemic AM and ingestion of pharmaceutical AM formulations containing either S-AM or different proportions of the S- and R-enantiomers. Therefore, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying AM enantiomers in urine was newly developed. The method comprised dilution with water, followed by injection of the diluted sample onto an achiral C18 trapping column for purification and subsequent backflush elution to a chiral Lux 3μm AMP LC column by means of a switching valve. An isocratic mobile phase of 25% acetonitrile in 0.1M aqueous ammonia was used for enantiomeric separation. Injection, cleanup, and backflush of the next sample were performed before the previous sample had eluted from the analytical column, thus enabling simultaneous enantioseparation of up to three samples within the analytical column. This novel chromatographic concept allowed for increased sample throughput by accelerating both the sample preparation and the LC analysis. Analyte detection was accomplished by electrospray ionization in positive ion mode and selected reaction monitoring using a triple-stage quadrupole mass spectrometer. The method was successfully validated through assessment of its linearity, lower limit of quantification, accuracy and precision, selectivity, matrix effect, carry-over, dilution integrity, and re-injection reproducibility. Linearity ranged from 0.05 to 25mg/L for both enantiomers. Proof of the method included analysis of urine samples obtained from drug abusers and patients receiving an S-AM prodrug. Graphical Abstract Enantioselective determination of amphetamine in human urine using liquid chromatography with achiral-chiral column-switching and tandem mass spectrometry.

DEVELOPMENT OF ANALYTICAL METHOD FOR IDENTIFICATION OF SIBUTRAMINE HCL IN TRADITIONAL MEDICINE USING SOLID PHASE EXTRACTION – HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

Object: The purpose of this study is to develop a rapid and sensitive method for identifying sibutramine HCl. Methods: Reversed phase solid phase extraction (SPE) method with Hydrophilic-Lipophilic Balance (HLB) cartridge was selected to be developed and optimized. Optimization was done by optimizing solvent in sample preparation and rinse solvent in washing step. The extract of SPE was injected into reversed phase HPLC with C18 column with PDA detector. Furthermore, the optimized results was validated which included specificity and determination of the detection limit. Validated analytical method was used to analyze sibutramine HCl qualitatively in slimming herbal medicine which was obtained from the market. Results: Analysis method optimization results showed that the optimum sample solvent to extract sibutramine HCl in solid phase extraction was 3% orthophosphoric acid. Then it was shaken for 30 min and filtered, the filtrate was put in SPE cartridge that had been conditioned using ethanol and water. After rinsing with NH4OH solution in water and NH4OH solution in 80% ethanol, the analyte was eluted with acetonitrile. Identification of sibutramine HCl was done by HPLC at wavelength 254 nm. Sibutramine HCl gave maximum wavelength at 222 nm. Sibutramine HCl calibration curve gave quite linear results in the range from 0.10 to 0.50 mg/ml with R2 = 0.9966. The detection limit of this assay was 2.326 µg/ml. Specificity of this method is quite good. Simulation sample gave resolution for diethylpropion 2.415; sibutramine HCl 2.877 and amphetamine sulfate 5.673.This methods recovery was 38.0 to 45.0 %. Conclusion: This study showed faster and specific method for identifying sibutramine HCl in traditional medicine. Keywords: sibutramine HCl, solid phase extraction, HLB, slimming herbal medicine, HPLC

The Royal Air Force, Bomber Command and the Use of Benzedrine Sulphate: An Examination of Policy and Practice During the Second World War

This article explores the development of policy in the Royal Air Force (RAF) relating to the use of Benzedrine, a potent amphetamine, by aircrews during the Second World War. This policy evolved from total prohibition in September 1939 to cautious approval for the use of the drug on operations in November 1942. Such caution reflected the subjective evidence available about Benzedrine, the media profile of the substance, and wider social and cultural factors relating to the use of drugs during this period. This challenges our understanding of drug history, demonstrating that while amphetamines were framed as a ‘miracle drug’, more nuanced, functional interpretations of the substance were in evidence. In turn, the article examines evidence from the operational context, including new data gathered from questionnaires and interviews with former Bomber Command aircrew and existing oral history material held by the Imperial War Museum. Both policy discussions and operational evidence allows for a re-evaluation of the arguments of Nicholas Rasmussen, who suggests the RAF made use of Benzedrine as a frontline ‘psychiatric medicine’. Such conclusions downplay the significance the RAF attached to the drug’s effects on wakefulness and concerns about the drug’s effects on wellbeing.

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys.

Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SARs) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in non-human primate models. The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, and (±)-methamphetamine and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively, to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full substitution, ≥90% cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than those of methamphetamine or previously published methcathinone (Smith et al. 2016). The presence of an N-methyl group blunted both the potency and the efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Repeated ventral midbrain neurotensin injections sensitize to amphetamine-induced locomotion and ERK activation: A role for NMDA receptors

Previous studies have shown that activation of ventral midbrain NMDA receptors is required to initiate sensitization by amphetamine. In view of the recent evidence that neurotensin modulates ventral midbrain glutamate neurotransmission, we tested the hypothesis that neurotensin is acting upstream to glutamate to initiate sensitization to the behavioral and neurochemical effects of amphetamine. During a first testing phase, adult male rats implanted with bilateral ventral midbrain cannulae were injected every second day for three days with D-[Tyr11]neurotensin (1.5 nmol/side), the preferred NMDA GluN2A/B antagonist, CPP (40 or 120 pmol/side), the selective GluN2B antagonist, Ro04-5595 (200 or 1200 pmol/side), CPP (40 or 120 pmol/side) + D-[Tyr11]neurotensin (1.5 nmol/side) or Ro04-5595 (200 or 1200 pmol/side) + D-[Tyr11]neurotensin (1.5 nmol/side) and locomotor activity was measured immediately after the injection. Five days after the last central injection, the locomotor response or the expression of phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) in neurons of different limbic nuclei was measured following a systemic injection of amphetamine sulfate (0.75 mg/kg, i.p.). Results show that amphetamine induced significantly stronger locomotor activity and pERK1/2 expression in the nucleus accumbens shell and infralimbic cortex in neurotensin pre-exposed animals than in controls (vehicle pre-exposed). These sensitization effects initiated by neurotensin were prevented by CPP, but not Ro04-5595. These results support the hypothesis that neurotensin is stimulating glutamate neurotransmission to initiate neural changes that sub-serve amphetamine sensitization and that glutamate is acting on NMDA receptors that are mostly likely composed of GluN2A, but not GluN2B, subunits.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.

"Ice" (crystal methamphetamine): concerns and responses.

Describes a pattern of increasing use of methamphetamine over the past decade. Summary There is no cause to feel impotent, despite disturbing media reports about methamphetamine. Methamphetamine has been around for some time. Although it is now available in a crystal form that is more potent and more readily smoked than earlier forms, no-one should feel impotent in the face of widespread alarmist commentary about this drug. The recent National Ice Taskforce Report describes a pattern of increasing use of methamphetamine over the past decade. Compounding the effect of the shift in use from the older amphetamine sulphate to methamphetamine (in powder or crystal form) is the increase in purity of illicit methamphetamine: the purity-adjusted price (the dose obtained for a given price) is now similar for both methamphetamine forms, so that users obtain much larger doses. This probably underlies the evidence of more regular and greater levels of dependent use among people who use the drug, and also some of the increases in observed harms.

The hydrochloride and hydrobromide salt forms of (S)-amphetamine.

Despite the high profile of amphetamine, there have been relatively few structural studies of its salt forms. The lack of any halide salt forms is surprising as the typical synthetic route for amphetamine initially produces the chloride salt. (S)-Amphetamine hydrochloride [systematic name: (2S)-1-phenylpropan-2-aminium chloride], C9H14N(+)·Cl(-), has a Z' = 6 structure with six independent cation-anion pairs. That these are indeed crystallographically independent is supported by different packing orientations of the cations and by the observation of a wide range of cation conformations generated by rotation about the phenyl-CH2 bond. The supramolecular contacts about the anions also differ, such that both a wide variation in the geometry of the three N-H...Cl hydrogen bonds formed by each chloride anion and differences in C-H...Cl contacts are apparent. (S)-Amphetamine hydrobromide [systematic name: (2S)-1-phenylpropan-2-aminium bromide], C9H14N(+)·Br(-), is broadly similar to the hydrochloride in terms of cation conformation, the existence of three N-H...X hydrogen-bond contacts per anion and the overall two-dimensional hydrogen-bonded sheet motif. However, only the chloride structure features organic bilayers and Z' > 1.

Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia

It has been proposed that spontaneous panic attacks are the outcome of the misfiring of an evolved suffocation alarm system. Evidence gathered in the last years is suggestive that the dorsal periaqueductal gray (dPAG) in the midbrain harbors a hypoxia-sensitive suffocation alarm system. We here investigated whether facilitation of 5-HT-mediated neurotransmission within the dPAG changes panic-like defensive reactions expressed by male Wistar rats submitted to a hypoxia challenge (7% O2), as observed in other animal models of panic. Intra-dPAG injection of 5-HT (20nmol), (±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) (8nmol), a 5-HT1A receptor agonist, or (±)-2,5-dimethoxy-4-iodo amphetamine hydrochloride (DOI) (16nmol), a preferential 5-HT2A agonist, reduced the number of upward jumps directed to the border of the experimental chamber during hypoxia, interpreted as escape attempts, without affecting the rats’ locomotion. These effects were similar to those caused by chronic, but not acute, intraperitoneal administration of the antidepressant fluoxetine (5–15mg/kg), or acute systemic administration of the benzodiazepine receptor agonist alprazolam (1–4mg/kg), both drugs clinically used in the treatment of panic disorder. Our findings strengthen the view that the dPAG is a key encephalic area involved in the defensive behaviors triggered by activation of the suffocation alarm system. They also support the use of hypoxia-evoked escape as a model of respiratory-type panic attacks.

The Efficacy and Safety of Evekeo, Racemic Amphetamine Sulfate, for Treatment of Attention-Deficit/Hyperactivity Disorder Symptoms: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled Crossover Laboratory Classroom Study.

Objective: The study goal was to determine the efficacy and safety of an optimal dose of Evekeo, racemic amphetamine sulfate, 1:1 d-amphetamine and l-amphetamine (R-AMPH), compared to placebo in treating children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting.Methods: A total of 107 children ages 6–12 years were enrolled in this multicenter, dose-optimized, randomized, double-blind, placebo-controlled crossover study. After 8 weeks of open-label dose optimization, 97 subjects were randomized to 2 weeks of double-blind treatment in the sequence of R-AMPH followed by placebo (n=47) or placebo followed by R-AMPH (n=50). Efficacy measures included the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP) administered predose and at 0.75, 2, 4, 6, 8, and 10 hours postdose on 2 laboratory classroom days. Safety assessments included physical examination, chemistry, hematology, vital signs, and treatment-emergent adverse events (TEAEs).Results: Compared to placebo, a single daily dose of R-AMPH significantly improved SKAMP-Combined scores (p<0.0001) at each time point tested throughout the laboratory classroom days, with effect onset 45 minutes postdose and extending through 10 hours. R-AMPH significantly improved PERMP number of problems attempted and correct (p<0.0001) throughout the laboratory classroom days. During the twice-daily dose-optimization open-label phase, improvements were observed with R-AMPH in scores of the ADHD-Rating Scale IV and Clinical Global Impressions Severity and Improvement Scales. TEAEs and changes in vital signs associated with R-AMPH were generally mild and not unexpected. The most common TEAEs in the open-label phase were decreased appetite (27.6%), upper abdominal pain (14.3%), irritability (14.3%), and headache (13.3%).Conclusions: Compared to placebo, R-AMPH was effective in treating children aged 6–12 years with ADHD, beginning at 45 minutes and continuing through 10 hours postdose, and was well tolerated.Trial registration: ClinicalTrials.gov identifier: NCT01986062. https://clinicaltrials.gov/ct2/show/NCT01986062

Free return trajectories or enmeshment? Some psychodynamic factors and thoughts on the role of social capital in the use of substituted cathinones (M-cats)

Purpose – The purpose of this paper is to suggest that the emergence of substituted cathinones or M-cat drugs (notably mephedrone and methylone) and their rapid proliferation of use, amongst drug users in the UK from 2009 onwards, signals changes in the habits, preferences and lifestyle choices made by certain drug users, whilst also indicating a pronounced increase in the levels of co-morbid mental health conditions experienced by another, yet often distinct, group of users. Design/methodology/approach – This latter group of users, it is suggested, tend to initiate use of psychoactive substances (including tobacco and alcohol) at a younger age. In addition, it is suggested, they often present to treatment and criminal justice services with a history of chronic childhood relational trauma, as a background against which severe patterns of drug abuse has evolved. In this light the lack of significant supplies of social capital, as a protective factor against the development of chronic drug use, is further considered in the paper that follows though a brief literature review and qualitative clinical case reports. Findings – Novel psychoactive substances ( Newcombe, 2013) appear so seductive, for a certain group of users, because they seem to provide a temporary form of cognitive and emotional anaesthesia, enabling users to self-medicate, often against experiences of profound psychological trauma and contemporary lives that are typically experienced as boring, hopeless and pointless. The euphoric effects of psycho-stimulants such as mephedrone are particularly appealing to individuals attempting to escape a subjective sense of daily dysphoria and may on this basis lead to, rather than recreational use, more persistent patterns of drug use. However, in contradistinction to this group of users, another recreational – mainly weekend leisure – group of users continues to evidence a voracious appetite for psycho-stimulant substances. Originality/value – It is suggested that this second group of users has been particularly influential in substitute displacement towards the emergence of legal highs, due to the poor quality and illegal status of street drugs such as cocaine, amphetamine sulphate and MDMA (ecstasy).

Experimental Study on Age Estimation of Bloodstains Based on Biological and Toxicological Analysis

The determination of the age of bloodstains in forensic investigations helps in estimating the time elapsed between incidents (such as accidents or violent crimes wherein the blood was shed) and sampling. In this study, bloodstains containing either ethanol or amphetamine sulfate and methamphetamine hydrochloride were prepared and incubated at 25°C and 50% humidity to determine their age, based on temporal changes in the relative levels of microRNA 16 (miR-16) and miR-451 after incubation. The miR-16 and miR-451 levels decreased significantly 5-28 days after incubation in the chamber. The concentration of ethanol in the bloodstains decreased rapidly during storage and became undetectable after 180 min. The concentrations of amphetamine sulfate and methamphetamine hydrochloride in the bloodstains remained almost constant throughout the experimental period. These findings indicate that the age of bloodstains can be calculated simply on the basis of the relative levels of miRNAs. Although it is difficult to utilize the concentrations of ethanol, methamphetamine, and amphetamine sulfate for estimating the age of the bloodstain, these data could provide evidence of the victim or assailant having used these substances at the scene of an accident or crime.